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Chapter 1.

Electronic Structure and Bonding

CHAPTER 1.

Review of General Chemistry and Introduction into


Organic Chemistry
Electronic Structure of an Atom and Bonding in the Molecules
___________________________________________________________________________

Structure of an Atom
n an atom, negatively charged electrons surround the nucleus, which is composed of positively
charged protons and neutral neutrons. The atomic number (Z) of an atom is the number of
protons in the nucleus. The mass number of an atom is the sum of the number of protons and
the number of neutrons in an atom. Not all the atoms of an element have the same number of the
neutrons in the nucleus. Isotopes of an element have the same atomic number (the same number of
protons) but different mass number (different number of neutrons). An example is hydrogen, which has
three isotopes. Ordinary hydrogen has only one proton. It has atomic number of one and mass number
of one. Sometimes we call this isotope of hydrogen protium. An atom of hydrogen that has one proton
and one neutron is called deuterium. It has atomic number of one and mass number of two. It has a
symbol D. Finally, an atom of hydrogen whose nucleus contains one proton and two neutrons is called
tritium. It has atomic number of one and mass number of three. It has a symbol T.

Isotopes of Hydrogen

protium deuterium tritium


(one proton) (one proton and (one proton and
one neutron) two neutrons)

Deuterium and tritium are the only isotopes that are given their own symbols. Usually, an
isotope of an element is indicated by a symbol of that element. Atomic number in the subscript and
mass number in the superscript precede the symbol of the element. Thus, alternative symbols for
deuterium and tritium, respectively, are:
2 3
1 H and 1 H

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These formulas may be simplified by omitting the atomic number, which is redundant since
all atoms of the same element contain the same number of protons. Therefore, these two isotopes of
hydrogen can be represented as 2H and 3H.
Subscript and superscript that follow the symbol of the element are used to indicate the
number of atoms and the charge, respectively. The following formula represents a deuterium ion,
which is composed of two atoms and carries one positive charge.
2
1 H2+
To a first approximation, atomic mass of a single atom is a whole number. Atomic mass is
expressed in atomic mass units (amu). Atom of 12C has been assigned a mass of 12.0000 amu and the
masses of the rest of the atoms are expressed based on that standard. The atomic mass of an element is
the weighted average mass of naturally occurring atoms of that element and usually is not a whole
number. Weighted average means that mass of each isotope contributes proportionally to its natural
abundance. Thus, naturally occurring carbon is a mixture of 12C (“carbon-12”), 13C (“carbon-13”) and
a small amount of 14C (“carbon-14”) atoms and its atomic mass is 12.0107 amu. As another example,
naturally occurring chlorine is composed of 75.76% of 35Cl (mass 34.9689 amu) and 24.24% of 37Cl
(mass 36.9659 amu). Therefore, its atomic mass is 0.7576 x 34.9689 amu + 0.2424 x 36.9659 amu =
35.453 amu.
12
C C Cl
atomic mass = 12.0000 amu atomic mass = 12.0107 amu atomic mass = 35.453 amu

In an atom, the number of protons equals the number of electrons and an atom is neutral. In
the course of a reaction, an atom may become charged by gaining or losing an electron. An atom, or a
molecule, that carries a charge is called an ion.

Distribution of Electrons in an Atom


Electrons and Orbitals
An electron has properties of both a particle and a wave. Each electron is restricted to a
certain amount of space within the atom. That space is called an orbital and its size and shape depend
on electron’s energy. Behavior of an electron is described by quantum mechanics.
According to concept of quantum mechanics, behavior of an electron can be described by a
wave equation. Solutions of the wave equation are wave functions. A wave function describes an
orbital – the shape and volume of space in which the electron can be found. An orbital is defined as a
region of space in which the probability of finding an electron is 90%. It is important to keep in mind
that orbitals are our constructs and have no physical meaning. They will be described in a more detail
latter in this chapter.

mathematical description solutions of


of behavior of electron wave function
electron wave function orbitals

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Chapter 1. Electronic Structure and Bonding

Core and Valence Electrons: Ground and Excited States of an Atom


Atomic orbitals are arranged into shells (energy levels), according to their principal quantum
number (n). Principal quantum number can have whole number values (1,2,3 and so on). Lower
energy level is assigned the lower number. Thus, the lowest energy level has a principal quantum
number of n=1, next level has n=2 and so on. Energy shells are further subdivided into subshells,
according to their angular momentum quantum number (l). Angular quantum number can have
values from 0 up to n-1. Instead of numbers, we usually use letters (s, p, d, f) to denote the angular
momentum quantum number. Thus, l=0 is an s orbital, l=1 is a p orbital, l=2 is a d orbital and l=3 is an
f orbital. Energy of an orbital depends both on n and l quantum numbers. Orbitals that are closest to the
atomic nucleus are the lowest in energy. Orbitals of the same energy are called degenerate orbitals.
Electrons in an atom can be divided into core electrons and valence electrons. Core electrons
occupy the inner shells. The inner shells are completely filled and electrons in them do not participate
in chemical reactions. Valence electrons occupy the outermost shell. The noble gases have their
valence shell completely filled. In all other elements, the outermost, valence, shell is only partially
filled. Only the valence electrons participate in chemical reactions.
In the ground state of an atom all the electrons occupy the lowest energy orbitals. If one, or
more, electrons occupy a higher energy orbital, the atom is in an excited state.
The magnetic quantum number (ml) defines the spatial orientation of the orbital. Magnetic
quantum number can have values from –l to +l, including 0.
The fourth quantum number is a spin quantum number (ms). It is usually explained by
analogy that this quantum number describes rotation of electron around its axis (that is where term
“spin” comes from). However, spin quantum number is not a result of an actual physical spinning of an
electron. Spin quantum number of an electron has been observed experimentally. It is theoretically
derived by application of theory of relativity on an electron and has no analogy in the macroscopic
world. Spin quantum number of an electron can have two values: +1/2 and -1/2.

Electron Configuration
The following three principles are applied to determine electron
configuration in an atom: 1s
1) Aufbau principle (Aufbau is German for building up) states that atomic 2s 2p
orbitals are filled in the order of increasing energies from the lowest energy orbital 3s 3p 3d
up. This is shown in the box on the right. Thus, 1s orbital is filled first, next 2s, then 4s 4p 4d 4f
2p, followed by 3s and so on. Note that 4s orbital is filled before 3d and 5s is filled 5s 5p 5d 5f
before 4d.
2) Pauli exclusion principle states that an orbital can accommodate two electrons with opposite
spins.
3) Hund’s rule, also called Hund’s rule of maximum multiplicity, states that when there are orbitals
of the same energy (degenerate orbitals) in an atom the electrons occupy them so that the number of
parallel spins is the greatest. In other words, since two electrons with parallel spins cannot fit into the
same orbital, electrons fill degenerate orbitals so that one electron fits into each orbital rather than
pairing up. Since electrons are negatively charged there is electrostatic repulsion between them.
Therefore, it is energetically favorable if they are as far away from each other as possible and that is
the case if they occupy different orbitals. The term “maximum multiplicity” comes from spectroscopy
and its meaning is not important at this point.

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“Maximum multiplicity”means that the more unpaired electrons there are the more lines appear in the
spectrum of that atom. In its most stable state atom will have the largest possible number of unpaired
electrons, or on other words spectrum will exhibit the largest number of lines (have a “maximum
multiplicity”).

In molecules, atoms occupy molecular orbitals. The above described principles (Aufbau
principle, Pauli exclusion rule and Hund’s rule) also apply to molecular orbitals, which we will cover
next.

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Chapter 1. Electronic Structure and Bonding

Molecules and Chemical Bonds


The reason why atoms undergo chemical reactions and form molecules is that in a molecule
they have lower energy (more stable) electronic configurations compared to isolated atoms. Therefore,
a molecules is more stable than the individual atoms it is composed of. In the course of a chemical
reaction a bond between the atoms is formed.

Duet and Octet Rules


The most stable electronic configurations are those of the noble gases. When forming a
chemical bond, an element usually achieves electronic configuration of the nearest noble gas.
According to the octet rule, main group elements undergo reactions that leave them with eight valence
electrons (the electronic structure of the nearest noble gas). For hydrogen atom a duet rule applies –
hydrogen is stable if it has two electrons. The octet rule is valid only for the second row elements. Due
to d orbitals in their valence shells, elements in the third and subsequent rows can have more than eight
electrons and, therefore, can expand their octet.

Duet and Octet Rules


1 1 2 First row elements
1 H H He obey the duet rule.
3 4 5 6 7 8 9 10 Second row
2 Li Be B C N O F Ne elements obey the
11 12 13 14 15 16 17 18 octet rule.
3 Na Mg Al Si P S Cl Ar Third and
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 subsequent row
4 K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn Ga Ge As Se Br Kr elements do not
obey the octet rule.
37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54
5 Rb Sr Y Zr Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te I Xe
55 56 57 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86
6 Cs Ba *La Hf Ta W Re Os Ir Pt Au Hg TI Pb Bi Po At Rn
87 88 89 104 105 106 107 108 109 110 111 112
7 Fr Ra Ac Rf Db Sg Bh Hs Mt

In a molecule atoms are held together by chemical bonds. Two extreme forms of chemical
bonding are ionic bond and covalent bond.

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Ionic Bonds
Formation of an ionic bond involves transfer of electron(s) from one atom to another. Ionic
compounds are formed when an element with a low tendency to attract shared electrons (an
electropositive element) transfers one, or more, electrons to an element with a high tendency to attract
shared electrons (an electronegative element). An example is bond between sodium and chlorine. In
the course of bond formation, sodium atom loses its valence electron to give sodium cation. This
process requires energy, which is called Ionization Potential. Chlorine atom accepts an electron in its
valence shell to give chloride ion. The energy released in this process is called Electron Affinity.
Finally, positive and negative ions bond together by electrostatic interactions.

Formation of sodium
Na Na + e chloride from the elements
involves formation of sodium
Cl + e Cl cation, chloride anion and
electrostatic interaction
Na + Cl Na Cl between the two ions.

Na Cl Na

Cl Na Cl
Na Cl
Na Cl Na
A diatomic molecule of sodium
chloride exists only in a gas phase. In a solid, sodium and chloride ions
are held together by non-directional
electrostatic interactions.

Atoms that have low ionization potentials form ionic bonds with atoms that have high
electron affinities.
A diatomic molecule of sodium chloride exists only in a gas phase. Under ordinary
conditions, sodium chloride consists of positive sodium ions and negative chloride ions packed in a
crystal lattice. The lattice is held together by electrostatic interactions between the oppositely charged
ions. Those interactions are non-directional. Therefore, each ion is surrounded by as many as possible
of the oppositely charged ions (in the case of NaCl six) and we cannot say that any particular sodium
ion is bonded to any particular chloride ion. Because of their non-directional nature ionic bonds are
very strong and ionic compounds have high melting and boiling points.

Covalent Bonds
Covalent bonding results from the sharing of electrons between atoms. One of the simplest
examples is the bond between the two hydrogen atoms in the hydrogen molecule. Some other
examples include bonding between the chlorine atoms in the
H + H H H
chlorine molecule and bonding between one hydrogen and one
chlorine atom in the molecule of hydrogen chloride. Note that, Cl + Cl Cl Cl
as a result of sharing of electrons, chlorine has its octet filled
and hydrogen has its duet filled. H + Cl H Cl

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Chapter 1. Electronic Structure and Bonding

Nonpolar and Polar Covalent Bonds


When the atoms that share the electron pair are identical, the electrons are shared equally and
the result is nonpolar covalent bond. If the atoms sharing the electron pair are not identical, the
electrons will be closer to the more electronegative atom, or
a group, and the bond will be polarized – it will have an "+" indicates a positive
uneven distribution of electrical charges. A polar covalent end of the dipole
bond is a covalent bond between the atoms of different
electronegativities. Electronegativity is a tendency of an
atom, an ion, or a group, to attract the shared pair of arrowhead indicates a
negative end of the dipole
electrons. A polar covalent bond is an electrical dipole.
Positive and negative ends of the dipole are indicated by
symbols δ+ and δ-, for partial positive and partial negative
δ+ δ−
charge. Alternatively, the direction of the dipole may be H Cl or H Cl
indicated by an arrow. The arrowhead points to the negative
end of the dipole while the end of the arrow that resembles δ−
symbol “+” is located at the positive end of the dipole. Two δ+ O δ+ or O
H H H H
examples of polar covalent bonds are hydrogen-chlorine and
hydrogen-oxygen bonds.
A number of different methods can be used to estimate magnitude of partial charges. Based
on their respective electronegativities, the partial charges in HCl molecule have been estimated at
+0.20 for hydrogen and -0.20 for chlorine. In H2O molecule, the partial charges are +0.35 for hydrogen
and -0.70 for oxygen. It is important to note that, while in an electrically neutral molecule the sum of
all ionic charges must be 0, that is not the case with the partial charges. The reason for it is that, since
value of δ varies from one case to another, one cannot simply add them up. Thus, in case of H2O
molecule, it takes two δ+ (+0.35 each) to compensate one δ- (-0.70) charge.
Nonpolar covalent bond and ionic bond are two extreme forms of a chemical bond. There is a
gradual change between covalent and ionic bonding depending on difference in electronegativities
between the atoms. Most bonds between atoms of different elements come somewhere in between the
two extremes. If difference in electronegativities between the two atoms is greater than 1.7 the bond
between them is considered to be ionic, if the difference is between 0.2 and 1.7 then the bond is polar
covalent and if it is less than 0.2 the bond is non-polar covalent. Electronegativities of atoms
commonly encountered in organic compounds are shown in the table below. Note the periodic trend.
The electronegativity increases within a period from left to the right and it decreases within a group
from top to bottom. The only main group element whose electronegativity cannot be estimated from its
position in the periodic table is hydrogen. However, note that its position in the periodic table is
ambiguous. In most periodic tables, hydrogen is placed both at the top of alkali metal group as well as
halogen group. Based on its electronegativity, it does not appear to belong to either group. It is the best
to assume that hydrogen has an electronegativity similar to that of carbon.

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Veljko Dragojlovic

Table 1.1. Electronegativities of elements commonly encountered in organic compounds and types of
bonds that are formed as a result of differences in electronegativities between the atoms that from the
bond.

Don’t confuse electronegativity with electron affinity!


Electron affinity is an energy that is released when a negative ion is formed (when an atom
gains an electron) and is an experimentally determined quantity. Therefore, electron affinity as a
concept is important only when considering formation of an ionic bond. Electronegativity is a
theoretical concept (cannot be determined experimentally) and it represents an ability to attract a
shared electron pair. Concept of electronegativity makes sense only if two atoms, or groups, are
connected by a covalent bond.

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Chapter 1. Electronic Structure and Bonding

Lewis Structural Formulas (Lewis Dot Structures)


Compounds that are composed of atoms of main group elements can be represented by Lewis
structures (also called Electron Dot Structures or Lewis Dot Structures). In Lewis structural formulas
valence electrons are represented as dots. Core electrons are not represented. Note that atoms that
belong to the same group of the periodic table have the same number of valence electrons.

H He

Li Be B C N O F Ne

Na Mg Al Si P S Cl Ar

K Ca Ga Ge As Se Br Kr

I Xe
Valence electrons in ground states of atoms
commonly encountered in organic compounds.

Lewis structures show connectivity in the molecule – which atom is connected to which one
and by what bond type (single, double, or triple). In Lewis structural formulas valence electrons are
represented as dots. Paired electrons can be represented as lines (Kekulé structures). Nonbonding
electrons (also called free electron pairs) may be omitted, if they are not considered to be important.
Condensed formulas further simplify the structure by omitting the bonds. Note that some, or all,
information about the connectivity is lost when one uses condensed formulas. Neither Lewis structural
nor condensed formulas show geometry of the molecule.

H C N H O Cl O Lewis structural formula


Lewis structural formula with
H C N H O Cl O nonbonding electrons omitted
HCN HOClO or HClO2 condensed formulas

Before we can draw Lewis structural formulas, we have to introduce a concept of formal
charges.

Formal Charge
Formal charges are assigned to atoms in molecules as a convenient way to keep track of
electrons in molecules. It is a convenient “book keeping” method, which among other things, allows us
to draw correct Lewis structural formulas. However, one should keep in mind that those charges are
only “formal” – that may not reflect the actual charge distribution in a molecule.
A formal charge is the difference between the number of valence electrons an atom has in a
ground state and the number of electrons assigned to in a molecule. The number of electrons in a

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Veljko Dragojlovic

ground state of an atom is shown in the figure above. To determine the number of assigned electrons,
one should assign the shared electrons from all the covalent bonds equally to both atoms. Non-bonding
electrons (free electron pairs and unpaired electrons) are assigned to the atom they belong to.

⎛ number of valence ⎞ ⎛ number of ⎞


⎜ ⎟ ⎜ ⎟
Formal Charge = ⎜ electrons in ground ⎟ − ⎜ assigned electrons ⎟
⎜ state of the atom ⎟ ⎜ in bonded atom ⎟
⎝ ⎠ ⎝ ⎠

Example: Calculation of Formal Charges in Water, Hydroxide Ion and Hydronium Ion

H O H O H O H

H H

H2O: FCO = 6 – (2 x 1 + 2 x 2) = 0
HO-: FCO = 6 – (1 x 1 + 3 x 2) = -1
H3O+: FCO = 6 – (3 x 1 + 1 x 2) = +1

The overall charge of a molecule, or an ion, is the sum of the individual formal charges.

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Chapter 1. Electronic Structure and Bonding

Drawing Lewis Structures


To draw a Lewis structure, one should follow these steps:

1. Determine the total number of valence electrons in the structure. It may be a molecule, an ion, or a
free radical. To do that, add up valence electrons of all the elements that make up the molecule,
the ion or the free radical. For each positive charge subtract one electron and for each negative
charge add one electron.
2. Identify the central atom. It is usually the atom that is one of a kind. For example, in SO3 it is the
sulfur atom, in HClO4 it is the chlorine atom. There are some exceptions to this rule, but you
cannot reason them out. Therefore, you have to be told when that is the case. Sometimes it is not
possible to identify the central atom by simple inspection and you have to be told which one(s) are
the central atom(s) (for example C2N2). Hydrogen atoms are usually bonded to the peripheral
atoms (for example, H3PO4). However, in some cases, one (for example, H3PO3), or more (for
example, H3PO2), of hydrogen atoms are bonded to the central atom. If it is the case, you have to
be told that. You cannot reason it out. Unless, you are told otherwise, assume that hydrogens are
bonded to the peripheral atoms.

P(OH)3O all hydrogens bonded to peripheral atoms


HP(OH)2O one hydrogen bonded to the central atom
H2P(OH)O two hydrogens bonded to the central atom

3. Write a structural formula of the molecule and connect all the central atoms to the peripheral
atoms with SINGLE bonds. You still don’t know the nature of the bonding between the atoms.
However, you know that the bond must be at least a single bond.
4. Calculate how many electrons were used up to make the single bonds and subtract this number
from the total number of valence electrons.
5. Distribute the remaining valence electrons as free electron pairs on the peripheral atoms. Make
sure that you do not exceed octet rule for each atom (duet rule for hydrogen).
6. Calculate how many electrons you used up to make the free electron pairs and subtract this
number from the remaining number of valence electrons.
7. If there are any electrons left, they should be placed on the central atom(s) as free electron pairs.
8. Calculate the formal charges of all the atoms. If the two neighboring atoms have opposite formal
charges make an additional bond between them, if possible. A multiple bond is made by moving a
free electron pair from the atom with a negative formal charge to make a multiple bond between
that atom and the one with a positive charge. This operation is possible only if the atom with a
positive formal charge does not have its octet filled. If the octet is filled (for example, nitrogen
atom in H3NO), then the charge separation should remain.

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Veljko Dragojlovic

Example: Lewis structural


Step 1: 1H 1x1= 1e
formula of chlorous acid, HClO2
2 O 2 x 6 = 12 e

Step 2: 1 Cl 1 x 7 = 7 e
HOClO
total = 20 e
Step 3: H O Cl O -6e Step 4:
total = 14 e
Step 5: H O Cl O -10 e Step 6:
total = 4e
Step 7: H O Cl O -4e
total = 0e

Step 8: H O Cl O H O Cl O

Lewis structure

Example: Lewis structural


formula of carbonate ion, CO32-
1C 1x4= 4e
CO32-
3 O 3 x 6 = 18 e
2 2x1= 2e
O An example of
total = 24 e molecule with a
O C O charge separation:
-6e
H
O total = 18 e
-18 e H N O
O C O
total = 0e H

O O

O C O O C O

Lewis structural formulas of ionic compounds (Li2CO3, Na2CO3, MgCO3):

Li 2
O Na O Mg O

Li O C O Na O C O O C O

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Chapter 1. Electronic Structure and Bonding

Reaction Intermediates
Hydrogen Ion, Hydride Ion, Hydrogen Radical
Under ordinary conditions, hydrogen exists as a diatomic molecule H2 in which two hydrogen
atoms are held together by a single bond. Cleavage of a chemical bond can be either heterolytic, or
homolytic. In a heterolytic cleavage one of the atoms leaves with the electron pair, leaving the other
atom electron deficient. In a homolytic cleavage the shared electron pair is split equally – each atom
leaves with one electron. A formal heterolytic cleavage of the hydrogen–hydrogen bond results in
formation of a positively charged hydrogen ion (proton) and a negatively charged hydride ion.
Homolytic cleavage of the hydrogen–hydrogen bond results in formation of hydrogen radicals.

H H H
hydrogen ion hydride ion hydrogen radical (hydrogen atom)

Note that hydrogen radical is identical to a hydrogen atom. When a radical is identical to an
atom, we refer to it as atom. Therefore, a species with unpaired electron that contains only one atom is
called an atom, while a species with an unpaired electron that contains several atoms is called a free
radical. Note that while some atoms are free radicals (hydrogen, halogens, alkali metals), some atoms
are not (alkaline earth metals, noble gases).

Carbocation, Carbanion, Carbon Radical, Carbene


The simplest organic molecule is methane, CH4. Lewis structural formula of methane is
shown below. A heterolytic cleavage of a carbon–hydrogen bond in which hydrogen atom takes the
electron pair with it results in formation of a carbocation (in this case the methyl cation). A heterolytic
cleavage of carbon–hydrogen bond in which carbon retains the electron pair results in formation of a
carbanion (in this case methyl anion). In a homolytic cleavage each fragment leaves with one electron.
A homolytic cleavage of a carbon–hydrogen bond results on formation of a carbon free radical (in this
case methyl radical). A homolytic cleavage of two carbon-hydrogen bonds results in formation of a
carbene. Formal charge of the carbon atom in carbocation is +1 and in carbanion it is -1. Free radical
and carbene are neutral species. Carbocation, carbanion, carbon radical and carbene are high energy
species and have short life times. Therefore, they are not stable species that can be isolated. Rather,
they are reaction H H H H
intermediates.
H C H H C H C H C H C

H H H H H
methane methyl cation methyl anion methyl radical methyl carbene

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Veljko Dragojlovic

Atomic Orbitals
An orbital is defined as a region of space in which a probability of finding an electron is 90%.
A node is region of space in which a probability of finding an electron is zero. Number of nodes in an
atomic orbital is n-1, where n is the principal quantum number. There are two types of nodes: planar
and spherical. Number of planar nodes is given by the angular momentum quantum number l, while n-
1 is the total number of nodes in an orbital.

1s and 2s Orbitals

An s orbital has spherical shape. 1s Orbital has no nodes, 2s orbital has one node, and so on.
Node in an s orbital has a spherical shape.

node
no nodes
1s 2s

2p and 3p Orbitals

A 2p orbital has two lobes and a planar node, which passes through the nucleus. The actual
shape of a p orbital has two spherical lobes. Usually, in order to avoid cluttering the drawing, we use a
stylized representation in which each lobe is shown as being smaller than the actual size. A 3p orbital
has two nodes, one planar and one spherical.

two nodes
(one planar and
one spherical)
node

2p

3p
actual shape stylized shape

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Chapter 1. Electronic Structure and Bonding

There are three degenerate p orbitals designated as: 2px, 2py and 2pz. p Orbitals are orthogonal
to each other. We usually draw them as being aligned to axes of Cartesian coordinate system.
y y y
z z z

x x x

The three p orbitals combine to give spherical distribution of electrons.


y
z

Models of Chemical Bonding


Two different models of chemical bonding are in general use. They are Valence bond theory
and Molecular orbital theory. We can determine positions of the atoms in space by an experiment (for
example by doing X-ray crystallography on a crystal of a molecule). However, positions of the
electrons cannot be determined by an experiment (recall Heisenberg uncertainty principle). To explain
bonding according to Valence bond theory, one starts with known spatial arrangement of atoms and
distributes bonding electrons in pairs so that each atom has its valence shell filled. Lewis structural
formulas are a result of application of Valence bond theory. When using Molecular orbital theory, one
again starts with the known arrangement of atoms in space. Next, molecular orbitals are generated as a
combination of individual atomic orbitals. Finally, molecular orbitals are filled with valence electrons
following the Aufbau principle, Pauli exclusion principle and Hund’s rule (page 3).
Molecular Orbital Theory

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Veljko Dragojlovic

Most of the bonds in organic compounds are covalent bonds. A covalent bond results from the
overlap of atomic orbitals (AO) to give molecular orbitals (MO). Like an atomic orbital, a molecular
orbital can accommodate two electrons with opposite spins.
A simplest molecular orbital is that of a hydrogen molecule:

H + H H H (dots represent electrons)

+ (dots represent hydrogen nuclei)

According to Molecular orbital theory, overlap of two atomic orbitals results in formation of
two molecular orbitals: a bonding MO and an antibonding MO. Electrons in bonding orbitals are
located in the space between the two nuclei. They attract both nuclei (recall that nuclei are positively
charged and electrons are negatively charged) and hold them together. Energy of a bonding molecular
orbital is lower than either of its constituent atomic orbitals. In an antibonding molecular orbital, most
of the electron density is located outside the internuclear space. Therefore, two positively charged
nuclei experience electrostatic repulsion. Energy of an antibonding molecular orbital is higher than
either of its constituent atomic orbitals. Overlap of atomic orbitals can give either σ or a π orbital.
Overlap of atomic orbitals along the internuclear axis results in a σ orbital. Overlap of two s
orbitals gives σs molecular orbital. Overlap of two p orbitals along their axes gives σp orbital. Finally,
overlap of an s and a p orbital gives σs-p orbital.

σs Bond: σp Bond:

σ∗
σ∗

1s 1s 2p 2p

σ
σ

Only one of the bonds between two atoms can be a σ bond. Additional bonds that result from
side to side overlap of atomic p orbitals are π bonds. A π bond is much weaker than a σ bond. A single
bond between two atoms is always a σ bond. A π bond is always second and third bond between the
atoms. By definition a chemical bond connects two atoms. Since a π bond cannot be the only bond
between the two atoms some scientists say that “there is no such thing as a π bond, only a π orbital.”

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Chapter 1. Electronic Structure and Bonding

σs-p Bond π Bond

π∗
σ∗

p 2p 2p
s

π
σ

Bonding in Methane and Ethane: Hybridization


Methane and ethane belong to a class of compounds known as alkanes. In alkanes, valence
requirements of a carbon atom are satisfied by formation a four single sigma (σ) bonds.

Bonding in Methane
Carbon atom has electronic configuration 1s2 2s2 2p2. Carbon’s 1s electrons are core electrons
and do not participate in bonding. The remaining four electrons are the carbon’s valence electrons and
are responsible for formation of carbon’s bonds.
When two atoms form a covalent bond either each atom contributes one electron to make a
bonding electron pair, or one atom donates an electron pair into the empty orbital of the other atom.
Experimental results show that all four carbon-hydrogen bonds have the same energy and all
the bond angles are 109.5° (angles of a regular tetrahedron). Different representations of a molecule of
methane are shown below.
H H

CH4 H C H C H
H
H H
molecular formula Lewis structure perspective drawing ball and stick model

Based on electronic configuration of carbon atom in the ground state, it is difficult to explain
formation of four equivalent carbon-hydrogen bonds. Even if one were to assume that, as a part of
bond formation process, one of the carbon’s s electrons is promoted into a p orbital, the resulting bonds
would be of two types: one σs bond and the remaining three σs-p bonds.
Bonding can be explained by assuming that in methane carbon atom is sp3 hybridized. Thus,
in the course of bond formation one of 2s electrons is promoted into the empty 2p orbital. The result is

17
Veljko Dragojlovic

a carbon atom in an excited state with four half-filled atomic orbitals. Next, these four orbitals
hybridize (“mix”) to give four new sp3 orbitals of equal energy.
C 1s2 2s2 2p2

2p promotion 2p hybridization
sp3
2s 2s

Here is the process of hybridization in general terms:

promotion
(if necessary) hybridization formation of new hybrid orbitals;
electron configuration electron configuration
electron configuration after
in the ground state after promotion
hybridization

Shape of sp3 hybrid orbitals is a combination of shapes of s and p orbitals. Note that the actual
shape of an sp3 hybrid orbital has one large lobe that participates in bonding. Usually, in order to avoid
cluttering the drawing, we use a stylized representation in which the direction of the bonding lobe is
represented, while it is shown as being much smaller than actual size. Sometimes we represent only the
bonding lobe and omit the small one.

+
the actual shape stylized shapes
s orbital p orbital (actual shape) sp3 hybrid orbital

Geometry of a Compound with an sp3 Hybridized Carbon Atom

Due to repulsion of electron pairs in bonds, substituents on an atom are as far apart as
possible. Thus, when four groups surround an atom they assume a tetrahedral arrangement. The atom
is at the center of the tetrahedron and the substituents are at its corners.

C C
H
H
tetrahedron carbon atom is at the center of the tetrahedron
substituents are at its corners

In organic chemistry we frequently use molecular models to represent three dimensional


structure of molecules. Two types of the commonly used molecular models are “ball and stick” and

18
Chapter 1. Electronic Structure and Bonding

“space filling.” Ball and stick models represent bond lengths and bond angles accurately (degree of
accuracy depends on the quality of a particular model set), but underestimate the size of atoms. On the
other hand, space filling models accurately represent the size and shape of a molecule, but bond length
and bond angles became difficult to visualize.

ball and stick model of methane space filling model of methane

Energy Changes in the Course of Formation of Methane Molecule

Hybridization is not an actual physical process. It is only a concept introduced to “fix” the
Valence bond theory, which otherwise could not explain bonding in molecules such as methane.
Energy changes in the course of hypothetical formation of methane from the elements are shown
below. Since hybridization is only a theoretical concept that does not require any energy, it doesn’t
appear in the energy diagram.

E carbon in excited state


(after promotion)
C + 4H in 96 kcal/mol
ground state formation of
4 C-H bonds
(CH4)

420 kcal/mol

reaction progress

19
Veljko Dragojlovic

Bonding and Geometry of Ethane


Ethane has a molecular formula of C2H6. Lewis structure of ethane is shown below.
H H
H C C H
H H

As in methane, carbon atom in ethane is sp3 hybridized. Carbon–carbon bond is formed by


overlap of one of sp3 hybrid orbitals from each carbon atom. Remaining three hybrid orbitals on each
carbon atom make bonds to hydrogen atoms.

Bonding in Ethane

2s orbital
2p orbitals hybrid sp3 orbitals

H
H
H
H
H
H

H H

H H

H H

Bond Angles and Bond Lengths

Bond angles in ethane are 109.5º, which are tetrahedral bond angles. Length of a carbon–
carbon single bond is 1.54 Å (1Å = 1 x 10-10 m) and length of carbon–hydrogen bond is 1.10 Å.
H H
109.5°
H
C C 1 Å = 1 x 10-10 m
1.54Å 1.10Å
H
H H

20
Chapter 1. Electronic Structure and Bonding

Van’t Hoff model ball and stick model space filling model

Bonding in Ethene (Ethylene)


Ethene, C2H4, belongs to a class of compounds known as alkenes. Ethene is also known by its
trivial name ethylene. A trivial name for alkenes is olefins. In alkanes (for example, methane), the
valence requirements of a carbon atom are satisfied by the formation of four σ bonds. In alkenes, the
valence requirements of a carbon atom are satisfied by the formation of three σ bonds and a π bond.

H H
C C
H H
A π bond can form only if there is already a σ bond between the atoms. Such atoms,
connected by both σ and π bonds, are connected by a double bond. A double bond is a functional
group. A functional group is the center of reactivity of the molecule and is responsible for its chemical
and physical properties.
Carbon atoms connected by a double bond are sp2 hybridized. In an sp2 hybridization, an s
and two p orbitals hybridize to give three hybrid sp2 orbitals. Remaining p orbital remains
unhybridized.
C 1s2 2s2 2p2

2p promotion 2p hybridization 2p

2s 2s sp2

Shape of an sp2 hybrid orbital is the same as that of an sp3 hybrid orbital.

The geometry of an sp2 hybridized carbon atom is trigonal planar, with unhybridized p
orbital being orthogonal to the plane of sp2 hybrid orbitals. In general, three electron pairs (three
substituents) on an atom assume a trigonal planar arrangement so that they are as far apart as possible.

21
Veljko Dragojlovic

sp2 Hybrid orbitals are


shown in grey. The two
lobes of the unhybridized
p orbital are shown as a
black and a white lobe.
90° 120°

Molecular Orbitals of Ethene

+
2s orbital
2p orbitals hybrid sp2 orbitals and
unhybridized p orbital

H H
H H

H H
H H

two lobes of a
single π orbital
π Orbital of ethene is formed by overlap of two atomic p orbitals.

H H
C C
H H

Bond Angles in Ethene Molecule

Bond angles in an alkene are approximately, but not exactly, 120º.

H 121.7° H

116.6° C C

H H

22
Chapter 1. Electronic Structure and Bonding

Bond Length and Bond Strength

Length of a single bond between the two sp3 hybridized carbons is 1.54 Å. Length of a double
bond between the two sp2 hybridized carbons is 1.34 Å. Length of a single bond between an sp3
hybridized carbon and an sp2 hybridized carbon is a bit shorter than a single bond between two sp3
hybridized carbon atoms and equals 1.50 Å.
H
H 1.10 Å

C 1.50 Å H
H
C C C 1.08 Å
1.54 Å
H
H 1.34 Å H
H

Representation of a Double Bond by Molecular Models

ball and stick model Van’t Hoff model space filling model

Bonding in Ethyne (Acetylene)


Ethyne, C2H2, belongs to a class of compounds known as alkynes (acetylenes). In alkanes (for
example methane), the valence requirements of a carbon atom are satisfied by the formation of four σ
bonds. In alkenes, the valence requirements of a carbon atom are satisfied by the formation of three σ
bonds and a π bond. In alkynes, the valence requirements of a carbon atom are satisfied by the
formation of two σ bonds and two π bonds.
H C C H

Atoms connected by one σ and two π bonds are connected by a triple bond. A triple bond is
alkyne’s functional group.

Carbon atoms connected by a triple bond are sp hybridized. In an sp hybridization, an s and


one of the p orbitals hybridize to give two hybrid sp orbitals. The two remaining p orbitals remain
unhybridized.

23
Veljko Dragojlovic

C 1s2 2s2 2p2

2p promotion 2p hybridization 2p
sp
2s 2s

Shape of an sp hybrid orbital is the same as that of an sp2 or an sp3 hybrid orbital.

Molecular Orbitals and Geometry of Ethyne

Geometry of an sp hybridized atom is linear. Two unhybridized p orbitals are at right angles
to each other and at right angles to the two hybridized orbitals. Hybridized orbitals are shown in grey
and two lobes of each unhybridized p orbital are shown in black and white.

H H

H H H H

24
Chapter 1. Electronic Structure and Bonding

π Electrons in Ethyne
The two unhybridized p orbitals on each carbon atom are orthogonal to each other. However,
keep in mind that use of “narrow” lobes is a stylized representation of p orbitals and that the actual
lobes are much larger (see page 14). Thus, overlap of atomic p orbitals does not give “narrow”
molecular π orbitals as a stylized representation would imply. Rather, π orbitals penetrate (overlap)
each other to give a uniform distribution of electrons.

π orbitals

C C σ orbital

nucleus
stylized representation actual π electron cloud in ethyne
(hydrogen atoms have been omitted for clarity)

Therefore, in a molecule of ethyne we have two π orbitals that are orthogonal to each other.

However, due to orbital penetration π electrons form a “tube” of electrons around a σ bond
and the actual distribution of electrons is better represented by these drawings:
H
C
C
H

Representation of a Triple Bond by Molecular Models

ball and stick model Van’t Hoff model space filling model

25
Veljko Dragojlovic

Bond Length and Bond Angle

180° 1.06 Å

H C C H

1.20 Å

Size and Shape of Hybrid Orbitals


All of the hybrid orbitals have the same shape. They, however, differ in size. An sp3
hybridized orbital is the largest as it has the highest contribution of p orbitals (75%). Remember that a
p orbital is further away from the nucleus compared to an s orbital. The smallest hybrid orbital is sp
hybrid orbital, which has the lowest contribution of p orbitals (only 50%).

actual shape

stylized shape

sp3 sp2 sp

26
Chapter 1. Electronic Structure and Bonding

Bonding in Methyl Cation, Methyl Radical, Methyl Anion and


Methyl Carbene
Organic reactions frequently involve formation of short lived, high energy, intermediates.
Knowledge of their structure and properties is essential for understanding mechanism and outcome of
an organic reaction. Some of the common reaction intermediates are carbocations, carbanions, carbon
radicals and carbenes.
Methyl cation has three substituents (three hydrogen atoms) "empty" p orbital
and is considered to be sp2 hybridized. Therefore, its geometry is
trigonal planar. The carbon atom is surrounded by six electrons and is
electron deficient. Methyl cation has an “empty p orbital,” which is H
perpendicular to the three substituents. An orbital is defined as a region CH3 H
H
of space in which probability of finding an electron is 90%. Therefore, sp2
one can argue that there is no such thing as an “empty orbital.” One can
understand that this orbital is a region of space that can accept an
electron pair.
Methyl radical has three substituents and a half-filled p orbital. H
It is sp2 hybridized with a free electron in the unhybridized p orbital. CH3 H
H
Methyl anion is sp3 hybridized and has trigonal pyramidal sp2
shape. It has three substituents and a free electron pair in its sp3
hybridized orbital. Methyl anion (:CH3-) is isoelectronic with ammonia
(:NH3). Isoelectronic means that the two species have the same number
and the same relative energy levels of electrons.
Carbene (also called methylene) has two substituents and two CH3 sp3
electrons. There are two possible structures for a carbene. If the two H
H
electrons are paired up, carbene is sp2 hybridized and the electron pair H
2
occupies sp hybrid orbital while unhybridized p orbital remains empty. This form is called singlet
carbene. Alternatively, the two electrons can be unpaired. Then, the carbene is sp3 hybridized and each
of the electrons occupies one sp3 hybrid orbital. Such carbene is called triplet carbene. Terms singlet
and triplet came from spectroscopy. Spectroscopy is a group of analytical techniques that are based on
the interaction between molecules and electromagnetic radiation and will be studied later in this course
(Chapter 16).

Number of unpaired spins 0 1 2 3 4


Spectroscopic designation singlet doublet triplet quartet quintet

H
CH2 H CH2 H
H
sp2 sp3
singlet carbene triplet carbene

27
Veljko Dragojlovic

Bonding in Ammonia and the Ammonium Ion


Nitrogen atom in ammonia is sp3 hybridized. Note that there is no promotion of nitrogen’s
electron in the course of bond formation. A promotion of an electron from an s into a p orbital requires
energy. Nitrogen atom in its ground state already has three unpaired electrons and a promotion would
not increase that number.

N 1s2 2s2 2p3


2p hybridization

2s sp3

The shape of electron cloud on the nitrogen atom is tetrahedral. Geometry of a molecule is
determined by position of atoms in space (free electron pairs “don’t count”). A molecule of ammonia
has trigonal pyramidal shape.

NH3 H N H N H
H
H 107.3°
H

Ammonium ion, NH4+, is tetrahedral and is isoelectronic with methane (CH4).


H H

NH4 H N H N H
H
H 109.5°
H

Bonding in Water
Oxygen atom in water is sp3 hybridized. As in the case of nitrogen, there is no promotion of
oxygen’s electrons.

O 1s2 2s2 2p4

2p hybridization

2s sp3

28
Chapter 1. Electronic Structure and Bonding

The shape of electron cloud on the oxygen atom is tetrahedral. Again, when determining
shape of a molecule, free electron pairs “don’t count.” A molecule of water has bent shape.

H2O O H O H

H 104.5°
H

Hybridization of Atoms with Multiple Bonds


Hybridization of a carbon, nitrogen, or an oxygen atom can be determined by application of
the following formula:
sp(3 - the number of π bonds)

Only one bond between the two atoms can be σ bond. Any additional bond must be a π bond.
A π bond is made by side to side overlap of unhybridized atomic p orbitals. Therefore, any atom with
multiple bonds must have the necessary number of unhybridized p orbitals needed to make those π
bonds. The remaining orbitals are hybridized to give σ bonds. For example, in ethene there is one
double bond. It means that there is one π bond and each carbon must have one unhybridized p orbital
to make that bond. The remaining three orbitals (one s and two p) are hybridized to give three sp2
hybrid orbitals, which form σ bonds. In ethyne, there is a triple bond, which has two π orbitals.
Therefore, each carbon must have two unhybridized p orbitals. That leaves two orbitals for
hybridization (one s and the other one p). They give two sp hybrid orbitals, which make σ bonds.
Hybridization of some carbon, nitrogen and oxygen atom is shown below.

sp3 : C C N N O O

sp2 : C C C O N

sp : C C N

29
Veljko Dragojlovic

Geometry of Molecules: Valence Shell Electron Pair Repulsion


Model
The shape of any molecule that contains main group elements can be predicted by applying
Valence Shell Electron Pair Repulsion model, or VSEPR (pronounced vespr). The structure around an
atom is determined by minimizing repulsions by electron pairs. Thus, valence electron pairs assume
orientation so that they are as far apart as possible.
The following are steps in applying VSEPR method:

1. Draw Lewis structure of the molecule. Lewis structure shows connectivity in a molecule and
number of electron pairs (both bonds and free electron pairs) on each atom.

2. Determine shape of the electron cloud. The shape of electron cloud is determined by the total
number of the valence shell electron pairs. Valence shell electron pairs are bonds and free electron
pairs. Each bond (single, double, or triple) counts as one electron pair. Electron pairs are arranged
to minimize repulsions. For two electron pairs the arrangement is linear, for three trigonal planar,
for four tetrahedral and for five trigonal bipyramidal. Note that those are shapes of electron clouds.
These shapes may, or may not, be shapes of the molecules as explained below.

3. Determine positions of the atoms and geometry of the molecule. Once shape of the electron
cloud is determined, one should determine positions of substituents and free electron pairs (if any).
Geometry of the molecule is determined only by positions of atoms and not by free electron pairs.
Therefore, shape of a molecule may be different from the shape of the electron cloud. Shapes for
molecules that contain up to five substituents are given in the following table.

30
Chapter 1. Electronic Structure and Bonding

Valence Shell Hybridization 2 3 4 5 substituents


Electron Pairs substituents substituents substituents

3 sp2
bent trigonal
planar

4 sp3

bent trigonal
pyramidal tetrahedral

5 dsp3
trigonal
linear “T” shape see-saw
bipyramidal

As an example, we can apply the three steps described above to determine shape of the
molecule of acetonitrile, CH3CN.

1. Lewis structure of acetonitrile is:


H

H C C N

2. Shape of the electron cloud. Only the two carbon atoms have more than one substituent. Therefore,
their substitution determines the shape of the molecule. Carbon bonded to nitrogen has two electron
pairs (one single and one triple bond). Therefore, shape of its electron cloud is linear. The other carbon
atom has four electron pairs (four single bonds). Therefore, its shape is tetrahedral.

3. Geometry of the molecule in this case is identical to the shape of the electron cloud. That is the case
because the geometry is determined by carbon atoms and they do not have any free electron pairs.
H

C C N
H
H

31
Veljko Dragojlovic

Bonding in Hydrogen Halides


In a molecule of hydrogen halide, a p atomic orbital of the halogen overlaps with the s orbital
of hydrogen to give the molecular σ orbital. Size and shape of fluorine’s 2p orbital is a good match for
hydrogens 1s orbital. Therefore, the resulting bond is short and strong. As we go down the period,
valence p orbitals of halogens became larger and more difused. Thus, the overlap with hydrogen’s 1s
orbital is less efficient and the bond becomes progressively longer and weaker.

Bond Bond Strength


Length (Å) (kcal/mol)
H-F 0.918 135
F H Cl H
H-Cl 1.274 102
2p orbital of fluorine 3p orbital of chlorine
overlaps with 1s overlaps with 1s H-Br 1.408 87
orbital of hydrogen orbital of hydrogen
H-I 1.608 70

Dipole Moments of Molecules


A polar covalent bond is a dipole due to an uneven distribution of the electron density. Some
examples are polar covalent bonds in organic molecules are shown below:

C F C O C O C N C SiMe3 C Li

Vector sum of the individual dipole moments is an overall dipole moment of the molecule, μ.
Therefore, the dipole moment of the molecule depends on the magnitude, direction and geometry of
the individual (bond and free electron pair) dipole moments. Unit for dipole moment is D (Debye).
Molecules that have a dipole moment are polar molecules, while molecules without a dipole moment
are nonpolar. Note that a nonpolar molecule may have polar bonds, but due to geometry of the
molecule the individual bond dipole moments cancel out. Therefore, overall dipole moment of a
molecule is determined by two factors: polarity of the individual bonds and geometry of the molecule
Dipole moments of water, ammonia and chloromethane are shown below. Note the role of
free electron pairs in the overal dipole
moment of the molecule. Unlike a
bond, which at either end contains a
positively charged atomic nucleus, a Cl
free electron pair is a point of negative
N O C
charge. A large dipole moment of H H H
H H
chloromethane may at first glance be H H H
surprising until one takes into account
that chlorine atom has three free μ = 1.47 D μ = 1.85 D μ = 1.87 D
electron pairs (not shown).

32
Chapter 1. Electronic Structure and Bonding

In molecules such as carbon dioxide, carbon tetrachloride and methane dipole moments of the
individual bonds cancel out and the molecule has no overall dipole moment.

Cl H

C Cl C H
Cl H
O C O Cl H
μ=0D μ=0D μ=0D

Here are general formulas of some simple non-polar molecules:

B B
B
B
B A B A B A
A B
B B
B B
B B

33
Chapter 2. Nomenclature and Representation of Organic Compounds

CHAPTER 2.

Nomenclature and Representation of Organic


Compounds
Naming of organic compounds. Representing organic compounds by means
of structural formulas. Relation between structure and properties of organic
compounds.
___________________________________________________________________________

Hydrocarbons
implest organic compounds are hydrocarbons. As their name indicates, hydrocarbons contain
only carbon and hydrogen atoms. There are four classes of hydrocarbons (trivial name is in
brackets):

• Alkanes (paraffins)
• Alkenes (olefins)
• Alkynes (acetylenes)
• Arenes (aromatic hydrocarbons)

Alkanes are saturated hydrocarbons. The remaining three classes are unsaturated
hydrocarbons. You are already familiar with the two simplest alkanes – methane and ethane. From the
molecular formulas of those two one can derive a general molecular formula of an alkane:

methane CH4 ethane C2H6 general formula CnH2n+2

Therefore, if you know the number of carbons, you can figure out how many hydrogens are
needed to form a saturated compound.
Before we continue the study of organic compounds, we are going to examine different types
of chemical formulas that are used in organic chemistry.

Chemical Formulas
A number of different types of chemical formulas are used in organic chemistry. We will
examine them on examples of butane, ethene and cyclopropane. A summary of their formulas is given
on the page 45.
An empirical formula shows the simplest ratio of atoms in a compound. Thus, the empirical
formula for butane is C2H5, while for both ethene and cyclopropane the empirical formula is CH2.
Empirical formula is a result of an experiment (you may wish to review your general chemistry
textbook) and is the first step in determination of molecular formula of a compound. Very different
compounds could happen to have the same empirical formulas.

39
Veljko Dragojlovic

A molecular formula shows the actual ratio of atoms in a molecule of a compound. Different
isomers have the same molecular formula, but either a different connectivity of the atoms, or a
different arrangement of the atoms in space.
A complete structural formula represents all of the atoms and all of the bonds in a molecule.
No abbreviations are used. This formula shows connectivity – which atom is bonded to which one and
with what type of the bond (single, double, or triple). In a complete structural formula no
stereochemistry (arrangement of atoms in space) is indicated nor implied. Lewis formulas are complete
structural formulas.
A condensed structural formula does not show carbon–hydrogen bonds. These bonds are
always single bonds and, therefore, any time a hydrogen atom is bonded to a carbon atom there is no
doubt about the nature of the bond. Thus, they can be omitted. Carbon–carbon bonds may be single,
double or triple and have to be represented. Often carbon–carbon single bonds are also condensed
(particularly when typing) and not represented. Carbon–carbon double and triple bonds must be
shown. A condensed structural formula of butane is:

CH3-CH2-CH2-CH3 or CH3CH2CH2CH3

Either H2C=CH2, or CH2=CH2, is an acceptable condensed structural formula of ethene. The


former is more accurate as it shows that two carbon atoms are connected by a double bond, but the
latter is more commonly used.
When there are several substituents (atoms other than hydrogen) on a single carbon atom, we
may have to use brackets in a condensed structural formula. Thus, a “complete” CH3
structural formula of t-butane (-CH3 groups are written in a condensed form) is shown
on the right. A condensed structural formula of t-butane is (CH3)3CH, not H3C C H
CH3CH3CH3CH. The former condensed formula clearly shows that three methyl (-
CH3
CH3) groups are bonded to a single carbon atom. That may not be clear in the latter
formula. Here are some other examples of use of brackets in condensed structural formulas:
CH3
CH3 CH2 H3C CH3
CH3
H3C CH H3C CH CH3 CH2 CH CH2 H3C C CH2
CH2 CH3 CH2 CH2 H3C CH2 CH2 CH3 CH2 CH2 CH3
or or or or
CH3CH2CH(CH3)2 CH3CH2CH(CH3)CH2CH3 CH3CH2CH2CH(CH2CH3)CH2CH2CH3 CH3CH2C(CH3)2CH2CH2CH3

Previous formulas gave us information about the connectivity of atoms in a molecule, but not
about stereochemistry (arrangement of atoms in space). There are three common types of formulas that
represent three-dimensional arrangement of atoms in space: perspective, sawhorse and Newman
projection formulas.
A perspective formula represents carbon chain of the molecule in the plane of the drawing.
The chain has a zigzag conformation (remember that saturated hydrocarbons have a tetrahedral bond
angle). On each of the terminal carbons (terminal carbons means end carbons) one hydrogen is also
represented as being in the plane of the drawing and thus at the ends of the chain there are two
hydrogen atoms. On each carbon atom there are two remaining hydrogen atoms. One of the hydrogen
atoms points toward us and is represented with a wedge bond, while the other one points away from us
and is represented with a dash bond. Make sure that the wedge and dash bonds point in the correct
directions. They point up on the carbon that points up in the chain (that is above the imaginary
horizontal line that bisects the zigzag chain) and down on the carbon that points down. Opposite
40
Chapter 2. Nomenclature and Representation of Organic Compounds

drawing does not represent a tetrahedral atom


and is not correct. Note that we could not make H H H H
a model of the molecule from such wrong
drawing. C C H C C H
H C C H C C
One cannot simply convert solid bonds
of a structural formula into wedge/dash bonds H H H H
to obtain a perspective drawing. A structural
formula indicates connectivity without H
implying three dimensional arrangement of H H
C C
substituents. Thus, a formula on the left is a C
correct structural formula. However, conversion H H H
of the vertical bonds into wedge/dash bonds correct wrong wrong
results in an incorrect perspective drawing. A
perspective drawing must represent a tetrahedral arrangement
of substituents and that is not the case with the middle
C C C
formula. Formula on the right is a correct perspective
drawing. wrong
correct correct
Note the “wrong perspective” of the dash bonds. In
print, it became accepted to represent dash bonds as in A. C C C
Since those are the bonds that point away from us, the correct representation
should be B, but that one is not usually used. When drawing by hand, we A B C
represent dash bond as in C.
Wedge and dash bonds eclipse H H H H H H H H
each other and one should not be able to
see the back (dash) bond. In order to C C H C C H
represent all the substituents on a carbon H C C H C C
atom, we “cheat” and move one of the H H H H H H H H
bonds to the left and the other one to the
correct wrong
right. If, for example, on the first carbon
you draw the wedge bond to the left and the dash bond to the right, draw
the wedge bond to the left and the dash bond to the right on all of the CH3 CH3
H C CH H C C H
remaining carbons. 2 2
CH3
When it comes to cyclic compounds, we usually draw carbon– H2C CH H2C C
CH3 H
carbon bonds of the ring in the plane of the drawing and indicate the ring
substituents by using wedge and dash bonds.
Also acceptable, and often used, is a perspective formula that omits the carbon atoms (it is
understood that at the intersection of bonds is a carbon
atom). Thus each carbon ring is drawn as a polygon CH3
(triangle to represent three-member ring, square to H
represent four-member ring, pentagon to represent CH3 S
O
five-member ring and so on). Heteroatoms (atoms H
other than carbon and hydrogen) must be represented.
A sawhorse formula is useful if one wants to represent the stereochemistry on the two
neighboring carbon atoms. For example, if we wish to
HH HH
represent the stereochemistry on the carbons 2 and 3 of CH3 H 3 H
butane, we will draw that bond at an angle and the C 2 C H
H C 3 C H 2 H CH3
substituents on each carbon atom in the forms of letter Y (on
H H HH
the one carbon) and inverted letter Y (on the other carbon). A

41
Veljko Dragojlovic

sawhorse formula is not usually used to represent alkenes or cycloalkanes.


A Newman projection formula is also used to represent the sterochemistry on the two
neighboring carbon atoms. In this case, we look at the molecule along the carbon–carbon bond (for
example, C2-C3 bond in butane). We represent the molecule in such a way that we see only the closer
carbon atom and not the back one which is eclipsed by it. In addition, we cannot see the carbon–carbon
bond that connects those two atoms. The substituents on the closer atom are represented as being
bonded to the center of the atom (again in the form of letter Y or inverted Y). The substituents bonded
to the back carbon are shown as appearing over the horizon of the closer atom. If the substituents
eclipse each other (as in the case of ethene’s hydrogens), we “cheat” and move the substituents a bit so
that we can represent all of them.
H
H H
H H
H H
H H
H H
H actual Newman "adjusted" Newman
Newman projection of ethane projection of ethene projection of ethene

A line formula represents only carbon–carbon bonds and heteroatoms. A complete structural
formula contains a number of redundancies. You already know that there is no need to represent a
carbon–hydrogen bond since it is always a single bond. Similarly, there is no need to indicate hydrogen
atoms either. The carbon has a valence of four. Therefore, if carbon atom represented by a line formula
appears to have a valence of less than four, any bonds on the carbon atom that are not indicated are
understood to be bonds to hydrogen atoms. It means that we can omit both the hydrogen atoms and the
bonds to them. As at the end of each bond we draw is a carbon atom, it is understood, and we do not
need to represent carbon atoms either. Thus a single line ( – ) represents a molecule of ethane. The line
represents the carbon–carbon bond and since on each carbon only one bond is shown, it means that the
remaining three bonds on each carbon are bonds to hydrogen atoms so that the carbon’s valence of
four is satisfied. If at the end of a bond is an atom other than a carbon or a hydrogen (a heteroatom), it
must be represented with a chemical symbol. Line formula is particularly useful in drawing rings of the
cyclic compounds.

42
Chapter 2. Nomenclature and Representation of Organic Compounds

Summary of Chemical Formulas

Name Butane Ethene Cyclopropane

Empirical Formula C2H5 CH2 CH2

Molecular Formula C4H10 C2H4 C3H6


H H H H H H H H
C
Complete Structural H C C C C H C C H H
Formula C C
H H H H H H
H H

Condensed CH2
Structural Formula CH3CH2CH2CH3 H2C=CH2
H2C CH2
H H H H H H H H
H
Perspective Formula C C H C C
H C C H H
H H H
H H H H

CH3 H H
Sawhorse Formula none none
H H CH3
CH3 HH
Newman Projection H H H H
H H
H
H H H H
CH3
H

Line Formula =

43
Veljko Dragojlovic

Alkanes
Now that you are familiar with commonly used chemical formulas, we can
resume the study of alkanes. You have encountered methane and ethane in Chapter H H H
1. Propane, C3H8 (shown on the right), is the next member of the homologous H C C C H
series of alkanes. In a homologous series of compounds each subsequent member H H H
has an additional –CH2– group compared to the preceding member.
After propane, the next member of the homologous series is butane, C4H10. Note that there are
two different structural formulas that satisfy C4H10 molecular formula. Therefore, butane has two
constitutional isomers. An old name for constitutional isomers is structural isomers. The first
compound is a straight chain, while the second one is a branched compound. As there are two different
compounds, we must have different names for each of them. We can name these two compounds using
trivial (common) names. The first one is called n-butane
(n- stands for normal, which indicates a straight chain of
H
carbon atoms) and the second one isobutane (iso- for H H
H H H H H C H
isomer of butane, note that isobutane is one word). Prefix
H C C C C H H C C C H
iso- is used for an isomer that has a methyl group on the
carbon next to the last carbon in the chain. These two are H H H H H H H
two distinct compounds with different properties (for n-butane isobutane
example different melting and boiling points, different
index of refraction, etc.).
When drawing pentane and hexane one begins to appreciate convenience of line formulas.
There is significant saving in space and time when drawing such large molecules using line formulas
as opposed to structural formulas. Furthermore, since in organic compounds carbon has four valences,
drawing all the carbon–hydrogen bonds does not provide any additional information about the
structure of a compound and one can easily fill in hydrogen atoms that are not shown. Line formulas
are particularly useful in representing different isomers. As already mentioned, we use prefix iso not
just for any isomer but for the specific one. The iso
compound is one that has a methyl substituent on the
carbon atom that is the next to the last carbon atom in the n-pentane isopentane neopentane
chain. Prefix neo (for “new”) is used to describe an isomer
that has two methyl groups on the carbon atom next to the
last carbon atom in a chain. The same rules can be applied n-hexane isohexane
on isomers of hexane. As you may have already noticed,
we cannot name all of the isomers of pentane and hexane
neohexane
using trivial names. Thus, we have to use systematic (or
IUPAC) nomenclature.
Be careful when representing different
isomers of an alkane. The molecules that have the
same connectivity are the same (they are not
two isomers two representations of
isomers) regardless of the way you draw the carbon an identical compound
chain.

44
Chapter 2. Nomenclature and Representation of Organic Compounds

Nomenclature of Alkanes
You should memorize the names of at least the first ten members of the homologous series of
alkanes. Alkanes in the table below are straight chain alkanes. A detailed procedure for naming
branched alkanes is provided on page 40. Names of alkanes have a suffix –ane (which obviously
stands for alkane). The first four alkanes were given trivial names. The names of the remaining alkanes
are derived from the corresponding Latin names (which indicate number of carbon atoms in the chain)
and the suffix -ane. An alkyl group (alkyl substituent) is named after the name of the corresponding
alkane by dropping the ending –ane and replacing it with –yl.

IUPAC Nomenclature of Alkanes

Formula Name Alkyl Group


CH4 methane methyl
C2H6 ethane ethyl
C3H8 propane propyl
C4H10 butane butyl
C5H12 pentane pentyl
C6H14 hexane hexyl
C7H16 heptane heptyl
C8H18 octane octyl
C9H20 nonane nonyl
C10H22 decane decyl

Primary, Secondary, Tertiary and Quaternary Carbon Atoms


Carbon
secondary H
atoms, based on the H H
degree of H H H H H C H CH3
substitution, can be
divided into four H C C C C H H C C C H H 3C C CH3
groups: primary,
secondary, tertiary H H H H H H H CH3
and quaternary. quaternary
Butane has two primary tertiary
types of carbons:
primary and secondary. A carbon atom that has only one substituent (a substituent is any atom other
than hydrogen), or no substituents (as in methyl group), is called a primary carbon atom. A carbon
atom with two substituents is called a secondary carbon atom. In isobutane (2-methylpropane) carbon
in the middle is a tertiary carbon atom (it has three substituents) and the other three carbon atoms are
primary. In neopentane the middle carbon atom is quaternary (it is bonded to four substituents) while
the other four are primary carbon atoms.
Prefixes primary, secondary and tertiary may be used to name substituents.

45
Veljko Dragojlovic

Nomenclature of Alkyl Substituents


According to IUPAC nomenclature, alkyl substituents are named after the name of the
corresponding alkane by dropping the ending –ane and replacing it with -yl. A general symbol for an
alkyl substituent is R (from German: Radikal; another interpretation is that the symbol R originates
from German: der Rest meaning the remainder).

CH3– methyl CH3CH2– ethyl R– alkyl

More complex alkyl groups are named using prefixes such as iso, n- s-, t- and the like. Prefix
n- is usually omitted. The following are examples of propyl and butyl substituents:
CH3 CH2 CH2 propyl CH3 CH2 CH2 CH2 butyl
CH3 CH3

H3C CH isopropyl CH3 CH CH2 isobutyl

CH3

CH3 CH2 CH s-butyl

CH3

H 3C C t-butyl

CH3

Note the difference between isobutyl and s-butyl. In isobutyl it is the primary carbon atom
that is bonded to the substituent, while in s-butyl it is the secondary carbon atom that is bonded to the
substituent. As already mentioned, prefix iso- denotes a chain in which the carbon atom next to the last
has a methyl substituent. If the bonding is to the tertiary carbon atom, the group is called t-butyl.
Designation secondary is used only for s-butyl. Thus, we have isopropyl and not s-propyl substituent.
The final substituent you need to know is neopentyl. As mentioned earlier, prefix neo is used
for the chain that has two methyl substituents on the carbon atom next to the last carbon atom.
CH3

H3 C C CH2 neopentyl

CH3

Summary of Prefixes

n – normal
s – (or sec - ) secondary
t – (or tert - ) tertiary
iso
neo

46
Chapter 2. Nomenclature and Representation of Organic Compounds

A Procedure for Naming Alkanes


Systematic nomenclature is called IUPAC nomenclature. IUPAC (International Union of Pure
and Applied Chemistry) sets the nomenclature rules. The rules consist of a “vocabulary” (names of the
compounds and substituents) and a “grammar” (how those names are put together). Current IUPAC
rules are available on a website (www.acdlabs.com/iupac/nomenclature/).
To name an alkane according to IUPAC rules one should apply the following steps:
1. Identify the longest carbon chain and name it. That chain is called the parent hydrocarbon (or the
parent chain) and it will be the last word in the name. Therefore, the naming works backwards
(from the last part of the name to the first).
2. Name each of the substituents on the carbon chain. Use prefixes di-, tri-, tetra-, and so on, to name
multiple substituents. Names of the substituents are placed before the name of the parent carbon
chain.
3. List the substituents in alphabetical order. Ignore prefixes that indicate the number of substituents
(di-, tri-, tetra-) (for example, ethyl comes before methyl), as well as those that are written
separately from the name of the substituent (n-, s- or t-). Do not ignore iso-, neo- and cyclo- (for
example, cyclopropyl comes before methyl). Those prefixes are a part of the parent hydrocarbon’s
name and are alphabetized.
4. Next, number the chain so that each substituent gets
the lowest possible number. If there are more than
two substituents, the substituents should be assigned
the smallest set of numbers (the smallest possible 4-ethyl-2,5-dimethylheptane 2 + 4 + 5 = 11
sum of numbers). Separate the numbers from each not
other by a comma and from the rest of the name by a 3 + 4 + 6 = 13
4-ethyl-3,6-dimethylheptane
dash.
5. In case of a tie, the first listed substituent gets the lowest number.
6. If two chains are of the same length, the parent hydrocarbon is the chain with more substituents, or
in other words, the more branched chain.
7. Trivial names for substituents are acceptable. Alternatively, one can use IUPAC names. IUPAC
names of the substituents are written in brackets with the numbering starting at the carbon atom
that is bonded to the parent chain. Usually, trivial names are used for simple substituents.
8. The entire name is written as a single
word (no spaces). As already CH3
mentioned, numbers are separated H3C CH2 CH CH2 CH2 CH3 isopentane (trivial)
from the rest of the name by dashes or
3-methylhexane 2-methylbutane (IUPAC)
and from each other by commas.
Make sure you include both 2
1 9
enough “numbers” as well as enough 1 2 8 10
prefixes for the substituents (one for 1 3 5 7
8 7
2 4 6 4 6
each). Thus, a prefix di- calls for two 3 5
numbers (one for each substituent), tri- 4-isopropyl-5-methyloctane
for three numbers, and so on. Therefore, or 7-ethyl-3,6-dimethyldecane
4-(1-methylethyl)-5-methyloctane
the correct name for the compound on
the right is 2,2-dimethylhexane. Names such as 2-dimethylhexane or 2,2-methylhexane are incorrect.
In the former case (2-dimethylhexane), a position of only one methyl substituent has been indicated –
the second one could be anywhere on the chain. In the latter case (2,2-
methylhexane) only one of the two substituents on the second carbon (methyl) has
been named and the other one could be anything.

47
Veljko Dragojlovic

Nomenclature of Cycloalkanes
Cycloalkanes are cyclic alkanes. A cycloalkane represents an alkane chain whose ends are
connected. Thus, formally two terminal hydrogens were removed and the terminal carbons were
connected to each other. The general formula for cycloalkanes is CnH2n.

CH2 CH2 CH2

H2C CH2 CH2 CH2

The cycloalkanes are named by naming the chain that makes up the ring and adding the prefix
cyclo-. As substituents, cycloalkanes are named the same way as other alkane substituents (by
dropping the final –ane and adding the suffix –yl). Prefix cyclo- is alphabetized when listing the
substituents.

A Procedure for Naming Cycloalkanes

To name a cycloalkane, use a prefix cyclo and name the hydrocarbon ring.
1. When naming cycloalkanes with substituents, the longest chain is the parent hydrocarbon. If that
is the ring, the compound is named as a substituted cycloalkane. If a straight chain is the longest
chain, then the ring is named as a substituent. In other words, the ring is the parent hydrocarbon if
it contains the most carbon atoms. If it does not, it is a substituent.
2. There is no need to number the position of a single substituent on a ring (it is understood that this
position is number 1). With two or more substituents, numbers must be used for all of the
substituents.
3. For two or more substituents, usual IUPAC rules about their numbering apply. Substituents are
listed in alphabetical order and the substituent that is listed first, gets the lower number.
CH3 CH2
CH3 H3C CH3

methylcyclopropane ethylcyclobutane 1,3-dimethylcyclopentane


1-cyclopentylhexane
(1 indicates position of
cyclopentyl substituent)

1-ethyl-3-methylcyclohexane 2-cyclopropylhexane 3-pentylcyclopentane, or


(1-ethylpropyl)cyclopentane

48
Chapter 2. Nomenclature and Representation of Organic Compounds

Nomenclature of Alkyl Halides


Alkyl halides, in addition to carbon and hydrogen, contain one or more halogen atoms
(fluorine, chlorine, bromine or iodine).

Primary, Secondary and Tertiary Alkyl Halides


Alkyl halides can be divided into primary, secondary and tertiary alkyl halides, according to
the degree of substitution of the carbon atom bonded to the halogen. In primary alkyl halides, carbon
atom bonded to halogen is bonded to only one other carbon
atom. Carbon atom of the methyl group, in which the H R R
carbon atom is not bonded to other carbon atoms, is also R C X R C X R C X
classified as a primary carbon atom. If two carbon atoms
are bonded to the carbon atom bearing halogen substituent H H R
primary secondary tertiary
we have a secondary alkyl halide. Finally, with three
groups on the carbon atom bonded to a halogen we have a X = F, Cl, Br or I
tertiary alkyl halide.

Common Names of Alkyl Halides


When using common (trivial) names compounds belonging to this class are named as alkyl
halides. It means that they are named as derivatives of hydrohalic acids (HF, HCl, HBr or HI) – as salts
of hydrohalic acids. Therefore, we name the alkyl group first followed by the name of the halogen
(named as the corresponding ion: fluoride, chloride, bromide, or iodide). The two parts of the name are
written separately. Note that despite the naming, alkyl halides are not ionic compounds. Carbon-
halogen bond is a polar covalent bond.
CH3 CH3
H3C CH2 F H3C CH Br H3C C Cl
CH3
ethyl fluoride isopropyl bromide t-butyl chloride

49
Veljko Dragojlovic

IUPAC Names of Haloalkanes


When using IUPAC (systematic) names, these compounds are named as haloalkanes. That
means that the root of the name is the corresponding alkane (the longest chain that contains the
halogen atom) and the halogen is named as a substituent (fluoro, chloro, bromo, or iodo) on the parent
hydrocarbon. This nomenclature is more convenient although less common, compared to the trivial
nomenclature. In particular, it is convenient for naming of larger, more complex, haloalkanes. Halogen
substituent and alkyl substituents are listed in the alphabetical order. For example, ethyl comes before
iodo. Different halogen substituents are also listed in alphabetical order. For example: 3-bromo-1-
chlorohexane. In case of a tie when numbering substituents, the first listed substituent should be
assigned the lower number.
CH3
CH3 H3C C Cl
H3C CH2 F H3C CH Br CH3
fluoroethane 2-bromopropane 2-chloro-2-methylpropane

Br

Cl
2-bromo-4-methylhexane
4-chloro-5-isopropyloctane
Cl Cl
Br

Br Br
Cl
3-bromo-4-chlorohexane 2-chloro-5-methylhexane 2,2-dibromo-4-chloropentane

Nomenclature of Alcohols
Alcohols can be considered to be derivatives of water where one of the hydrogen atoms is
replaced by an alkyl substituent.
R–O–H

Primary, Secondary and Tertiary Alcohols


The classification of alcohols into primary, secondary and tertiary follows the classification of
alkyl halides. Alcohols are classified according to
the degree of substitution of the carbon bonded to H R R
hydroxyl (-OH) group. Primary alcohols have only R C OH R C OH R C OH
one substituent on the carbon that is bonded to the – H H R
OH group. Methyl alcohol (methanol) is also a primary (1°) secondary (2°) tertiary (3°)
primary alcohol. A secondary alcohol has two
substituents on the carbon bonded to the –OH group and a tertiary alcohol has three substituents on the
–OH group bearing carbon atom. Sometimes instead of writing terms primary, secondary or tertiary,
we write a degree of substitution in brackets. However, we do not call such alcohols “first degree,”
“second degree,” or a “third degree.” They are still called primary, secondary and tertiary alcohols.

50
Chapter 2. Nomenclature and Representation of Organic Compounds

Common Names of Alcohols


Common names of alcohols are descriptive. Alcohols are named by naming the alkyl group
followed by “alcohol.” Prefixes (n-, s-, t-, iso, cyclo-) are commonly used. The two words are written
separately. Common names are used only for simpler alcohols (alcohols that contain up to five carbon
atoms). Cyclic alcohols are an exception and trivial names can be used for larger alcohols (for
example, cyclooctyl alcohol). The trivial name for pentanol (for IUPAC names see the next section) is
amyl alcohol and that for cyclopentanol the trivial name is cyclopentyl alcohol. Note the trivial name
phenol (for phenyl alcohol). That trivial name has been accepted as a systematic (IUPAC) name.

OH OH
H3C OH OH OH
OH
methyl alcohol propyl alcohol isopropyl alcohol isobutyl alcohol s-butyl alcohol t-butyl alcohol

OH OH
OH
OH
OH
amyl alcohol isoamyl alcohol s-amyl alcohol cyclopentyl alcohol phenol

IUPAC Nomenclature of Alcohols


According to IUPAC nomenclature, alcohols are named by adding the suffix -ol to the name
of the corresponding longest chain that
contains the –OH group as the parent H3C OH OH OH
OH
name. The final –e in the name of
methanol 1-propanol 2-propanol 2-methyl-1-propanol
alkane is dropped to avoid having two
vowels next to each other. Use of OH
OH OH
prefixes is allowed and, therefore, for OH
some simpler alcohols we can use
prefixes (for example isopropanol). 2-butanol 2-methyl-2-propanol cyclopentanol 1-pentanol

IUPAC names are convenient when we are dealing with complex alcohols such as the one
shown below.
OH

4-ethyl-2-heptanol

51
Veljko Dragojlovic

Nomenclature of Ethers
Ethers can be considered to be derivatives of water where both of the hydrogen atoms have
been replaced by alkyl groups. There are two types of ethers: symmetrical ethers where two alkyl
groups are identical and unsymmetrical ethers where the two alkyl groups are different. Note that
different R groups are labeled by using numbers or symbols in superscript. Number in subscript, for
example R2, would indicate the number of R groups (two R groups).

O O
R R R1 R2
symmetrical ether unsymmetrical ether

Common Names of Ethers


For naming of simple ethers trivial, or common, names are used almost exclusively. Naming
is descriptive. Thus, names of the two substituents are listed in the alphabetical order, followed by the
word “ether.” A prefix (di-) when naming symmetrical ether can be omitted. Each word in the name is
written separately.

O O
O O
O O
ethyl methyl ether diethyl ether allyl vinyl ether cyclopentyl ethyl ether t-butyl methyl ether phenyl propyl ether

Older nomenclature named the substituents in the order of increasing complexity. For
example, the first compound in the table above was named methyl ethyl ether instead of ethyl methyl
ether. Sometimes such obsolete names are still used in industry. Thus, t-butyl methyl ether is known by
the abbreviation MTBE (for methyl t-butyl ether).

IUPAC Nomenclature of Ethers


According to IUPAC, ethers are named as substituted alkanes, with RO- (alkoxy-) being the
substituent. Thus, the parent hydrocarbon is the one with the longest chain and RO- group is named as
an alkoxy substituent (methoxy, ethoxy, propoxy, etc.). Note the spelling – alcohol spells with “c”
while alkoxy and alkoxide with ‘k” (for “alkyl oxide”).

O
O O
methoxyethane ethoxyethane 2-methoxy-2-methylpropane

52
Chapter 2. Nomenclature and Representation of Organic Compounds

Nomenclature of Amines
Amines can be considered to be derivatives of ammonia. In amines, one, or more, of
hydrogens of ammonia is replaced by an alkyl group. Note the letters “m” in spelling of amine and
ammonia. Ammonia has two, while amine only one.
H N H R N H R N H R N R
H H R R

Primary, Secondary and Tertiary Amines and Quaternary Ammonium Salts


Similarly to alkyl halides and alcohols, amines can be classified as primary, secondary and
tertiary amines. In addition, there are quaternary ammonium salts. Unlike alkyl halides and alcohols,
amines are classified according to the degree of substitution of the nitrogen atom. Thus, a primary
amine has one substituent on the nitrogen, a secondary two and a tertiary three. With four substituents
on it, nitrogen atom becomes a cation, which must
be accompanied by an anion (for example, a halogen R N H R N H R1 N H
anion or a hydroxide anion). Such compounds are H R R2
R
called quaternary ammonium salts and are named as R N R R1 N R2 R1 N R3 R N R X
derivatives of ammonium salts. R R1 R2 R

Common (Trivial) Names of Amines


Common (trivial) names of amines are descriptive. Name(s) of the substituent(s) are followed
by the suffix “amine.” The entire name is written as a single word. Note that it is a different convention
from the trivial nomenclature of alkyl halides, ethers, and alcohols where the words in the name were
written separately.
Primary amines are named by naming the alkyl substituent followed by the suffix –amine.
Note that, for example, isopropylamine has a secondary carbon, but it is classified as a primary amine
because the nitrogen atom is primary.
Secondary and tertiary amines are named by naming each substituent in the alphabetical
order. When necessary, prefixes di- and tri- must be used. Note that, unlike an ether, which must have
two substituents, the term amine does not specify how many substituents are on the nitrogen atom.
Therefore, prefixes must be used. The following are
H3C N H H3C N H H3C N CH3
formulas of methylamine, dimethylamine and
H CH3 CH3
trimethylamine:

53
Veljko Dragojlovic

Substituents are listed in alphabetical order. Note the difference between phenylmethylamine
and methylphenylamine.

NH2 NH2 NH N N
NH2
allylamine isopropylamine isobutylamine ethylisobutylamine triethylamine ethyldimethylamine
H
N H H
N CH3 N N CH3
H
t-butylethylamine s-butylmethylamine diethylamine cyclopentylmethylamine
NH2

H NH2
N CH3

methylphenylamine phenylmethylamine (benzylamine) aniline

An alternative trivial nomenclature names amine as substituted alkenes. Thus, amino group is
named and numbered as a substituent and the longest chain is named as an alkane chain. For example:
2-aminopentane, 3-amino-4-methylhexane and 1-amino-2-ethylcyclopentane.

IUPAC Nomenclature of Amines and Quaternary Ammonium Salts


To name an amine according to IUPAC nomenclature, one should identify the longest
hydrocarbon chain that contains the
amino group, drop the final –e in the H3C CH2 CH3 CH3
H3C NH2 CH2 N N
name of the hydrocarbon and add suffix - H H
amine. Use numbers as necessary. When methanamine N-methyl-1-propanamine N-methyl-2-propanamine
there is more than one substituent, the
longest chain containing the amino group NH
is the parent name and the remaining N
groups are named as substituents.
Substituents on nitrogen are indicated by N,N-dimethyl-1-propanamine N-ethyl-3-methyl-2-hexanamine

N- instead of a number. CH2


Quaternary ammonium salts are named as derivatives of Cl
H3C N CH3
ammonium salts.
CH3
tetramethylammonium chloride

54
Chapter 3. Structure and Properties of Organic Compounds

CHAPTER 3.

Structure and Properties of Organic Molecules:


Intermolecular Interactions
Relation between structure and properties of organic compounds. Types of
intermolecular interactions in organic compounds.
___________________________________________________________________________

Alkyl Halides
n order to examine bonding in alkyl halides, we will compare relative bond lengths and bond
strengths of carbon–halogen bonds in methyl halides. Bond length and bond strength are
inversely proportional. Therefore, bond strength decreases with increasing bond length. As the length
of carbon–halogen bond increases with the increase in atomic number of halogen, the bond strength
decreases in the same order. The reason for it is that the halogen atom’s p orbital used in bonding
increases in size resulting in the longer and weaker carbon–halogen bond. Thus, the strongest bond is
C–F bond and the weakest one is C–I bond. Similarly to hydrogen halides (Chapter 1), the reason for
the difference in bond length lies in different
orbitals halogen atoms use for bonding. Alkyl halide Bond length Bond strength
In each case, carbon atom uses the same
orbital for bonding – an sp3 hybrid orbital. Halogen (Å) (kcal/mol)
atom uses its valence p orbital. In case of fluorine CH3-F 1.39 115
that is 2p orbital, chlorine 3p, bromine 4p and
iodine 5p. Therefore, as the size of halogen atom CH3-Cl 1.78 84
increases, halogen uses a p orbital that is CH3-Br 1.93 72
progressively larger and further away from the
nucleus (and thus experiences less of the attraction CH3-I 2.14 58
by the nucleus). An orbital that is further away
from the nucleus is more diffuse, occupies larger region of space and has poor overlap with carbon sp3
orbital resulting in a long and weak bond.

Alcohols and Ethers


Organic compounds that contain sp3 hybridized oxygen can be considered to be derivatives of
water. There are two classes of such compounds: 1) Alcohols, R-OH, where one of the hydrogens is
replaced by an alkyl group, and 2) Ethers, R-O-R, where both hydrogens are replaced by alkyl groups.
Therefore, both alcohols and ethers have the same geometry as water, which means that the
arrangement of the electron cloud on the oxygen atom is tetrahedral. The shape of the molecule of
water is bent (we do not consider free electron pairs when determining shape of the molecule) with the
angle of 104.5°, which is a bit smaller than the ideal tetrahedral
angle. The reason for the deviation is in repulsion of free
O O O
electron pairs, which require more space compared to bonds. H H R
The actual bond angle in alcohols and ethers is larger than H R R
104.5° (frequently it is larger than 109.5º) and it depends on water alcohols ethers

57
Veljko Dragojlovic

size and nature of the substituents. Both free electron pairs as well as large substituents require more
space. Therefore, bond angle opens up to accommodate them.

Amines
Organic compounds that contain sp3 hybridized nitrogen can be considered to be derivatives
of ammonia. In amines, one, or more, of hydrogens of ammonia is replaced by an alkyl group.
Therefore, an amine has the same geometry as ammonia. An amine will consist of an sp3 hybridized
nitrogen atom with one or more alkyl substituents. The geometry of an amine is trigonal pyramidal
and the shape of electron cloud on the nitrogen atom is tetrahedral with bond angle of 107.3°, which is
close to the ideal tetrahedral angle. Again, as in the case of alcohols and ethers, the deviation is a result
of the repulsion between the free electron
pair and bonds. As is the case with alcohols
and ethers, the actual bond angles depend N N N N
H H R R
on the size and nature of the substituents. H H H R
H R R R

Intermolecular Interactions
Ionic Interactions (Bonds)
Ionic interactions, or ion – ion interactions, are interactions between oppositely charged ions.
An example is interaction between Na+ and Cl⎯ encountered in Chapter 1. A result is ionic bond – a
strong chemical bond. As a general rule intermolecular interactions are defined as interactions weaker
than chemical bonds. Therefore, strictly speaking ionic interactions are chemical bonds and not
intermolecular interactions.

Intermolecular Forces
Types of intermolecular forces are: van der Waals Interactions, dipole-dipole interactions,
dipole-induced dipole interaction and hydrogen bonding. An additional type of intermolecular forces,
ion-dipole interaction, may exist in solution. The type of intermolecular interactions depends on the
type of functional groups that are present.

Van der Waals Interactions

Van der Waals interactions are due to temporary and induced dipoles in molecules. These are
the weakest of all the intermolecular interactions. Van der Waals interactions depend on the size (and
therefore polarizability) of a molecule and on its surface area. Therefore, van der Waals interactions
are stronger in linear isomers, which have a larger surface area, compared to the branched ones. For
example, pentane is a liquid while neopentane is a gas. The larger the molecule (or an atom) is, the
more polarizable it is and the stronger van der Waals interactions are. Molecules that contain large
atoms (for example iodine) exhibit relatively strong van der
Waals interactions, while in the molecules with small
substituents (for example fluorine) van der Waals interactions b.p. = 36°C b.p. = 28°C b.p. = 9.5°C
are relatively unimportant.

58
Chapter 3. Structure and Properties of Organic Compounds

Van der Waals interactions are present in all molecules (polar and non-polar). However, in
polar molecules there are other interactions (dipole – dipole interactions and hydrogen bonding) that
are so much stronger compared to van der Waals interactions that usually van der Waals interactions
can be ignored.

temporary induced
dipole dipole

two nonpolar random thermal temporary dipole


molecules motion gives rise induces a dipole
to a temporary in the neighboring
dipole on one of molecule resulting
the molecules in brief electrostatic
attraction

Polarizability is an ability of a molecule to distort its electron cloud. Large molecules, or large atoms,
are polarizable while small ones are not.

Dipole–Dipole Interactions

Dipole-dipole interactions are strong compared to van der Waals interactions. Dipole-dipole
interactions are due to permanent dipoles in the molecules. Recall from the Chapter 1 that permanent
dipoles are a result of polar covalent bonds and geometry of a molecule. Like other intermolecular
interactions, those interactions are electrostatic in nature. A dipole moment, μ, exists when the
resultant (the vector sum) of the individual dipoles due to charge separation in polar covalent bonds, is
not zero.

or

As an example, molecules of an ether exhibit a dipole moment due to polarized C–O bonds
and free electron pairs on the oxygen. Thus, the intermolecular forces between ether molecules are
mainly due to dipole-dipole interactions, while contribution from the van der Waals interactions is
negligible. The same type of interactions exists in alkyl halides. Ethers and alkyl halides have higher
boiling points compared to similar compounds that exhibit only van der Waals interactions (for
example alkanes). Note that diethyl ether has a boiling point that is almost identical to that of pentane.
The reason for it is that two alkyl substituents provide steric hindrance and prevent effective dipole-
dipole interactions between molecules of diethyl ether. On the other hand, in the molecule of
tetrahydrofuran steric hindrance is not
possible (substituents are part of a ring O
and are “held back”) and the boiling O
point is considerably higher than the b.p. = 36°C b.p. = 35°C b.p. = 49°C b.p. = 65°C
boiling point of cyclopentane. pentane diethyl ether cyclopentane tetrahydrofuran

59
Veljko Dragojlovic

Carbonyl compounds contain sp2 hybridized oxygen and, therefore, a carbon–oxygen double
bond. Such bond exhibits rather large charge separation and, as a consequence, carbonyl compounds
exhibit strong dipole – dipole interactions.
O O H3 C CH3
O C
C C
R H R R C O
aldehydes ketones H3 C CH3

Dipole–Induced Dipole Interactions

When molecules of a polar compound and a non-polar compound are mixed, dipole-induced
dipole interactions will exist between them. Permanent dipoles of polar compound generate (induce) a
temporary dipoles in the molecules of non-polar compound and the two are held together by
electrostatic interactions. In general, dipole-induced dipole interactions are weaker than dipole-dipole
interactions.

Hydrogen Bonding

Attraction between hydrogen atom bonded to a highly electronegative atom (F, O, or N only)
and a free electron pair is called hydrogen bonding. Thus, a hydrogen bond involves three atoms:
hydrogen bond
hydrogen bond
Y H :X CH3
O H :N CH
Y=N,Oor F H3 C 3
X=N,O or F CH3

Hydrogen bond is a special case of dipole-dipole interaction. It is an unusually strong dipole-


dipole interaction and for that reason it is classified separately. It is about one hundred times stronger
compared to an average dipole-dipole interaction. As a highly electronegative element attracts the
shared electron pair, the hydrogen atom is left electron deficient. Thus, a hydrogen nucleus (remember
it is a proton) is available to interact with a free electron pair from another atom. Since there are no
core electrons on hydrogen free electron pair can approach the nucleus and form a very strong
interaction (“bond”) with it. Note that no other element, other than
hydrogen, is capable of such interaction as all other elements have hydrogen hydrogen
bond donor bond acceptor
core electrons, which prevent free electrons from other atoms from
approaching the nucleus. CH3
In a hydrogen bond one molecule is a hydrogen bond O H :N CH
3
donor (contains Y-H bond and provides a suitable hydrogen atom) H3C CH3
and another is a hydrogen bond acceptor (provides an electron pair).

60
Chapter 3. Structure and Properties of Organic Compounds

Hydrogen bond is common and the most important interaction in alcohols (unless the
substituent R is too large and gets in the way) and carboxylic acids. Note the dimers that are formed as
a result of hydrogen bonding of carboxylic acids. Only primary and secondary amines exhibit
hydrogen bonding. Tertiary amines do not have a hydrogen atom bonded directly to the nitrogen atom.
They may function as hydrogen bond acceptors, but are not capable of forming hydrogen bonds among
themselves. Main intermolecular forces between the molecules of a tertiary amine are dipole – dipole
interactions.
H
CH3 CH
O H :O N H :N H 3
H3 C H H3C H
alcohols primary amines CH3 CH3
:N CH :N CH
3 3
CH3 CH3 CH3
O H O CH3
R C C R N H :N H
H3C tertiary amines
O H O CH3
dipole-dipole interactions
carboxylic acids secondary amines
hydrogen bonding

Strength of a hydrogen bonding (Y–H---X) depends on the two factors – electronegativities of


the elements X and Y and the number of hydrogen bond donor-acceptors that can be formed. The more
electronegative X and Y are the stronger the hydrogen bond. Highly electronegative atom Y results in
a highly polarized Y–H bond while highly electronegative X results in a high degree of partial negative
charge on it. Of course, the larger the number of hydrogen bond donor-acceptor pairs the stronger the
hydrogen bonding. Hydrogen bonding in alcohols is stronger than in amines (oxygen is more
electronegative than nitrogen). As a result, alcohols have a higher boiling points compared with
amines. There is no possibility for hydrogen bonding in ethers and, therefore, boiling points of ethers
are lower compared to the corresponding alcohols. Due to hydrogen bonding between molecules of the
solvent and molecules of the solute, lower molecular weight alcohols are soluble in water and polar
solvents.

O H

H R R

R N H N R
H O H O H O
H
H H H

H N R
O H
R
H
A molecule of water is capable of making four hydrogen bonds.
A secondary amine can make only two.

Boiling points of various classes of organic compounds increase in the following order:

alkanes < ethers < amines < alcohols

61
Veljko Dragojlovic

Boiling points of amines increase in the following order:

tertiary amine < secondary amine < primary amine

A hydrogen bond can be intermolecular (between different molecules) or intramolecular


(within the same molecule):
CH3
H O CH O H :O
O H3 C
CH2 C
C H
H
H3C CH2 CH2
intermolecular
intramolecular

Gecko Lizard and Intermolecular Interactions

Gecko lizard is renowned for its ability to walk on any surface including smooth vertical
surfaces and ceilings. It does so because of millions of tiny hairs on its feet. The hairs are capable of
van der Waals interactions with various surfaces. Although individual van der Waals interactions are
weak, a large number of them makes for a relatively strong interaction between gecko’s feet and
surface. One may think that gecko may be better off with stronger dipole-dipole interactions, but then
its feet would stick only to polar surfaces. By being capable of van der Waals interactions, its feet stick
to any surface.

Solvation and Solubility


When a substance (solute) is dissolved in a solvent, there is an interaction between molecules
of the solvent and molecules of the solute. Interaction between a solvent and a dissolved particle
(molecule, ion or atom) is called solvation. For a solid to be dissolved, its crystal lattice has to be
broken up first and for a liquid intermolecular forces between its molecules have to be broken up.
These processes require energy. The process of solvation (formation of intermolecular bonds between
the solute and the solvent) releases energy. If the amount of energy released during solvation is enough
to compensate for the lattice energy, the compound will be soluble, otherwise it will not. Therefore,
formation of similar or stronger interactions between the molecules of solute and solvent as compared
to interactions between the molecules of the solute will be favored.
For example, a polar solvent such as water
is capable of forming hydrogen bonds and strong H O H O H O
dipole-dipole interactions. Thus, solutes that make
strong hydrogen bonds and strong dipole-dipole R H R
interactions are likely to be soluble in water.
However, substances capable of van der Waals H
interactions, or weak dipole – dipole interactions
only, are unlikely to be soluble in polar solvents like O H O H
water. For a nonpolar compound to dissolve in
water, hydrogen bonds between the molecules of R
water must be broken to make room for the
hydrogen bonding between molecules
incoming molecules of the solute. Thus, strong of water and an alcohol
intermolecular interactions would be replaced by
62
Chapter 3. Structure and Properties of Organic Compounds

weaker dipole-induced dipole and van der Waals interactions as the solute is not capable of hydrogen
bonding. The process is not energetically favorable and such solute is not soluble in polar solvents. In a
non-polar solvent the only interactions are van der Waals interactions. Process of dissolving the solute
replaces one set of van der Waals interactions (between the molecules of the solute) with another
(between the molecules of the solvent and the molecules of the solute) and is likely to be favorable.
Thus, a non-polar solvent dissolves a non-polar solute.
Similar analysis allows us to conclude that a polar solute will not be soluble in a non-polar
solvent (one has to break strong hydrogen bonding or dipole-dipole interactions between the molecules
of solute and replace them with van der Waals interactions between the solute and solvent).
In solution there is yet another type of intermolecular interactions. They are ion-dipole
interactions. Ionic compounds are soluble in polar
solvents because of the ion-dipole interactions. In H H O
the course of solvation, ionic compound dissociates H O H
into individual ions, which are then surrounded by H H H
polar molecules of the solvent. Negative ions are H O Li O H O H Cl H O
surrounded by the positive ends of the solvent H
dipole and positive ions are surrounded by the O H H
negative ends of the solvent dipole. Therefore, like H H O
other intermolecular interactions, ion-dipole ion - dipole interactions
interactions are electrostatic in nature.
Finally, it should be mentioned that in
addition to factors considered so far (enthalpy factors),
entropy plays a role in a solvation process. As a general
rule, in the course of solvation entropy increases (this is Li Cl
only a general rule and there are some exceptions to it) and
is a favorable process. Overall, solubility depends on the
change in free energy of the system which is composed of
enthalpy and entropy components:

ΔG = ΔH – TΔS

63
Veljko Dragojlovic

Thus, as a general rule increased temperature increases solubility of a compound because it


increases contribution of the change in entropy factor to overall change in free energy.

H
δ- O δ+
H
electron cloud of a water molecule
has tetrahedral shape

H δ+ H δ-
O O
H δ+
δ- H
H H H H
δ+ O δ- δ- O δ+ δ+ O
Na O δ+ Cl δ-
H H δ- H H

H
δ- H δ+
O
O
H δ+ δ-
H

ion-dipole interactions between NaCl and water

Solubility of Whip Scorpion’s Spray

Whip scorpion, Mastigoproctus giganteus, when attacked sprays a mixture that contains 84%
acetic acid, 11% water and 5% octanoic acid. The role of octanoic acid is to allow acetic acid to spread
and pass through the waxed epicuticle of an enemy arthropod. Such simple and effective chemical
defense may have enabled whip scorpion’s survival. It has been around for about 400 million years.

Summary: Strength of Intermolecular Interactions


ion-ion >> ion-dipole > hydrogen bond > dipole-dipole > dipole > induced dipole > van der Waals
interactions

Boiling Points
A large number of organic compounds are liquids. In condensed states of matter (liquid and
solid) molecules are held together by intermolecular forces. If it were not for the intermolecular forces,
all of the matter would be in the form of gas. For a compound to boil, intermolecular forces that hold
the molecules of a liquid together must be overcome. The boiling point of a compound is directly
proportional to the strength of those forces. As we heat up the liquid, molecules acquire additional
energy and began to move faster and faster. Eventually they gain enough energy to leave the surface of
the liquid and pass into the gas phase. When the vapor pressure of the liquid equals the atmospheric
pressure, the liquid boils (conversion of a liquid into a vapor).

64
Chapter 3. Structure and Properties of Organic Compounds

Melting Points
Most of the organic compounds crystallize in the form of molecular crystals. Melting points
of molecular crystals depend on the magnitude of intermolecular forces and on the packing (how well
the molecules fit into the crystal lattice). The better (tighter) packing allows for more contact between
the molecules (larger surface areas of the molecules are in contact with one another). Furthermore, the
molecules that fit well into a lattice are close to one another. Therefore, the interaction between them is
stronger. More symmetrical molecules pack better compared to less symmetrical and have higher
melting points compared to those that do not pack well. Thus, among the isomeric pentanes the most
symmetrical one is neopentane. It
packs the best into a crystal lattice
and has the highest melting point. m.p. = -130°C m.p. = -160°C m.p. = -17°C
Linear n-pentane has an intermediate
value for melting point, while
isopentane, which has no symmetry
elements does not pack well into a
crystal lattice and has the lowest
melting point. Line formulas and space filling models of the three isomers of pentane.

Structure and Properties of Organic Compounds


Physical and chemical properties of an organic compound are functional
related to its structure. By examining structural formula of a compound, we group - skeleton
can estimate its physical and chemical properties. bond
A structural formula can be divided into two parts: the carbon
skeleton, usually represented by a general symbol R, and the functional R Y
group, in this case represented as Y. Mode of bonding of functional group to
the skeleton is also important. carbon functional
Some forms of carbon skeleton include liner, branched, cyclic, or skeleton group
aromatic. Usually, a compound with larger skeleton has higher
boiling and melting points, due to stronger van der Waals Y
interactions. Larger, and particularly branched, skeletons may Y
prevent functional groups from forming polar intermolecular
linear
interactions. As a consequence, such compounds may be more
soluble in nonpolar solvents, while compounds with polar
functional groups and smaller skeletons are more soluble in polar Y
solvents.
You already encountered a number of functional groups. branched cyclic aromatic
Simplest hydrocarbons, alkanes, do not have a functional group.
Alkenes have a carbon-carbon double bond as a functional group, alkynes a carbon-carbon triple bond,
haloalkanes a halogen atom, alcohols a hydroxyl group, etc. A functional group affects properties of
compound either through its polarity (it may be an electrophile, a nucleophile, an acid, a base, a good
leaving group and so on) or through the bond it makes to the rest of the molecule (strong or weak).
Concepts such as electrophile, nucleophile and a leaving group will be explained in the Chapter 5. A
functional group also affects physical properties (melting point, boiling point, solubility) through is
polarity. Strength of intermolecular forces is related to the polarity and the nature of the functional
group (for example, whether it is capable of hydrogen bonding).

65
Veljko Dragojlovic

Chemical properties of a compound are mainly due to its functional group. Therefore,
compounds with the same functional group undergo the same general set of reactions. That is why we
classify organic compounds according to their functional groups. Once you learn set of reactions that a
particular compound undergoes, it is likely that the rest of the compounds with the same functional
group undergo the same set of reactions, while the carbon skeleton usually remains unchanged.
However, carbon skeleton may modify reactivity of particular compound. For example, sometimes
compounds with large skeletons are less reactive, or completely unreactive, compared to compounds
with small, simple, carbon skeletons. A list of common functional groups is given in Table 3.1.
As already mentioned, mode of Y
attachment of functional group to the carbon
skeleton is important. It is particularly important Y Y
primary secondary tertiary
with respect to chemical properties of a Y Y
compound. Based on the mode of attachment, Y
compounds are classified as primary, secondary, Y
tertiary, allylic, benzylic, vinylic and aryl. allylic vinylic benzylic aryl
Double and triple bonds are classified according to the degree of substitution, rather than
mode of attachment. Thus, alkenes are classified as mono-, di-, tri- and tetrasubstituted. Alkynes are
classified as terminal (monosubstituted) and internal (disubstituted). Compounds with carbonyl group
(C=O) are classified into different classes according to degree of substitution: monosubstituted
(aldehydes) and disubstituted (ketones).

R H R R R R
R H H R R R
H H R H R R
R H R H H H
monosubstituted trisubstituted tetrasubstituted
disubstituted
O O
R H R R R H R R
terminal internal aldehyde ketone

A larger, more complex, molecule may have several functional groups and may posses a
number of features described above. An example of molecule of morphine is shown below.
Most of you have heard of morphine. It is a potent narcotic. Its chemical formula is rather
complex. It has an aromatic ring with a hydroxyl group attached to it. Therefore, it is a phenol. It also
has an ether group, and a double bond. aromatic
Next, it has another hydroxyl group, which ring
makes it an alcohol in addition to being a phenol HO
(aryl alcohol)
phenol. In this case the hydroxyl group is
next to a double bond, which makes this (2°) benzylic
carbon
alcohol an allylic alcohol. Finally, the
ether O
molecule contains a tertiary nitrogen atom –
it is a tertiary amine. We would expect that N (3°) amine
this molecule will exhibit chemical
properties characteristic of the morphine’s (2°) allylic
alcohol HO H (3°) allylic carbon
functional groups: a phenol, an ether, an
allylic alcohol, an alkene and a tertiary disubstituted double bond
amine. Structural elements present in a molecule of morphine.

66
Chapter 3. Structure and Properties of Organic Compounds

As far as physical properties go, van der Waals interaction are present in this molecule as in
any other. Aromatic ring and double bond, being more polarizable compared to single bonds, will
make van der Waals interaction somewhat stronger. In addition, ether and amine functional group will
be responsible for presence of dipole-dipole interactions. Finally, the two hydroxyl groups are
responsible for presence of hydrogen bonding in the molecule. Overall, due to its size (strength of van
der Waals interactions increases with size) and presence of rather strong dipole-dipole interactions and
hydrogen bonding, we would expect that this molecule is going to have a rather high boiling point.
Indeed, it does. In fact, under ordinary conditions, it is a solid. Structure of the molecule also reveals a
hydrophilic part – the “western part” of the molecule as represented above with three oxygen atoms
and a hydrophobic part – the “eastern part” of the molecule that is composed mainly of non-polar
carbon-carbon and carbon-hydrogen bonds.
For a more detailed examination of physical and chemical properties of morphine, one should
make a model, or generate one by means of a suitable computer program, and examine three-
dimensional arrangement of the molecule. Finally, structure of certain compounds cannot be
represented by a single structural formula. To represent them and explain their properties we apply
concepts of electron delocalization and resonance. Such compounds are discussed in Chapter 16.

Table 3.1 List of some common functional groups.


Class of Functional group Class of Functional group
compounds compounds
O
Alkanes none Aldehydes
R H
R R O
Alkenes R R Ketones
R R
R R O
Alkynes Carboxylic acids
R OH
O
Arenes Esters R1 OR2
aromatic ring(s)
O
Haloalkanes -X (X = F, Cl, Br, or I) Acyl halides
R X
(X = F, Cl, Br, or I)
Alcohols -OH Nitriles R C N
O
Ethers -O- Amides
R NR2
H O
Amines R NH2 R1 N R2 R1 N R2 Sulfonic acids R S OH
R3 O
O
Thiols -SH Sulfonic esters R1 S OR2
O
Thioethers -S- Nitro compounds -NO2

67
Chapter 4. Conformational Analysis

CHAPTER 4.

Alkanes and Conformational Analysis


Study of three dimensional structures of molecules.
___________________________________________________________________________

Conformations of Alkanes
onformation is a three dimensional arrangement of atoms in space. Different arrangements of
atoms in space that are a result of rotation about a single bond are called conformational
isomers, or more commonly, just conformations. Conformational analysis is the study of
relative energies of conformational isomers. Since rotation about a single bond is free,
conformations are not actual isomers as they cannot be separated and isolated. They are different
shapes of the same molecule.

Conformational Analysis of Ethane


One of the simplest organic compounds that exhibits different
conformations is ethane. Different conformations of ethane are a result of
rotation about the carbon–carbon bond. Obviously, there is an infinite number
of such conformations. Fortunately, to conduct conformational analysis of
ethane we need to consider only the two extreme conformations – staggered
and eclipsed. In the eclipsed conformation, each of the carbon–hydrogen bonds
is in the same plane as the carbon–hydrogen bonds on the neighboring carbon.
In a staggered conformation, each of the carbon–hydrogen bonds is in between
the two carbon–hydrogen bonds on the neighboring carbon atom. In order to do
the conformational analysis, we have to be able to represent individual
conformations by means of chemical formulas. Some of the convenient
H H
H H
C H C C Perspective Formula Ball and stick models of
H C staggered conformation
H H of ethane.
H H
H H
H H H
H H
Newman Projection
H
Formula
H H H H
H H
H
H H
H H
H H H Saw-horse Formula

H H H H
staggered conformation eclipsed conformation

71
Veljko Dragojlovic

representations are Perspective formula, Newman Projection formula and Sawhorse formula. In a
perspective drawing, two carbons and two hydrogens (one bonded to each carbon) are in the plain of
the drawing. Two hydrogens (again one on each carbon) are above the plane of the drawing and are
represented by wedge bonds. The remaining two hydrogen atoms are behind the plane of the drawing
and are represented by dash bonds.
The change in energy due to the rotation from a
staggered to an eclipsed conformation is called torsional strain.
A dihedral angle (also called torsion angle) is an angle between

the bonds on the neighboring atoms. In case of ethane, the
dihedral angle is the angle between the carbon–hydrogen bonds 60°
on the neighboring carbon atoms. A dihedral angle of 0° (and also dihedral angles in eclipsed and
of 120° and 240°) represents an eclipsed conformation, while a staggered conformations
dihedral angle of 60° (and of 180° and 300°) represents a staggered conformation.
Thus, a rotation about a carbon–carbon bond by 60° converts an eclipsed conformation into a
staggered one and vice versa. As you can see from the graph, an eclipsed conformation is higher in
energy compared to a staggered conformation. Until recently, it was believed that the reason for a high
energy of the eclipsed conformation
was steric hindrance between the HH
eclipsing hydrogen atoms as well as H
the electrostatic repulsion between the H
eclipsing carbon–hydrogen bonds.
HH
Both the hydrogen atoms and the
carbon–hydrogen bonds are as close as
possible to each other in an eclipsed
conformation and as far apart as
possible in a staggered conformation. E
Recent results indicate that the reason
for energy difference may lie in
stabilization of the staggered
0 60 120 180 240 300 360
conformation by hyperconjugation
(Chapter 9) – electron delocalization H H
Degrees of Rotation
between bonding and antibonding C–
H orbitals, which is not possible in an θ H H
eclipsed conformation.
H H

Conformational Analysis of Butane


A molecule of ethane has only one type of each staggered and eclipsed conformation. In a
more complex molecule, such as butane, one can identify different types of staggered and eclipsed
conformations. A perspective drawing of a staggered conformation has all the carbon atoms as well as
two hydrogen atoms at each end of the chain (terminal hydrogen atoms) in a single plain – the plain of
the drawing. That leaves two hydrogen atoms on each carbon atom. One of the hydrogen atoms is
above the plain of the drawing (wedge bond) and the other one is
below the plane (dash bond). HH HH
CH3
A Newman projection formula is drawn in such a way H C C H H
2 3
that one observes butane molecule along the C – C bond. C C H
H H
Therefore, the two terminal methyl groups are represented as H H HH CH3
substituents.

72
Chapter 4. Conformational Analysis

Gauche and Anti Conformers of Butane

A dihedral angle in butane can be defined as the angle between C1 – C2 and C3 – C4 bonds. A
conformation where the methyl groups eclipse each other has dihedral angle of 0°. Such a
conformation is going to have a high degree of strain. First, there is torsional strain, which is present in
all the eclipsing conformations. Furthermore, there is not enough room for both methyl groups, which
are supposed to be in the same plain in this conformation. That strain is a result of steric repulsion
between the substituents and is called steric strain – van der Waals repulsion of groups that are close
to each other. Rotation about the C2 – C3 bond by 60° results in a staggered conformation in which
methyl groups are still relatively close to each other and there will still be considerable steric strain
between them. This conformation is called gauche conformation. Note that this conformation does not
have torsional strain. Rotation about the C2 – C3 bond by another 60° results in another eclipsing
conformation. This conformation has torsional strain and some steric strain that results from eclipsing
of methyl groups and hydrogen atoms. As degree of steric strain is lower compared to eclipsing
conformation with dihedral angle of 0°, the overall energy of this conformation is going to be
somewhat lower. Rotation by another 60°, results in a staggered conformation where two methyl
groups are 180° apart. Therefore, the methyl groups are as far away from each other as possible. This
conformation has no strain and is the conformation of the lowest energy for butane molecule. It is
called anti conformation of butane. Rotation by another 60° results in a conformation with dihedral
angle of 240°. This conformation is a mirror image of the eclipsed conformation with dihedral angle of
120°. Thus, the energies of the two conformations are the same. Rotation by another 60° gives the
other gauche conformation – mirror image of the first one. Rotation by another 60° completes the full
circle and gives the original eclipsing conformation.
CH CH CH
CH
H3 3 H H3 3
H
H H
H H
H H
H H H
HH H C HH
H 3
CH H HH
HH H 3
H H
CH H
H 3
H H
H H
H H C H
HH 3 H

HH H
E CH CH
H 3H 3
H
HC H
3
H H CH3 H
H H H
H H H HC H
3
H H H H H
H H H H H H
H CH3 H H
H
H

0 60 120 180 240 300 360

θ() o

Butane as a more complex molecule than ethane has an eclipsed conformation of maximum
energy and a staggered conformation of the minimum energy (anti conformation). There are also two
eclipsed conformation which represent local energy maxima, and two staggered conformations (gauche

73
Veljko Dragojlovic

conformation) which represent local energy minima. Note that gauche and anti conformations are
special cases of staggered conformations.

H3C CH3 CH3 H CH3 CH3 H CH3 CH3


H CH3 H H H3C H
H CH3 H
H H H H H H H H H H H H
H H H CH3 H3 C H
gauche anti gauche

type of torsional and steric torsional and none torsional and steric
strain steric ("Me"-"Me") steric ("Me"-"H") steric ("Me"-"H")

In conclusion, butane conformations, in addition to the torsional strain, may have steric
strain.

Conformations of Cycloalkanes
In this section we will examine cycloalkanes that contain 3 – 6 carbon atoms in the ring.
These rings adopt conformations that minimize the angle strain and the torsional strain. The concept
of angle strain was developed in XIX century by Adolf von Baeyer and it refers to a deviation from the
ideal bonding angle (109.5° in case of sp3 hybridized carbon).

Cyclopropane
The simplest cycloalkane molecule is cyclopropane. Cyclopropane molecule is planar and has
a shape of an equilateral triangle. That is obvious since three points in space define a plane (unless, of
course, all three points are co-linear). Cyclopropane has both a high degree of torsional strain and a
high degree of angle strain (don’t attempt to make a model of it – you are likely to break the bonds
unless you have a model set with flexible bonds).
Since cyclopropane molecule is planar, all carbon– H H
hydrogen bonds are in eclipsed conformations (note that there is H
C C
no possibility for bond rotation in cyclic compounds). Thus, this C
molecule has a high degree of torsional strain. line formula H H
H
The ideal tetrahedral angle is 109.5°. In cyclopropane
bond angles are 60°. Therefore, there is a large deviation form the ideal bond angle and, as a result,
there is a high degree of angle strain. If bonding electron pairs in cyclopropane were along the
internuclear axes, the angle strain would have been too large. In an energetically more favorable
arrangement, the electron pairs form a “bent,” or a “banana” bond. Cyclopropane bonds are shown
below as internuclear axes are shown in grey. Such a bond reduces angle strain, but, since the orbital
overlap is not as good as in an ordinary σ bond, this bond is considerably weaker. Strength of carbon–
carbon bond in cyclopropane is only ~65 kcal/mol, while strength of an ordinary carbon–carbon bond
(for example carbon–carbon bond in ethane) is ~83-85 kcal/mol. Note a similarity between the shapes
of cyclopropane’s σ orbitals and π orbital in an alkene. As you will learn in the next chapter, energy of
a π orbital is ~60-65 kcal/mol. This is an important consideration since sometimes reactivity of
cyclopropane resembles that of an alkene. In fact, there is a view that a double bond can be considered
to be a two-carbon ring. Cyclopropane orbitals were first described as “banana” bonds by Linus
Pauling in 1931.

74
Chapter 4. Conformational Analysis

Unlike other cycloalkanes, and alkanes in general, cyclopropane is very reactive since a
reaction that results in a ring opening will relieve both the angle strain and the torsional strain.
C

C C
C C

bonds in cyclopropane double bond

Cyclobutane
Cyclobutane molecule adopts a puckered conformation to minimize torsional strain. If it were
planar, there would have been eight C-H eclipsing interactions and the torsional strain would have
been rather high. In a puckered conformation, C-H bonds are in a conformation that is closer to
staggered and, therefore, it has a relatively small torsional strain. On the other hand, cyclobutane still
has a relatively high angle strain. Bending of the ring not only H
does not relieve its angle strain, but actually increases it. H
When a ring bends (“puckers”), C-C-C angles become H
H H
smaller (they change from 90° to 88°), which in case of
H
cyclobutane results in an increased angle strain. However, the line formula
angle strain is not as high as in the case of cyclopropane. H H
As you can see from the example of cyclobutane, a cyclic molecule can better tolerate high
angle strain than a high torsional strain. Overall, cyclobutane has a high degree of angle strain and
some torsional strain.

Cyclopentane

Angles in a regular pentagon are 108°. That is very close to the ideal H H
tetrahedral angle (109.5°) and, therefore, if it were planar, cyclopentane would H H
not exhibit any significant angle strain. However, a cyclopentane molecule is not H
H H
planar. In a planar cyclopentane there would be a high degree of torsional strain.
All ten of the carbon–hydrogen bonds would be in eclipsing conformations. H H
As in the case of cyclobutane, the molecule puckers to avoid high H
torsional strain, which increases angle strain since puckering of the molecule reduces C-C-C bond
angles. Preferred conformations of cyclopentane are the envelope and the half-chair (also called the
“twist” form). In an envelope conformation four carbon atoms are in the same plane and one is above
(or below) it. In a half-chair
conformation, three carbon atoms H H
are in a single plain, one carbon H H
H H H H
atom is above it and one below it. H
Thus, when you place a model of an H
H
envelope conformation on the table, H
four carbon atoms (or four H H H
H
hydrogen atoms, if you made a H H
H H
model that includes hydrogen
envelope half-chair

75
Veljko Dragojlovic

atoms) will rest on the table top. When you place a model of a half-chair conformation on the table,
three carbon atoms (or three hydrogen atoms, if you made a model that includes hydrogen atoms) will
rest on the table top. Note that either of the two conformations still has some torsional strain (in
cyclopentane some eclipsing interactions cannot be avoided).
In conclusion, cyclopentane has torsional strain and a very small angle strain.

Cyclohexane
In XIX century, von Baeyer represented cyclohexane as a planar molecule. Von Baeyer’s
description of cyclohexane was apparently a result of consideration of inadequate type of molecular
models (which were appropriately called von Baeyer models). Those
models had very long carbon-carbon bonds and with them one was able
to make large planar rings. In von Baeyer model of cyclohexane, there is
some angle strain and a rather high degree of torsional strain.
As expected, cyclohexane molecule twists to relieve the torsional strain. In the previous two
cases (cyclobutane and cyclopentane) twisting (or puckering) of the molecule resulted in an increased
angle strain. The reason for it was that C-C-C bond angle in those molecules was already smaller than
the ideal tetrahedral angle and twisting further reduced C-C-C bond angle. However, in a hypothetical
“planar cyclohexane” C-C-C bond angles would have been larger (120°) than a tetrahedral angle and
twisting of the molecule
actually reduces the angle "flagpole hydrogens"
strain. Thus, twisting of the H H H
cyclohexane reduces both the H
H
H H H H
torsional and the angle strain. H H
In fact, one of the resulting H H
H H H
cyclohexane conformations H H
HH H
has no strain at all. The two H H H
extreme conformations of
chair boat
cyclohexane are chair and
boat. Chair conformation is the one without strain. In a chair conformation all of the bond angles are
tetrahedral angles and all of the C-H bonds are in staggered conformations. In a boat conformation
there are a total of four pairs of eclipsing C-H bond
H H H H
interactions. Thus, boat conformation of cyclohexane has H H H H
a high torsional strain. The best way to see that is by
drawing cyclohexane molecule in a Newman projection. H H
H H H H
Boat conformation, due to its high torsional H H
strain, has a relatively high energy. In fact, due to its chair boat
torsional strain, a boat conformation is a rather high
energy conformation and is considered to be a transition state rather
flagpole hydrogens
than an actual conformation. You may recall from a general chemistry
course that a transition state is a maximum on an energy diagram and H H
that a molecule only passes through it, but does not spend any time in 1 H 4
it. A more stable conformation is a twist-boat conformation. Thus, the H H
H H
boat “twists” as illustrated below, to reduce the torsional strain. H
However, even twisting of the ring cannot entirely remove the torsional H
strain. Besides torsional stain, a twist boat conformation also has a H H
small degree of angle strain. Finally, there is also a small steric strain H
present in this conformation. At first glance it may appear that the twist-boat

76
Chapter 4. Conformational Analysis

“flagpole” hydrogens may be responsible for the steric strain. However, that is not the case. Both in a
boat and a twist boat conformations there is enough room for the “flagpole” hydrogens. The cause of
steric strain is not apparent from a “ball and stick,” or a “wire frame” molecular models of
cyclohexane. Examination of a space-filling molecular model reveals that the carbon atoms 1 and 4
“bump” into each other and are responsible for the steric strain. One should keep in mind that both the
angle and the steric strain in this conformation are very small and for practical purposes we consider
that twist boat conformation has only torsional strain. From the space filling model one can see that
there is enough space for the flagpole hydrogens, but that the carbons bonded to them “bump” into
each other.

flagpole H
flagpole H

wire frame model ball and stick model space filling model

Axial and Equatorial Bonds of Cyclohexane


In a chair conformation of cyclohexane we can identify two types of carbon-hydrogen bonds:
axial and equatorial.

axis

Axial bonds are parallel


equatorial bonds to the ring axis.

Equatorial bonds are


distributed around the
equator equator of the ring.

axial bonds

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Veljko Dragojlovic

Bond Angles
Throughout the text the ideal tetrahedral bond angle was stated to be 109.5°. That is not quite
correct. It is correct only if the carbon atom has four identical substituents (for example: CH4 or CCl4).
If the substituents are different, the bond angle deviates to accommodate different steric requirements
of different substituents (to make more space for larger substituents). Thus, in propane C-C-C bond
angle is 112°. Open chain compounds do not exhibit angle strain (they may have steric and/or torsional
strain). In cyclohexane, C-C-C bond angle (it is 111.5°) is very close to that of propane and therefore it
doesn’t have angle strain. Therefore, puckering of cyclohexane ring results in a reduction of C-C-C
bond angle from 120° to 111.5° (not to 109.5°).

Drawing of Cyclohexane Conformations

It is important to draw cyclohexane conformations correctly (with correct bond angles and
correct placement of the axial and equatorial bonds). One way to draw cyclohexane ring and its
equatorial and axial bonds is shown here.
One should start by drawing a five-atom chain in a zigzag conformation (a). The
conformation resembles letter M. You should keep in mind that the tetrahedral angle (109.5º) is closer
to 120º than to 90º. The angles in the chain should actually be 135-150° because one is drawing a
projection of three-dimensional ring in two dimensions. Next, one draws another five-atom chain
parallel to the first one in a form of a letter W as in (b). Starting point is approximately one half bond
length below the midpoint of the first bond in M. The first bond in W should be parallel to the second
bond in M. The second atom of the one chain should be connected to the second atom of the other
chain and the second last atom of the first chain should be connected to the second last atom of the
other chain (c). As an aid in determining which atoms to connect, one can place hydrogen atoms at the
ends of each chain and than connect the terminal carbon atoms (d). The resulting drawing depicts all
carbon-carbon bonds and four of the six equatorial carbon-hydrogen bonds. The remaining two
equatorial bonds can be drawn by making letters M and W as depicted in (e). The axial bonds are
parallel to the edge of the
paper as in (f). Steps (g) –
(l) show drawing of the
(a) (b) (c) alternate chair
conformation.
H H
H H

(d) (e) (f)

(g) (h) (i)

Parallel carbon-carbon
H H
H H bonds in cyclohexane

(j) (k) (l)

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Chapter 4. Conformational Analysis

Interconversions of Cyclohexane Conformations

There are two possible chair conformations of cyclohexane. The two conformations are mirror
images of each other. Note that they are identical and, therefore,
have the same energy. At room temperature cyclohexane
molecules constantly flip from one chair conformation to another.
The following mechanism of a chair flip includes first
formation of a “half-chair” 2 (five carbons are in the same plane). Half-chair, as expected, has a very
high energy and is only a transition state, which gives rise to the actual conformation – twist boat 3.
Next, the twist boat conformation flips into the alternative twist boat conformation 5. The transition
state for this flip is the boat conformation 4. Note that the two twist boats are mirror images of each
other. Then, the cyclohexane molecule passes through another half-chair transition state 6 (mirror
image of the first one) and finally arrives at the alternative chair conformation 7. You should learn how
to perform a chair flip on a model of cyclohexane. Arrows in the scheme below should help you. You
may note that, when using molecular models, twist boat conformation is not necessary for a chair flip
and it is not obvious why it should be a part of the process. Computer based molecular models and
calculations show that it is. Keep in mind that the two chairs (1 and 7) and the two twist boats (3 and 5)
are the actual conformations. Half-chairs (2 and 6) and boat (4) are only transition states. Therefore,
twist boat is the intermediate between the two transition states (whenever there are two transition states
there must be an intermediate between them – that follows from definitions of intermediates and
transition states). A problem with molecular models is that they do not distinguish between a
conformation and a transition state and with them one can go directly from one conformation to
another! Molecular models are just that – models. They are not actual molecules.

1 2 3

7 5
6

Here is an abbreviated version of the same chair flip (the way one would do it with a
molecular model):

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Veljko Dragojlovic

Monosubstituted Cyclohexanes
As we have just seen the two alternate chair conformations of cyclohexane have the same
energy. However, chair conformations of substituted cyclohexanes do not have the same energy. When
one chair conformation of a substituted cyclohexane flips into the alternative chair conformation, an
axial substituent becomes equatorial and vice versa. A chair conformation with an axial substituent is
less stable compared to a chair conformation with an equatorial substituent. The reason for lower
stability is in steric interactions between the axial substituent and the axial hydrogens on the same side
of the ring. If the carbon atom with the axial substituent is numbered as carbon 1, then each carbon that
has axial hydrogen on the same side of the ring will have a number 3 (in one case the numbering is
clockwise and in the other counterclockwise). Steric interactions between the axial substituent and the
axial hydrogens are called 1,3-diaxial interactions.
H H H H H
H H
H 3 H H
H H H
1 H H
CH3 3 CH3 H
H H
H
H H H
HH H CH3 HH H CH
H H H 3

no diaxial interacions 1,3-diaxial interacions equatorial substituent axial substituent


As a general rule, a conformation in which the substituent is equatorial is going to be more
stable.

Conformations of Disubstituted Cyclohexanes: cis/trans Isomerism


Disubstituted cyclic compound exhibit a form of geometric isomerism that is called cis/trans
isomerism. In a cis isomer both substituents are on the same side of the ring, while in a trans isomer
the two substituents are on the opposite sides of the ring. cis/trans Isomerism is a consequence of
restricted rotation about carbon–carbon bonds in cyclic compounds. In disubstituted (and
polysubstituted) cyclohexane the most stable conformation is going to be the one in which the largest
number of substituents are in equatorial positions. If the number of equatorial and axial substituents of
the same size in two conformations is the same, then the two conformations are equally stable.
Examples shown below illustrate this concept. The arrows indicate the position of the equilibrium.
Note that in a cis isomer both substituents point “up” (or “down”) and that in a trans isomer one
substituent points “up” and the other one “down.” Chair flip does not change the orientation of a
substituent. One that was pointing “up” still points “up” and the one that was pointing “down” still
points “down.” However, chair flip changes an equatorial substituent into an axial one and vice versa.
cis-1,4-dimethylcyclohexane

trans-1,4-dimethylcyclohexane

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Chapter 4. Conformational Analysis

cis-1,3-dimethylcyclohexane

trans-1,3-dimethylcyclohexane

If the two substituents are of different size, then, in a more stable conformation, the larger
substituent will occupy the equatorial position.

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Veljko Dragojlovic

Fused Six-Member Rings: Decalin

Two fused six member carbon rings form a molecule called decalin (note that it has ten
carbon atoms). Its IUPAC name is bicyclo[4,4,0]decane. Decalin can be in a form of a cis or a trans
isomer. A cis-decalin has two hydrogens at angular positions (those where the two rings meet) on the
same side, while the trans-decalin has the two angular hydrogens on the opposite sides of the ring (one
“up” and the other one “down”). Both cis-decalin and trans-decalin have two fused cyclohexane rings
in chair conformations. Note that a chair flip into the alternative conformation is possible only with
cis-decalin. In trans-decalin, chair flip would result in two axial carbon substituents, which could not
form the other cyclohexane ring because the distance between them would be too large.

cis-decalin
H
H

chair flip is not possible:

H
trans-decalin this bond would
be broken

The common name for bicyclo[4,4,0]decane is decalin, not decaline. Decaline is a naturally
occuring compound of a rather complex structure.

O H
H

decaline
N

O
OCH3

OCH3

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Chapter 5. Acids and Bases

CHAPTER 5.

Acids and Bases


An introduction into organic acids and bases.
___________________________________________________________________________

Brønsted – Lowry Definition of Acids and Bases


ccording to Brønsted and Lowry definition an acid is a proton donor, a base is a proton
acceptor and an acid-base reaction is a proton-transfer reaction. After an acid, HA, donates its
proton, it produces the corresponding anion, A-. That anion can accept a proton and is now a
base, called a conjugate base. The base, B-, accepts a proton to give the corresponding protonated
species, BH. This is now a proton donor, or in other words an acid, and it is called a conjugate acid.
Result of a Brønsted – Lowry acid-base reaction is formation of a conjugate acid – conjugate base pair.

HA + B HB + A
acid base conjugate conjugate
acid base

Whether a compound is an acid, or a base, depends on the reaction conditions. In the


following two examples, water acts first as a base and then as an acid.

HCl + H2 O H 3O + Cl
acid base conjugate conjugate
acid base

H 2O + NH3 NH3 + OH
acid base conjugate conjugate
acid base

In more general terms an acid is any species (a molecule or an ion) from which a proton can
be removed and a base is the species that removes it. Some examples are given below.
O O
H C OH + H2O H C O + H3O
acid base conjugate conjugate
base acid

O O
C + Na H C + H2
H3C CH3 H3C CH2 Na
acid base conjugate conjugate
base acid
H
HI + O O + I
H3C CH3 H3C CH3
acid base conjugate conjugate
acid base

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Veljko Dragojlovic

Lewis Acids and Bases


While Brønsted – Lowry definition of acids and bases is useful, it has some limitations. For
example; it cannot explain a reaction like this:

H3 N + BF3 H3N BF3

Ammonia and boron trifluoride yield a salt without a proton transfer. In order to explain such
reactions we need a more general definition of acids and bases. Such definition is Lewis Acid – Base
theory. According to Lewis, an acid is an electron pair acceptor and a base is an electron pair donor.
To memorize which is which, remember that an acid is an electron pair acceptor. Thus, according to
Lewis, proton itself is an acid as it can accept an electron pair.
H
H + NH3 H N H
Lewis Lewis H
acid base

According to Bronstead – Lowry theory, a compound is an acid because it can donate proton.
According to Lewis, it is an acid because it is a source of the actual acid – the proton. Note that a
Lewis acid must have an empty orbital and a Lewis base must have a free electron pair. Every
Brønsted – Lowry base is also a Lewis base. The main difference between the two theories is in
description of the acids. Thus, not every Brønsted – Lowry acid is a Lewis acid. In fact, there is a
relatively large number of known Brønsted – Lowry acids (compounds that are proton donors) and
comparatively few Lewis acids (compounds, or ions, with an empty orbital).
Lewis acid – base theory can explain a large number of reactions, including organic reactions
that do not involve a proton transfer. Examples are reactions between dimethyl ether and boron
trifluoride as well as reaction between aluminum chloride and trimethylamine.

F F
F B + O CH3 F B O CH3
F CH3 F CH3
Lewis Lewis
acid base

Cl CH3 Cl CH3
Cl Al + N CH3 Cl Al N CH3
Cl CH3 Cl CH3
Lewis Lewis
acid base
Carbocations are an important class of Lewis acids. They are common reaction intermediates
in organic chemistry.

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Chapter 5. Acids and Bases

CH3 CH3
H3C C + O CH3 H3C C O CH3
H H H H
Lewis acid Lewis base

Lewis acid – base theory is used extensively in organic chemistry. However, one has to
distinguish between it and Brønsted – Lowry theory. We use terms acid and base when we apply
Brønsted – Lowry definition and terms Lewis acid and Lewis base when we apply Lewis definition.

Organic Acids
Carboxylic Acids
Carboxylic acids are typical organic acids. Carboxylic acids contain a carboxylic group (-
CO2H) and are weak acids. It means that in an aqueous solution they are dissociated only to a small
extent.
O O
H3C C OH + H2O H3C C O + H3O

Two simplest carboxylic acids are formic acid and acetic acid. Hydrogen atom bonded to the
oxygen atom is the acidic hydrogen atom.

O O
H C OH H3C C OH
formic acid acetic acid
pKa = 3.75 pKa = 4.76

As their name indicates carboxylic acid usually react as acids. It takes a rather strong acid to
protonate a carboxylic acid.

O O
H3C C OH + OH H3C C O + H2O
pKa = 4.76

O O
H3C C OH + H3O H3C C OH2 + H2O
pKa = -6.1

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Veljko Dragojlovic

Protonated Organic Cations


Protonated organic cations such as R3
oxonium, sulfonium and ammonium react as 1
R O H 1
R S H 1
R N H
acids. In organic reactions they play various roles R2 R2 R2
including those of reagents, catalysts or reaction oxonium ion sulfonium ion ammonium ion
intermediates.

H3CH2C O H H3CH2C O
+ H3C NH2 + H3C NH3
CH2CH3 CH2CH3

Cations
Carbocations are strong acids and easily donate one of the protons next to the cationic carbon
to give alkenes.
H3C H H3C
C CH2 + OH C CH2 + H2O
H H
acid base conjugate conjugate
acid base

Organic Bases
Amines
H3C NH2
Amines are nitrogen-containing organic compounds. They are relatively
weak organic bases. An example of an amine is methylamine. Basicity of amines is methylamine
pKa = 40
similar to that of ammonia.

H3C NH2 + OH H3C NH + H2O


pKa = 40

H3C NH2 + H3O H3C NH3 + H2O

pKa = 10.7

Ethers
Ethers are weaker bases than amines. However, they are common solvents for organic
reactions and their role as bases is important.

H3CH2C O H2SO4 H3CH2C O H HSO4


+ +
CH2CH3 CH2CH3

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Chapter 5. Acids and Bases

Alkenes
Note that alkenes are conjugate bases of carbocations (p. 90). Therefore, in a reverse reaction,
alkenes can be protonated to give the corresponding carbocations.

CH3 CH3
H3O + H2C C H2O + H3C C
H H
acid base conjugate conjugate
base acid

Alcohols
Alcohols contain a hydroxyl group (-OH). Two simplest H3C OH CH3CH2 OH
alcohols are methanol and ethanol. Hydrogen atom bonded to the methanol ethanol
oxygen atom is the acidic hydrogen atom. Acidity of an alcohol is pKa = 15.5 pKa = 15.9
similar to that of water (pKa = 15.7).
Therefore, alcohols can easily react as either acids or bases depending on the reaction
conditions.

H3C OH + OH H3C O + H2O


pKa = 15.9

H3C OH + H3O H3C OH2 + H2O


pKa = -2.5

Carbonyl Compounds
Carbonyl compounds have a carbonyl oxygen that can be protonated. Therefore, they are
organic bases. Note that the protonated carbonyl compound is an oxonoium ion. It is different from the
oxonium ions encountered earlier as it has an sp2 hybridized oxygen atom.

H
O O
C C
H3C CH3 + H3O H3C CH3 + H2O
oxonium ion

Hydrogen atoms next to the carbonyl carbon are acidic. Thus, carbonyl compound can also
react as organic acids. The resulting conjugate base is called enolate ion.
O O
C OH C +
H3C CH3 + H3C CH2 H2O

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Veljko Dragojlovic

pKa and pH
An acid – base reaction is an equilibrium reaction. Therefore, dissociation of an acid in an
aqueous solution is characterized by the equilibrium constant (Keq).

HA + H2O H3O+ + A-

[H 3 O + ] [A − ]
K eq =
[HA] [H 2 O]

An acid – base reaction is usually carried out in a dilute aqueous solution and for practical
purposes one can consider that concentration of water is constant. The equilibrium constant for
dissociation of an acid that includes concentration of water is called the acid – dissociation constant,
Ka.

[H 3 O + ] [A − ]
K a = K eq [H 2 O] =
[HA]

Negative logarithm of the acid – dissociation constant, Ka, is pKa and negative logarithm of
concentration of hydronium ions, [H3O+], is pH.

pKa = -log Ka pH = - log [H3O+]

A strong acid has a large value of Ka and a small value of pKa. The reverse is true for weak
acids.

Position of the Acid-Base Equilibrium


An acid-base reaction is a thermodynamically controlled process (see next chapter) that
results in formation of more stable species – the more stable acid-base pair. The more stable acid-base
pair is the weaker acid-base pair. Therefore, in a spontaneous process, a strong acid and a strong base
react to give a weak acid and a weak base. To determine acid strength one can examine Ka, or pKa,
values. Keep in mind that the higher value of Ka, or the lower value of pKa, indicates the stronger acid.
A strong acid, after loss of proton, gives a weak conjugate base, while a weak acid gives a strong
conjugate base. The same is true for bases. Upon protonation, a weak base gives a strong conjugate
acid and a strong base gives a weak conjugate acid. Thus, to determine strength of a base, one can
examine Ka, or pKa, values of the corresponding conjugated acid. A strong conjugated acid (large Ka,
or small pKa) means that the original base was weak, while a weak conjugate acid (small Ka, or large
pKa) means that the original base was strong.

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Chapter 5. Acids and Bases

O O

H3C C OH + NH3 H3C C O + NH4


pKa = 4.76 pKa = 9.4

CH3CH2 OH + CH3NH2 CH3CH2 O + CH3NH3


pKa = 15.9 pKa = 10.7

The equilibrium constant for an acid – base reaction is a ratio of Ka values of the original acid
(the reactant acid) and its conjugate acid (the product acid).

K a (reactant)
K eq =
K a (product)

The equation above can be derived as follows. In a reaction between an acid (HA) and a base
(B), the products are conjugate base (A) and conjugate acid (HB).

HA + B A + HB

Equilibrium constant for the reaction can be expressed as:


[A][HB]
K eq =
[HA][B]

Acidity constants for the reactant acid (HA) and the product acid (HB) are:
[A][H 3 O + ] [B][H 3 O + ]
K aHA = K aHB =
[HA] [HB]

Therefore, equilibrium constant is a ratio of acidity constant of the reactant acid and the
acidity constant of the product acid:

[A][H 3 O + ] [A]
K a (reactant) K aHA [HA] [HA] [A][HB]
K eq = = = +
= =
K a (product) K aHB [B][H 3 O ] [B] [HA][B]
[HB] [HB]

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Veljko Dragojlovic

Acid Strength
A strong acid is the one that has a high tendency to donate its proton. An acid will easily
donate the proton only if the resulting conjugate base is stable. The resulting conjugate base is going to
be a weak base, which is stable and does not accept proton readily. The reverse is true for weak acids.
Conjugate base of a weak acid is a strong base (an unstable species), which readily accepts proton to
give a more stable species (the corresponding weak acid). Therefore, when considering acid strength
one should consider stability of the corresponding conjugate base.

HA + B HB + A
strong base conjugate stable
acid acid conjugate
base

HA + B HB + A
weak base conjugate unstable
acid acid conjugate
base

The main factor that affects stability of a base is its ability to tolerate charge (if any). As
charged species are less stable than the corresponding neutral species, a conjugate base that is not
charged is more stable than one that is.

H3O + B HB + H2 O
strong stable
acid conjugate
base

H2 O + B HB + OH
weak unstable
acid conjugate
base

Most conjugate bases are charged. Their stability depends on the ability of the charged atom
to tolerate the charge (for example, oxygen can tolerate negative charge while sodium cannot) and on
the charge density. As a general rule species with a high charge density (charge concentrated on a
single small atom) are unstable, while those with a low charge density (charge spread over several,
preferably large, atoms) are stable. The following factors affect ability of an atom to tolerate charge as
well as charge density:

Electronegativity
Hybridization
Bond Energy
Inductive Effect
Electron Delocalization (Resonance)

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Chapter 5. Acids and Bases

Electronegativity
Electronegativity is an ability of an atom, or a group, to attract the shared electron pair. When
the atoms are similar in size, such as those that belong to the same row of the periodic table, the more
acidic compound has the hydrogen atom attached to the more electronegative atom. For example, in a
series of hydrides of the second row elements we will note that, in each case, as we go from left to
right across the row hydrogen atom is bonded to a more and more electronegative atom. We can
compare the acidities of these compounds by comparing their respective pKa values. Methane has pKa
value of about 50, which means that it is not acidic at all. Ammonia has pKa value of 36. Therefore, it
is a very weak acid. In fact, due to a pair of free electrons on the nitrogen, it usually reacts as a base.
However, as its pKa indicates it is considerably more acidic than methane. Next compound, water, with
a pKa value of 15.7, is more acidic than ammonia. Finally, hydrogen fluoride has a pKa value of 3.2
and is classified as an acid. When we compare electronegativities of the atoms the hydrogen is bonded
to, we find that fluorine has the highest electronegativity while carbon has the lowest.

CH4 < NH3 < H2O < HF


pKa ~50 36 15.7 3.2

electronegativity

acid strength

Therefore, with increase in electronegativity, acidity of the compound increases. The reason
for it is in stability of the corresponding conjugate bases. The more electronegative Y atom more easily
tolerates negative charge and has lower tendency to accept a proton to form the original acid.. Thus,
fluoride ion is going to be the weakest, and therefore the most stable, base while methyl anion is going
to be the strongest and the least stable base.
-
stability: CH3 < -NH2 < -OH < F-

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Veljko Dragojlovic

Hybridization
In general, acidity of a compound depends on the hybridization of the atom bonded to the
acidic hydrogen. In order to examine the effect of hybridization, we are going to compare acidities of
three simple hydrocarbons: methane, ethene (ethylene) and ethyne (acetylene). Methane has pKa value
of about 50, while ethene has pKa value of about 44. Thus, ethene is about one million times stronger
acid compared to methane (keep in mind that pKa is a logarithmic scale). Still it is a very weak acid (it
is considered to be non-acidic for all practical purposes). Ethyne has pKa value of 25. Thus, it is
substantially more acidic compared to the other two.
In the three compounds we examined, the only difference between the carbon atoms bonded
to hydrogens is in their hybridization. Hybridization of an atom is related to its electronegativity.
Electronegativity of an atom increases with increasing s orbital character of the hybridized orbital. An
s orbital is closer to the nucleus compared to a p orbital (keep in mind that a p orbital has a node at the
nucleus) and, thus, electrons in an s orbital are closer to the nucleus and experience stronger attraction
by it. The same applies to hybrid orbitals and an electron in
an orbital with higher s character is experiencing stronger H H H
attraction by the nucleus than one in an orbital with less s H C H C C H C C H
3
character. Thus, an sp hybridized carbon has orbitals that H H
H
are only 25% s and 75% p character (one s and three p
orbitals), an sp2 orbital has 33% s character and 67% p pKa ~50 ~44 ~25
character (one s and two p orbitals) and an sp orbital has sp3 sp2 sp
50% s and 50% p character (one s and one p orbital). 25% s 33% s 50% s
Therefore, s character increases as we go from sp3 to sp2 to 75% p 67% p 50% p
sp carbon. An sp hybridized carbon is the most
electronegativity
electronegative, while an sp3 hybridized carbon is the least
electronegative. Thus, an sp hybridized carbon tolerates acid strength
negative charge relatively well, while a negatively charged
3
sp hybridized carbon is highly unstable. The acidity of
H
hydrocarbons follows electronegativity of carbon bonded to H
the acidic hydrogen atom. Therefore, since hybridization H C < C C < H C C
H H
affects electronegativity of an atom, effect of hybridization is H
a special case of the effect of electronegativity on acid stability
strength.

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Chapter 5. Acids and Bases

Atom Size
One can use electronegativity only to compare relative acidities of compounds that contain
hydrogen atom bonded to the elements of the same row of periodic table. We can examine effect of
atom size on strength of H-X acids (HF, HCl, HBr and HI). Electronegativities of atoms in the same
group decrease when going down a group. Therefore, based on effect of electronegativity on acidity,
one would expect that hydrofluoric acid would be the strongest and hydroiodic acid the weakest of the
four hydrohalic acids. When we compare pKa values we find that hydrofluoric acid has the highest pKa
value (it is the weakest acid) while hydroiodic acid has the lowest pKa value (it is the strongest acid).
Thus, in this case, electronegativity is inversely proportional to
HF < HCl < HBr < HI
the acidity of a compound. When going down the group the size
of atom increases. The larger the atom, and the corresponding pKa 3.2 -7 -9 -10
ion, the more diffuse the charge is. The charge is spread over a
larger volume of space resulting in a more stable ion. electronegativity
atom size
acid strength

When comparing acid strength of hydrogen compounds of the elements that belong to the
same group of the periodic table one should compare atom sizes and not electronegativities.
Electronegativities should be used only when comparing acid strengths of the acids of the elements
that belong to the same row of the periodic table. In fact, when going across a row the atom size
decreases (recall periodic properties from General Chemistry course) and one can conclude that atom
size However, the decrease in atom size across a row is relatively small and the increase in acid
strength is due to increase in electronegativity.

97
Veljko Dragojlovic

Inductive Effect
The two effects examined so far, electronegativity and atom size, are usually studied in a
general chemistry course and you should be familiar with them. Now, we are going to examine the
effects that operate primarily in organic compounds and are likely to be new to you.
If there are polar functional groups in a molecule (that means electronegative or
electropositive substituents on a carbon atom), they affect acidity of the molecule. Individual polar
covalent bonds polarize bonds next to them, which in turn polarize neighboring bonds and so on. Thus,
electron withdrawing or electron donating effect of a polar substituent propagates throughout the
molecule. Polarization, or displacement, of electrons through σ bonds due to the presence of a
substituent (electropositive or electronegative) is called inductive effect. It is sometimes described as
displacement of electrons through σ bonds. However, keep in mind that electron pairs never leave their
σ orbitals. They only shift closer to one of the atoms of the bond.
When we compare a series of acids that have the same carbon skeleton with different
substituents we can examine the effect of those substituents on acidity. We will compare acidities of
fluoroacetic acid, chloroacetic acid, bromoacetic acid, iodoacetic acid and acetic acid by comparing
their respective pKa values. We can see that acetic acid has the highest value for pKa (4.76) while
fluoroacetic acid has the lowest (2.66).
O O O O O
F Cl Br I
OH OH OH OH OH
2.66 2.86 2,89 3.12 4.76

In this case inductive effect of halogen atom propagates through four bonds. More
electronegative atom polarize the bond to a greater extent. Therefore, more electronegative atoms
exhibit stronger inductive effect resulting in stronger acids. Thus, in this series of carboxylic acids, the
one with the most electronegative substituent, fluorine, is the strongest one while one with the least
electronegative substituent, hydrogen, is the weakest one.
Negative inductive effect diffuses (spreads) negative charge to several atoms making the
conjugate base more stable. We can explain inductive effect on example of fluoroacetic acid.
Fluoroacetic acid in a solution is ionized to give fluoroacetate ion:

O O
F F
OH + H2O O + H3O
fluoroacetate
ion

1) Fluorine atom as more electronegative than carbon atom, attracts the shared electron pair. Thus,
the electron pair is closer to fluorine, which leaves the carbon atom electron deficient.
2) That carbon atom, in order to compensate for its electron deficiency, attracts electrons from the
neighboring bonds, including the neighboring carboxylic carbon (carbon of the –COOH group),
which now in turn becomes electron deficient. O
3) The carboxylic carbon then attracts electrons it shares with oxygen taking 1 3
2
away some of its negative charge. Thus, even though oxygen atom carries a F < < C <
C O
formal negative charge (and in fact most of the negative charge is still on
oxygen), the charge is spread over four atoms (shown in bold). H H

98
Chapter 5. Acids and Bases

The magnitude of an inductive effect sharply decreases with distance between the substituent
and the reactive site. Thus, in a series of chlorobutanoic acids, the closer the chlorine atom is to the
carboxylic group the stronger the acid is. The decrease of magnitude of inductive effect with distance
is rather sharp and when chlorine atom is on the fourth carbon its inductive effect is very small.

O O Cl O O
Cl
OH OH OH OH
Cl
4.82 2.84 4.06 4.52

Inductive effects are additive. It means that the more substituents that exhibit an inductive
effect are present in the molecule, the stronger the inductive effect. Two electronegative substituents
exhibit a stronger effect than one, and three substituents exhibit a stronger effect than two substituents
(provided, of course, that we are comparing compounds with identical substituents). Thus, in a series
of chloroacetic acids, trichloroacetic acid is the strongest acid due to the inductive effect of three
chlorine atoms, while monochloroacetic acid is the weakest. Electropositive substituent has the
opposite effect and decreases the acidity through electron donation. Electropositive substituents are
rare. There are only a few organic substituents that are more electropositive compared to carbon
(silicon is one of them).

O O O O
Cl
Cl Cl Cl
OH OH OH OH
Cl Cl
2.86 1.29 0.65 4.76

Inductive effect of substituents on bases (for example amines) operates in opposite direction.
Electron withdrawing substituents decrease base strength while electron donating substituents increase
it. However, solvation has important effect on basicity of a compound and is often more important than
inductive effect.
Inductive effects are among the most important effects in chemistry and we will encounter
them all throughout our study of organic chemistry. In summary of inductive effects are a consequence
of shift of electron density within a molecule by polar functional groups. A charge polarization through
σ bonds is called inductive effect. An electronegative substituent increases the acidity of an acid, while
an electropositive decreases it. The effect decreases with increasing distance of the substituent from the
Y–H bond.

99
Veljko Dragojlovic

Electron Delocalization (Resonance)


Polarization (a shift in electron density) through π bonds is called resonance effect.
Resonance effect involves delocalization of electrons. Electrons are delocalized if they do not belong
to a particular atom or a particular bond.
Earlier, we encountered acetic acid and ethanol as examples of O
organic acids. Both compounds have two carbon atoms and an acidic H 3 C C OH CH3CH2 OH
hydrogen atom bonded to an oxygen atom. If we compare pKa values of acetic acid ethanol
acetic acid (pKa = 4.76) and ethanol (pKa = 15.9), we can see that acetic pKa = 4.76 pKa = 15.9
acid is more than a hundred billion times more acidic (~11 pKa units).
O
One explanation for increase in acidity could involve stabilization fo the
acetate ion through inductive effect of the additional oxygen atom. However, as you H3C C O
can see from the section on inductive effects, their magnitude is relatively modest inductive effect
(at most increase in acidity by 2 – 3 pKa units) compared to the increase in acidity in acetate ion
of 11 pKa units in this example. Therefore, inductive effect alone is not sufficient to
explain such high increase in acidity. The increase in acidity is explained by delocalization of
electrons, or resonance effect. Resonance effect involves displacement (or shift) of electrons through π
bonds. Remember that the other electronic effect, inductive effect, operates through σ bonds.
A compound with delocalized electrons cannot be represented with a single structural
formula. Structural formulas that represent a compound with delocalized electrons are called
resonance structures (an old name is canonic structures) and the actual structure is a resonance hybrid
of the individual resonance structures. Thus, the actual structure is a combination or an average of the
individual resonance structures. Thus, actual structure of the acid in our example, acetic acid, cannot
be represented by a single Lewis formula. We need two Lewis formulas to represent its structure. The
actual structure is a resonance hybrid (a combination) of the individual resonance structures. The
structural formula that is lower in energy contributes more to the overall structure of the molecule. In
the case of acetic acid the structure without a charge separation contributes more to the overall
structure of acetic acid. However, the structure that involves the charge separation still contributes to
an extent. That resonance structure shows that, due to electron delocalization, there has been some
electron withdrawal from the oxygen atom of the O-H group. Resonance effect stabilizes the conjugate
base – the carboxylic acid anion. The anion has two equivalent resonance structures and, thus, is
exceptionally stable – the more equivalent resonance structures one can draw for a compound the
greater the electron delocalization and the more stable the compound is. Acid – base reactions are
equilibrium reactions.
Therefore, increased
stability drives the O O O O
equilibrium to the right H3C C OH H3C C OH -H H3C C O H3C C O
to a much greater stable
extent compared to resonance forms of resonance forms of
acetic acid acetate ion
equilibrium involving δ−
ethanol, whose anion, O
electron and charge
ethoxide, is not H3C C delocalization in acetate ion
resonance stabilized. δ−
O
Although oxygen atom
is electronegative, it is CH3CH2 OH -H CH3CH2 O
relatively unstable if it unstable
carries a negative electrons in ethanol and ethoxide ion are localized
charge. Resonance

100
Chapter 5. Acids and Bases

stabilization of the carboxylate anion allows for the delocalization of the negative charge (it is shared
by two oxygen atoms) and its additional stabilization. A way to represent the structure of carboxylate
anion is as shown below. Note that there is no possibility for delocalization of negative charge on
ethoxide oxygen – the charge is localized on the single oxygen atom.
The more resonance structures contribute to the resonance hybrid the greater stabilization.
Thus, for sulfuric acid we can draw three resonance structures for its conjugate base. The negative
charge is delocalized over three oxygen atoms, which means that each of them carries only -1/3 charge.
Therefore, degree of resonance stabilization as well as the stability of the anion are greater compared to
acetic acid. Therefore, sulfuric acid is stronger acid than acetic acid. Resonance stabilization is only
one effect that contributes to the strength of sulfuric acid. Inductive effects of additional oxygen atoms
also play a role.

O O O O
HO S OH HO S O HO S O HO S O + H
O O O O

However, the number of resonance structures is not the only factor that determines the degree
of resonance stabilization. Stability of individual resonance structures also plays a role. Thus, phenol
has five resonance structures and negative charge is delocalized over four atoms. However, three
resonance structures are rather unstable, high energy, structures with a negative charge on carbon atom.
Phenol is weaker acid compared to acetic acid, but, due to resonance stabilization it is stronger than
ethanol.

OH O O O O O
-H

OH
O O
CH3CH2 OH < < H3C C OH < HO S OH
O

Note that in the previous discussion we used curved arrows to indicate delocalization of
electrons. A more detailed explanation of use of curved arrow to indicate flow of electrons will be
provided in next chapter.

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Veljko Dragojlovic

The Effect of pH on the Structure of an Organic Compound:


Henderson-Hasselbalch Equation
Whether an acidic compound is in protonated or deprotonated form (in other words, weather it
will be in the form of an acid or its conjugate base) in an aqueous solution depends on the pKa of the
acid and the pH of the solution. This relationship is given by Henderson-Hasselbalch equation.
[HA]
pK a = pH + log
[A - ]
If pKa equals pH, log [HA]/[A-] will be 0. Since log of 1 is 0 that means that [HA]/[A-] ratio is
1 or [HA]=[A-]. According to Henderson – Hasselbalch equation, as pH increases we have [HA]<[A-]
and if pH decreases [HA]>[A-]. An acid exists as a mixture of protonated and deprotonated forms if the
pH of the solution is in the range pKa ± 1. Outside that range the acid exists predominantly in either
protonated (pH < pKa – 1), or deprotonated (pH > pKa + 1) form. The actual amounts of each form can
be calculated using Henderson-Hasselbach equation.
Thus, if one knows the pKa of the compound and the pH of the solution, one can estimate, or
calculate, the relative amounts of the acid and its conjugate base present in the solution. For a typical
carboxylic acid pKa is approximately 4.5. For a
protonated amine pKa value is approximately 10. O O
Therefore, an acid will be in its protonated form if C + H 2 O C + H3O
R OH R O
pH ≤ 3.5 and deprotonated if pH ≥ 5.5, while an
amine will be in its protonated form if pH ≤ 9 and
R NH2 + H2O R NH3 + OH
deprotonated if pH ≥ 11.

Determination of Base Strength


To estimate strength of a base, one should apply the principles learned in this chapter. The
discussion of acid strength also applies to base strength except that the various effects, as expected,
operate in reverse. Thus, low electronegativity, small atom size and electron donating substituents
make a base strong. When considering base strength salvation effects also play important role.
However, that is beyond the scope of this course.
Another, more accurate, way to estimate strength of a base is to examine Ka, or pKa, values of
the corresponding conjugated acid. A strong conjugated acid (large Ka, or small pKa) means that the
original base was weak, while a weak conjugate acid (small Ka, or large
pKa) means that the original base was strong.
For example, if we wish to arrange F-, HS- and H2As- in the order
of base strength we can compare strengths of the corresponding conjugate
acids HF, H2S and H3As.. As the three are arranged diagonally in the
periodic table, it is not possible to consider electronegativity of an atom or
its size. Therefore, for a correct answer we have to consider pKa values.
They are 3.19 for HF, 7.04 for H2S and ~23 for H3As. Therefore, acid strength from the weakest to the
strongest is H3As < H2S < HF. The order of base strengths is the opposite F- < HS- < H2As-.

102
Chapter 6. Organic Reactions

CHAPTER 6.

Organic Reactions
Theory of organic reactions. Hammond postulate. Principle of microscopic
reversibility.
___________________________________________________________________________

tudy of organic chemistry involves a large number of, at first glance, very different reactions.
However, all of the organic reactions can be classified into relatively few reaction mechanisms.
Once you know the reaction mechanism, you will be able to describe the pathway the reactants
take as they are converted into products and you will be able to predict the reaction products.
All organic reaction mechanisms can be divided into two large groups: polar and non-polar.
Polar reaction mechanisms involve either ions as reaction intermediates, or charge separation in the
intermediate, or in the transition state. A number of addition, elimination and substitution reactions are
polar reactions. A non-polar reaction mechanism does not involve charge separation. Some of the non-
polar reaction mechanisms involve free radical substitution and addition reactions as well as some, but
not all, of concerted reactions such as electrocyclic reactions. In a concerted process all the bonds are
broken and formed in a single step.

Functional Group
Organic compounds are classified according to their functional groups. Functional group is
the center of reactivity of a molecule. For example, in an alkene the functional group is the carbon–
carbon double bond and in an alcohol it is the hydroxyl group. Alkanes are the only class of
compounds that do not have a functional group.

Electrophiles and Nucleophiles


Electrophiles
Electrophile is an electron deficient species. Therefore, an electrophile has an empty orbital.
An electrophile may be a neutral species (for example BF3, AlCl3), or it may be a positively charged
species (for example H+, R3C+). Note that a positively charged ion without an empty orbital is not an
electrophile (for example NH4+). By definition, Lewis acid is an electrophile.
While an empty orbital is necessary for an electrophile, not every species with an empty
orbital is an electrophile. Some, such as Na+ and K+ have very weak affinity for electron pair and are
not electrophilic. Lithium ion, Li+, is a weak electrophile.
A free radical is a species with an unpaired electron and, therefore, one of its orbitals is half-
filled. A free radical is considered to be an electrophile.

Nucleophiles
A nucleophile is an electron pair donor. An electron pair donor (a species with a free electron
pair) is a Lewis base. Therefore, any Lewis base is also a nucleophile. In general, anions are better
nucleophiles, rather than neutral species. Nucleophilicity is a measure of how fast a Lewis base
displaces a leaving group.

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Veljko Dragojlovic

Basicity and Nucleophilicity – Bronsted and Lewis Bases


Besides solubility, nucleophilicity is also affected by polarizability of atom, group or ion.
Basicity and nucleophilicity are related, but not identical properties. When the nucleophilic atoms of
two reagents are in the same row of the periodic table, the relative nucleophilicity of the reagents is
directly related to their relative base strengths. A stronger base is also a stronger nucleophile. To
determine base strength, we start with the corresponding conjugate acids. For example, fluorine and
oxygen are in the same row of the periodic table, therefore one can use basicity to compare relative
nucleophilicities of methoxide (CH3O¯ ) and fluoride (F¯ ) ions. The Ka values for the conjugate acids
of those nucleophiles are 10-5 for HF and 10-16 for CH3OH. They correspond to pKa's of 5 for HF and
16 for CH3OH. Lower pKa value indicates a stronger acid, which has a weaker conjugate base and
higher pKa value indicates a weaker acid, which has a stronger conjugate base. Therefore, we can
conclude that methoxide is a stronger base and a stronger nucleophile than fluoride.

Solvation and Nucleophilicity


Anions (such as some of the nucleophiles) can form strong hydrogen bonds in protic solvents.
Protic solvents are the ones that can donate hydrogen bonds. Water, alcohols, amines and carboxylic
acids are examples of protic solvents. In general, the smaller the anion (higher in the periodic table),
the stronger its hydrogen bond to a protic solvent. In order for a solvated nucleophile to react, it must
shed some of its solvent molecules. This hinders its ability to donate electron pair and makes solvated
nucleophiles less reactive than they would be in an aprotic solvent. This is the main reason why
bromide is listed as a stronger nucleophile than fluoride in the table below. Fluoride is a much stronger
base, but it is much more strongly solvated.

Polarizability and Nucleophilicity


Polarizability is a measure of how easily the electron cloud around an atom can be distorted.
In substitution reactions, the transition state involves a partially formed bond to the nucleophile, which
is longer than a normal bond. If the nucleophile can allow some of its electron cloud to distort closer to
the electrophile (usually a carbon atom), the transition state is more stable and the reaction will
proceed more rapidly. Polarizability increases toward the bottom of the periodic table due to the larger
distance between the positively charged nucleus and the valence electrons. When comparing
nucleophilicities of atoms that belong to the same group of the periodic table, one should compare their
polarizabilities. Thus, iodide ion is a stronger nucleophile than chloride ion and chloride ion is a
stronger nucleophile than fluoride ion.

Table 6.1. Relative Nucleophilicities of Common Nucleophiles (in Methanol)


Type Nucleophile

very strong iodide (I¯ ), hydrogen sulfide (HS¯ ), alkyl sulfides (RS¯ )

strong bromide (Br¯ ), hydroxide (HO¯ ), alkoxides (RO¯ ), cyanide (CN¯ ), azide (N3¯ )

moderately strong ammonia (NH3), chloride (Cl¯ ), fluoride (F¯ ), carboxylates (RCO2¯ )

weak water (H2O), alcohols (ROH)

very weak carboxylic acids (RCO2H)

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Chapter 6. Organic Reactions

Polar Reactions

A large number of organic reactions (those that are classified as polar organic reactions)
involve reaction of an electrophile with a nucleophile. The flow of electrons is from the nucleophile
toward the electrophile.
Since an electrophile is a Lewis acid and a nucleophile is a Lewis base, we can say that a
polar organic reaction involves a reaction between a Lewis acid and a Lewis base. Usually, organic
chemists use terms electrophile and nucleophile, while
inorganic chemists use terms Lewis acid and Lewis base. Nu: + E Nu E
Therefore, terms electrophile/nucleophile and Lewis
acid/Lewis base describe the same concepts and can be used Nu: + E Nu E
interchangeably.

Organic Reactions
In an organic reaction we can define substrate as the organic compound. It is also called
starting material, or very generally a reactant. Substrate reacts with reagent to give a product.
Usually reagent is an inorganic molecule. If both molecules are organic (assuming that only two
participate in the particular reaction) then usually the smaller one is considered to be the reagent and
the larger one is the substrate. This rule is rather arbitrary and there are a number of exceptions to it.
Sometimes, to avoid designating one species as substrate and the other one as a reagent, we call both of
them reactants.
Organic reactions are represented as shown below. Reaction arrow points from the substrate
to the product, while the reagent is written above the reaction arrow. Frequently experimental
conditions and sometimes reaction yield are included above and below the arrow. Equations like this
are usually not balanced.

substrate, reagent
starting material, X
or reactant R P
product

Why organic reactions are not balanced?

Consider the following reaction:

Br
EtO /EtOH
+
41% 14%

How would you balance it? The two products are formed in unequal amounts and,
furthermore, their total yield does not add to 100%. Therefore, other products are formed in lower
yields. Any attempt to correctly balance it would end up with large numbers for the reaction
coefficients, and they would change with small change in the reaction conditions as the yields change.
Moreover, balancing the equation would add little to information already provided by the equation.

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Veljko Dragojlovic

Reaction Mechanism
A reaction is a process in which a reactant is converted into a product. A reaction mechanism
describes how the reaction proceeds, from the reactants to the products, including description of the
electron flow and all the intermediates. Mechanism must also account for the formation of any of the
byproducts. You should understand that no one has ever observed a reaction mechanism and no
mechanism can be proven. We can only design experiments that can disprove the mechanism.
Therefore, once the mechanism is proposed, we conduct experiments in order to disprove it. If we
cannot disprove it, we accept it as a correct mechanism. However, future work may show that it is
incorrect and we may have to replace it with a better one.

Thermodynamics and Kinetics


Reaction Profiles (Energy Diagrams)
A chemical reaction can be represented by means transition
of a diagram with energy represented on a y-axis and E state
reaction progress on the x-axis. It is understood that x-axis
represents reaction progress and its designation can be
omitted. We can divide the diagram into three parts and
I II III
use them to define the areas of study of thermodynamics
and kinetics. Thermodynamics deals with parts I and III, or
in other words, with the initial and the final state, while reactants
kinetics deals with part II, or how the reactants are
converted into the products (the path the reactants take to
be converted into the products).
products

reaction progress

Thermodynamics
Thermodynamics is concerned only with the initial and the final states of a chemical reaction.
To describe a chemical reaction in which a moles of A react with b moles of B to produce c moles of C
and d moles of D, we can define the equilibrium constant Keq, which is the product of concentrations of
the products divided by the product of concentrations of the reactants:

aA + bB cC + dD
[products] [C ] [ D] d
c
K eq = =
[reactants] [ A] a [ B]b

From the equilibrium constant we can determine the extent of the reaction. If the equilibrium
constant is large, the reaction proceeds almost to completion (the equilibrium lies to the right), while if
the equilibrium constant is small the reaction proceeds hardly at all (the equilibrium lies to the left).
Equilibrium constant is a result of an experiment and does not tell us why the reaction proceeds the
way it does.

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Chapter 6. Organic Reactions

Free Energy
The reason for any chemical reaction to proceed is the change (a decrease) in free energy.
Free energy is the energy content of a system (molecules of the reactants before the reaction and the
molecules of the products after the reaction). It is a measure of the potential energy of a molecule.
Change in free energy is the difference in free energies of the products and the reactants. Change in
free energy is related to the equilibrium constant by equation ΔGº = – RT lnKeq where R is the
universal gas constant and T is the absolute temperature (in K). ΔG is inversely proportional to Keq.
Therefore, for a spontaneous reaction ΔG (a change in free energy) is negative.
ΔGº = Gºproducts – Gºreactants
ΔGº = – RT lnKeq

Reactions are classified as:


exergonic when ΔG < 0
endergonic when ΔG > 0, and
thermoneutral when ΔG = 0

Free energy has two components – enthalpy and entropy. Thus, the change in free energy is
sum of the change in enthalpy and the change in entropy.

ΔGº = ΔHº – TΔSº


Enthalpy is related to bond energies in a molecule. With respect to change in enthalpy
reactions are classified as exothermic (ΔH <0) and endothermic (ΔH >0). Entropy is a degree of
randomness or disorder of a system. Negative value for change in enthalpy contributes to negative
value for ΔG, while positive value for change in entropy contributes to negative value for ΔG.
Therefore, a reaction with negative value for enthalpy change and positive value for entropy change
will always be spontaneous, while a reaction with a positive value for enthalpy change and negative
value for entropy change will never be spontaneous. Note that the entropy factor is multiplied by
temperature. If both changes in enthalpy and entropy are negative, or if they are both positive, then
whether a reaction will be spontaneous, or not, depends on their relative magnitudes and on the
reaction temperature. At higher temperatures, entropy factor becomes important, or predominant, while
at low temperatures it may become negligible. For most, but not all, organic reactions we can ignore
the change in entropy as it is usually relatively small compared to a change in enthalpy.
Bond energy is labeled as DH° and, by convention, is given a positive sign. Therefore, bond
energy is the amount of energy needed to break a bond. The same amount of energy is released when
such bond is formed.
A reaction between ethene and hydrogen bromide can serve as an example of calculation of
changes in free energy. In a reaction of ethene and hydrogen bromide carbon–carbon π bond is broken.
It has the energy of 61 kcal/mol. The other bond that is broken is hydrogen–bromine bond, with the
energy of 87 kcal/mol. Two bonds that are formed are carbon–hydrogen bond and carbon–bromine
bond, with energies of 101 kcal/mol and 69 kcal/mol, respectively. Thus, the change in enthalpy for
this reaction is a difference between the energies introduced into the system in order to break the bonds
and energies released by the system as a result of bonds being made. The energies introduced into the
system have a positive sign while those released by the system have a negative sign. From the
calculation shown below, it is clear that the overall addition of hydrogen bromide to ethene is an
exothermic reaction and, therefore, a spontaneous reaction.

111
Veljko Dragojlovic

DHº = 101 kcal/mol H Br DHº = 69 kcal/mol


H H

C C + H Br H C C H

H H
H H

DHº = 61 kcal/mol DHº = 87 kcal/mol

ΔHº = DHºreactants - DHºproducts = 148 kcal/mol - 170 kcal/mol = -22 kcal/mol


An alternative way to do the calculation is to designate all bond energies as being negative
(note that the convention designates them as being positive – as the amount of energy needed to break
the bond) and from the sum of the energies of the products subtract the sum of the energies of the
reactants.
Note that the change in entropy for addition of hydrogen bromide to ethene is negative (one
molecule of the product from two molecules of reactants – therefore the magnitude of randomness
(disorder) decreases). Would you expect the reaction to be still spontaneous at high temperatures?
Which reaction will be spontaneous at high temperatures?

Role of Entropy: Isomerization of cis- and trans-2-Butene


Either isomer of 2-butene, cis or trans, is stable under ordinary conditions. However, when
heated, 2-butenes undergo isomerization reaction. The trans isomer of 2-butene is more stable than the
cis isomer by 0.6 kcal/mol. Regardless of whether one starts with cis-2-butene, trans-2-butene, or some
mixture of the two, after the equilibrium is reached a mixture of 61% trans-2-butene and 39% cis-2-
butene is obtained. One may expect that under such conditions (high temperature and long reaction
times) the thermodynamically more stable, trans-2-butene, would be the only product. However, if all
the chemical reactions were driven by change in energy only, there would be a constant decrease in
energy of our Universe (a closed system). That would violate the Law of Conservation of Energy.
Therefore, one also has to take change in entropy of the system into account.

H
H3C CH3 400ºC H3C H3C H
C C C C C C
H H H H CH3
CH3
cis- or (Z) trans- or (E)
39% 61%

A mixture has higher entropy compared to a pure compound. Therefore, formation of a


mixture is favored. Thus, thermodynamically more stable product is formed predominantly, but not
exclusively. The larger the difference in stabilities between the two compounds the larger amount of
the more stable one that will be present in the equilibrium mixture. An endergonic reaction gives an
equilibrium in which the starting material predominates. An exergonic reaction gives an equilibrium in
which the product predominates. A thermoneutral reaction gives an equilibrium that contains equal
amounts of starting material and the product. When change in the free energy of a reaction is ~4
kcal/mol, or more, essentially only the more stable compound is present in the equilibrium mixture
(99.9%). The preceding analysis applies to reactions in which the number of molecules of the starting
material equals the number of molecules of the product.

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Chapter 6. Organic Reactions

Reaction Kinetics
Kinetics deals with reaction rates, or how fast a reaction proceeds. Kinetics is concerned with
the reaction pathway by which reactants are converted into the products.
The energy maximum on the reaction diagram is called the transition state or the activated
complex. In a transition state, the bonds are partially formed and partially broken. Usual rules about
chemical bonding and valence do not apply to a transition state. Therefore, in a transition state an atom
may make more bonds than it is “allowed” (for example, carbon can make five bonds). Transition state
is not a real molecule and does not have a finite existence (it does not exist for any period of time). It is
only a state the reactants pass through on their way to products and it is the state of the highest energy
on their path. For a reaction to proceed, the reactants must have enough energy to reach it. Difference
in energy between the transition state and the reactants is called the activation energy (labeled either as
ΔG‡ or Ea). Reaction rate is inversely proportional to the activation energy. Therefore, high activation
energy means low reaction rate and vice versa.
For a multi-step transformation to occur, the transition state of highest energy must be
reached. This is the slowest step and it is the rate-determining or rate-limiting step.
For a reaction to proceed, both kinetics and thermodynamics must be favorable. If only
thermodynamics is favorable (ΔG is negative), but kinetics is not, the reaction will proceed very slowly
or, in extreme cases, not at all. Thus, conversion of diamond into graphite is an energetically favorable
process (exothermic by 4 kcal/mol), but due to the high activation energy the reaction does not
proceed. We say that there is a kinetic block for such a reaction and for substances, like diamond, we
say that they are kinetically stable.
There are four general combinations of kinetic and thermodynamic factors for a one-step
chemical reaction. They are represented by reaction diagrams on the following page. In the first one
(1), activation energy is relatively low and the products are lower in energy compared to the reactants.
In the second case (2), the activation energy is high and the products are still lower in energy compared
to the reactants. In the third case (3), the activation energy is low and the products are higher in energy
compared to the reactants. Finally, in the fourth case (4), the activation energy is high and the products
are higher in energy compared to the reactants. Therefore, the first two reactions are exothermic, with
the first one being fast and the second one being slow. The last two reactions are endothermic
reactions, with the
third reaction
being fast and the Gº Gº
ΔG ‡
fourth reaction ΔG ‡
being slow. ΔGº
For a ΔGº
two-step reaction
we can identify I II
two general
situations. In the
first example, the
first step is the Gº Gº
ΔG ‡
slow, or rate ΔG ‡
determining step. ΔGº
Depending on the ΔGº
particular reaction
and reaction III IV
conditions, we

113
Veljko Dragojlovic

may have to supply energy (for example as heat) to molecules of the reactant, R, so that they can be
converted into the intermediate, I. Once the intermediate is formed, it will undergo fast and exothermic
second step to give the product, P. In the second example, the first step is endothermic with relatively
low activation energy. It means that this step is going to be reversible and that the reactant, R, and the
intermediate, I, will be at equilibrium. The second step is the slow, or the rate determining step. As the
intermediate is taken out of the equilibrium in the second step, a fast reactant – intermediate
equilibration will generate more until all of the starting material has been converted into the product.

slow fast fast slow


R I P R I P

Gº rds
Gº I ΔG2‡
rds
ΔG2‡
ΔG1‡
I
R
ΔG1‡
ΔGº R
P
ΔGº P

I II

rds – rate determining step

Rate of Reaction; Arrhenius Equation


Reaction rate depends on the following factors:
• Fraction of the molecules with sufficient energy – that is those that have energy equal or larger
than the activation energy (E ≥ ΔG‡).
• Number of collisions per unit of time – the more the collisions the faster the reaction.
• Fraction of the molecules with proper orientation for the reaction – the orientation must be proper
for the right bonds to be broken and the right bonds to form.

All these factors are taken into account in the Arrhenius equation (the rate constant is labeled
as k).
Ea
k = Ae − RT or ln k = ln A − Ea
RT
Symbol A represents the frequency factor (number of effective collisions – those that lead to
the reaction) and is related to the frequency and orientation of the reactants in collisions. Ea stands for
the activation energy. R is the universal gas constant. T is the absolute temperature (in K) and e is the
base of natural logarithm.
From the Arrhenius equation, we can conclude that the magnitude of a rate constant is directly
proportional to the temperature and inversely proportional to the activation energy.
In addition to the rate constant, reaction rate depends on concentrations of the reactants.

114
Chapter 6. Organic Reactions

Reaction Order
Reaction order tells us on how many different compounds the reaction rate depends on. For a
simplest reaction, where compound A is converted into compound B, the reaction rate will depend on
the concentration of the compound A and on the rate constant. We call such reaction a first order
reaction. If two molecules react (they may be the molecules of the same compound or the molecules of
two different compounds) the reaction rate will depend on their concentrations and, of course, the rate
constant. Such reaction is a second order reaction. If the rate depends on the concentrations of three
reactants the reaction is a third order reaction and so on.

A → B rate = k[A] first order


A + A → B rate = k[A]2 second order
A + B → C rate = k[A][B] second order

Chemical Equilibria
An equilibrium constant Keq is related to the rate constants of the forward (kf) and the reverse
(kr) reaction. A chemical equilibrium is a dynamic equilibrium, which means that both the forward and
reverse reactions are still going on, but the concentrations of the reactants and the products remain
constant. Therefore, at equilibrium rates of the forward and the reverse reactions are equal.

kf
A B
kr
rate of forward reaction = rate of reverse reaction
kf[A] = kr[B]
kf [ B]
K eq = =
kr [ A]

Kinetic and Thermodynamic Control of a Reaction


Organic reactions often produce different products under different conditions. The outcome of
a reaction is controlled by the stability of the products (thermodynamics) and the magnitude of the
activation energies for their formation (kinetics).
When more than one product can result from a reaction, the one with the lowest energy
content will be the most stable and, therefore, the favored product under the thermodynamically
controlled conditions. When there is sufficient activation energy to overcome the activation barriers of
all the competing reactions, and when the reaction time is sufficient to allow the reaction to reach
equilibrium, the most stable, thermodynamically favored product will accumulate (thermodynamic
sink).
If a reaction is conducted at a lower temperature and for a shorter time, kinetically controlled
product may be obtained. At low temperatures, most of the reactant’s molecules have just enough
energy to overcome the lower (or the lowest, if there are more than two possible pathways) energy of
activation (Ea). Thus, the only reaction that occurs to any significant extent is one with lower (or the

115
Veljko Dragojlovic

lowest) Ea. Short reaction times do not allow for the equilibration of products and accumulation of
significant amount of the more stable (thermodynamic) product.
Although in some reactions the thermodynamic and the kinetic products are different, in most
chemical reactions the thermodynamic product is also kinetically favored. Thus, regardless of the
reaction conditions the same product may be obtained.

TS1

TS2
P2 R P1
1
Ea

E a2
R

P2 ΔH2
ΔH1
P1

Principle of Microscopic Reversibility


According to the principle of microscopic reversibility, the reaction pathway (reaction
mechanism) is the same in both directions (for the forward and the reverse reaction). It means that for
both the forward and reverse reaction the reactants pass through the same intermediates and transition
states. Thus, if we know the mechanism of the forward reaction, we also know the mechanism of the
reverse reaction.

Principle of Microscopic Reversibility: The reaction pathway is the same for both the forward and
the reverse reaction.

116
Chapter 6. Organic Reactions

Transition State: The Hammond Postulate


There are three possible transition states:
(I) Early transition state resembles the reactants.
(II) Central transition state lies exactly at the mid-point between the reactants and the products.
(III) Late transition state resembles the products.
These three possibilities are illustrated in the following diagrams:

(I) A B C

A B + C (II) A B C A + B C

(III) A B C

Hº Hº Hº

(I) (II) (III)

Hammond Postulate: A transition state most closely resembles the stable species that lies closest to it
in energy.

According to Hammond postulate, in an exothermic reaction transition state is similar to the


reactant and in an endothermic reaction transition state is similar to the product.

Arrow Formalism: Pushing Electrons


To show the flow of electrons in organic chemistry we use curved arrows. Movement of a pair
of electrons between different molecules, or within a molecule is indicted by a curved “full” arrow.
Movement of a single electron is indicated by a curved half-arrow (“fish-hook arrow”). “Full” arrows,
which indicate movement of two electrons, always follow each other in head to tail fashion. “Fish-
hook” arrows, which indicate movement of a single electron, always point towards each other, or away
from each other.

full arrows follow each other "fish-hook" arrows point toward,


or away from, each other

Other arrows that you should know include: reaction arrow, which shows the direction of a
chemical reaction, and an equilibrium arrow, which indicates that the reactants and products are in an
equilibrium. One can draw the equilibrium arrow either as two half-arrow, or as a two complete

117
Veljko Dragojlovic

arrows. Sometimes one of the two arrows is made longer to indicate position of the equilibrium. Do
not confuse an equilibrium arrow with a resonance arrow. A resonance arrow indicates that a
molecule is a resonance hybrid of individual resonance structures.
Arrows used in more advanced organic chemistry topics include a retrosynthetic arrow,
which indicates that the actual reaction proceeds in the opposite direction, and a coupled reaction
arrows, which indicate that two, or more, processes are coupled.

Movement of two electrons

Movement of one electron


Other Arrows You Should Know

Reaction

Equilibrium

Resonance

Retrosynthetic Analysis

Coupled Reaction
(usually used in Biochemistry)

Classification of the Reaction Mechanisms


Reactions can be classified either according to the reaction mechanism or according to the
substrate’s functional group.
The main features of individual reactions are:

1. A general equation that includes substrate, reagent, product(s) and reaction conditions.
2. The reaction mechanism.
3. The scope of the reaction.
4. The order of reactivity.

In a nonradical reaction, the overall reaction is the sum of all the individual steps. In a free
radical reaction, the overall reaction is the sum of the propagation steps only.

There are only four fundamental reactions in organic chemistry:


• Proton transfer reactions (acid-base reactions)
• Electron pair transfer reaction (Lewis acid base reactions or nucleophile-electrophile
reactions). Proton transfer reaction are a special case of Lewis acid-base reaction (proton is a
Lewis acid), or nucleophile-electrophile reaction (proton is an electrophile).
• Electron transfer reaction (oxidation-reduction reactions)
• Reactions that involve unpaired electrons (Free radical reactions)

118
Chapter 6. Organic Reactions

The Thirteen Reaction Mechanisms


Some reactions involve a sequence of steps that include several of the reactions described
above. The only limitation is that a sequence cannot involve a combination of both transfer of an
electron pair (ionic mechanism) and unpaired electrons (free radical reaction) steps.
1) Free Radical Substitution Free Radical Mechanisms
2) Free Radical Addition
3) Addition
4) Unimolecular Elimination (E1)
5) Bimolecular Elimination (E2_ Ionic Mechanisms
6) Conjugate Base Unimolecular Elimination (E1cB)
7) Unimolecular Nucleophilic Substitution (SN1)
8) Bimolecular Nucleophilic Substitution (SN2)
9) Nucleophilic Acyl Substitution Reactions on Carbonyl
10) Nucleophilic Acyl Addition Compounds
11) Electrophilic Aromatic Substitution Reactions on Aromatic
12) Nucleophilic Aromatic Substitution Compounds
13) Pericyclic Reactions (Diels-Alder Reaction)) Concerted Mechanisms
These are the basic thirteen reaction mechanisms. In the following chapters we will study
these mechanisms in detail. These basic mechanisms explain almost all of the reactions that are studied
in an introductory organic chemistry course. Some reaction mechanisms may include modifications, or
a sequence of the above mechanisms.

119
Chapter 7. Reactions of Alkanes

CHAPTER 7.

Reactions of Alkanes: Free Radical Substitution


Reactions of saturated hydrocarbons.
___________________________________________________________________________

Halogenation of Alkanes
lkanes are saturated hydrocarbons. Therefore, they contain only carbon–carbon and carbon–
hydrogen σ bonds, both of which are rather strong bonds. Furthermore, electronegativity of an
sp3 hybridized carbon atom is similar to that of hydrogen atom. Thus, there is no charge
separation in a carbon–hydrogen bond. As a result, these bonds are inert to attack by either a
nucleophile or an electrophile.
Most common mode of reaction of alkanes is by homolytic cleavage of a carbon–hydrogen
bond. Result is a free radical substitution (replacement) chain reaction. An example of a free radical
substitution reaction is reaction of alkanes with halogens.
Among the halogens (X = F, Cl, Br, or I) fluorine reacts too violently and the highly
exothermic reaction cannot be controlled (ΔHº = –109 kcal/mol). Under ordinary conditions, reaction
of fluorine with an alkane results in an explosion.
Chlorine and bromine give the corresponding Δ or hν
R H + X2 R X + HX
haloalkanes in good yields. Iodine does not react with
Δ or hν
alkanes under ordinary conditions – starting iodine CH4 + Br2 CH3Br + HBr
and alkane are more stable compared to the possible Δ or hν
reaction products (ΔHº for iodonation is +10 CH3CH3 + Cl2 CH3CH2Cl + HCl
kcal/mol).
Besides free radical substitution reactions, alkanes also undergo fragmentation (cracking),
dehydrogenation and combustion reactions, which will not be studied in this course.

Chlorination and Bromination of Alkanes


Mechanism of a free radical chain reaction includes initiation, propagation and termination
steps. In an initiation step free radicals are generated by homolytic breaking of a relatively weak bond.
Energy for breaking of such bond is supplied either in a form of heat or light. Propagation usually
involves two steps and it is the actual chain reaction. Free radicals generated in the first propagation
step generate next generation of free radicals in the subsequent step. These newly formed radicals take
part in the first step and so on until the reactants are used up. A common side reaction in the course of
propagation is termination. In theory, propagation steps could continue for as long as there are
reactants available and a single free radical could cause all of the molecules of the reactant to be
converted into the product. Free radicals are high-energy, short-lived, reaction intermediates.
Occasionally two free radicals encounter and combine to give a stable molecule. Such process ends
propagation and is named termination. At the end of the reaction, after the starting materials have been
used up, the remaining free radicals combine to form stable molecules in termination steps.

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Veljko Dragojlovic

Monochlorination of Ethane

In chlorination of ethane, the initiation step involves generation of free radicals by breaking
the chlorine–chlorine bond under the influence of heat (Δ) or light (hν). Temperatures needed for this
reaction are relatively high (400ºC). Use of light (ultraviolet radiation) as a source of energy
(photochemical reaction) allows us to run the reaction at room temperature. In the two propagation
steps a chloride radical (chlorine atom) initiation:
forms a bond with a hydrogen atom. Cl Δ or hν
Cl 2 Cl
Carbon–hydrogen bond is
homolyticaly broken to give carbon propagation:
radical as the intermediate. Carbon
radical reacts with a molecule of H3C CH2 H + Cl H3C CH2 + HCl
chlorine to form a carbon–chlorine
bond and chlorine radical, which
participates in another propagation H3C CH2 + Cl Cl H3C CH2Cl + Cl
cycle. Finally, at the end of the
reaction, the remaining free radicals termination:
combine in termination reactions. A
reaction mechanism is shown below. H C CH +
3 2 Cl H3C CH2Cl
Note that the movement of a single
electron is indicated by using half-
arrows (“fish-hook” arrows). Those H3C CH2 + CH CH3 H3C CH2 CH2 CH3
2
arrows always point toward each other
(bond formation), or away from each
other (bond breaking). They never Cl + Cl Cl Cl
follow each other in head to tail
fashion as full arrows do.
This mechanism also explains formation of di- and polyhalogenated byproducts, which have
been observed in the course of halogenation of ethane.

H3C CH H + Cl H3C CH + HCl

Cl Cl

H3C CHCl + Cl Cl H3C CHCl2 + Cl

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Chapter 7. Reactions of Alkanes

Monobromination of Ethane
Bromination of an alkane follows the same free radical chain mechanism described earlier for
chlorination of alkanes.

Δ or hν initiation
Br Br 2 Br

H3C CH2 H + Br H3C CH2 + HBr


propagation
H3C CH2 + Br Br H3C CH2Br + Br

H3C CH2 + Br H3C CH2Br


termination

H3C CH2 + CH2 CH3 H3C CH2 CH2 CH3 formation of termination
a dimer products, such as dimers,
is an indication that the
Br Br Br reaction proceeds by a
+ Br
free radical mechanism.

Distribution of Products: Regioselectivity


Free radical substitution of methane, or ethane, can give only one possible monosubstitution
product – the corresponding halomethane, or haloethane. A free radical substitution of an alkane with
three or more carbon atoms can give more than one product. For example, chlorination of propane may
give 1-chloropropane, or 2-chloropropane (or a mixture of the two isomers). 1-Chloropropane and 2-
chloropropane are regioisomers. A reaction that gives one of the regioisomers in higher than expected
amount is called a regioselective reaction. The “expected amount” is a statistically expected amount of
the particular isomer. A statistically expected amount is obtained by assuming that each of the
hydrogen atoms will be replaced at random. Thus, in the reaction shown below, halogen atom X can
replace any of the four secondary hydrogens to give a secondary haloalkane, or it can replace any of
the six primary hydrogens to give a primary haloalkane. Therefore, statistically expected ratio for the
formation of secondary haloalkane to primary X
haloalkane is 4:6. If the two are obtained in any other X2, hν
ratio, formation of one of the products is favored and + X
the reaction is regioselective.

Chlorination of Butane
Chlorination of butane gives two possible regioisomers: 1-chlorobutane and 2-chlorobutane.
Substitution of any of the six hydrogens on primary carbon atoms with a chlorine atom gives 1-
chlorobutane. Substitution of any of the four hydrogens on the two secondary carbon atoms gives 2-
chlorobutane. Since the ratio of the two types of hydrogens is 6:4, one would expect that, if the
chlorination were not regioselective, the two products would be obtained in 60%:40% yields. The
actual ratio of the two products is 28%:72%. Therefore, reaction is regioselective.

125
Veljko Dragojlovic

From the distribution of the products and the number of hydrogen atoms available for a
reaction, one can calculate the intrinsic reactivity ratio. In this case, one can calculate the intrinsic
reactivity ratio for secondary and primary hydrogen
atoms in a chlorination reaction. There are four CH2 CH3 6 primary hydrogens
H3C CH2 4 secondary hydrogens
secondary hydrogen atoms and their substitution gives
72% of the product. Reactivity of secondary hydrogen
atoms is 72/4. Substitution of six primary hydrogen Cl
Cl2, hν
atoms gives 28% of the product and, thus, their + Cl
reactivity is 28/6. The intrinsic reactivity ratio is: calculated 40% 60%
observed 72% 28%
72
(2°) 4
3.9
28
(1°) 6

Therefore, in a free radical chlorination secondary hydrogen atom is 3.9 times more reactive
than primary. The intrinsic reactivity ratio is highly dependent on the reaction temperature.

Intrinsic Reactivities of Bromination


One can apply the same procedure to calculate intrinsic Br
reactivity ratio for reactivity of hydrogens on secondary and Br2, hν
+ Br
primary carbon atoms towards a bromination. 96% 4%
96
(2°) 2
72
4
(1°) 6

Thus, in a free radical bromination secondary hydrogen atom is 72 times more reactive than
primary.

Calculation of the Expected Ratio: Bromination of Butane


Once the intrinsic reactivity ratio is known, it can be used to predict distribution of the
products. Since, in a bromination reaction, hydrogen atom is 72 times more reactive than primary they
react in a ratio of (2°):(1°) = 72:1. The amount of product Br
generated by substitution of each type of hydrogens is Br2, hν
+
(number of atoms) x (reactivity). Therefore, for secondary Br
hydrogens it is 4 x 72 and for primary 6 x 1. The expected
ratio of the products is the ratio of the two. (2°) 4 4 x 72
48
(2°) (1°) 6 6x1
48
or 98% vs 2% as observed
(1°) 1

Therefore, the two products, 2-bromobutane and 1-bromobutane, will be produced in a ratio
of 48:1. We usually express that ratio as percent yield of each product.

126
Chapter 7. Reactions of Alkanes

The Reactivity – Selectivity Principle: Relative Reactivities of Chlorine versus


Bromine
The Reactivity – Selectivity Principle

Sometimes a reaction can lead to formation of two or more products, which are a result of
competing reaction pathways. The relative ratios in which the products are formed depend on the
differences in the two activation energies. Reaction pathway that involves a reactive reagent proceeds
through an Early Transition State and there is little difference in energy between the competing
pathways and the selectivity is low (example (I)). As the transition state is very early, it is reagent-like.
Products A and B are formed in approximately equal amounts. On the other hand, pathway involving a
less reactive reagent proceeds through a transition state that is product-like, or at least less reagent like
than was the case involving the more reactive reagent. Thus, in the second case (example (II)), the
difference in energy between
(I) (II)
the two transition states is E
greater and the selectivity is E
higher. Product D is formed in a
higher amount than product C.
reactants
For a high selectivity, it is
reactants C
necessary that the energies of A
the transition states involved in D
B
the competing reaction
pathways to be significantly
different.

Reactivity – Selectivity Principle: The greater the reactivity of a reagent, the less selective it is
and vice versa, the less reactive reagent is more selective.

Therefore, a highly reactive reagent is usually non-discriminating and reacts randomly with
all reactive sites of the reactant while a less reactive reagent is selective and reacts preferentially with
more reactive sites of the reactant. The Reactivity – Selectivity Principle represents an application of
the Hammond Postulate to kinetically controlled reactions (see previous chapter). If one, or both,
reaction pathways are reversible the relative ratio of the products depends on their relative stabilities
and the Reactivity – Selectivity Principle cannot be applied.

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Veljko Dragojlovic

Relative Reactivities of Chlorine and Bromine


Carbon–hydrogen bond strength depends on the degree of H 96 kcal/mol
substitution of the carbon atom. Thus, a primary carbon–hydrogen bond is
slightly stronger (100 kcal/mol) than a secondary carbon–hydrogen bond CH H
H3C CH2
(96 kcal/mol). Changes in enthalpy in the first propagation step of
chlorination and bromination of alkanes are: 100 kcal/mol

X + CH C + HX (X = Cl, Br)

Primary (-CH3) Secondary (-CH2-) Tertiary ( CH )

ΔH° (X = Cl, kcal/mol) -2 -4 -6


ΔH° (X = Br, kcal/mol) +14 +12 +10

Therefore, the first propagation step of a chlorination reaction is an exothermic process (early
transition state) while the first propagation step of a bromination reaction is an endothermic process
(late transition state).
In an Early Transition State, there is little bond breaking and therefore carbon–hydrogen bond
strength does not have much influence on the distribution of the products. However, if the reaction
proceeds through a Late Transition State strength of carbon–hydrogen bond becomes important.
It means that the relative strengths of carbon–hydrogen bonds have little importance in a
chlorination reaction (early transition
state – bond have not been broken to a
significant extent), while the relative (1°)
carbon–hydrogen bond strengths have (2°)
considerable effect on regioselectivity
of a bromination reaction (late (3°)
. .
alkane, Cl alkane, Br
transition state – bonds are almost (1°)
completely broken). It is reflected in
the approximate intrinsic reactivity (2°)
ratios for chlorination and bromination (3°)

Primary (-CH3) Secondary (-CH2-) Tertiary ( CH )

Chlorination (relative rates) 1 4 5


Bromination (relative rates) 1 70 1600

Therefore, chlorine is an example of a reagent with a high reactivity and low selectivity, while
bromine is an example of a less reactive and a more selective reagent.

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Chapter 7. Reactions of Alkanes

Free Radical Substitutions of Benzylic and Allylic Hydrogens


The more stable the radical is, the faster it forms. Substitution occurs preferentially on free
radicals that are formed the fastest. Relative stabilities of free radicals are:

~
~ > > > > ~
~ CH3
allyl (3°) (2°) (1°) vinyl methyl
benzyl

X
Free radicals next to unsaturated carbon
atoms are particularly stable and form faster than X2, Δ or hν + HX
any other (ordinary primary, secondary or
tertiary). Therefore, reactions involving such
radicals usually give only one product. X2, Δ or hν + HX

Bromine readily adds across a carbon-carbon double bond. Thus, use of bromine in an allylic
substitution would likely result in formation of tribromo product. For example, reaction of 1-butene
with bromine would result
Br
in formation of 1,2,3- Br2 (xs), hν Br O
tribromobutane. To avoid + HX
addition of bromine, we use Br N Br
O
N-bromosuccinimide as a
reagent in free radical NBS, hν O
+ NH
bromination. N-bromosuccinimide
Br (NBS)
O

129
Chapter 8. Alkenes

CHAPTER 8.

Unsaturated Hydrocarbons: Alkenes and Alkynes


Nomenclature and properties of hydrocarbons with a multiple carbon–carbon
bond.
___________________________________________________________________________

Alkenes (Olefins)
lkenes are unsaturated hydrocarbons. In saturated hydrocarbons, alkanes, the valence
requirements of a carbon atom are satisfied by the formation of four σ bonds. In alkenes, the
valence requirements of a carbon atom are satisfied by the formation of three σ bonds and one
π bond. A π bond can form only if there is already a σ bond between the atoms. Such atoms, connected
by both σ and π bonds, are connected by a double bond. A double bond is a functional group and is
responsible for physical and chemical properties of alkenes. Bonding in alkenes is described in Chapter
1 (pages 21-23). General formula for an alkene is CnH2n.

Degree of Unsaturation (Index of Hydrogen Deficiency)


Open chain alkanes have the maximum number of hydrogen atoms for a given number of
carbon atoms. That number is 4n + 2, where n is the number of carbon atoms. Compounds that have
fewer than the maximum number of hydrogens are unsaturated, or “hydrogen deficient.” Degree of
Unsaturation, or, as it is also called, Index of Hydrogen Deficiency equals the sum of the number of
rings and the number of π bonds in a molecule.

Degree of Unsaturation = number of rings + number of π bonds

DoU = 1 DoU = 2
DoU = 1 DoU = 2
DoU = 3

It can be calculated from the following formula:


(2n + 2) − m
Degree of Unsaturation =
2

n – number of carbon atoms


m –number of hydrogen and halogen atoms

If m = 2n+2, then the compound is saturated and the Degree of Unsaturation is 0. Either a
double bond (one π bond), or a ring, represents one degree of unsaturation. A triple bond (two π bonds)
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Veljko Dragojlovic

represents two degrees of unsaturation. When calculating degree of unsaturation, oxygen atoms don’t
count. This formula can be applied if the compound contains carbon, halogen and oxygen atoms. It can
be also applied to silicon-containing organic compounds if n is the number of carbon and silicon atoms
combined. However, the formula does not work if the molecule contains other atoms such as boron,
nitrogen, sulfur, or phosphorus.

As cyclic compounds such as cyclopentane are not unsaturated the term Degree of
Unsaturation may be misleading. Thus, some authors prefer to use term Index of Hydrogen Deficiency
instead. However, term Index of Hydrogen Deficiency is not any more accurate as a cycloalkane is not
hydrogen deficient either.

Nomenclature of Alkenes
To name an alkene according to IUPAC nomenclature one should apply the following steps:
1. Identify the longest chain that contains the double bond. That chain is called the parent chain.
2. Replace the suffix –ane of the parent chain with the suffix –ene.
3. Assign the first carbon of the double bond the lowest possible number and place that number
before the name of the parent chain.
4. Name and give numbers to the substituents. List the substituents in alphabetical order before the
name of the parent chain.
CH2

H3C CH CH CH2 CH2 CH3 H3C CH2 C CH2 CH2 CH2 CH3
2-hexene 2-ethyl-1-hexene

Cycloalkenes
Cycloalkenes are named according to the same rules given for naming of the alkenes. If the
longest chain that contains the double bond is a ring, then it is the parent chain and has a prefix cyclo.
Carbon atoms of the double bond are assigned numbers 1 and 2. Number 1 is not listed. Note the
naming of 4-methylcyclohexene. As the carbons of the double bond must be numbered 1 and 2, the
lowest number for the methyl group is 4. In the case of 5-chloro-1-methylcyclopentene, the carbon of
the double bond with a methyl substituent is assigned the number 1 and the other carbon of the double
bon number 2. It means that the chlorine substituent is on carbon 5.
3 3 2
4
2 1
4
5 1 5
6 Cl
cyclopentene 4-methylcyclohexene 5-chloro-1-methylcyclopentene

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Chapter 8. Alkenes

Vinyl and Allyl Groups

Substituents that contain a double bond are vinyl and allyl. Earlier you encountered primary,
secondary, tertiary and quaternary carbon atoms. Now we can define allylic and vinylic carbon atoms.
Substituent H2C=CH- is called vinyl group. Carbons and hydrogens that belong to it are called vinylic
carbons and vinylic hydrogens (or protons). Substituent H2C=CH-CH2- is an allyl group. A carbon
next to C=C bond and hydrogens attached to it are called allylic carbon and allylic hydrogens (or
protons).
vinylic carbon atoms
CH2 CH vinyl group
R CH2 CH CH CH2 R
CH2 CH CH2 allyl group
allylic carbon atoms

Properites of Alkenes
Hybridization in Alkenes
Carbon atoms connected by a double bond are sp2 hybridized (Chapter 1, pages 21-23).
Geometry of an sp2 hybridized carbon atom is trigonal planar. Each sp2 hybridized carbon atom has
one unhybridized p orbital (its two lobes are shown: one in black and the other one in white) and three
hybrid sp2 orbitals (shown in grey, or as lines in the structure on the right). Hybrid sp2 orbitals overlap
along the internuclear axes (internuclear axis
is a line that connects the two nuclei) to make
σ bonds (shown as lines), while side to side
overlap of p orbitals makes π bond (shown as
two lobes).

Bond Angle
Bond angles in a molecule of an alkene are approximately 120° (trigonal planar). The angles
vary somewhat from one alkene to another. The reasons for difference in bond angles may be size of
the substituent (steric hindrance), electrostatic interactions between free electron
pairs of the substituents and fractional hybridization (for example sp2.3) of the R R
carbon orbitals. Discussion of fractional hybridization is beyond the scope of an ~120º
introductory organic chemistry course. As a general rule, you should assume that R R
~120º
bond angles of an alkene are 120°.

Bond Length
Length of a single bond between the two sp3 hybridized carbons is 1.54 Å (1Å = 1 x 10-10 m).
Length of a double bond between the two sp2 hybridized carbons is 1.34 Å. Length of a single bond
between an sp3 hybridized carbon and an sp2 hybridized carbon is a bit shorter than a single bond
between two sp3 hybridized carbon atoms and equals 1.50 Å. The reason for a shorter bond is that a

135
Veljko Dragojlovic

difference in electronegativities between sp3 and sp2 hybridized carbons results in a formation of a
polar bond – a bond that involves a partial charge separation. Charge separation results in a bond
contraction due to electrostatic attraction between the two oppositely charged carbon atoms.
H
1.10 Å δ+
H
CH2 H
C 1.50 Å H δ-
H sp3
H3 C C C
C C C 1.08 Å sp2
1.54 Å H H
H
H H
1.34 Å
H

Hindered Rotation
The energy required for a rotation about a carbon-carbon double bond is ~60-65 kcal/mol.
Since in the course of rotation π bond is broken, it means that the energy needed to break carbon–
carbon π-bond is ~60-65 kcal/mol.
Note that cis and trans forms are the two stable configurations of an alkene. The high energy
intermediate in a rotation about a carbon–carbon double bond is a biradical and has only a carbon–
carbon single bond (σ bond). A free radical is a species with an unpaired electron. A species with two
unpaired electrons is called biradical.

H3C CH2CH3 H H3 C H
Δ or hν H3C
C C C C C C
H
H H CH2CH3 H CH2CH3
cis trans
biradical

Bond Strength
Strength of a carbon–carbon double bond in an alkene, such as ethene, is 170 kcal/mol.
Strength of a π bond is ~65 kcal/mol. It means that the strength of the remaining σ bond is 170 – 65 =
105 kcal/mol. Strength of σ bond in a saturated hydrocarbon, such as ethane, is only ~85-88 kcal/mol.
Can you explain why is σ bond in ethene stronger than one in ethane? (Hint: Consider hybridization of
carbon atoms.)

Isomerism in Alkenes: Geometric Isomers


Geometric isomers are compounds that have the same structural formula and different spatial
arrangement of atoms because of the presence of bonds with restricted rotation. A double bond is an
example of a bond with restricted rotation. In general, a rotation about a single bond is free. However,
rotation about a single bond that is a part of a ring is not free. You can convince yourself of it by
making a molecular model. Therefore, compounds that exhibit geometric isomerism contain either
double bonds or rings. In alkenes, geometric isomerism occurs when each carbon of the double bond
bears two different substituents. When two identical, or similar, substituents are on the same side of the

136
Chapter 8. Alkenes

double bond, the isomer is designated as cis. When these substituents are on opposite sides, the isomer
is trans. The same concept applies to cyclic structures where substituents may be on the opposite
(trans) or the same (cis) side of the plane of the ring.

H3 C H H H
different different
substituents substituents
on the carbon H CH3 on the carbon
atom atom H3C CH3
trans-2-butene cis-2-butene
identical substituents on the identical substituents on the
opposite sides of the double bond same side of the double bond

cis-1,2-dimethylcyclohexane trans-1,2-dimethylcyclohexane

identical
substituents

no cis/trans isomerism

(E)/(Z) Nomenclature
Sometimes cis/trans nomenclature of an alkene is ambiguous. In case of 2-pentene it is easy
to establish whether the molecule is a cis, or a trans isomer. However, when a molecule has four
different substituents on the double bond, such as 3-ethyl-2-hexene, it is H CH2 CH3
diffucult to assign configuration without introducing new rules. The same is
the case with 1-bromo-2-chloro-2-fluoro-1-iodoethene. Clearly there are two H3C H
isomers, but it is difficult to say which one is cis and which one is trans. trans

H CH2 CH3 H3 C CH2 CH3 F Br Cl Br


H3 C CH2 CH2 CH3 H CH2 CH2 CH3 Cl I F I
cis or trans?

An alternative, and unambiguous, is systematic or (E)/(Z) nomenclature. The two substituents


on each sp2 carbon are considered individually and are assigned priorities according to the Cahn-
Ingold-Prelog (CIP) convention. If the highest priority groups on each sp2 carbon are on the opposite
sides of the double bond, the designation is (E). If they are on the same side of the double bond, the
isomer is (Z). In the example below, the asterisks mark the highest priority groups on each double
bonded carbon. With (E)/(Z) nomenclature there is no ambiguity.

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Veljko Dragojlovic

(E) (from German: Entgegen) stands for opposite. (Z) H3CO CH3 H3CO Cl*
(from German: Zusammen) stands for together. Alternatively, you H Cl* H CH3
can memorize that (Z) stands for “Zame Zide.” (E)-isomer (Z)-isomer
Cahn-Ingold-Prelog priority rules:
• Priorities are assigned to the atoms bonded to each sp2 carbon, not groups bonded to those
carbons.
• Atom with the higher atomic number (not mass!) has higher priority.
• If two atoms have the same priority move along the chain, following the path of the highest
priority, until there is a difference in the atomic number.
2 H CH2 CH3 2 2 F Br 2
C C C C
1 H3C CH2 CH2 CH3 1 1 Cl I 1

(Z)-3-ethyl-2-hexene (Z)-1-bromo-2-chloro-2-fluoro-1-iodoethene

1 D CH3 2
C C
2 H Cl 1
(E)
• Between the two isotopes, the heavier isotope has priority.

For an atom that is bonded with a double or triple bond, the bond is converted into the same
number of single bonds by using “virtual” atoms. Therefore, a carbon–carbon double bond is converted
into two carbon–carbon single bonds on each carbon atom. At the end of each new single bond is a
“virtual” carbon atom. A “virtual” atom has the same priority as a real one. “Substituents” on a virtual
atom have priority of zero (there are none).
To convert a substituent with multiple bonds into a substituent with single bonds and virtual
atoms follow these steps:
1) Redraw the Lewis structure of the substituent and represent all the bonds as single bonds.
2) Add “dangling bonds” to satisfy valence requirements of each atom. Thus, if carbon had a total of
4 bonds (σ and π) in the original substituent, it should now have four single bonds. If oxygen had
two, it should now have two single bonds
1 Cl CH2 CH3 2
and so on. R H C C
C C
3) At the end of each dangling bond place a C C R C C H H3C CH CH CH2 1
H H H H
2
virtual atom. It is the atom that is at the CH3
other end of the multiple bond. (E)-

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Chapter 8. Alkenes

Nomenclature of Dienes
Diene is a compound with two carbon-carbon double bonds. To name compound as a diene,
according to IUPAC nomenclature, one should apply the following rules:
• Identify the longest chain that contains both of the double bonds. That chain is the parent chain.
• Replace the suffix –ane of the parent chain with the suffix is –diene.
• Assign the two double bonds the lowest possible set of numbers.
• Number and name the substituents. List the substituents in alphabetical order before the name of
the parent chain.

1,3-pentadiene 1,4-cyclohexadiene 2-methyl-1,3-pentadiene

.
1,2-butadiene Br 1,3,5-hexatriene
5-bromo-2-methyl-1,3-cyclohexadiene

Isomerism of Dienes
An ordinary alkene with one double bond have two isomers (cis/trans, or (E)/(Z)). A molecule
with n double bonds has a
maximum of 2n isomers as each
double bond can have two (2E, 4E)-2,4-heptadiene (2Z, 4E)-2,4-heptadiene
configurations. Note that 2n is the
maximum number of isomers. If
there is symmetry in the molecule,
the actual number may be less (2E, 4Z)-2,4-heptadiene (2Z, 4Z)-2,4-heptadiene
than that. 2,4-Heptadiene has no
symmetry and has four stereoisomers.

(2E, 4E)-2,4-hexadiene (2Z, 4Z)-2,4-hexadiene


Due to presence of symmetry in
the molecule 2,4-hexadiene has only
three isomers. Note that the two (E, Z)-,
or cis-, trans- isomers are identical.

(2E, 4Z)-2,4-hexadiene (2Z, 4E)-2,4-hexadiene


identical
Finally, dienes such as 2-
methyl-2,4-hexadiene have only two
isomers. Note that only one double bond
exhibits isomerism. The other one has two
identical substituents (two methyl grups)
on the carbon 2. (E)-2-methyl-2,4-hexadiene (Z)-2-methyl-2,4-hexadiene

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Veljko Dragojlovic

Alkynes (Acetylenes)
In alkynes, valence requirements of a carbon atom are satisfied by formation of two σ bonds
and two π bonds. Alkynes are compounds that contain a carbon–carbon triple bond. A triple bond is a
functional group of an alkyne. Carbon atoms connected by a triple bond are sp hybridized. A triple
bond, with its two π orbitals, represents two degrees of unsaturation.

Structure of Alkynes: sp Hybridization


Carbon atoms connected by a triple bond are sp hybridized. Each sp hybridized carbon atom
has two unhybridized p orbitals (each orbital is shown with its two lobes: one in grey and the other one
in white) and two hybrid sp orbitals (shown as lines). Hybrid sp orbitals overlap along the internuclear
axes (internuclear axis is a line that connects two nuclei) to make σ bonds (shown as straight lines),
while side to side overlap of p orbitals makes π bonds.

H H
C C
+ C C
H H

Structure of the simplest alkyne, ethyne, was discussed in detail in the Chapter 1, pages 23-26.

Nomenclature of Alkynes
Common, or trivial name, of the simplest alkyne, C2H2, is acetylene. After that, the simplest
member of the homologous series alkynes, as a class of compounds, are sometimes called acetylenes.
To name an alkyne according to IUPAC nomenclature one should apply the following steps:
• Identify the longest chain that contains the triple bond. That chain is the parent chain.
• Replace the suffix –ane of the parent chain with suffix –yne.
• Assign the first carbon of the triple bond the lowest possible number and place that number before
the name of the parent chain.
Br Cl
• Name and give numbers to the substituents.
List the substituents in alphabetical order
before the name of the parent chain. 5-methyl-1-heptyne 2-bromo-5-chloro-3-hexyne

Alkynes are divided into two groups: H3C CH2 C CH H3C C C CH3
terminal alkynes and internal alkynes. A terminal 2-butyne
1-butyne
alkyne has the triple bond at the end of the carbon
chain, while an internal alkyne has the triple bond a terminal alkyne an internal alkyne
inside the carbon chain.

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Chapter 8. Alkenes

Ethynyl and Propargyl Groups

Substituents that contain a triple bond are ethynyl and propargyl. Ethynyl is a triple bond
equivalent of vinyl group and propargyl of allyl.

HC C ethynyl HC C CH2 propargyl

HC C Br ethynyl bromide HC C CH2 Br propargyl bromide

HC C CH2 OH propargyl alcohol

Nomenclature of Bifunctional Compounds


To name a bifunctional compound one should apply the following rules:
• Identify the longest chain that contains both of the functional groups. That chain is the parent
chain.
• Suffix contains both functional group designations.
• Suffix –ene is written first with the final –e omitted.
• The number corresponding to the first functional group (double bond) is written before the name
of the parent chain.
• The number corresponding to the second functional group is written before its suffix and separated
from the rest of the name by dashes.
• Name and number the substituents and list them in alphabetical order.
• If the chain contains both a double and a triple bond, the chain is numbered so that the name of
compound contains the lowest possible numbers. Only in case of a tie, the double bond has
priority.
CH2 CH2 CH3

H3C CH CH CH2 CH2 C CH H3C CH CH CH C CH

5-hepten-1-yne 3-propyl-4-hexen-1-yne

H3C CH CH CH2 C C CH3

2-hepten-5-yne

If the other functional group has a higher priority than the alkene, the chain is numbered so
that the higher priority functional group gets the lowest possible number.
OH

H3 C CH CH CH2 CH2 OH

3-penten-1-ol 4-methyl-2-cyclohexenol

141
Chapter 9. Reactions of Alkenes

CHAPTER 9.

Reactions of Alkenes
___________________________________________________________________________

Electrophilic Addition Reaction

n alkene has a carbon–carbon double bond as its functional group. As mentioned in the earlier
chapters, a functional group is the center of reactivity of the molecule. A double bond contains
two electron pairs shared by the two carbon atoms. Since one electron pair is enough to bond
the two carbon atoms (with a single bond), we can conclude that a carbon–carbon double bond
has an “excess” of one electron pair. In other words, it is an electron-rich functional group. Such a
functional group will readily react with electron deficient species. Earlier, you learned that such
molecule or ion has an empty orbital and is called an electrophile (literally “electron loving”). In the
course of a reaction an electrophile adds to the molecule of alkene. Thus, the most common reaction of
alkenes is an electrophilic addition reaction. An electrophile is a Lewis acid and may be neutral or a
positively charged species. Free radicals are also considered to be electrophiles. Reaction of an alkene
with an electrophile may lead to one of the following intermediates:
E E
E H H E
H C C H C C H C C H
H H H H H H
E

H E H
C C
H H

Reactions of alkenes can be classified according to the reaction mechanism as:

• Additions that proceed through carbocation as a reaction intermediate (additions of hydrogen


halides, water, alcohols),
• Additions that proceed through free radicals as reaction intermediates (additions of hydrogen
halides),
• Reactions that proceed through cyclic intermediates or transition states (halogenation,
oxymercuration-demercuration, hydroboration-oxidation),
• Catalytic hydrogenation (addition of hydrogen), and
• Oxidation reactions.

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Veljko Dragojlovic

Addition Reactions that proceed through a Carbocation


Intermediate
One of the most common electrophiles in organic reactions is proton (H+). An electrophilic
addition reaction starts by addition of proton (an electrophile) to the carbon–carbon double bond to
give the intermediate carbocation. Note that the electron flow is from the double bond (nucleophile)
toward the hydrogen ion (electrophile). Carbocation, as a newly formed electrophile, reacts with a
nucleophile (in this case bromide anion) to give the final product.

H H H H Br
slow fast
C C + H Br H C C H + Br H C C H
H H H H H H

As there are other cations than proton, in general terms, a reaction can be illustrated by the
following sequence:

E E Nu
H δ+ δ− slow
H fast
C C + E Nu +
H C C H Nu H C C H
H H H H H H

Formation of the intermediate carbocation, in the course of an electrophilic addition to an


alkene, is inferred from three observations about the reaction:

1. Loss of stereochemistry in the product (both cis and trans isomers of an alkene give the same
product).
2. Reaction rates are related to stabilities of the intermediate carbocations.
3. Reaction rates are higher in polar solvents due to stabilization of the transition state for the
formation of the intermediate carbocation.

Electrophilic Addition of Hydrogen Halides


H Cl
Among the hydrogen halides, hydrogen chloride, HCl
hydrogen bromide and hydrogen iodide add across a double
bond to give the corresponding alkyl halides. Reaction of
Br
hydrogen fluoride with alkenes gives mixtures of products
H3CHC CHCH3 HBr H3CH2C CHCH3
and is not a useful reaction.
HI I

HF
mixture of products

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Chapter 9. Reactions of Alkenes

Mechanism of Electrophilic Addition of Hydrogen Halides: Addition of HCl

Mechanism of the Addition in Gas Phase


When hydrochloric acid and ethene react in a gas phase, the first step involves the interaction
of the positive end of H-Cl dipole (hydrogen atom) and the π orbital of the carbon–carbon double
bond. Therefore, hydrogen is an electrophile and carbon–carbon double bond a nucleophile. The
electrons flow from the π orbital to the proton and, in the transition state, form partial bond to the
hydrogen. In the transition state, hydrogen-chlorine bond is partially broken. At the end of the first
step, the carbon–hydrogen bond is fully formed and the hydrogen–chlorine bond is completely broken.
As a result, a carbocation and a chloride ion are formed as the reaction intermediates. This first step
involves breaking of two bonds (hydrogen–chlorine and carbon–carbon π bond) and formation of only
one (carbon–hydrogen bond). This is thermodynamically unfavorable process. Therefore, the first step
is an endothermic process. This step also involves a charge separation, which is another
thermodynamically unfavorable process. Note that the starting molecules are neutral species, while the
intermediates are ions. There is a partial charge separation in the transition state and the process of
charge separation is completed when the intermediates are formed. A considerable amount of energy is
needed to reach the transition state (this is the activation energy). High activation energy means that
the process is relatively slow. Therefore, both the kinetics and the thermodynamics of the first step are
unfavorable. In the second step, carbocation combines with the chloride ion to form a carbon–chlorine
bond. This step involves only bond formation and, therefore, is highly exothermic. Since two opposite
charges combine to give a neutral molecule, only a small activation energy is needed and this is a fast
step. In the second
Clδ−
step, both the
kinetics and the
Hδ+
thermodynamics H H Cl
are favorable. H H H
Overall change in H C C C C Cl C C
H slow H fast H
H H
enthalpy of the
H H H
reaction can be
calculated:
H-Cl σ bond is broken DHº = 103 kcal/mol
C=C π bond is broken DHº = 63 kcal/mol
C-H σ bond is formed DHº = 99 kcal/mol
C-Cl σ bond is formed DHº = 81 kcal/mol
ΔHº = (103 + 63) - (99 + 81) = -14 kcal/mol
Therefore, addition of hydrogen chloride to an alkene is an exothermic reaction.

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Veljko Dragojlovic

Mechanism of the Addition in a Solution

In an aqueous solution hydrogen chloride, as a strong acid, is ionized. Charge separation is


stabilized by water. Therefore, the process of a charge separation already occurred before the addition
reaction. Since there is no charge separation in the initial addition step, the activation energy of that
step is much lower compared to the same step in the gas phase. It means that the addition reaction is
faster in a solution. As in the gas phase reaction, the first step is the slow rate determining step.

HCl + H2O H3O + Cl

H H H H
slow
+ H OH2 + Cl + H2O + Cl
H

fast
Note that there is no additional charge
separation. Thus, reaction is much faster H H
compared to the reaction in the gas phase. Cl
H

In an aqueous solution there are two nucleophiles: chloride ion and water. Therefore, there are
two possible products:

H H H2O H H H H
OH Cl Cl
H H H
-H

Chloride anion is much better nucleophile, but it is present in much lower concentration than
water (water is the solvent and surrounds the carbocation). Often in an aqueous solution a mixture of
products (alkyl halide and alcohol) is obtained.
The alcohol can be made a major product of the addition reaction by using an acid whose
conjugate base is a weak nucleophile. Two such commonly used acids are phosphoric, H3PO4, and
sulfuric, H2SO4.

H H H2O H H HSO4 H H
OH OSO3H
H H H
-H
unstable
H2O

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Chapter 9. Reactions of Alkenes

Stability of Carbocations
Carbocations are the intermediates in addition of hydrogen halides to alkenes. They are
classified according to degree of
substitution of the cationic carbon as H C H R C H R C H R C R
primary secondary, or tertiary. While
H H R R
formally methyl cation is a primary
carbocation, it is often considered methyl cation primary secondary tertiary
carbocation carbocation carbocation
separately.
The relative stability of
carbocations depends on two main factors.
One is the degree of substitution of the
R C R > H C R > H C R > H C H
carbocation, the tertiary carbocation being
the most stable, and the other one is the R R H H
degree of resonance stabilization. The tertiary secondary primary methyl cation
order of stability of simple carbocations is: carbocation carbocation carbocation
Carbocation is an electron
deficient species. Therefore, it is an electrophile. A carbocation readily reacts with a nucleophile (Nu:)
to from C–Nu bond. Formation of a carbocation is an endothermic process. Thus, it involves a late
transition state, which resembles the carbocation (Hammond postulate). From the Hammond postulate
it follows that the more stable carbocation is the faster it forms.

Hyperconjugation
Substituted carbocations are stabilized by hyperconjugation. Hyperconjugation is a concept
introduced to explain the stabilizing effect of substituents. Hyperconjugation means that an electron
pair (in this case the electron pair from a neighboring carbon–hydrogen bond) is delocalized into the
“empty” p orbital on the carbocation. A delocalized
electron pair is spread over a larger volume of space,
H
which minimizes electron – electron repulsion.
Furthermore, donation of electron density into p R
orbital of the carbocation partially compensates for R H
electron deficiency of the carbon atom. Each alkyl H
substituent on the carbocation can stabilize it through a carbocation
hyperconjugation. Therefore, a carbocation with more "empty" p orbital
substituents has more hyperconjugative stabilizing H
interactions and, therefore, will be more stable C-H sp3 orbital
R
compared to a carbocation with fewer substituents. R H
H
stabilization of carbocation
by hyperconjugation

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Veljko Dragojlovic

Regioselectivity: Markovnikov’s Rule

Regioselective Reactions
Some reactions can potentially give two or more structural isomers as reaction products. In a
regioselective reaction one structural isomer is either the major, or the only reaction product.

A → B + C, B and C are structural isomers.

Addition of Hydrogen Halides

Addition of a hydrogen halide to an alkene, such as 2-methylpropane, is a regioselective


reaction. It means that out of the two possible regioisomers one is formed either predominantly or
exclusively. Recall that regioisomers differ in the position of the functional group. If the two products
were formed in a statistically expected ratio (50%:50% in this
case), the reaction would not have been selective. Therefore, HCl Cl
+ Cl
addition is regioselective. Regioselectivity of the addition can
major minor
be predicted by application of Markovnikov rule.

Markovnikov Rule: In an addition of hydrogen halide or water to an unsymmetrical alkene, the


hydrogen (electrophile) adds to the carbon atom of the double bond that is bonded to more hydrogens.

The first step in an electrophilic addition to an alkene is formation of the corresponding


carbocation. Since this is an endothermic step, the transition state resembles the carbocation (late
transition state). Therefore, transition state for formation of a more stable carbocation is going to be
lower in energy compared to a transition state for formation of a less stable one. Therefore, formation
of a more stable carbocation is both kinetically and thermodynamically favored.

Formation of the carbocations in the course of addition of HCl to propene.

H
HCl + H
(1º) (1º) (2º)
H
(2º) Cl Cl
H Cl
Cl H

HI I
+
Here are two additional examples of addition of I
hydrogen halide to an alkene according to Markovnikov major minor
rule.
Br H
HBr +
H Br
major minor

152
Chapter 9. Reactions of Alkenes

Markovnikov rule is an empirical rule and it usually correctly predicts the outcome of an
addition. However, regioselectivity is determined by addition of hydrogen ion, which always results in
formation of a more stable carbocation, and not by the number of hydrogen atoms on the carbons of
the double bond. It just happens that, in most cases, application of the Markovnikov rule correctly
predicts the mode of addition that will give the more stable carbocation. However, with more complex
substrates that may not be the case. For example, Markovnikov rule does not work if a substituent on a
double bond is a benzene ring or another double bond. Therefore, in the following example, one may
predict that the two regioisomers will be formed in equal amounts since each carbon of the double
bond contains one hydrogen. However, one carbocation is a secondary benzylic carbocation and is
considerably more stable compared to the alternative simple secondary carbocation. Therefore,
addition is highly regioselective and chlorine adds to benzylic position only.

Cl
Cl
H
H
(2°) benzylic carbocation the only product
HCl or

H H
Cl
X
Cl
(2°) carbocation

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Veljko Dragojlovic

Addition of Water
Under ordinary conditions water does not add to an alkene. Although hydrogen–oxygen bond
in water is polar, hydrogen in a molecule of water is a relatively
weak electrophile. Therefore, hydrogen is not electrophilic H2O no reaction
enough to attract the electron pair from the carbon–carbon π
orbital.
For an addition of water across the carbon–carbon double bond to occur, one has to use an
acid catalyst (a source of electrophilic hydrogen). Role of an acid is two fold. One is to provide a
source of electrophilic hydronium ions. Another role is to “tie up” water molecules through hydrogen
bonding. Given a choice, hydronium ion would rather interact with water molecules (nucleophile) than
with π electrons of an alkene (weaker nucleophile). By taking up water molecules through hydrogen
bonding, an acid ensures that mainly alkene molecules are available for reaction with hydronium ions.
Only acids whose anions (conjugate bases) are non-
nucleophilic are suitable. Such acids include phosphoric,
H2O/ H3O H
H3PO3, and sulfuric, H2SO4, acids. Other acids (for example
hydrohalic acids) may give a mixture of products, since their OH
anions may compete with water for reaction with the
intermediate carbocation.
Mechanism of the addition includes an initial attack of hydronium ion on the carbon–carbon
double bond, followed by attack of the nucleophile (water) on the intermediate carbocation. Note that
mechanism of addition of water to an alkene has an extra step compared to addition of hydrogen
halides. That final step is loss of a proton from the oxonium ion (in this case a protonated alcohol –
ROH2+). A base in the final deprotonation step may be any of a number of bases present in the reaction
mixture. Some of the possible bases involve acid anion, water, another molecule of the resulting
alcohol as well as unreacted
alkene. This is an acid-base
H OH2 H
reaction and the products are an +
alcohol (result of addition of slow
water to an alkene) and a H
minor major
hydronium ion, which can in
turn catalyze another reaction fast H2O fast H2O
sequence. Therefore, the
H H
catalyst is regenerated in the O
two intermediate H
final step. oxonium ions: O + H
H H
In the final step, acid -base H2O
reaction, protons may be H2O
taken up by a base, such as
water, or they may protonate OH
OH
another alkene. + H
H
minor major

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Chapter 9. Reactions of Alkenes

Addition of Alcohols
Like water, under ordinary conditions alcohols do not
add to an alkene. Therefore, one has to use an acid catalyst CH3OH
no reaction
(H3PO3 or H2SO4) as a source of the electrophilic hydrogen
ions.
Mechanism of the addition is similar to the mechanism
for addition of water to an alkene. After an initial attack of an CH3OH/ H
OCH3
oxonoium ion (H3O+ is hydronium ion, ROH2+ is an oxonium
ion) on the carbon–carbon double bond, the nucleophile H
(alcohol) combines with the intermediate carbocation to give
the intermediate oxonium ion. Like
addition of water, this addition also H
has the extra acid-base reaction step slow
H O CH3
compared to addition of hydrogen H
halides. Loss of a proton from the
oxonium ion (in this case a
protonated ether) gives the H O
fast
corresponding ether (result of CH3
addition of an alcohol to an alkene). H H
H O CH3 + fast
A trivalent positively charged oxygen H O +
species is called an oxonium ion: CH3 CH3
H O CH3 O
H
ROH2 R2OH R3O
oxonium ions

Rearrangements
Whenever possible, the initially formed carbocation will rearrange into a more stable
carbocation. In the course of a rearrangement, a substituent next to the carbocation undergoes 1,2-shift
to give a more stable carbocation. Two of the most common rearrangements involve 1,2-hydrogen shift
and 1,2-alkyl (usually methyl) shift.

H H H H3 C CH3 CH3

1,2-hydride shift 1,2-alkyl shift

As a general rule, the smallest group undergoes rearrangement. Therefore, in order of ease of
rearrangement that would be a hydrogen atom, then a methyl group and finally larger alkyl groups.

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Veljko Dragojlovic

H Cl
H
(2°) Cl
minor
methyl
shift
Cl

Cl H

major (3°)

Rearrangement is favored over a reaction of the carbocation with a nucleophile because it is


an intramolecular reaction. A rearrangement happens only if a more stable carbocation can be formed.
Otherwise, the addition proceeds without a rearrangement.
Br
HBr Br
H H
X

In case of small rings (3-4 atoms), formation of a larger ring may be favored rearrangement
process because formation of a larger ring relieves angle strain in the carbocation. Formation of a more
substituted carbocation in a four member ring would introduce too much angle strain. Recall that the
bond angles in a carbocation are 120° and in four member ring 90°. Formation of a five-member ring
increases bond angle to 108°.
Br
HBr Br
H

Addition and its reverse, elimination,


reaction (studied latter in this course, Chapter H
13) may be, and frequently are, reversible
reactions. Position of the equilibrium depends H H
on the reaction conditions. However, since
formation of the more stable carbocation is the
reason for a rearrangement, the rearrangement
is never a reversible process. Br
A carbocation on the carbon next to a
Br H
double bond, a triple bond, or an aromatic ring
is particularly stable due to resonance H
stabilization (Chapter 16). Rearrangements to
form such carbocations are highly favorable.

156
Chapter 9. Reactions of Alkenes

When considering possibility of a rearrangement in a reaction, keep in mind that primary


carbocations are unstable and are unlikely to be reaction intermediates. They would rearrange to more
stable carbocations, but are not very likely to form to start with. Tertiary carbocations are already
rather stable and are not likely to rearrange. However, they may if it is possible to rearrange into a still
more stable carbocation. Carbocations most likely to undergo rearrangement are secondary
carbocations. They are stable enough to form as initial reaction intermediates and they may rearrange
into more stable carbocations.

Addition Reactions that proceed through Free Radical Intermediates


Addition of HBr
A molecule of hydrogen bromide can add to an alkene under free radical conditions. The
regioselectivity is opposite from the
addition under polar conditions (when HBr/ CH2Cl2
carbocation is the intermediate) and polar (ionic) reaction
Br
such addition is a so-called anti-
Markovnikov addition. It means that HBr/ diethyl ether
the hydrogen atom adds to the carbon Br free radical reaction
atom of the double bond that contains fewer hydrogens. A free
radical addition occurs when solvent is an ether, usually diethyl Initiation Steps:
ether. Ethers usually contain hydroperoxides (ROOH) or generation of free radicals
peroxides (ROOR) as impurities. hν
Mechanism of the reaction is a free radical chain HO OH 2 HO
reaction and it involves the steps that are usually associated or
with a free radical chain reaction: initiation, propagation and hν
RO OR 2 RO
termination. Unlike polar addition, where proton was the
electrophile, in a free radical addition bromine atom (bromine initiation of radical chain reaction
radical) is the electrophile. In both additions, polar and free RO + H Br RO H + Br
radical, the electrophile adds to the less substituted carbon atom
of the double bond to give a more stable intermediate.
Propagation Steps:

+ Br Br Br + Br
H
H Br

Termination Steps:
Br
Br + Br
Br

Br + Br Br
Br
Br + Br Br2

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Veljko Dragojlovic

Peroxide Effect
A free radical addition, to give anti-Markovnikov regioselectivity, works only with hydrogen
bromide and fails with other hydrogen halides (HCl or HI). That is the so-called peroxide effect.
Hydrochloric and hydroiodic acids give Markovnikov addition products even in the presence of
peroxides.

(I) H2C CH2 + X X


H + X
(II) X + H X X

X=Cl X=Br X=I


ΔH° (I) (kcal/mol) 61-82=-21 61-69= -8 61-55= 6
ΔH° (II) (kcal/mol) 103-101= 2 87-101= -14 71-101= -30
ΔH° (I + II) (kcal/mol) -19 -22 -24

From the data given in the table above one can see that only when hydrogen bromide adds to
an alkene in a free radical chain reaction both propagation steps are exothermic. With hydrogen
chloride, the second propagation step is endothermic and exothermic termination steps are favored.
With hydrogen iodide the first propagation step is endothermic and any free radicals that were formed
in the initiation step will preferentially undergo termination (a termination is always exothermic) rather
than free radical addition. Thus, even in the presence of free radical initiators, such as peroxides,
hydrogen chloride and hydrogen iodide can undergo only ionic addition to an alkene.

Stability of Free Radicals


Free radicals are reactive intermediates. Relative stabilities of the reactive intermediates are
evaluated based on:
(1) the rate (speed) of formation of the intermediate, and
(2) the lifetime of the intermediate.
late transition states:
The species that is formed faster is energies of transition
considered to be more stable compared to a states resemble energies
of the products
species that is formed slower. Keep in
mind that reactive intermediates are high
(1º)
energy species and that their formation
involves a late transition state. (2º)
When it comes to lifetimes, the
more stable species is going to have longer (3º)
lifetime while the less stable ones are going
to have a shorter lifetime. This is a
consequence of a higher reactivity of less
stable species which will be quickly
converted into a more stable species.

158
Chapter 9. Reactions of Alkenes

The main factors that affect stability of free radicals are steric factors. More hindered free
radicals are formed faster due to relief of steric strain. As a tetrahedral molecule is converted into a
trigonal planar free radical, the substituents get farther apart relieving the steric strain.

Br
H3C
CH3
H3C
CH3 H 3C
H3C

t-Butyl bromide exhibits steric strain In t-butyl radical methyl groups


due to crowding of three methyl groups. are farther apart.

More hindered free radicals also have longer lifetimes due to steric hindrance to the approach
of the reagent.

R
R

H H3C
H CH3
H H3C

Methyl radical reacts faster t-Butyl radical reacts more slowly


because there is no hindrance because a reagent experiences steric
to approaching reagent. hindrance when approaching it.

Therefore, both free radicals and carbocations exhibit the same order of stability ((3°) > (2°) >
(1°) > methyl), but for different reasons. In the case of free radicals the reasons are steric while in the
case of carbocations electronic.

R C R >R C H > R C H >H C H


R R H H
tertiary secondary primary methyl

Free Radical Reaction Mechanisms


In a free radical reaction the overall reaction is the sum of the propagation steps. Initiation and
termination steps “do not count.” However, they explain how a free radical reaction begins, how it
ends, and how are some of the byproducts formed. When considering thermodynamic factors (changes
in enthalpy, entropy, free energy) again only propagation steps are considered (remember only the
propagation steps add to the overall reaction) while initiation and termination steps are ignored.

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Veljko Dragojlovic

Reactions that proceed through a Cyclic Intermediate or Transition


State
Addition of Halogens
Halogens (Cl2 and Br2) add to alkenes to form dihaloalkanes. This reaction occurs rapidly in
the dark and, unlike free radical substitution on alkanes by a halogen, hydrogen halide (HCl or HBr) is
not evolved in the course of it. The addition works well only with Cl2 and Br2. Fluorine is too reactive
and gives complex mixtures of products, while iodine is unreactive.

Addition of Bromine

Bromine test for unsaturation involves addition of


bromine to an alkene. A positive test is a color change from Br
red-brown color of bromine to a colorless solution (the reaction + Br 2
product bromoalkane is colorless). The test is positive only (red-brown) Br
with double and triple carbon–carbon bonds. Thus, it can be (colorless)
used to distinguish between multiple bonds and rings as
unsaturations.
Reaction mechanism involves interaction of a molecule of bromine with π orbital of the
alkene. Therefore, the electrophile is a molecule of bromine. The first step involves a charge
separation. Note that the
carbocation is formed in Br
the transition state. + Br
+ Br Br
Therefore, it is not an
intermediate. The
Carbocation is a transition
intermediate is a cyclic state, not an intermediate.
bromonium ion. The
bromide ion attacks the
bromonium ion from the Br H
side opposite to carbon– Br
Br bromonium ion
bromine bond to give the H
product – dibromoalkane. Br
anti addition bromide ion attacks from the
Therefore, the two atoms of two bromine atoms add to side opposite to the bond that
bromine add to the opposite opposite sides of the double bond is being broken
sides of the double bond.
This is called anti addition.
The reaction product is a vicinal dibromide, which means that the two bromine
atoms are on the neighboring carbon atoms. A geminal dibromide, on the right, has two Br Br
bromine atoms on the same carbon atom.
Other functional groups, such as carboxylic group and an aromatic ring do not
interfere with addition of bromine and can be present elsewhere in the molecule.

160
Chapter 9. Reactions of Alkenes

O Br O
Br2, CH2Cl2 Br
(CH2)8 OH (CH2)8 OH

O Br O

OH Br2, CH2Cl2 OH
Br

Addition of Chlorine
Cl
Chlorine adds the same way as bromine, following an
analogous reaction mechanism. The products are vicinal dichlorides. Cl2

Cl

Addition of Fluorine and Iodine

Fluorine is extremely reactive. It even reacts with C-H bonds. Therefore, the reaction is not
synthetically useful. Iodine does not react (ΔGº > 0).

Water as Solvent in Additions of Halogens to Alkenes


When addition of halogen is carried out in OH Br
water as a solvent, water molecule preferentially reacts Br2/ H2O Br + OH
with the intermediate carbocation as opposed to
major minor
halogen ion. The products are halohydrines (in the
example on the right the product is a bromohydrine).
Although halogen ions (chloride and H H
O
bromide) are better nucleophiles compared to water, Br
Br Br H2O Br
they are present in a low concentration. Thus,
carbocation has much greater odds of encountering a
Br H2O
water molecule and reacting with it than encountering
a halogen ion. The reaction is regioselective. The Br OH
molecule of water forms a bond to the more Br Br
substituted carbon atom (the carbon atom that better
tolerates a partial positive charge) of the intermediate bromonium ion.
When an alcohol is used as a solvent, the reaction Cl
mechanism is similar and the intermediate carbocation reacts OCH3
preferentially with the alcohol. If a salt that is a source of a Cl2/ CH3OH
nucleophile is added to the reaction mixture in large excess,
then its nucleophile will preferentially react with the
intermediate carbocation. Cl
Br2/ NaCl Br

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Veljko Dragojlovic

Oxymercuration-Demercuration
Oxymercuration means addition of oxygen and mercury across a double bond. Demercuration
is removal of mercury and its replacement by hydrogen. Oxymercuration-demercuration reaction
sequence results in a net addition of a molecule of water across a double bond of an alkene. The
reagent for an oxymercuration reaction is mercuric acetate, Hg(CH3CO2)2, or mercuric trifluoroacetate,
Hg(CF3CO2)2. Note the difference between an acetate group and an acetyl group.

O O
OAc = O C CH3 Ac = C CH3
acetate acetyl

Hg(OAc)2 HO NaBH4 HO

H2O, THF KOH, H2O


HgOAc H

Oxymercuration reaction is usually performed in a mixture of water (to dissolve mercuric


salts) and tetrahydrofuran (to dissolve organic compounds). In an aqueous solution, mercuric acetate is
ionized. The electrophile is electron deficient mercury(II) ion. Reaction is somewhat similar to
addition of bromine in that there is a cyclic reaction intermediate (and not a carbocation). In this case,
the intermediate is a cyclic mercurinium
ion. The nucleophile is water (the
solvent) and the final step involves loss Hg(OAc)2 HgOAc + AcO
of a proton from the oxonium ion. The
product is a result of an oxymercuration
OAc
reaction. In the next step, which involves
a separate reaction, mercury substituent Hg HgOAc
HgOAc
is replaced by a hydrogen atom by
adding alkaline sodium borohydride H O
solution. Replacement of mercury by H
H2O
hydrogen is the demercuration part of the
sequence. A source of hydrogen is - AcOH
AcO
sodium borohydride (NaBH4).
H HgOAc
NaBH4
HO HO

162
Chapter 9. Reactions of Alkenes

In an oxymercuration-demercuration sequence, Markovnikov’s Rule is still valid, but for a


different reason. Attack of the nucleophile results in breaking of the weaker carbon–mercury bond. A
more substituted carbon atom makes a weaker bond to mercury compared to a less substituted carbon
atom.
OAc

Hg HgOAc H
HgOAc NaBH4

HO HO
H2O
OH
1) Hg(CH3CO2)2, H2O, THF
2) NaBH4, KOH, H2O

OH

1) Hg(CH3CO2)2, H2O, THF


2) NaBH4, KOH, H2O

Oxymercuration-demercuration reaction can also be used to effect addition of an alcohol to an


alkene. The reaction is chemoselective – the least hindered double bond undergoes oxymercuration-
demercuration.
1) Hg(CH3CO2)2, CH3OH O
O
2) NaBH4, KOH, H2O
OCH3
OCH3 H3CO
H

Main advantage of the oxymercuration reaction is that, since carbocation is not an


intermediate, there are no rearrangements.

1) Hg(OAc)2/H2O OH
H2SO4/H2O 2) NaBH4
OH
reaction proceeds no rearrangement
with rearrangement - cation is not an
as cation is an intermediate
intermediate

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Veljko Dragojlovic

Hydroboration-Oxidation
Hydroboration reaction involves addition of borane (BH3) to alkenes to prepare alkylboranes.
Alkylboranes are then oxidized with hydrogen peroxide to give the corresponding alcohols. Thus, the
overall process is an addition of water across the double bond. For his work on organoboron
compounds Herbert C. Brown shared a Nobel Prize with Georg Wittig (who received it for his work on
organophosphorus compounds) in 1979.
Borane (BH3) cannot be prepared as a stable H
pure compound. In a molecule of borane, the boron H H H
atom has an empty orbital and is a strong electrophile. B B H B O
To alleviate boron’s electron deficiency, borane
dimerizes to diborane B2H6. Borane is also H H H
H
commercially available in the form of complexes with diborane borane-THF complex
dimethyl sulfide, tetrahydrofuran, or tertiary amines.
An alkene reacts with diborane (B2H6), or
BH3⋅THF BH2
borane-tetrahydrofuran complex (BH3⋅THF) to form R R
a trialkylborane, a synthetic intermediate for the
preparation of alcohols. The addition proceeds
R
rapidly at room temperature. In a hydroboration
reaction, three equivalents of an alkene can react
B BH
with an equivalent of BH3. The balanced equation R R R
for the hydroboration of an alkene, using a borane- 3 2
tetrahydrofuran complex is shown on the left.
In borane molecule, boron, as the atom with an empty orbital, is the electrophile and hydrogen
is the nucleophile. The addition proceeds by a nucleophile adding to a more substituted carbon and an
electrophile to a less substituted one. However, the regioselectivity is controlled mainly by steric
factors, although electronic factors play a part. Another way to look at this reaction is that borane is a
Lewis acid and, as an electron deficient species, attacks electron-rich centers (less substituted carbon
atoms). The addition of borane to an alkene is both regio- and stereoselective reaction.
Hydroboration is a concerted reaction (a single – step reaction with no intermediates) and a
pericyclic reaction (proceeds via a cyclic transition state). Hydroboration reaction proceeds via a four-
member cyclic transition state:
H
H H R
C CH2 C CH2 BHR
R + R
H H
H B H B
R R H
vs.
H
C CH2
R
steric hindrance H B H
R

Boron and hydrogen add from the same side of the double bond. Such addition is called syn
addition.

164
Chapter 9. Reactions of Alkenes

Once the organoborane intermediate is formed, it can be oxidized with a basic solution of
hydrogen peroxide to give the corresponding alcohol. In
the course of oxidation, boron atom is replaced with a H2O2
B NaOH, H2O OH
hydroxyl group. In the course of oxidation, -OH group R 3R
replaces boron atom with retention of configuration. 3
Hydroboration-oxidation sequence is an indirect way of adding water to an alkene in an anti-
Markovnikov manner. The reaction actually follows Markovnikov’s rule, if we consider it in its
broader form – that the more positive atom adds to the carbon atom of the double bond that contains
more hydrogens, since in borane
boron is more positive than 1) BH3⋅THF, THF
hydrogen. 2) H2O2, NaOH, H2O
OH

Addition of Hydrogen: Catalytic Hydrogenation of Alkenes


In the presence of a suitable metal catalyst (usually one
from the platinum group of metals Ni, Rh, Ru, Pt are the most H2/ PtO2
frequently used) a molecule of hydrogen adds to an alkene. Product
is the corresponding alkane. Reaction is usually carried out in the H2/ Pd-C
presence of a heterogeneous catalyst - in a solution with solid metal
powder or piece of metal (called a sponge because it is very porous)
as a catalyst. Sometimes instead of the metal catalyst, a metal oxide H2/ Ru-C
(such as PtO2) is used. Most of the platinum group metals are
expensive. Since the actual reaction occurs on the surface of the
H2/ Ni
metal, sometimes in order to increase catalyst surface and reduce
amount catalyst needed for a reaction, a metal is adsorbed on an
inert support such as carbon (this is indicated as Pd-C, Ru-C, Pd/C
or Ru/C).
A soluble complex of platinum group metal may be used as a homogeneous catalyst.
Homeogeneous catalysts are considerably more expensive. However, one needs to use much less of it
and such catalysts offer better reaction rate and selectivity. Rhodium complexes are common
homogeneous hydrogenation catalysts.

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Veljko Dragojlovic

A transition metal catalyst makes addition possible by breaking hydrogen–hydrogen bond and
facilitating addition of individual hydrogen atoms to an alkene. Alkene attaches to the surface of the
catalyst by forming a π-complex (it uses its π orbital for bonding). Note that although hydrogen atoms
add one at a time, both hydrogen atoms are added from the same side of the double bond. Thus, the
addition of the two hydrogens occurs faster than a rotation about a carbon–carbon single bond. This is
called a syn-addition. There are exceptions and sometimes anti- addition, or formation of a mixture of
isomers have been observed. Note that the reaction product is formed in an eclipsing conformation.

H H
H H

surface of a catalyst (for example. Pt [Xe]6s24f145d8)

H
H H H

H H

Stability of Alkenes: Heat of Hydrogenation


Addition of hydrogen across the double bond in the presence of a catalyst is an exothermic
reaction (conversion of a π bond into a σ bond). Therefore, in the course of a hydrogenation energy is
released. A compound with a higher energy content (a less stable compound) has more energy to
release and, therefore, its heat of hydrogenation is higher compared to a compound with a lower energy
content (a more stable compound). Thus, the heat of hydrogenation is related to the relative stability of
carbon–carbon double bond and to the relative stability of the molecule as a whole.
If we want to compare stabilities of differently substituted double bonds, we should compare
alkenes that, as a result of hydrogenation, give the same alkane. If that is the case, only the differences
in the stabilities of the double bonds will be reflected in the differences among the heats of
hydrogenation. As an example, we can compare heats of hydrogenation of 1-butene (a monosubstituted

166
Chapter 9. Reactions of Alkenes

alkene) and two disubstituted alkenes: cis-2-butene and trans-2-butene. All three alkenes give butane
as the product of hydrogenation.

-30.3 kcal/mol -28.6 kcal/mol -27.6 kcal/mol

From the values for heats of hydrogenation given in the above figure, one can see that the
disubstituted alkenes are more stable than the monosubstituted alkene. As a general rule, a more
substituted alkene is more stable compared to a less substituted one. Between the isomeric alkenes, cis
isomer has a higher heat of hydrogenation (is less stable) than the trans isomer: The reason for lower
stability of the cis isomer is in steric hindrance of the substituents that are on the same side of the
double bond.

Hydrogenation and the Degree of Unsaturation


An unsaturation in an organic molecule may be due to the presence of a double bond, or a
ring, or both. In a hydrogenation reaction a carbon–carbon double bond is converted into a carbon–
carbon single bond. However, rings composed of carbon atoms are unaffected by a hydrogenation
reaction (there are a few exceptions that involve small rings, but we can ignore them at the moment).
Thus, a hydrogenation reaction can help us determine the nature of unsaturation in a molecule –
whether it is due to multiple bonds, rings,
or both. In the examples below, several
+ H2 Pd no reaction
compounds with a molecular formula
C8H14 (2 degrees of unsaturation) have
been hydrogenated. The first one, did not
undergo hydrogenation. Therefore, this + H2 Pd
compound does not contain multiple bonds
and all the unsaturations must be due to the
Pd
presence of rings. Thus, we conclude that + H2
the compound has two rings. In the next
two examples, the compounds reacted with + 2 H2 Pd
one equivalent of hydrogen. Therefore,
each one has one carbon–carbon double + 2 H2 Pd
bond and the remaining unsaturations are
rings. Thus, those compounds have one + 2 H2 Pd
double bond and one ring. The remaining
compounds reacted with two equivalents of
hydrogen. This is an indication that they contain either a triple bond, or two double bonds. Note that
167
Veljko Dragojlovic

this experiment provides information only about the number of rings and the number of unsaturations
due to multiple bonds, but does not provide any information about the nature of the rings (ring size),
nor does it provide any information about the nature of multiple bonds. For example, questions such
as: Is there a triple bond, or two double bonds? and What are the positions of the double bonds?
cannot be answered by hydrogenation experiments.

Oxidation Reactions
Reaction of Alkenes with Peroxyacids: Epoxidation
Alkenes react with peroxyacids (“peracids”) to give the corresponding epoxides.
O O
O +
+ OH H
R1 R2 O R1 R2 O

Peroxyacids, or peracids for short,, are organic compounds with a H O


general formula RCO3H. They are similar to hydrogen peroxide and organic O H
peroxides in that they have an oxygen-oxygen single bond. Oxygen-oxygen hydrogen peroxide
single bond is weak and peroxy compounds are highly reactive reagents. R O
Peroxyacids are prepared in a reaction between hydrogen peroxide and the O H
corresponding carboxylic acid. alkyl hydro peroxide

O O R O
O + H O O + H2O O R
H3C O H O H H3C O H dialkyl peroxide
peracetic acid hydrogen peroxide peracetic acid

Some of the commonly used peracids are peracetic acid, m-chloroperbenzoic acid (m-CPBA)
and trifluoroperacetic acid. m-Chloroperbenzoic acid is a mild oxidizing reagent, while
trifluoroperacetic acid is a highly reactive one.
O
O Cl O O
O O H O
H3C O H F3 C O H
peracetic acid m-chloroperbenzoic acid trifluoroperacetic acid

Epoxidation is a concerted reaction. The reaction is thermodynamically favorable as it


involves breaking of the weak peracid’s oxygen–oxygen single bond and formation of stronger
carbon–oxygen bonds.

R4 R3 H O R4 R3 H O
O O +
O R O R
R1 R2 R1 R2

168
Chapter 9. Reactions of Alkenes

Epoxidation proceeds with retention of stereochemistry. A cis-alkene gives a cis-epoxide and


a trans-alkene gives a trans epoxide. Therefore, the reaction is both stereoselective and stereospecific.
O
H H O H O H
H3C O H

cis-2-butene cis-2,3-dimethyloxirane
O
H O H O
H3C O H
H H
trans-2-butene trans-2,3-dimethyloxirane

Epoxidation is also chemoselective. The more substituted


(the more electron-rich) double bond reacts faster than a less m-CPBA O
substituted double bond and can be selectively epoxidized.

Hydroxylation of Alkenes: OsO4 and KMnO4 Oxidations


Term hydroxylation reaction, or more accurately dihydroxylation reaction, describes
addition of two OH groups to a double bond. Either permanganate ion under mild conditions (in
presence of a base and at a low temperature), or osmium tetroxide, oxidize alkenes to the
corresponding vicinal diols.
OH
KMnO4, OH, H2O
5ºC OH
1) OsO4 OH
2) NaHSO3, H2O

OH

Mechanisms of both permanganate and osmium tetroxide oxidations involves syn-addition of


the oxidizing agent to the double bond. Therefore, the reaction is both stereoselective and
stereospecific. The cyclic manganese intermediate is not stable and hydrolyzes under the reaction
conditions to the corresponding diol. Cyclic osmate ester is stable and it is hydrolyzed to the diol by
sodium bisulfite, NaHSO3, in ethanol.

O O OH
O O H2O
+ Mn Mn + MnO2
O O O O OH

O O NaHSO OH
O O 3
+ Os Os + OsO3
CH3CH2 OH
O O O O OH

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Veljko Dragojlovic

Hydroxylation of alkenes can also be carried out with a catalytic amount of osmium tetroxide
and a stochiometric oxidant such as potassium hexacyanoferrate(III), K3[Fe(CN)6], hydrogen peroxide,
or N-methylmorpholine oxide (NMO).
OH
OH
OsO4 (cat.), NMO
O

N
H3C O
OH NMO
OsO4 (cat.), NMO OH

Oxidative Cleavage of Alkenes: Ozonolysis


Ozone (O3) is an electrophilic reagent. Its structure can be represented by the following four
resonance structures.

O O O O
O O O O O O O O

The middle two resonance structures are the main resonance forms, while the first and the last
structure are high energy resonance forms and contribute little to the overall resonance stabilization of
ozone. However, these two structures best show electron deficient oxygen atom (which one is an
electrophile).
Ozone oxidatively cleaves alkenes into the corresponding carbonyl compounds. Mechanism
involves initial formation of a five-member cyclic molozonide (also called a “primary ozonide”). The
molozonide contains two weak oxygen–oxygen single bonds and rearranges into a more stable
ozonide.

O
O O O O
O O O O
R1 R4 R1 R4 R1 R4
R2 R3 R2 R3
R2 R3 primary ozonide
(molozonide)
O R4
O R3
O O R1
carbonyl R2 R3
compounds O R4 O
R1
ozonide R2

170
Chapter 9. Reactions of Alkenes

An ozonide is potentially explosive and usually it is not isolated. It is converted into the
corresponding carbonyl compounds either under reducing or oxidizing conditions. Depending on their
structure, alkenes are oxidized either to the corresponding aldehydes or to the corresponding ketones, if
the work up is done under reducing conditions. Common reducing agents are zinc, dimethyl sulfide, or
H2/Pd.

1) O3
O
2) Zn, H2O O +
H

1) O3 O O
2) (CH3)2S
+
H H

When sodium borohydride is used as a reducing agent, the corresponding alcohols are
obtained.

1) O3
2) NaBH4, CH3OH HO OH

Depending on their structure, alkenes are oxidized to either the corresponding carboxylic
acids or the corresponding ketones, if the work up is done under oxidizing conditions. Usual oxidizing
agent for oxidative work up of an ozonide is hydrogen peroxide.

OH
1) O3
2) H2O2
O O O
+
OH HO OH

1) O3 O
2) H2O2 OH HO H
+ CO2 + H2O
O

171
Veljko Dragojlovic

Permanganate Oxidation of Alkenes


Permanganate oxidatively cleaves alkenes to the corresponding carbonyl compounds under
vigorous conditions. Vigorous conditions include basic permanganate oxidation at an elevated
temperature, or a permanganate oxidation under acidic conditions. Depending on the structure of the
starting alkene, reaction products are ketones or carboxylic acids. Terminal carbon atom of an alkene is
oxidized to carbon dioxide.

O
KMnO4, OH, H2O
+ CO2
heat

O
KMnO4, OH, H2O OH
HO
heat
O
O
KMnO4, NaOH
OH + CO2
H2O, heat
O
KMnO4, H3O

Reactions of Cyclic Compounds


As a general rule, cyclic compounds react the same Br2, hν Br
way as acyclic (open chain) compounds. Therefore, one + HBr
should identify the reactive site, which is usually the Cl
functional group of the molecule, and provide a product of Cl2, hν
+ HCl
reaction of the reagent with it. Shown here are several
examples of free radical substitution on cyclic compounds.
Br
The first two examples involve usual free radical NBS, hν
substitution. The third reaction is an example of an allylic
substitution. As was the case with acyclic (open-chain)
compounds, carbon atom next to unsaturated functional
groups reacts the fastest (Chapter 7, page 129).
The same applies to reactions of polycyclic
compounds. As an illustration we can examine addition of Br2
bromine to the large polycyclic molecule shown on the right.
CH2Cl2
?
The molecule belongs to a large class of compounds know as
steroids.
1) First, one should identify the functional group present in the molecule that reacts with bromine. In
this case it is the double bond.

172
Chapter 9. Reactions of Alkenes

2) Next, how does a double bond react with bromine? What is the product? The reaction is an
addition reaction and the product is a geminal dibromide.
3) Finally, one should redraw the structure of the product to include the complete skeleton of the
molecule.
1) 3)

Br2 Br

CH2Cl2
Br
functional group that
reacts with Br2
2) Br
Br2
CH2Cl2
Br
Br2
Br Br
Cyclopropane, as a small strained ring, is an exception.
Due to high angle strain it readily undergoes ring opening reactions.
Elements of the reagent bond to the ends of the newly formed chain HBr H Br
to give an open chain compound.

173
Chapter 10. Reactions of Alkynes

CHAPTER 10.

Reactions of Alkynes
___________________________________________________________________________

Reactivity of Alkynes
eactivity of alkynes is similar to that of alkenes. A common reaction of alkynes is an addition
reaction. Electrophilic addition reaction proceeds via the intermediate vinyl cation.

TS
H3C C C CH3 + H Br H3C C CH CH3 + Br
R
TS
Br
H3C C CH CH3 R R

Vinylic cations are less stable compared to


the corresponding alkyl cations. It means that a R
secondary vinylic cation is less stable compared to a
secondary alkyl cation, but more stable than a
primary alkyl cation, and that a primary vinylic
cation is less stable than the corresponding primary alkyl cation and so on.

R R
>
R R R R > > R > R > CH3
R R

Since vinylic cation is so unstable, an alternative cyclic intermediate has been proposed for
addition of a hydrogen halide to an alkyne. The fact that addition of hydrogen bromide to an alkyne is
trans supports this mechanism. However, one should keep in mind that the trans isomer is the more
stable one and in reactions that have been shown to proceed via a carbocation, the trans isomer was
still the predominant one. Furthermore, cyclic proton-contiaining intermediate is rare, if plausibe at all.
Finally, while there is no doubt that a vinyl cation is less stable than the corresponding alkyl cation,
alkynes are considerably less
stable than alkenes and H
formation of a vinyl cation from H3C C C CH3 + H Br H3C C C CH3 + Br
an alkyne is not that dificult – it
requires about the same amount
H CH3
of energy as formation of an C C
alkyl cation from an alkene (see H3C Br
the reaction diagram above).

181
Veljko Dragojlovic

While, due to the formation of a high energy intermediate, alkynes are less reactive compared
to alkenes, they are also less sensitive to steric
hindrance. The reasons for it are two-fold. Since an E+
alkyne has only two substituents, they take up less
space than four substiuents of an alkene. An even E+
more important reason lies in the electronic E+
E+
structure of an alkyne. Its two π electron pairs form
a uniform tube of electron density around the C-C
axis. Thus, an electrophile can approach the π E+ E+
electrons from any angle avoiding any possible
steric hindrance. Once the bond to an electrophile is
formed, the other π orbital appears at 90º to the E+ E+
carbon–electrophile bond. In an alkene the
approaching electrophile has to be aligned with the E+
+
π orbital and bulky substituents may get into the E
way.

Acidity of Hydrogen Bonded to an sp Hybridized Carbon


Acidity of Terminal Alkynes
As you learned earlier (Chapter 5, p. 96), electronegativity of an element depends on its
hybridization. Thus, sp hybridized carbon atom is more electronegative then sp2 hybridized carbon,
which in turn is more electronegative then sp3 hybridized carbon.
Acidity of a compound is related to
electronegativity
electronegativity of the atom that hydrogen is bonded to. The
more electronegative the atom is, the stronger the acid. sp3 < sp2 < sp
Therefore, hydrogen bonded to an sp hybridized carbon is CH3CH3 < H2C=CH2 < HC≡CH
going to be more acidic compared to hydrogens bonded to
pKa ~50 44 25
either sp2 or sp3 carbon atoms.
In fact, acidity of hydrogen bonded to sp hybridized
carbon (pKa 25) is stronger then acidity of hydrogen bonded electronegativity
to sp3 hybridized nitrogen (pKa 36). It means that amide
N < O < F
anion (deprotonated ammonia) is a stronger base compared
NH3 < H2O < HF
to an acetylide ion (a deprotonated alkyne is called acetylide
ion). pKa 36 15.7 3.2

Therefore, amide anion can be used to deprotonate NH3 < HC CH


alkyne to acetylide ion. Remember that an acid-base
equilibrium is always at the side of weaker acid-base pair. acid strength
Hydroxide ion not sufficiently strong base to deprotonate an NH2 > HC C
alkyne and the equilibrium is to the left. base strength

RC CH + NH2 RC C + NH3

RC CH + OH RC C + H2O

182
Chapter 10. Reactions of Alkynes

Use of Acetylide Ions in Synthesis


Acidity of the hydrogen atom bonded to sp hybridized carbon atom has been exploited in
organic synthesis. This is an important method for preparation of new carbon–carbon bonds. Reaction
of a terminal alkyne with a strong base, such as sodium amide, results in formation of an acetylide
anion. Acetylide anion is both a strong base and a strong nucleophile and, in a substitution reaction
(mechanism of substitution reactions will be covered in detail in Chapter 12) replaces halogen
substituent of an alkyl halide.

NaNH2 H3C CH2 Br


H3C C CH H3C C C H3C C C CH2 CH3

1) LiNH2
C CH 2) H3C CH2 I C C CH2 CH3

Therefore, starting with ethyne (acetylene) and suitable alkyl halides, one can prepare a higher
alkyne. Dimethyl sulfate, (CH3)2SO4, is an alkylating agent and can be used instead of alkyl halides.
Like a halogen ion, sulfate group, SO4-, is a good leaving group.
1) NaNH2
1) NaNH2
2) (CH3)2SO4 2) Cl
HC CH HC C CH3

183
Veljko Dragojlovic

Additions of Hydrogen Halides to Alkynes


Addition of one molecule of a hydrogen halide (HCl, HBr or HI) gives the corresponding
vinyl halide. In the presence of an excess of hydrogen halide, two equivalents of hydrogen halide add
across the triple bond. Markovnikov rule applies
to addition to alkynes. The product of an addition HBr Br H HBr Br H
H H
of two equivalents of a hydrogen halide is a Br
H H
geminal dihalide.

H H Br H

Br
H
Reaction mechanism
involves a sequential addition of two Br Br
molecules of hydrogen halides. Note +
that addition of the first molecule, Br
secondary carbocation secondary
directs addition of the second – a carbocation
stabilized by resonance
halogen substituent stabilizes the
intermediate carbocation through
resonance. Br Br
Br +
Br
major minor
(a geminal dihalide) (a vicinal dihalide)

In the presence of a peroxide, mechanism of the reaction is a free radical addition and the
regioselectivity is anti-Markovnikov. As with alkenes, a free radical addition to an alkyne works only
with hydrogen bromide.

RO OR 2 RO
RO + H Br ROH + Br

H3C CH2 C CH + Br H3C CH2 C CHBr

H3C CH2 C CHBr + H Br H3C CH2 CH CHBr + Br

184
Chapter 10. Reactions of Alkynes

Addition of Halogens to Alkynes


The addition of halogens works well only with Br Br
2Br2/ CH2Cl2 H
chlorine and bromine. In the presence of an excess of H3C C CH
halogen, a second addition occurs to give a 2 DoU Br Br
tetrahaloalkane. Addition of bromine is the well known Br
bromine test for unsaturation. A triple bond represents Br2/ CH2Cl2
two degrees of unsaturation and, therefore, reacts with
Br
two equivalents of bromine. 2 DoU

The mechanism of the addition is analogous to the mechanism of addition of bromine to an


alkene. Since the bromine atoms add in anti fashion (to the opposite sides of the triple bond), the
product of addition a trans isomer. Therefore, the reaction is stereoselective. A stereoselective reaction
produces predominantly, or exclusively, one stereoisomer.

Br R Br
Br Br
R C C H
R H Br H
Br

Addition of Water to Alkynes


Acid Catalyzed Addition and Oxymercuration-Demercuration
Acid Catalyzed Addition of Water

As in the case of addition of water to an alkene, addition of water to an alkyne occurs only in
the presence of an acid catalyst. Addition of water to an alkyne gives the intermediate vinyl alcohol.
Vinyl alcohols are unstable and under the reaction conditions (acidic aqueous solution) isomerize to
the corresponding carbonyl compounds.

OH isomerization O
H2O/ H2SO4 (tautomerization)
H3C C C CH3 H3C C CH CH3 H3C C CH2 CH3

Therefore, overall reaction is a formation of a carbonyl compound from an alkyne. Carbonyl


compounds are class of compounds that have a carbonyl
group (C=O). Two classes of carbonyl compounds are O O O
aldehydes, which have hydrogen bonded to the carbonyl C C C
R H R R
carbon, and ketones, which have two alkyl or aryl groups carbonyl group aldehyde ketone
bonded to the carbonyl carbon.

185
Veljko Dragojlovic

Oxymercuration-Demercuration

Another way to add water to an alkyne is an addition catalyzed by mercuric ion. Note that
with alkynes, unlike alkenes, demercuration step
happens in the course of the reaction and a separate O
HgSO4/ H2O/ H2SO4 C
step is not necessary. Thus, this is one step R C C H R CH3
transformation and it is catalytic with respect to
mercuric ion.
Mechanism of mercuric ion catalyzed addition of water to alkynes is similar to that of
oxymercuration-demercuration of an alkene and involves a mercuric ion as the electrophile.
2
Hg R Hg
2
Hg
R C C H
R H H O H

H2 O H

H2 O H H2O

R CH3 R H R H R Hg
C - Hg 2 Hg

O O H HO H HO H

H OH2
H2O H

Hydroboration – Oxidation of Alkynes


An alkyne reacts with diborane
H B
(B2H6), or borane-tetrahydrofuran complex BH3/ THF C C
(BH3⋅THF) to form a trivinylborane. In a 3 H3C C C CH3
H3C CH3
hydroboration reaction, three equivalents 3
of an alkyne can react with one equivalent trivinylborane
of borane (BH3). H2O2, NaOH, H2O
Hydroboration-oxidation of an
internal alkyne gives the corresponding O H OH
ketone as the reaction product. Note that 3 C C
3 H3C C
the intermediate vinyl alcohol is not a CH2 CH3 H3C CH3
stable compound. It isomerizes into the ketone vinyl alcohol
corresponding carbonyl compound. This
particular form of isomerism is called tautomerism and is covered in detail latter in this course
(Chapter 20). Only hydroboration-oxidation of symmetric alkyne is a useful reaction. Such alkynes can
give only one possible product. Unsymmetric alkynes would give a mixture of products.

186
Chapter 10. Reactions of Alkynes

A terminal alkyne, upon hydroboration-oxidation, gives the corresponding aldehyde. Again,


the intermediate is the corresponding vinyl alcohol.
H B H2 O2 , O
C C H OH
BH3/ THF NaOH, H2O C C C
3 CH3 C C H H3 C H 3 3 3 H3C
H3 C H CH2 H
trivinylborane vinyl alcohol aldehyde

In practice, for hydroboration of alkynes we usually use disiamylborane. Disiamylborane is a


more selective reagent. It has two bulky siamyl substituents on the boron atom, which make boron
atom hindered and, thus, it bonds to the less hindered, terminal carbon of the alkyne. Ordinary
diborane molecule is not hindered and would bond to both carbons of the triple bond with equal ease.
Thus, such reaction would result in formation of a mixture of regioisomeric vinylboranes. This is
another application of reactivity – selectivity principle (Chapter 7, pages 127) where a less reactive
reagent is more selective and gives better results.
CH3

H3C CH C CH + THF
HB
2 B
2
trivial: disiamylborane
IUPAC: bis(1,2-dimethylpropyl)borane
siamyl - seconday iso amyl H2O2, NaOH, H2O

O OH
aldehyde vinyl alcohol

Therefore, addition of disiamylborane is regioselective. Overall, regioselectivity of addition of


water across the triple bond is anti-Markovnikov. Upon oxidation, the intermediate vinyl alcohol
isomerizes into the corresponding aldehyde. Note that hydroboration – oxidation of a terminal alkyne
results in formation of an aldehyde, while either acid-catalyzed addition of water, or mercuric ion
catalyzed addition, result in formation of the corresponding ketone.

1) HB 2 HgSO4/ OH
R H2O/ H2SO4 C
OH R C C H R CH2
2) H2O2, NaOH, H2O

H O
R C
O R CH3
aldehyde ketone

187
Veljko Dragojlovic

Hydrogenation of Alkynes
Alkynes readily undergo catalytic hydrogenation. Since they are less hindered than alkenes,
they are more reactive. However, as both classes of compounds are highly reactive, usually it is not
possible to stop the reaction after an alkyne has been hydrogenated to the corresponding alkene and the
alkene is hydrogenated further to the H2, Pt/C
H2, Pt/C
corresponding alkane.
In order to selectively reduce an
alkyne to the alkene without formation of the alkane, we reduce the activity of the catalyst by adding a
catalytic poison (usually a nitrogen containing aromatic compound such as pyridine or isoquinoline).
An example of such poisoned catalyst is Lindlar catalyst, which consists of palladium on calcium
carbonate that has been treated with lead acetate and an amine. A poisoned, or deactivated, catalyst is
less reactive and will not catalyze hydrogenation of alkenes, while it is still reactive enough to catalyze
reduction of alkynes. Since addition of hydrogen is syn (both hydrogens are added from the same side)
the reaction is stereoselective and results in formation of a cis alkene. This is yet another application of
the reactivity –selectivity principle. This time we intentionally reduce reactivity of the catalyst in order
to make it more selective. With such deactivated catalyst, a triple bond can be reduced in the presence
of a double bond. This type of selectivity is called chemoselectivity (one functional group reacts while
another functional group
elsewhere in the molecule is
not affected).
H2, Pd, pyridine N N
cis-2-pentene pyridine isoquinoline

H2, Pd, pyridine

Dissolving Metal Reduction: Reduction of Alkynes


In a dissolving metal reduction an active metal (a very reactive metal such as lithium, sodium,
or magnesium) is added to the substrate, in this case an alkyne. In the course of the reduction, the metal
is oxidized to the corresponding ion and dissolves in the reaction mixture. That is why the reaction is
called a dissolving metal reduction. The
reaction is carried out in ammonia as a solvent. Na/ NH3, -78°C
At room temperature ammonia is a gas. That is
why the reaction has to be performed at a low trans-2-pentene
temperature (-78°C) at which ammonia is a
liquid.
The reaction mechanism involves a transfer of an electron from the metal to the alkyne to give
the intermediate radical anion (a species that is both a free radical and an anion). Such carbanion is a
strong base and, as a base, it deprotonates ammonia to give the intermediate vinylic radical. The
vinylic radical takes an electron from another metal atom to give the vinylic anion, which in the final
step deprotonates ammonia to give the final product – an alkene.

188
Chapter 10. Reactions of Alkynes

H
Na H NH2

a radical anion a vinylic


radical
Na
H H
H2N H

Dissolving metal reduction is stereoselective reaction and a trans alkene is preferentially


formed. The reason for it is that in the intermediate carbanion, trans form is preferred over cis due to
steric hindrance in the latter. Note that dissolving metal reduction gives trans alkenes while catalytic
hydrogenation gives cis alkenes.
H CH3 H
C C vs. C C
H3C H3C CH3

steric hindrance

Oxidation of Alkynes
Alkynes are oxidized by permanganate, under mild conditions, to give the corresponding
diketones. A more vigorous ozonization oxidatively cleaves alkynes to the corresponding carboxylic
acids. Note that, unlike ozonization of alkenes, in the ozonization of alkynes there is no need for an
oxidative or reductive work up. Hydrolysis of the intermediate ozonide with water gives the carboxylic
acids. A terminal carbon atom of an alkyne is oxidized to carbon dioxide.

OH
KMnO4, H2O, r.t., pH = 7

O O O

OH

1) O3 OH HO
+
2) H2O O O

O
1) O3
OH + CO2
2) H2O

189
Veljko Dragojlovic

A smallest ring that can accommodate a triple bond is an eight-member ring. Ozonization of
cyclooctyne gives suberic acid.

1) O3 O
2) H2O HO
OH
O

190
Chapter 11. Stereochemistry

CHAPTER 11.

Stereochemistry
Study of molecules in three dimensions.
___________________________________________________________________________

tereochemistry is a study of structure of molecules in three dimensions, and effect of that


structure on the physical and chemical properties of molecules.

Review of Isomerism
Compounds that have the same molecular formula but different structural formulas are called
isomers. The two main types of isomers are:
Constitutional isomers, and
Stereoisomers.

Constitutional Isomers (Structural Isomers)


Constitutional isomers have the same molecular formula, but the connections among their
atoms are different. In organic molecules we can recognize three types of constitutional isomers (old
term is structural isomers):

Skeletal isomers, in which the carbon skeletons of the compounds differ.


Positional isomers (Regioisomers), in which the carbon skeletons are identical, but the positions of
functional groups are different.
Functional isomers, in which the functional groups differ.
skeletal isomers

CH3CH2CH2CH2CH3 and (CH3)CH2CH2CH3

positional isomers

CH3CH2CHOHCH2CH3 and CH3CH2CH2CH2CH2OH

functional isomers

CH3CH2CH2OCH2CH3 and CH3CH2CH2CH2CH2OH

It is helpful to use line formulas to identify isomers and type of isomerism:


OH
OH O OH
skeletal isomers positional isomers functional isomers

193
Veljko Dragojlovic

Stereoisomers
Stereoisomers have the atoms connected in the same way and, therefore, have the same
structural formula, but they differ in the positions of the atoms in space.
Stereoisomers belong to two classes:
• Conformational isomers, and
• Configurational isomers.

Configurational isomers are further divided into:


• Geometric isomers (cis/trans isomers), and
• Optical isomers.

Conformational Isomers
Conformational isomers, or just conformers, can be interconverted by bond rotation. Since
individual conformers are readily interconverted into one another at a room temperature, they cannot
be separated and isolated. For that reason, usually conformers are not considered to be true isomers.
We studied them in Chapter 4.

Configuration and Configurational Isomers


Three dimensional structure of a molecule is called its configuration. Geometrical (cis/trans
or (E)/(Z)) isomers have the same formula and connections between atoms but have different three-
dimensional structures because of the way that groups are attached to different sides of a double bond
or a ring. This type of isomerism arises due to restricted rotation about a carbon–carbon bond (either a
single, or a double bond). We studied geometrical isomers in Chapter 5.
Optical isomerism occurs when a molecule is nonsuperimposable on its mirror image, and
always occurs in molecules that contain a chirality center. An example of a chirality center is a carbon
atom with four different substituents. Optical isomers have identical properties except that they rotate
plane-polarized light in opposite directions, and that they react differently with other optically active
compounds. Although the optical isomers may appear to be identical, they are non-superimposable
mirror images of each other.
Usually, only the configurational isomers are considered to be true stereoisomers and
sometimes the term stereoisomers applies to them only. Another division of configurational isomers is
into enantiomers (stereoisomers that are mirror images of each other) and diastereomers
(stereoisomers that are not mirror images of each other).

ISOMERS

CONSTITUTIONAL STEREOISOMERS

POSITIONAL
SKELETAL (regioisomers) FUNCTIONAL CONFIGURATIONAL CONFORMATIONAL

GEOMETRICAL OPTICAL

194
Chapter 11. Stereochemistry

Chirality
Chirality in Nature
Objects found in nature may or may not be identical with their mirror images. Those that are
not identical to their mirror images are said to be chiral. Objects identical to their mirror images are
achiral (non-chiral). Besides an object, a process as well as a function may be chiral.

Chiral Objects

A large number of everyday objects are chiral. In general, if we can distinguish a “left” and a
“right” forms (even if we don’t call them left and right) of an object, it is chiral. Thus, for example a
shoe is chiral, while a sock is not. Gloves, such as driving gloves are chiral, while inexpensive
protective gloves (which fit on either hand) are not. Screws are chiral, with most of them being “right”
– with an ordinary screwdriver, we use our right hand and turn clockwise to screw them in. Sometimes
it is not obvious that an object is
chiral. For example, an ordinary
pencil appears to be achiral – it
fits equally well in either right or
left hand. However, a closer en
cil
inspection reveals that, it there is
p
cil
l
ira
en
an inscription on it, it is chiral. ch
l p
ira
Thus, pencils are made for right ch
handed people. When a pencil is
held in a right hand, the
inscription is the correct side up
and reads from left to right. When
held in a left hand, the inscription
is up side down and reads from
right to left.
There are numerous examples of chirality in living organisms from the simplest organisms to
humans. Bacteria Bacillus subtillis forms right-handed spiral colonies. Almost all species of snail, with
a few exceptions, coil in form of a right handed screw. Only a few individuals coil in the mirror image
form as a result of genetic mutation. Chirality in plants is most readily observed on plants that coil
around other objects as they grow. Individual species of such plant exhibit a preferred direction of
coiling – either to the right or to the left. Humans are obviously chiral. Our heart and spleen are on the
left side, while the liver is on the right.

Functional Chirality

Humans are either left, or right handed, with a marked preference for right-handedness. A
preference for using one hand over the other is an example of functional chirality. Very few people are
functionally achiral (ambidextrous).

195
Veljko Dragojlovic

Chiral Processes

A number of processes can be considered to be chiral processes. For example, imagine that
you are driving a car in a large empty parking lot. Suddenly a large stone, maybe a meteorite, falls in
front of your car. To avoid it, do you stir to the right, or to the left? You should answer this question
without much thinking – follow your instinct. If you are like most people, you would steer to the right.
This is an example of a chiral process. Spin of Earth is another example of a chiral process.
A number of chemical reactions are chiral processes.

196
Chapter 11. Stereochemistry

Chirality of Subatomic Particles and Atoms


Elementary particles, such as electrons, are spheres and, therefore, are not chiral:

Electron has a spin, which can be crudely described as rotation of an elementary particle
about its axis. For an electron, there are two possible spin orientations. However, even electrons with
opposite spins are not chiral. One can be superimposed on another simply by turning it up side down.
Therefore, two electrons at rest are not chiral, even if they have opposite spins.

However, if electrons are moving, then electrons with opposite spins cannot be superimposed
and they are two non-superimposable mirror images. Thus, they are chiral. They are related to each
other as left and right screw.

Therefore, electron at rest is not chiral, while electron that is moving is.
Chirality of subatomic particles and atoms is mainly of interest to physicists. From a
chemists’ point of view, atoms and electrons are achiral. Chemists are concerned with chirality of
molecules.

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Veljko Dragojlovic

Chirality of Molecules: Optical Isomerism and Optical Activity


An optically active material rotates the plane of polarized light. Optical isomers differ with
respect to their interaction with polarized light. Except for their interaction with polarized light and
each other, optical isomers are chemically and physically identical. This type of isomerism is also
called chirality (chirality – handedness) and a molecule that exhibits such type of isomerism is a chiral
molecule. In chiral molecules, all the connectivities between the atoms are the same. However, the
arrangement of atoms in space is different and the isomers cannot be interconverted by bond rotation.
The shapes of isomers of chiral molecules are related as two non-superimposable mirror images.

Superimposability and Chirality


Saying that two molecules are superimposable is the same as saying that they are identical.
Therefore, two molecules of any single compound are superimposable. Isomers of any type, including
conformational isomers are nonsuperimposable. Isomers that are related to each other as
nonsuperimposable mirror images are optical isomers or enantiomers. They exhibit a property called
chirality.
H H H Br H H H Br
isomers are
nonsuperimposable
Br Br Br H Br Br Br H

CH3 CH3 H3C CH3


identical molecules
H H H H are superimposable
Cl Cl Cl Cl
Br Br Br Br

CH3 CH3 H3C CH3


nonsuperimposable
mirror images are
H H H H optical isomers
Cl Br Cl Br or enantiomers
Br Cl Br Cl

If an object that has a mirror plane through it, it is superimposable on its mirror image and
therefore non-chiral (achiral). Objects (including molecules) are either chiral or not. A molecule is
achiral (non-chiral) as long as at least one of its energetically accessible conformations has a mirror
plane or symmetry, even if other more stable conformations lack such a plane. Such symmetrical
conformation does not have to be a stable, or a low energy, conformation. Therefore, two molecules
are superimposable if a conformation (of any energy, including high energy conformations – for
example, eclipsed conformations of alkanes or boat conformations of substituted cyclohexanes) exists
in which each substituent of one molecule can be placed over the same substituent of the other
molecule. Note that a high energy conformation is usually more symmetrical compared to a low energy
conformation.
The ultimate test of whether two molecules, which are mirror images of each other, are
enantiomers is their nonsuperimposability. Therefore, one can make models of the two mirror images

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Chapter 11. Stereochemistry

and compare them. It is not always feasible to make models of the two isomers. A molecule has a
nonsuperimposable mirror image if it lacks the following three elements of
symmetry: OH

1) Plane of symmetry. A plane of symmetry reflects one half of the


molecule into another. The two halves are mirror images of each C
other. For example, a compound with two identical substituents on a H
carbon atom, such as molecule of ethanol, has a plane of symmetry H3C
and is achiral. H

OH OH
2) Center of symmetry. Center of symmetry H H
is a point. A line drawn from an atom, or a
group, through that point and extended an CH3 H3C
equal distance beyond it meets an identical H H
atom, or a group. For example, the cyclic H H
compound shown below is not chiral due CH3 CH3
to the presence of a center of symmetry.
H H
OH OH
3) Alternate axis of symmetry. An alternate axis of symmetry is an axis that is perpendicular to the
plane that divides the molecule into two halves. Rotation
of the molecule around the axis, by any suitable angle, OTs
followed by reflection through the perpendicular plane H CH3
gives the molecule that is identical to the starting one. Of CH3
the three symmetry elements, this one is the most difficult N H
to identify. Compared to the first two symmetry elements, H
it is relatively rare. The compound shown above, in H3C CH3
H
addition to center of symmetry, has an alternate axis of
symmetry (rotation by 180º followed by reflection through a plane that bisects the molecule). The
compound shown below is not chiral due to the presence of an alternate axis of symmetry.

Lack of the above symmetry elements is an indication that a compound is chiral. When testing
whether a molecule is chiral, one should check for possible presence of the three elements of symmetry
listed above. Only if all three are absent, one can conclude that the molecule is chiral. In this course,
you should concern yourself only with the most common cases of compounds that are chiral due to the
lack of a plane of symmetry, or achiral due to its presence. Compounds that are achiral because of the
presence of a center of symmetry, or an alternate axis of symmetry, are considerably less common.

Isomers with One Center of Chirality


Molecules that have a chirality center are chiral. Usually chirality center overlaps with an
atom. Chirality centers that overlap with atoms are sometimes called chiral atoms (although an atom
cannot be chiral), chiral centers, asymmetric atoms, stereogenic centers or stereocenters. Most of those
terms are obsolete, but a number of them are still in use.
The most common cause of chirality in an organic molecule is the presence of a carbon atom
bonded to four different substituents. An sp3 hybridized atom has three-dimensional structure

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Veljko Dragojlovic

necessary to be the chirality center provided that the four


substituents are different. One should keep in mind that chirality OH OH
is a property of the entire molecule (not individual atoms),
whereas a chirality center is the cause of chirality. Thus, optical C C
Cl Cl
isomers usually contain at least one carbon atom that is bonded to H3 C CH3
H H
four different substituents. Since there is no plane of symmetry,
such carbons are chirality centers. Chiral molecules have two mirror
nonsuperimposable mirror images called enantiomers.
An sp or sp2 hybridized atom has a mirror plane and cannot be a center of chirality. Thus,
alkenes, arenes and alkynes are not chiral. Exceptions are allenes, which have an axis of chirality, and
biphenyls, which may be chiral due to restricted rotation about a single bond (atropisomerism).
If you were to attempt to superimpose enantiomers
you will find that two groups can be placed in the same OH OH
orientation of both molecules (for example, the CH3 and OH
groups on the right) but the other two substituents (H and Cl) C C
Cl H
are reversed in their spatial orientation. H3C
H
H3C
Cl
Molecules that contain the central carbon bonded to a
less than four different groups are achiral because they contain a plane of symmetry in the plane of the
central carbon atom and two different substituents. These mirror images are superimposable
(identical). They may be rotated so that all substituents have the same spatial orientation in both
molecules.

OH OH OH OH

C C C C
H H or H H
H3 C CH3 H3 C H3 C
H H H H

mirror
two molecules of an identical compound

We indicate a chirality center by placing an asterisk next to it. Some examples of chirality
centers are shown below.

O O
∗ ∗
∗ ∗ ∗

2-methylcyclohexanone trans-1,2-dimethylcyclopropane
limonene carvone

O O

∗ ∗
∗ ∗ HO O-Na+
N NH2
O
monosodium glutamate (MSG)
coniine nootkatone

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Chapter 11. Stereochemistry

Enantiomers
As already mentioned, stereoisomers that are related to each other as two nonsuperimposable
mirror images are called enantiomers. Enantiomers can be interconverted only by breaking covalent
bonds.

OH OH

C C
H H
CH3CH2 CH2CH3
CH3 H3 C

mirror

Representations of Enantiomers in Two Dimensions


Formulas such as Lewis structures, or condensed structural formulas show connectivity in a
molecule, but do not show spatial arrangement of the atoms. To represent stereoisomers such as
enantiomers on paper (in two dimensions) we have to use formulas such as Perspective drawings or
Fischer projections. These formulas follow conventions that allow us to represent three dimensional
arrangement of atoms in two dimensions.

Perspective Formulas
Perspective formulas make use of dash and wedge bonds to indicate spatial arrangement of
atoms. Perspective drawing may be applied to both condensed structural formulas and line formulas. A
dash bond indicates an atom, or a group, that is below the plane of the drawing (plane of the paper). A
wedge bond indicates an atom, or a group, that is above the plane of the drawing. Examples of
perspective drawings of the two enantiomers of 2-pentanol are shown below. Note that with line
drawings we usually do not show hydrogen atoms that are bonded to carbon atoms. However, if their
stereochemistry is important they may be shown as in the middle structures. Alternatively, hydrogen
atoms may be omitted as in the structures on the right.

OH H OH OH
H2CH2CH3C C CH
3
H
OH HO H OH
H C CH
3
H2CH2CH3C

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Veljko Dragojlovic

Fischer Projections
CHO CHO
Chiral molecules may be represented by Fischer
Projection Formulas. They are especially useful for H OH H OH
representing molecules with multiple centers of chirality. In
a Fischer Projection, the chirality center is located at the CH2OH CH2OH
intersection of horizontal and vertical bonds. To represent
tetrahedral arrangement of the substituents, the chirality CH3 CH3
center is in the plane of the drawing, the vertical bonds
project away from the viewer and the horizontal bonds H Cl H Cl
project toward the viewer. This is the so-called “bow-tie
convention” (see the next page). Fischer Projections are CH2CH3 CH2CH3
drawn without the perspective wedge bonds illustrated
below, but the orientation of the vertical and horizontal CH3 CH3
groups relative to the chirality center is inferred. Carbon
chain, when shown, is oriented vertically and is in the plane Br H Br H
of the drawing.
H Br H Br

CH3 CH3

perspective Fischer
formulas projections

Bow-tie Convention

An easy way to remember which bonds in Fischer projection point towards and which ones
away from you is a bow-tie convention. When the two horizontal bonds are represented as wedge
bonds they resemble a bow-tie.

CH3 CH3

H C OH H OH

CH2CH3 CH2CH3
perspective drawing Fischer projection

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Chapter 11. Stereochemistry

“Small Animal” Convention

In a Fischer projection of a compound with two, or more, contiguous chirality centers, the
bond connecting them is drawn in the plane of paper. Horizontal bonds are still projecting towards the
viewer and the terminal vertical bonds are projecting away from the viewer. A way to memorize this is
a “small animal convention.” If you imagine someone throwing a small animal at you, its legs
(horizontal bonds) will project towards you, the body (vertical bond connecting two chirality centers)
will be in the plane of the drawing, while the head and tail (terminal vertical bonds) will point away
from you.

CH3 CH3

H C OH H OH

H C OH H OH

CH2CH3 CH2CH3
perspective drawing Fischer projection

Configuration of Chiral Compounds


Naming Enantiomers: The R,S System of Nomenclature
Configuration is a three-dimensional arrangement of substituents. Two enantiomers have
different configurations. The Cahn-Ingold-Prelog convention has been developed to assign
designation to each enantiomer. According to the convention, the four different atoms bonded directly
to the chirality center are assigned priorities based on a set of sequence rules for specifying
configuration:
1. Priority is assigned to atoms bonded to 8 H 2 H
carbon in the order of decreasing atomic O O
number (highest atomic number is
1 4
assigned the highest priority – priority 1, H 6 C H 3 C
H H
the lowest atomic number is assigned the C
Cl
C
Cl
lowest priority – priority 4). H 17 H 1
H H
atomic numbers priorities

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Veljko Dragojlovic

2. When two or more atoms of the same priority are bonded to the chirality center, there is a tie and
the rule 1 doesn’t work. To break the tie one should compare atomic numbers of the highest
priority atoms (atoms with the highest atomic numbers) bonded to the atoms involved in the tie
and, if necessary follow the atoms of the highest priority along the each respective chain, until
there is a difference. In the example shown below, there is a tie between the two carbon atoms
bonded to the chirality center. The path of highest priority in each case is C-C-F and C-C-Cl.
Therefore, the second chain has a higher priority (Cl higher atomic number than F).

2) The two atoms of the highest priority


bonded to the atoms involved in the tie
H H again have the same priority.
H
C
H C F H
3) Finally, there is a difference.
∗ Chlorine has higher priority than
C fluorine.
H
C Cl
1) These two Cl H
atoms have H H
the same
priority.

3. Multiple-bonded atoms are considered to be equivalent to the same number of single-bonded


atoms (“virtual atoms”).

Review: Cahn-Ingold-Prelog’s Virtual Atoms

To convert a substituent with multiple bonds into a substituent with single bonds and virtual
atoms follow these steps:
1) Redraw the Lewis structure of the substituent and represent all the bonds as single bonds.
2) Add “dangling bonds” to satisfy valence requirements of each atom. Thus, if carbon had a total of
4 bonds (σ and π) in the original substituent, it should now have four single bonds. If oxygen had
two, it should now have two single bonds and so on.
3) At the end of each dangling bond place a virtual atom. It is the atom that is at the other end of the
multiple bond.

4. Among the isotopes of an element, heavier isotope has higher priority.

To determine the configuration of a molecule, view it from the side


opposite the lowest priority substituent (it means that the lowest priority group 2
is projecting away from the viewer). Next, determine whether the remaining OH
three groups, from the highest to the lowest priority, form a clockwise (R) or
counterclockwise (S) array. If the order of the priorities around the chirality C 4
3
H
center from 1st to 3rd proceeds in a clockwise direction, the configuration is H3C
Cl
designated (R). If the sequence around the chirality center proceeds in 1
counterclockwise direction, the configuration is (S). Symbols (R) and (S) are
(S)-1-chloroethanol
derived from Latin: rectus – right, and sinister – left.

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Chapter 11. Stereochemistry

If you imagine that the substituents are three positions on a steering wheel, clockwise turn
would of the wheel result in a right turn of the car. Therefore, stereochemistry of the molecule is (R).
Conversely, a counterclockwise turn, which would result in a left turn of a car, indicates
stereochemistry that is (S).
If the lowest priority
group projects toward the viewer,
the same procedure may be
followed, but the direction of the 1 1
priority sequence must be
reversed because the structure is
being viewed from behind,
according to the Cahn-Ingold- 3 2
2 3
Prelog convention.

2
OH (S)- (R)-
1 [sinister] [rectus]
3 C left turn right
Cl
H3C
H
4
(R)-1-chloroethanol

Application of Fischer Projection Formulas

One can determine configurations of a molecule from its Fischer projection formula.
Configuration is determined by assigning priorities and
determining the direction of rotation around the chirality CHO CHO
center from priority 1 through 3 (as below). It is important
that the lowest priority group should be located on a H3C OH H3C OH
vertical bond (recall that a vertical bond projects away
from the viewer). In this case, it is projecting away from H H
the viewer and the direction of the priority sequence is
(S)-2-hydroxypropanal
determined by the substituents with priorities 1 through 3.
If the lowest priority group is on a horizontal bond, one or more of the allowed
transformations should be performed on the Fischer formula:
• Exchange of the position of two substituents in pairs. Positions of both pairs must be
exchanged simultaneously. Rotation by 180° also belongs to this category and therefore is
allowed transformation. Exchange in positions of only one pair of substituents will result in
the enantiomer of the original molecule and, therefore, is not allowed.
• Exchange of the positions of three substituents, clockwise or counterclockwise, while keeping
the fourth substituent in its original position.
Not allowed transformations are:
• exchange of positions of a pair of substituents, and
• rotation of the molecule by 90º.
Therefore, Fischer projections may be rotated by 180o in the plane of the paper but never
“removed from the plane of the paper” (flipped over horizontally or vertically) because that changes
the perspective. Allowed transformations amount to a rotation of the molecule, while not allowed
transformation amount to breaking of the bonds.

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Veljko Dragojlovic

Chiral Methyl Group


Since a methyl group contains three hydrogens bonded to a carbon, at first glance it appears to
be impossible to have a chiral methyl group. However, if you recall that hydrogen has three isotopes, it
becomes clear how a methyl group can be chiral. A methyl group that contains one atom of each
isotope of hydrogen is chiral. Such chiral methyl substituents are used in biochemical studies of
metabolic pathways. H H H H

D T T D
T T
R R
D D R R

Designating Configuration of Compounds with a Single Center of Chirality


When in a given formula the lowest
priority substituent does not point away from the CO2H H
viewer, one can redraw the formula so that in a
new representation such substituent is behind the H OH HO2C CH3
plane of the drawing. To do that one should use
only the allowed transformations described CH3 OH
earlier. Note that the allowed transformations
amount either to a rotation of the molecule in (R)-lactic acid
space, or to rotation about a single bond, but
2 4
never to breaking of a bond. Some examples are
shown below.
4 1 2 3

3 1

H3C H CHO CH3


H OH
H3C CO2H HO2C CHO
OH
COCH3 COCH3
(R)-2-butanol
(S)-
4 1 3 4
3 4

4 1 1 3
2 3 2 1

2 2

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Chapter 11. Stereochemistry

C N H

H2NH2C H H3CHNH2C C N

CH2NHCH3 CH2NH2
(R)-

2 4

3 4 1 2

1 3

CHO CH3

H3C CH2OH HOH2C CHO

CH2OCH3 CH2OCH3

(S)-
2 4

4 3 3 2

1 1

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Veljko Dragojlovic

Physical Basis of Optical Activity: Optical Rotation


As mentioned earlier, optical isomers differ with respect to their interaction with polarized
light. The extent and sign of rotation of an optically active material can be determined with the use of a
polarimeter. Polarimeter contains a source of monochromatic (a single wavelength) light. Usually it is
either a sodium, or a mercury lamp. The light emitted by the lamp is polarized by passing it through a
polarizer. A polarizer is either a Nicol prism, or, more commonly a Polaroid plate – similar to the one
used in Polaroid sun glasses. Polarized light next passes through an optically active solution and is
rotated either to the right or to the left. The light that reaches the eyepiece diminishes in intensity. By
rotating the analyzer (another Nicol prism, or Polaroid plate) so that it is aligned with new plane of
polarization of light, the initial intensity of the light is restored. The angle of rotation (α) can be read
from the scale.

graduated
scale
sodium
lamp polarizer
α
tube with an
optically active
compound

analyzer
eyepiece

Schematic of a polarimeter

The sign and magnitude of rotation depend on the nature of


the compound, its concentration, nature of the solvent, wavelength of
α α
light and temperature. There is no connection between the
configuration of a compound ((R)- or (S)-) and the sign of rotation (+)
or (-). An old convention denotes dextrorotatory and levorotatory
rotation with letters d and l, respectively. Those symbols should not be
mistaken for D and L symbols which were used to denote
configurations relative to glyceraldehydes, according to Fischer- levorotatory dextrorotatory
(-) (+)
Rosanoff convention. Absolute configuration and Fischer-Rosanoff (l) (d)
convention are discussed at the end of this chapter.

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Chapter 11. Stereochemistry

Optical Purity: Specific Rotation [α]λ


Specific rotation of a chiral compound is the rotation that was observed under the standard
conditions. Standard conditions are defined as sample cell of 10 cm (1 dm) length and concentration of
1 g/mL. Since the rotation also depends on the temperature and wavelength of light they also have to
be reported. Usually, measurements are done at 25ºC and a source of light is a sodium lamp with a
filter, which provides light of a single wavelength (589.6 nm).
observed rotation , [α]( o )
[α] Dt =
g
path length, l (dm) x concentration , c ( )
mL
D stands for the sodium D-line, λ = 589.6 nm

Sometimes, with the change in conditions (solvent, temperature, wavelength), the sign of
rotation may change, even though we are still dealing with the same enantiomer.

Properties of Enantiomers
Enantiomers differ only with respect to chirality. Therefore, they
differ from one another only in properties that are also chiral. Thus,
enantiomers rotate plane of polarized light in opposite directions. The
magnitude of the rotation, which is an achiral property, is the same.
Enantiomers react differently with other chiral molecules. Enzymes and
various receptors on surfaces of cells are chiral. Thus, enantiomers have
different physiological effects. For example, (R)-limonene has fragrance of (R)-limonene (S)-limonene
(orange) (lemon)
orange, while (S)-limonene has a fragrance of lemon. Another example are
amino acids. While natural L-amino acids have “meaty” taste, non-natural
D-amino acids have bitter taste.

Natural and Nature Identical


Natural materials are frequently, but not always single enantiomers. Thus, synthetic vitamins may not
be single enantiomers (synthetic vitamin E is a mixture of D and L α-tocopherols). A nature identical
material is, as the name indicates, identical to the natural material even if it is made in a laboratory.
Thus, nature identical is a single enantiomer if naturally occurring material is also a single enantiomer
(for example commercially available vitamin C, ascorbic acid, is a nature identical product).
Interestingly, “natural” is not necessarily nature identical! Retailers are allowed to use label “natural” if
the material is obtained from a natural source, prepared from a natural starting material, or made by
natural means – such as genetically engineered bacteria. Thus, vitamin E sold as “natural” is a single
enantiomer of α-tocopherol. Naturally occurring vitamin E is a mixture of several tocopherols (α−, β−,
γ− and δ−), and its actual composition depends on the source.

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Veljko Dragojlovic

Racemic Mixture
A racemic mixture, or a racemate, is composed of equal amounts of the two enantiomers.
Note the difference between a racemic mixture and an achiral compound. Neither rotates the plane of
polarized light – neither is optically active. However, a racemic mixture is composed of chiral
molecules. It just happens that the two enantiomers are present in an equal amount and their rotations
cancel out. Symbols for a racemic mixture are (±) or (d,l). For example (±)-lactic acid, or (d,l)-2-
butanol. Thus, a racemic mixture is not optically active because it is composed of chiral molecules,
while an achiral compound is not optically active because it is composed of achiral molecules.
Therefore, the fact that a compound is not optically active does not mean that it is not chiral.
Properties of racemic mixtures are sometimes different from those of the individual
enantiomers. Thus, a racemic mixture of a solid may have different melting point, or a different
solubility, compared to pure enantiomers. Properties of racemic mixtures in a gas phase, a liquid phase
and a solution are usually identical to those of pure enantiomers.

Optical Purity and Enantiomeric Excess


Optical purity of a mixture is the ratio of its rotation to the rotation of a pure enantiomer
expressed as a percent.
observed specific rotation
optical purity = x 100%
specific rotation of the pure enantiomer

Enantiomeric excess of a mixture is the ratio of the amount of the excess of the predominant
enantiomer over the minor one to the entire mixture.
[p] - [q]
enantiomeric excess = x 100% p and q are a pair of enantiomers
[p] + [q]

Note that both optical purity and enantiomeric excess have the same values and neither has
units (they cancel out in the course of calculation). For example, pure (S)-(+)-monosodium glutamate
(MSG) has a literature value for specific rotation of [α]D=+25.5º. If a sample of monosodium
glutamate has [α]D=+20.4º, then optical purity and enantiomeric excess are:
+ 20.4 o
optical purity = × 100% = 80%
+ 25.5 o
Therefore, in the mixture, (S) enantiomer is in 80% excess and it is called the enantiomeric
excess. Remaining 20% of the mixture is a racemic mixture (10% (R) enantiomer and 10% (S)
enantiomer). It means that the mixture contains a total of 90% of (S) enantiomer and 10% of (R)
enantiomer. If you knew in advance that a mixture contained 90% of (S) enantiomer and 10% of (R)
enantiomer, you could have calculated the enantiomeric excess:

90 − 10
enantiomeric excess = × 100% = 80%
90 + 10
and from the enantiomeric excess the expected rotation of the mixture:

[α]D= (enantiomeric excess/100) x (rotation of pure enantiomer) = (80/100) x (+25.5º) = +20.4º

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Chapter 11. Stereochemistry

Calculations of optical purity and enantiomeric excess can be applied only to mixtures of
enantiomers. They cannot be applied if other chiral compounds are also present.

Isomers with more than One Chirality Center


Diastereomers
Molecule with one chirality center has two isomers (enantiomers). A molecule with n
chirality centers can have a maximum of 2n isomers (enantiomers and diastereomers combined). This
is called van’t Hoff rule. Diastereomers are stereoisomers that are not mirror images of each other.
Note that van’t Hoff rule (2n) gives the maximum number of isomers, the actual number may be less
than that.

n=2; 2n = 22 = 4

Fischer Projections are convenient to represent molecules with Cl Br


more than one center of chirality. The following projections represent the ∗ ∗
two enantiomers of 2-bromo-3-chlorobutane. Note that in the pair of H3 C CH CH CH3
enantiomers the orientation of the groups on both horizontal bonds are
reversed.

CH3 CH3 CH3 CH3


R S S R
Br H H Br H Br Br H
R S R S
H Cl Cl H H Cl Cl H

CH3 CH3 CH3 CH3

all four isomers of 2-bromo-3-chlorobutane

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Veljko Dragojlovic

CH3 CH3 CH3 CH3


S R
H Br Br H H Br Br H
R S
H Cl Cl H H Cl Cl H

CH3 CH3 CH3 CH3

a pair of enantiomers

Stereoisomers with more than one center of chirality that are not mirror images of each other
are diastereomers. Diastereomers have different physical and chemical properties.

CH3 CH3

Br H Br H

H Cl Cl H

CH3 CH3

a pair of diastereomers

Diastereomers

The proper term for diastereomer is diastereoisomer, which originates from Greek: δια -
through; στερεος - space; ισος - equal; μερος -part (or isomers through space). In the past, the term
diastereoisomer was abbreviated as diamer, but that was too similar to the term dimer and, hence, that
abbreviation was abandoned. Nowadays, we abbreviate diastereoisomer as diastereomer.

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Chapter 11. Stereochemistry

Erythro/Threo Isomerism
CHO CHO
A type of isomerism that exist in compounds with
two contiguous (neighboring) chirality centers is called H OH HO H
erythro/threo isomerism. It is named after monosaccharides
erythrose and threose. In a Fischer projection erythro H OH H OH
isomer has identical, or similar, substituents on the same
side of the chain, while the threo isomer has them on the CH2OH CH2OH
opposite sides.
erythrose threose

diastereomers

CH3 CH3 CH3 CH3

Br H H Br H Br Br H

H Cl Cl H H Cl Cl H

CH3 CH3 CH3 CH3

threo pair of enantiomers erythro pair of enantiomers


(similar groups are on the opposite sides) (similar groups are on the same side)

Erythro and threo isomers of 2-bromo-3-chlorobutane

Note that Fischer projection formulas of compounds with more than one chirality center,
show compounds in their less stable, eclipsed, conformations. Erythro and threo isomers may be more
difficult to recognize when they are represented by perspective drawings of staggered conformations.
If you cannot visualize it, or cannot work it out on paper, you should make a model. After you make a
model, rotate the bonds so that the substituents are in the eclipsed conformation. Now look at it as if
you wanted to draw Fischer projection ("small animal convention").

H3C H H CH3 H3C H H CH3


Br Br Br Br
C C C C C C C C
Cl Cl H H
H CH3 H3C H Cl CH3 H3C Cl
Br Br Br Br

Cl Cl Cl Cl
erythro pair threo pair

Perspective drawings of staggered conformations of erythro and threo isomers.

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Veljko Dragojlovic

When the two chirality centers are not next to each other, Cl Br
erythro/threo isomerism is not possible. However, there are still up
to four possible isomers (two pairs of enantiomers). An example of ∗ ∗
H 3C CH CH2 CH CH3
such compound is 2-bromo-4-chloropentane.

CH3 CH3 CH3 CH3

H Br Br H H Br Br H

CH2 CH2 CH2 CH2

H Cl Cl H Cl H H Cl

CH3 CH3 CH3 CH3

Chirality of Cyclic Compounds

Cyclic compounds are more symmetrical than acyclic ones. When considering
stereochemistry of cyclic compounds we usually represent them as planar rings. That is the most
symmetric (and highest in energy!) conformation. Such representations are called Haworth’s
Projections. They allow us to easily determine if a cyclic compound contains a plane or a center of
symmetry. In the examples of cyclic compounds below, each of the compounds contains a plane of
symmetry as shown and is not chiral.

OH H
Cl Cl Cl OH OH H

H OH H H H Cl
H H

The following are examples of chiral cyclic compounds. Each of them has two chirality
centers.
Br Cl Cl Br Br H H Br

H H H H H Cl Cl H

Cl Cl H H
Br Br Cl Cl

H H Br Br
H H H H

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Chapter 11. Stereochemistry

Meso Compounds: Tartaric Acid


Compounds that are achiral (non-chiral) and yet contain chirality centers are called meso
compounds. A molecule may have a maximum of 2n possible stereoisomers (including enantiomers
and diasteriomers) where n is the number of chirality centers. Existence of a meso form reduces the
number of possible stereoisomers. Molecules with multiple centers of chirality with a plane or a center
of symmetry (that would be a horizontal plane of symmetry in a Fischer projection) are meso
compounds. They do not rotate plane-polarized light (they are optically inactive or achiral) and they
are identical to their mirror images because they can be superimposed by a 180° rotation of one
structure in the plane of the paper. Note that a 180° rotation is an allowed transformation of a Fischer
Projection Formula.
In a molecule that has two contiguous (neighboring) centers of chirality a meso form exists if
both chirality centers have the same set of substituents. Some examples are 2,3-butenediol, 2,3-
dibromobutane and tartaric acid.
CH3 CH3 CH3 CH3

H OH HO H H OH HO H plane of
symmetry
HO H H OH H OH HO H

CH3 CH3 CH3 CH3


pair of enantiomers meso-form (two molecules of an identical compound)
2,3-butenediol

CH3 CH3 CH3 CH3

Br H H Br H Br Br H

H Br Br H H Br Br H

CH3 CH3 CH3 CH3

enantiomers meso isomer


2,3-dibromobutane

CO2H CO2H CO2H CO2H

H OH HO H H OH HO H

HO H H OH H OH HO H

CO2H CO2H CO2H CO2H

enantiomers meso isomer


tartaric acid

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Veljko Dragojlovic

Meso forms also exist in cyclic compounds. When chirality centers of a cyclic compound
have the same set of substituents, one should check if the cis isomer is also the meso form of the
compound. Haworth projections are suitable for that purpose.

Br H H Br H H

H Br Br H Br Br
trans-1,2-dibromocyclohexane cis-1,2-dibromocyclohexane
pair of enantiomers meso isomer

Br
H H H Br

Br Br Br Br H
Br Br
cis-1,2-dibromocyclohexane: cis- and trans-1,4-dibromocyclohexane
there is no plane of symmetry in the not chiral and not meso isomers
chair conformation, but there is a plane
of symmetry in the boat conformation.

You should be able to distinguish between cyclic compounds that are achiral because they are
meso compounds and those that are achiral because they do not contain any chirality centers.

OH H
OH H H OH OH OH OH OH

H OH
H OH OH H H H H H
trans cis cis trans
(pair of enantiomers) (meso compound) (no chirality centers)

three isomers two isomers

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Chapter 11. Stereochemistry

Nomenclature of Isomers with more than One Chirality Center


When naming compounds with two, or more, chirality centers we have to indicate
configuration of each chirality center. Therefore, we assign configuration to each of the centers and list
them in parenthesis before the name of the Cl H
H3 C H3 C
compound. Thus, if the relative configuration H CH3
of the carbon 2 in 3-chloro-2-butanol is (S) H C C H
C C
and that of the carbon 3 is (R), its complete HO CH3 HO Cl
name is (2S,3R)-3-chloro-2-butanol. As was rotation about this bond (2S,3R)-3-chloro-2-butanol
the case with compounds that contained a
single chirality center, sometimes it is 1 4

necessary to rotate the bonds in the molecule 4 3


2 C 2 C
in order to determine the configuration of
each center. 3 1

CH3 H

H OH HO CH3

H Cl Cl CH3

CH3 H
(2S,3R)-3-chloro-2-butanol

If there is a possibility for existence of a meso compound, the meso form always has the (R,S)
configuration, while the enantiomers are (R,R) and (S,S) pair.

CO2H CO2H CO2H

H OH HO H H OH

H OH H OH HO H

CO2H CO2H CO2H


(2R,3S)-tartaric acid (2S,3S)-tartaric acid (2R,3R)-tartaric acid
meso form pair of enantiomers

Separation of Enantiomers
Separation of a racemic mixture into individual enantiomers is called the resolution of a
racemic mixture. Some of the methods for resolution of a racemate are conversion to diastereomers
and separation of them, chromatographic separation, biochemical resolution and mechanical
separation.

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Veljko Dragojlovic

Conversion to Diastereomers
Unlike enantiomers, which differ only with respect to interaction with polarized light and
other chiral materials, diastereomers are isomers that have different chemical and physical properties.
Therefore, a mixture of diastereomers is much easier to separate compared to a mixture of enantiomers.
A number of naturally occurring molecules are available as pure single enantiomers. When a
racemic mixture is allowed to react with such chiral molecule (called the resolving agent), a pair of
diastereomers is formed.

(R)-A (R,R)-A⎯B (R,R)-A⎯B (R)-A


separation removal of the
+ (R)-B + + resolving agent
(S)-A resolving (S,R)-A⎯B (S,R)-A⎯B (S)-A
agent separated
diastereomers
racemic enantiomers
mixture

Diastereomers are separated by physical methods (such as crystallization or chromatography).


Finally, in another reaction, the resolving agent is removed and the pure enantiomer is isolated.
Common resolving agents are various alkaloids (strychnine, brucine, morphine and quinine) and acids
(mandelic, tartaric, as well as various amino acids)

CO2H

H CH3
O O O O
NH2 NH3 NH3

H CH3 H3C H H CH3 H CH3 H CH3

+ + +
CO2H

H3C H
1) separation of
diastereomers
2) HCl hydrolysis
of salts

CO2H CO2H
racemic mixture
H3C H H CH3

pure enantiomers

218
Chapter 11. Stereochemistry

Chromatographic Separation
Chromatography is a group of techniques based on selective partitioning of material between
two phases – a stationary phase (a liquid or a solid) and a mobile phase (a gas or a liquid). A mixture to
be separated is applied to a stationary phase and a mobile phase is allowed to flow past it. Each
component of the mixture adsorbs on the stationary phase and dissolves in the mobile phase to a
different extent. Compounds, which are adsorbed less tightly to the stationary phase and which are
more soluble in the mobile phase, travel further than other components. We say that such compounds
have lower retention times (are retained by the stationary phase for a shorter time).
In order to separate a racemic mixture into individual enantiomers, one has to use stationary
phase made of a chiral material. A chiral stationary phase interacts differently with each of the
enantiomers. It forms stronger intermolecular interactions with one enantiomer than with the other one.
Thus, the enantiomer that forms weaker interactions is eluted first followed by the other enantiomer.
Some of the chromatographic methods that are used to identify and separate enantiomers include
column chromatography, thin layer chromatography, gas liquid chromatography (GLC) and high
performance liquid chromatography (HPLC). Various carbohydrates, including paper (cellulose), are
among the suitable chiral stationary phases.
1) Racemate is 2) Column is eluted 3) Solution of each
applied on a with solvent enantiomer is
chiral stationary (mobile phase). collected separately.
phase.

plate is
eluted with
solvent
bands of
separated
enantiomers
racemate applied separated
on a chiral enantiomers
stationary phase

thin layer chromatography


column chromatography

Biochemical Resolution
Living organisms may metabolize only one enantiomer. Thus, when they are fed a racemic
mixture, one enantiomer is digested while the other one is unaffected. The method has some
disadvantages. Since one enantiomer is destroyed in the process, half of the starting material is lost.
Furthermore, the enantiomer that is left may not be the desired one (often the biologically active
enantiomer is the one that is desired). Usually, the living organisms that are employed are bacteria and,
once suitable bacteria are found, the process may be highly efficient.

219
Veljko Dragojlovic

An example of early biochemical resolution of enantiomers involved feeding racemic sodium


phenyl-γ-butyrate to a dog and isolation of a mixture that contained an excess of (-)-enantiomer from
its urine published in the Archiv für die gesamte Physiologie des Menschen und der Tiere (Thierfelder
and Schempp, Arch.ges. Physiol., 167, 280 (1917)).

Mechanical Separation
This is the earliest method for resolution of enantiomers. If a racemic mixture is allowed to
crystallize at a low temperature, individual enantiomers may crystallize separately. The crystals are
then mechanically separated from each other with an aid of a pair of tweezers and a microscope. In the
very first separation of a racemic mixture into enantiomers, Louis Pasteur applied this method on
racemic sodium ammonium salt of tartaric acid in 1848. Only a few racemic mixtures can be resolved
by this method. In addition, considerable time and skill are required. Thus, while this method is
historically important, it is no longer in use.

Absolute Configuration
Absolute configuration is the actual orientation of atoms at a chirality center. To know
absolute configuration of a compound is to be able to assign a particular formula to it. For example, if
we have two bottles of 2-butanol, one is pure (+)-2-butanol and the other one is (–)-2-butanol. How do
we know which one is (S) and which one is (R) enantiomer? Sign of the rotation is not related to
absolute configuration. Until mid-XX century absolute configurations of chiral compounds were not
known. Early in the XX century, after some debate, an arbitrary Rosanoff’s convention was adopted.
The convention was based on configuration of glyceraldehydes as a standard. Rosanoff assigned to
(+)-glyceraldehyde the Fischer projection in which the hydroxyl group was on the right (now it is
called (R) configuration, or, according to the old nomenclature, D configuration) and the (-)-

220
Chapter 11. Stereochemistry

glyceraldehyde one with hydroxyl group on the left ((S) configuration, or L). There was no particular
reason for such assignment. Rosanoff had 50% odds of guessing it correctly. Other chiral compounds
were assigned configurations relative to glyceraldehydes through chemical reactions of known
stereochemistry. Interestingly, at the time Fischer was opposed to Rosanoff’s proposal and yet, today,
this convention is often called Fischer convention, or Fischer-Rosanoff convention. Emil Fischer
established structure of D-glucose. Glucose is a carbohydrate with six carbon atoms and four chirality
centers. Therefore, there are 16 possible isomers, or 8 pairs of enantiomers. Since, at the time, it was
not possible to establish absolute configuration, Fischer was able only to prove that D-glucose is one of
the two enantiomers. He than made a guess that D-glucose has a formula on the left.

CHO CHO

CHO CHO H OH HO H

H OH HO H HO H H OH

CH2OH CH2OH H OH HO H
(+) (-)
H OH HO H
(R)-glyceraldehyde (S)-glyceraldehyde
or or
D-glyceraldehyde L-glyceraldehyde CH2OH CH2OH
D-glucose
(Fischer's guess)

In 1951, Bijvoet and co-workers were able to determine the absolute configuration of (+)-
sodium rubidium tartarate, whose configuration relative to glyceraldehyde was known, by using a
special X-ray diffraction technique called anomalous dispersion. They showed that both Rosanoff and
Fischer guessed correctly.

221
Chapter 12. Substitution Reactions of Alkyl Halides

CHAPTER 12.

Substitution Reactions of Alkyl Halides


Reactions at an sp3 hybridized carbon.
___________________________________________________________________________

ubstitution is a replacement of one arom, or group, by another. Usually, it is an electronegative


atom, or group, that is replaced by another electronegative atom or group.

RCH2CH2 L + :Nu RCH2CH2 Nu+ :L

Organic reactions can be divided into two large groups – those that form new carbon–carbon
bonds and those that convert one functional group into another (Functional Group Interconversions).
Most of the substitution reactions studied in this chapter belong to Functional Group Interconversion
(FGI) reactions.

Reactivity Considerations
In a substitution reaction, a leaving group (L) is replaced
H
by a nucleophile (Nu). Leaving group is an electronegative atom, or δ+ δ− L - leaving group
a group. The carbon–leaving group bond (C–L bond) is polarized, R C L(X)
H X = F, Cl, Br, I
with carbon being a positive end of the dipole. Therefore, carbon
atom is electron deficient. Some of the most common leaving substitution bimolecular
groups are halogen atoms. A symbol for halogen atoms is X.
Substitution reactions are another example of nucleophile-
electrophile reactions. In this case the electrophile is carbon atom that carries
S 2 N
a partial positive charge. There are two general mechanisms for a nucleophilic
nucleophilic substitution reaction. The first one is a single step reaction in
which formation of the carbon-nucleophile bond occurs simultaneously with breaking of the carbon–
leaving group bond (1). Such mechanism is called SN2 (Bimolecular Nucleophilic Substitution)
mechanism. In an
alternative mechanism, the H H
carbon–leaving group bond δ+ δ-
is broken in the first step to (1) Nu: + R C L R C Nu + :L
give the intermediate
carbocation, which in the H H
next step combines with the R R R
nucleophile to give the δ+ δ-
substitution product (2). (2) R C L + :L R C Nu
That mechanism is called R R
R R
S N1 (Unimolecular
Nucleophilic Substitution) Nu:
mechanism.

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Veljko Dragojlovic

Reactions of Chiral Compounds


Reactions of Substituents away from the Chirality Center
Reactions of the substituents that are not bonded to a chirality center do not change spatial
arrangements of the substituents on it. Thus, we say that both the reactant and the product have the
same relative configuration. Such reactions are said to proceed with retention of configuration.
However, designation of configuration may, or may not, be the same. That depends on whether the
order of priorities of the substituents is the same before and after the reaction. This is illustrated by the
following two examples.
Substitution of chlorine by a hydroxyl
group in (S)-1-chloro-3-methylhexane CH2CH2CH3 CH2CH2CH3
NaOH
results in formation of 3-methyl-1- H3C CH2CH2Cl H3C CH2CH2OH
hexanol that also has (S) configuration as H H
the order of priorities remains the same. (S) (S)

In the same compound, (S)-1-chloro-3- CH2CH2CH3 CH2CH2CH3


methylhexane, replacement of chlorine LiAlH4
H3C CH2CH2Cl H3C CH2CH3
by hydrogen changes the order of
priority of the substituents and the H H
(S) (R)
product is (R)-3-methylhexane.

Reactions on the Chirality Center


When the reaction occurs on the chirality center itself, it may proceed with retention of
configuration, with inversion of configuration, or with racemization. A reaction proceeds with
retention of configuration if the product has the same relative configuration as the starting material. A
reaction proceeds with inversion if the product has the opposite relative configuration compared to that
of the starting material. Finally, reaction proceeds
CH2CH3 CH2CH3 CH2CH3
with racemization if a single enantiomer as a Y
starting material gives a mixture of the two H3 C X H3 C Y + Y CH3
enantiomers as the reaction products. H H H
retention inversion

230
Chapter 12. Substitution Reactions of Alkyl Halides

Mechanism of Bimolecular Nucleophilic Substitution (SN2) Reaction


Bimolecular nucleophilic substitution (SN2) is a concerted reaction. A concerted reaction
proceeds in a single step, without formation of any intermediates. The reagent has a free electron pair
and is a nucleophile. In a bimolecular reaction, reaction rate depends on concentration of two species.
In this case, the reaction rate depends on the concentration of the substrate (organic compound) and the
reagent (the nucleophile).
rate = k[R-X] [Nu:]

RX + Nu RNu + X

Example of an actual reaction is reaction of iodomethane with a hydroxide ion (for example,
aqueous sodium hydroxide).

CH3I + OH CH3OH + I
-
rate = k[CH3I] [OH ]

Reaction mechanism involves a back side attack, on the carbon atom that contains the leaving
group, by the nucleophile. In the transition state, carbon–nucleophile bond is partially formed while
carbon–leaving group bond is partially broken. Note that in the transition state carbon atom is sp2
hybridized.

H H H
δ- δ-
H O + C I HO C I HO C + I
H H
H H H H
3 2 3
sp sp sp

Why mechanism of SN2 reactions involves backside attack?


Why mechanism of SN2 reactions involves backside attack? Why nucleophile cannot attack at
a different angle, or from the side? To answer these questions, one must consider antibonding orbitals.
A nucleophile donates electron pair to the carbon-leaving group antibonding orbital. Keep in mind that
when both bonding and antibonding orbitals are filled the bond order is zero – the bond is broken.
Thus, due to the geometry of H
H
antibonding σ* orbital the
δ- δ-
attack of the nucleophile must H O C I HO C I
occur from the backside. H
Backside attack is common in Electron pair is H H H
organic chemistry. Two donated to
empty σ* orbital
examples we already covered H O
There is no orbital
include attack of a available to
nucleophile on bromonium H accept electrons.
X

ion (p. 160) and attack of a


nucleophile on a mercurinium C I
ion (p. 162). H
H

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Veljko Dragojlovic

Stereoselectivity of SN2 reactions: Inversion of Configuration

If the carbon atom that carries the leaving group is a chirality center, an SN2 reaction on it
proceeds with inversion of the relative configuration, called Walden inversion,. The inversion is a
consequence of the reaction mechanism. Attack of the nucleophile from the back displaces the leaving
group and forces the remaining three substituents to invert (move away from the incoming substituent).
An example is reaction of (S)-2-bromobutane with hydroxide ion. The product is (R)-2-butanol.

H H H
δ- δ-
H O + Br HO Br HO + Br
H3C CH3
CH2CH3 H3C CH2CH3 CH2CH3

Therefore, the product and the starting material have the opposite relative configurations.
CH3 CH3

NaOH
Br HO
H3CH2C CH2CH3
H H
(S)-2-bromobutane (R)-2-butanol

H H
NaOH
H3CH2C Br HO CH2CH3

CH3 CH3

Since an SN2 reaction proceeds with inversion of configuration, it is both stereoselective and
stereospecific.

Factors That Affect the Rate of SN2 Reactions


Factors that affect the rate of SN2 reactions in decreasing order of importance are:
• Steric hindrance in the substrate
• Electronic effects
• Nature of the nucleophile
• Nature of the leaving group
• Solvent

232
Chapter 12. Substitution Reactions of Alkyl Halides

Steric Hindrance in the Substrate


The most important factor that affects the rate of an SN2 reaction is degree of steric hindrance
at the reactive center (the carbon that carries the leaving group). A nucleophile can easily approach a
substrate that is not hindered (a methyl, or a primary alkyl halide) and the resulting reaction is going to
be relatively fast. On the other hand, steric hindrance in the substrate interferes with approach of the
nucleophile and results in a slow reaction. Therefore, reaction rate of an SN2 reaction depends on the
degree of substitution of the substrate:

(3°)
E
(2°)
(1°)
-CH3 > (1°) > (2°) >> (3°)
doesn't undergo
CH3
SN2 reactions

If a degree of steric hindrance is large, as in the case of a tertiary compound, an SN2 reaction
does not proceed at all. The above given order of reactivity is only general and one should always
consider degree of steric hindrance. Even primary substrate with a large neighboring substituent reacts
very slowly due to steric hindrance.
H H
H
H H
H Nu: Br
H H
Nu: Br Nu: X H Br H
H CH3
H
H H H
H CH3
fast (no steric hindrance)
H very slow (steric hindrance)
no reaction (steric hindrance)

Space filling models of the three bromoalkanes shown above.

233
Veljko Dragojlovic

Electronic Effects
H H
Compounds that contain a double or a triple bond next to the reactive
center are very reactive. Some examples of such compounds include: allylic, Nu L
benzylic and propargylic halides and α-haloketones.

X O
X X
X
X = Cl, Br, I

High reactivity is in part due to decreased steric hindrance. An sp2 hybridized carbon atom is
trigonal planar and offers less steric hindrance compared to a tetrahedral sp3 hybridized carbon atom.
However, high reactivity is mostly due to the stabilization of the transition state through electron
delocalization between the p orbital of sp2 hybridized carbon and the unsaturated substituent as shown
on an example of benzylic substrate on the right.

Nucleophile
Properties of nucleophiles have been covered earlier (Chapter 6). Here is a brief review.
1) An anion is more nucleophilic and, therefore, more reactive than the corresponding neutral
molecule. An anion has an excess of negative charge that makes it less stable and more reactive. A
negatively charged nucleophile is stabilized when it donates its electron pair to form a neutral
molecule.

H2O < OH

H3N < NH2

2) If the charge on the nucleophile is the same, then a less electronegative atom is a better
nucleophile. A less electronegative atom does not attract its electron pairs as strongly as a more
electronegative one. Thus, those electron pairs are more available for donation. Electronegativity is a
periodic property. It increases going from left to right across a period and degreases going down a
group. Therefore, in the same period the element to the left is a better nucleophile and within a group
the heavier element is a better nucleophile.

F < OH

F < I
H2O < NH3

234
Chapter 12. Substitution Reactions of Alkyl Halides

3) Nucleophilicity is affected by steric effects, because steric hindrance interferes with anion’s
ability to donate the free electron pair. Thus, sterically hindered anions are poor nucleophiles, while
small non-hindered anions are strong nucleophiles.
H3 C CH3
OH > OCH3 > C
strong base O CH3
strong nucleophile strong base
weak nucleophile

Common nucleophilic reagents in the order of decreasing strength are:

RS > CN > I > OH > N3 > Br > Cl > H2O

Leaving Group
The best leaving group is the one that forms the weakest bond with carbon. Therefore, it is the
bond strength that is important and not electronegativity of the leaving group. Polarizability of a
leaving group also plays a role with more polarizable groups being better leaving groups. As a general
rule, the weaker the base a group or an atom is, the better leaving group it is. Therefore, a weak base is
a good leaving group, while a strong base is a poor leaving group. Carbon-fluorine bond is
exceptionally strong and fluorine is not considered to be a leaving group. Differences among the
leaving groups are most noticeable when the reaction involves relatively weak nucleophile. Strong
nucleophiles exhibit a leveling effect and react with most leaving groups at a fast rate. This is an
application of reactivity-selectivity principle on SN2 reactions.

RCH2X + OH RCH2OH + X
X= F Cl Br I
relative rate 1 200 10,000 30,000

Among the best leaving groups are alkane- and arenesulfonate ions, which we will study later
(Chapter 14). Hydroxide ion, alkoxide ion and amide ion are poor leaving groups and, therefore,
alcohols, ethers and amines do not undergo SN2 reactions.

leaving ability

I > Br > Cl > F


base strength

235
Veljko Dragojlovic

Effect of the Solvent on the Reaction Rate of SN2 reactions


SN2 reactions are usually carried out in polar solvents. Non-polar solvents cannot dissolve
ionic or highly polar reagents that are necessary for an SN2 reaction. If polar solvent is protic (can
donate a proton), the strength of a nucleophile is reduced due to ion-dipole interactions, or in some
cases, hydrogen bonding. Electron pairs of the nucleophile are used up to make hydrogen bonds to
molecules of the solvent and are no longer available for donation to an electrophile. Thus, polar protic
solvent reduces strength of a nucleophile. Common protic solvents are water and alcohols. A polar
aprotic solvent is capable of solvating polar, or ionic compounds but cannot form hydrogen bonds.
Such solvent may increase nucleophilicity of dissolved species. Most commonly used aprotic solvents
are acetone, dimethyl sulfoxide (DMSO) and dimethyl formamide (DMF).
H O O
O
C S
H H H3C CH3 H3C CH3
acetone dimethyl sulfoxide (DMSO)
O H Nu H O
CH3
H H
N O
O H3C
H N,N-dimethylformamide (DMF)
H

Effect of a solvent depends on the nature of the nucleophile:


1) If the nucleophile and the substrate are not charged, then polar solvent stabilizes the transition state
(decreases its energy and, hence, decreases the energy of activation) and increases the reaction rate. As
the reaction progresses from reactants to the transition state, there is a change from neutral species to a
charge separation. A polar solvent better interacts with species with a charge separation than neutral
species.
H
H
δ+ δ-
+ Br (CH3)3N Br
(CH3)3N H
H H H

2) If the nucleophile is charged, then polar solvent retards the reaction rate by stabilizing the
nucleophile better than it stabilizes the transition state. . As the reaction progresses from reactants to
the transition state, there is a change from a charged ion to a charge separation. A polar solvent better
interacts with charged species then with those that involve only a partial charge separation.
H
H
δ- δ-
HO + Br HO Br
H
H H H

236
Chapter 12. Substitution Reactions of Alkyl Halides

Functional Group Transformations (FGIs)


Conversion of one functional group into another is an important operation in organic
chemistry. Such reactions are called Functional Group Transformations or Functional Group
Interconversions (FGIs). FGI in an SN2 reaction involves replacement of the leaving group with a
nucleophile:

RCH2CH2 L + :Nu RCH2CH2 Nu+ :L

Some of the common nucleophiles are listed in the following table:


Halogen Oxygen Nitrogen Sulfur Carbon Hydrogen
F-, Cl-, Br-, H2O, HO-, NH3, RNH2, R2NH, R2S, RSH, RS-, -CN, RC≡C-, -
AlH4,
I- RO- R3N, NO2-, N3- HS-, -SCN -
CH(CO2R)2 -
BH4

Some examples of SN2 FGI reactions are shown below.

CH3Cl + OH CH3OH + Cl

CH3Br + I CH3I + Br
+-
CH3I + NH3 CH3NH3 I

CH3Br + P(CH3)3 (CH3)4P+Br-

CH3Br + SH CH3SH + Br

A convenient source of hydride ion (H:¯ ) in organic synthesis is a complex metal hydride
such as lithium aluminum hydride (LiAlH4). Ordinary metal hydrides such as NaH, KH or CaH2 are
strong bases and are not suitable as sources of
CH3Cl + LiAlH4 CH4 + LiAlH3Cl
hydride nucleophile.
Although most of the SN2 reactions are FGIs, those involving carbon nucleophiles can be used
to make new carbon–carbon bonds. Two of the common carbon nucleophiles are acetylide ion and
cyanide ion. Note that both of them are sp carbon nucleophiles.

CH3Br + C CR H3CC CR + Br

CH3Br + C N H3CC N + Br

237
Veljko Dragojlovic

Now you know two way to accomplish anti-Markovnikov addition of water to an alkene: 1)
hydroboration-oxidation reaction and 2) Addition of HBr in the presence of peroxide followed by
reaction with a hydroxide ion. Note that each procedure involves two steps.

1) BH3⋅THF, THF
1) 2) H2O2, NaOH, H2O
OH

1) HBr, peroxides
2) NaOH, H2O-THF
2) OH

Reversibility of an SN2 Reactions: Application of Le Châtelier’s Principle


Position of the equilibrium for a chemical reaction is determined by a change in free energy
and is represented by the equilibrium constant. Sometimes position of the equilibrium is not favorable
for a desired transformation. For example, a substitution reaction of an alkyl bromide with iodide ion
results in an equilibrium that contains both the starting materials and the products.

CH3CH2Br + I CH3CH2I + Br

To shift such equilibrium we apply Le Châtelier’s principle – add one of the reagents in
excess, or remove product(s) from the reaction mixture.
A + B C + D
[C] [D]
Keq =
[A] [B]

Sodium iodide is soluble in acetone while sodium bromide is not. Therefore, if the reaction is
carried out in acetone as the solvent and sodium iodide is used as a source of iodide ions, the reaction
is not reversible and proceeds to completion:

acetone
CH3CH2Br + Na + I CH3CH2I + NaBr (s)

238
Chapter 12. Substitution Reactions of Alkyl Halides

Mechanism of Unimolecular Nucleophilic Substitution (SN1)


Reaction
In an SN1 reaction, the rate of substitution depends only on the concentration of the substrate.

R X + H2O R OH + HX
rate = k [R-X]

An example of SN1 reaction is substitution of t-butyl bromide in water. Reaction rate depends
only on the concentration of t-butyl bromide.
CH3 CH3

H3C C Br + H 2O H3C C OH + HBr

CH3 CH3
rate = k [(CH3)3CBr]

An SN1 reaction:

• is unimolecular.
• proceeds with racemization.
• rate decreases with the decrease in the degree of substitution at the reactive center:
H2O
R Br R OH
50°C
H H CH3 CH3
R= H C H3C C H3C C H3C C
H H H CH3
relative rate 1.05 1 11.6 1,200,000

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Veljko Dragojlovic

Rate Determining and Product Determining Steps in an SN1 Reaction

Step 1 – The Rate Determining Step: Formation of a Carbocation

In the first step of an SN1 reaction carbon–leaving group bond is broken to give the
intermediate carbocation. This is an endothermic step. It involves only bond breaking, which requires
energy. Furthermore, this step involves a charge separation, which is another process that requires
energy. Therefore, the first endothermic step has high activation energy and is the slow step. It is the
rate determining step.

Step 2 – The Product determining Step: Reaction of Carbocation with a Nucleophile

In the second step, a bond between the nucleophile and the carbocation is formed. This is a fast
exothermic step. It involves only bond formation and is the product determining step.
CH3 CH3 CH3 CH3
δ+ δ- slow fast
H3 C C Br C + Br H3C C O H H3C C OH
H3C CH3
CH3 CH3 H CH3

H2 O H2 O

Stereochemistry
An SN1 reaction proceeds with a racemization of a chiral substrate. Therefore, this reaction is not
stereoselective. The reason for racemization is that the nucleophile can approach either side of the
intermediate carbocation with equal probability and the two enantiomers are formed in 1:1 ratio.
Frequently, racemization in SN1 reactions is incomplete and one enantiomer is obtained in excess.

H2O
CH3 CH3 CH3
CH2CH3 -H
H +
H CH3 H H
H3CH2C CH2CH3 H3CH2C
Br HO OH
(R)-2-bromobutane H2O (S)-2-butanol (R)-2-butanol

CH3 CH3 CH3


H2O
H3CH2C Br HO CH2CH3 + H3CH2C OH

H H H
(R)-2-bromobutane (S)-2-butanol (R)-2-butanol

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Chapter 12. Substitution Reactions of Alkyl Halides

SN1 reaction on cyclic compounds may be stereoselective. The reason for stereoselectivity is
in the fixed conformation of the ring system. One product is usually formed in excess, but not
exclusively.

Br Br

or H2O
heat

OH2 OH
-H

H2O minor
X
steric
H
hindrance H
by axial
hydrogens
H2O

OH2 -H OH
major

Factors That Affect the Rate of SN1 Reactions


Factors that affect the rate of SN1 reactions in decreasing order of importance are:
• Degree of substitution
• Leaving group
• Nucleophile and the Solvent
• Rearrangements

Degree of Substitution
The most important factor that affects rate of SN1 reaction is the degree of substitution at the
reactive center. In the course of the reaction a carbocation forms at the reactive center. Since primary
(3°) > (2°) >> (1°)
doesn't undergo
SN1 reactions
carbocations are not stable, a primary substrate does not undergo SN1 reaction. Due to stabilization by
hyperconjugation (Chapter 9), secondary and tertiary carbocations are stable and such substrates
undergo SN1 reactions. The more substituted the carbocation is the more stable it is and, therefore, the
higher the rate of SN1 reaction.

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Veljko Dragojlovic

Leaving Group
A good leaving group easily leaves to give the corresponding carbocation. Therefore,
compounds with good leaving groups react at high rates, while compounds with poor leaving groups
react at low rates. As mentioned earlier, a good leaving group is a weak base, while a poor leaving
group is a strong base. Order of reactivity of alkyl halides is:
RI > RBr > RCl >> RF

Nucleophile and the Solvent


Usually the nucleophile is the solvent. Such reaction is called a solvolysis. If the solvent is
water the reaction is called hydrolysis and if it is an alcohol it is called an alcoholysis.

CH3 CH3
H3C C Br + H2O (solvent) H3C C OH + HBr
CH3 CH3

Rearrangements
Carbocations are the intermediates in SN1 reactions. If possible, the intermediate carbocation
will rearrange into a more stable carbocation. The most common rearrangements are a hydride shift
and an alkyl shift.

Hydride Shift
In a hydride shift, hydrogen atom together with an electron pair shifts. Hydrogen that has an
electron pair is called a hydride ion (H:-)
CH3 H CH3 H CH3 H
H3C CH3 H3C CH2 H3C CH3
H Br H H
(2°) H2O (3°)

CH3 H CH3 H
H3C CH3 H3C CH3
OH H -H OH2 H

On a rare occasion when a primary substrate reacts by SN1 mechanism, the rearrangement is a
concerted process:

CH3 H CH2 H CH3 H


H3C Br H3C H H3C H
H H H I H
I (3°)

242
Chapter 12. Substitution Reactions of Alkyl Halides

Alkyl Shift
When there are no hydrogens available on the neighboring carbon, an alkyl group shifts.
Usually, it is the methyl group that shifts.

CH3 CH3 CH3 H CH2 H


H3C Br H3C CH2 H3C CH3
CH3 H CH3 H2O CH3
(2°) (3°)

CH3 H CH3 H
H3C CH3 H3C CH3
OH CH3 -H OH2 CH3

An alkyl group shift is also called a “Wagner-Meerwein rearrangement.”

Competition between SN1 and SN2 Reactions: Factors that Affect Reaction Mechanism

Main factors that affect outcome of any reaction are nature of the substrate, nature of the
leaving group, nature of the reagent (in this case nucleophile) and the nature of the solvent. Depending
on the reaction, other factors, such as temperature and concentration of the reactants mat play a role.
When it comes to competition between SN1 and SN2reaction mechanisms, the most important factors
are substrate, nucleophile and the solvent. Leaving group plays a role in determining the reaction rate,
but has no effect on the mechanism of a substitution reaction.

leaving group solvent

acetone
H3C CH2 CH2 Br + I H3C CH2 CH2 I + Br

nucleophile
substrate

Role of the Leaving Group


A good leaving group reacts at a high rate and a poor leaving group reacts at a low rate. That
is the case for both SN1 and SN2 reaction mechanisms. Thus, the nature of the leaving group affects the
reaction rate, but usually does not affect the reaction mechanism.

Role of the Substrate


The most important factor that affects the mechanism of a substitution reaction is the degree
of substitution at the reactive center. Tertiary compounds are too hindered to undergo SN2 reaction and
primary compounds do not undergo SN1 reaction as the intermediate cation would be too unstable.
Therefore, other factors are usually considered only when a substrate is secondary.

243
Veljko Dragojlovic

Role of the Nucleophile


A strong nucleophile is capable of replacing (“pushing out”) the leaveing group. Thus, a
strong nucleophile favors SN2 reaction mechanism. On the other hand, a weak nucleophile is capable
of reacting only with a strong electrophile, such as carbocation. Thus, a weak nucleophile favors SN1
reaction mechanism.
H
Role of the Solvent O H H
H O
H H H
As explained earlier, a polar protic solvent O H X H O O Y O
reduces strength of a nucleophile by making hydrogen H H H
bonds with it. Therefore, such solvent favors SN1 reaction H O
mechanism. O H H
H
A procedure for determining mechanism SN1 SN2
of a substitution reaction is shown in the diagram mechanism mechanism
on the right. Note that it is only a rough guide and
there are exceptions. For example, a solution of tertiary, substrate methyl,
benzylic, primary
an alkoxide in the corresponding alcohol, such as allylic
EtO- in EtOH, usually reacts by SN2 mechanism
even though is it carried out in a protic solvent. secondary

weak nucleophile strong

strong

protic solvent aprotic

244
Chapter 12. Substitution Reactions of Alkyl Halides

Review: Stereochemistry of SN2 and SN1 Reactions


Stereochemistry of SN2 reactions
CH3 CH3

H NaOH H
H3CH2C CH2CH3
Br HO
An SN2 reaction proceeds with inversion of
configuration. Note that we can specify the configuration CH3 CH3
NaOH
of the product only if we know the configuration of the H3CH2C Br HO CH2CH3
starting material. H H
(R)-2-bromobutane (S)-2-butanol

Stereochemistry of SN1 Reactions


SN1 reactions proceed with racemization. Racemization may be complete (50%:50% mixture
of two enantiomers is obtained) or partial (one enantiomer is obtained in an excess).
CH3 CH3 CH3
H2O
H3CH2C H H CH2CH3 + H3CH2C H
Br HO OH
CH3 CH3 CH3
H O
H3CH2C Br 2 HO CH2CH3 + H3CH2C OH
H H H
(R)-2-bromobutane (S)-2-butanol (R)-2-butanol

Stereochemistry of Reaction on Cyclic H


H OH H OH
Compounds
CH3 Br SN2 CH3 H
As an SN2 reaction proceeds with a
complete inversion of configuration, it is both H Br
stereoselective and stereospecific. With a cyclic OH H H
H2O H
compound, a trans starting material gives a cis CH3 H +
product and vice versa. An SN1 reaction on a or
H H SN1 CH H CH3 OH
3
cyclic system may be stereoselective, but it is not
major minor
stereospecific. CH3 Br

245
Veljko Dragojlovic

Reactivity of Benzylic Halides, Allylic Halides, Vinylic Halides and


Aryl Halides
Allylic and Benzylic Halides
Allylic and benzylic halides are highly reactive both in SN1 and SN2 reactions.

SN2 Reaction Conditions

The rate of an SN2 reaction of a benzylic compound is increased, compared to an ordinary


alkyl halide, because the neighboring π system stabilizes
the transition state. In addition, presence of an sp2 Cl OCH3 OCH3
hybridized carbon atom next to the reactive center results
in a reduced steric hindrance. Note that an sp2 hybridized
atom is planar while and sp3 hybridized atom is tetrahedral.
An SN2 reaction on an allylic compound
proceeds with an allylic rearrangement. That is one of OH
a few SN2 reactions that proceeds with a HO + Br
rearrangement.

SN1 Reaction Conditions

Both benzylic and allylic halides react at a high rate under SN1 conditions. The rate of an SN1
reaction is increased because the neighboring π electrons stabilize the intermediate carbocation through
resonance.

CH3
Cl O -H OCH3
CH3OH
H

HOH H -H
Br O OH
H

246
Chapter 12. Substitution Reactions of Alkyl Halides

Vinylic and Aryl Halides


Vinylic and arylic halides are unreactive towards
nucleophilic substitution reactions. In an SN2 reaction, the approach of
the nucleophile is not possible because of the electrostatic repulsion
between the π electrons (of the aromatic ring or a double bond) and
the approaching nucleophile as well as the steric hindrance in the
aromatic substrate – in order to approach from the backside the
nucleophile would have to attack from within the aromatic ring.

Ball and stick model of


Iodobenzene - nucleophile
is repelled by π electrons
of the aromatic ring.

R Cl R
In an SN1 reaction, the intermediate would be a X vinylic cation
H H H H
highly unstable vinylic or aryl cation. Either of the two
cations is less stable than a primary carbocation. Br
X aryl cation

Application of Substitution Reactions I: Williamson Ether Synthesis


A suitable method for preparation of ethers
is Williamson ether synthesis. In it, an alkoxide R O + R Br R1 O R2 + Br
1 2
reacts with an alkyl halide to give the corresponding
ether. The reaction mechanism is SN2.
Alkoxides can be prepared in a number of ways. Usually, the alcohol is treated with sodium to
give a solution of sodium alkoxide in the corresponding alcohol.

2 CH3CH2OH + 2 Na 2 CH3CH2O Na + H2

CH3CH2O + CH3CH2CH2Br CH3CH2OCH2CH2CH3 + Br

An alternative is to use sodium hydride (NaH) as a base. In the subsequent step, alkyl halide is
added to the solution of alkoxide.
1) NaH
OH O
2) Br

247
Veljko Dragojlovic

Note that there are two alkoxide/alkyl halide combinations to prepare any ether.
Br
O + O

O
+ Br O

Since the reaction mechanism is SN2, Williamson ether synthesis is a poor method to prepare
tertiary ethers. If the alkoxide (base) is tertiary, the favored reaction is elimination (E2 – see next
chapter) and the tertiary ether is obtained in a low yield.

(this product
+ Br is formed in
O O
a low yield)

On the other hand, if the alkyl halide is tertiary, SN2 reaction is not possible at all and the only
product is the result of elimination reaction.

+
Br O

Aromatic ethers can be prepared in high yield.


However, only one combination of the alkoxide (in this O O
case phenoxide) and alkyl halide will give the desired + Br
product. Aryl halides do not react under SN2 conditions.
Br
+ O no reaction

Application of Substitution Reactions II: Synthesis of Alkynes


Synthesis of alkynes, which was covered in Chapter 10, is also an SN2 reaction. Since this is a
bimolecular reaction, it does not work with tertiary substrates – elimination occurs instead. Therefore,
this reaction is limited to primary and secondary alkyl halides.

Br
Br
+ H3CC CH H3C C C: H3C C C CH2 CH3

248

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