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CHAPTER 1.
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
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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Veljko Dragojlovic
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.
2
Chapter 1. Electronic Structure and Bonding
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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Veljko Dragojlovic
“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
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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Veljko Dragojlovic
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
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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.
8
Chapter 1. Electronic Structure and Bonding
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.
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.
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.
10
Chapter 1. Electronic Structure and Bonding
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.
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
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
O O
O C O O C O
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).
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
14
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
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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:
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.”
16
Chapter 1. Electronic Structure and Bonding
π∗
σ∗
p 2p 2p
s
π
σ
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
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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
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
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
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.
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.
420 kcal/mol
reaction progress
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Veljko Dragojlovic
Bonding in Ethane
2s orbital
2p orbitals hybrid sp3 orbitals
H
H
H
H
H
H
H H
H H
H H
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
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Chapter 1. Electronic Structure and Bonding
Van’t Hoff model ball and stick model space filling model
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.
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Veljko Dragojlovic
+
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
H 121.7° H
116.6° C C
H H
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Chapter 1. Electronic Structure and Bonding
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
ball and stick model Van’t Hoff model space filling model
Atoms connected by one σ and two π bonds are connected by a triple bond. A triple bond is
alkyne’s functional group.
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Veljko Dragojlovic
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.
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
ball and stick model Van’t Hoff model space filling model
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Veljko Dragojlovic
180° 1.06 Å
H C C H
1.20 Å
actual shape
stylized shape
sp3 sp2 sp
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Chapter 1. Electronic Structure and Bonding
H
CH2 H CH2 H
H
sp2 sp3
singlet carbene triplet carbene
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Veljko Dragojlovic
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
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.
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
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
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Veljko Dragojlovic
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
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.
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
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Veljko Dragojlovic
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
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.
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:
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
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
41
Veljko Dragojlovic
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
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.
45
Veljko Dragojlovic
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
CH3
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
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.
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.
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
48
Chapter 2. Nomenclature and Representation of Organic Compounds
49
Veljko Dragojlovic
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
50
Chapter 2. Nomenclature and Representation of Organic Compounds
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 names are convenient when we are dealing with complex alcohols such as the one
shown below.
OH
4-ethyl-2-heptanol
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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
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).
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
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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
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.
54
Chapter 3. Structure and Properties of Organic Compounds
CHAPTER 3.
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.
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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 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
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
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
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
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:
61
Veljko Dragojlovic
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.
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
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
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.
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.
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.
67
Chapter 4. Conformational Analysis
CHAPTER 4.
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.
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
0°
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
72
Chapter 4. Conformational Analysis
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
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.
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
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
axis
axial bonds
77
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°).
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
Parallel carbon-carbon
H H
H H bonds in cyclohexane
78
Chapter 4. Conformational Analysis
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):
79
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
trans-1,4-dimethylcyclohexane
80
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.
81
Veljko Dragojlovic
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
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
82
Chapter 5. Acids and Bases
CHAPTER 5.
HA + B HB + A
acid base conjugate conjugate
acid base
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
87
Veljko Dragojlovic
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.
88
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
89
Veljko Dragojlovic
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.
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.
90
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.
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
91
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.
A strong acid has a large value of Ka and a small value of pKa. The reverse is true for weak
acids.
92
Chapter 5. Acids and Bases
O O
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
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.
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.
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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
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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.
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Veljko Dragojlovic
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
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.
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
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¯ )
108
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
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.
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.
110
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
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.
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Veljko Dragojlovic
C C + H Br H C C H
H H
H H
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%
112
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
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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.
Gº rds
Gº I ΔG2‡
rds
ΔG2‡
ΔG1‡
I
R
ΔG1‡
ΔGº R
P
ΔGº P
I II
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.
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]
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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: The reaction pathway is the same for both the forward and
the reverse reaction.
116
Chapter 6. Organic Reactions
(I) A B C
A B + C (II) A B C A + B C
(III) A B C
Hº Hº Hº
Hammond Postulate: A transition state most closely resembles the stable species that lies closest to it
in energy.
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
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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.
Reaction
Equilibrium
Resonance
Retrosynthetic Analysis
Coupled Reaction
(usually used in Biochemistry)
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.
118
Chapter 6. Organic Reactions
119
Chapter 7. Reactions of Alkanes
CHAPTER 7.
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.
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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.
Cl Cl
124
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 + 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.
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.
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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.
Thus, in a free radical bromination secondary hydrogen atom is 72 times more reactive than
primary.
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
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
X + CH C + HX (X = Cl, Br)
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°)
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.
128
Chapter 7. Reactions of Alkanes
~
~ > > > > ~
~ 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.
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.
DoU = 1 DoU = 2
DoU = 1 DoU = 2
DoU = 3
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)
133
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
134
Chapter 8. Alkenes
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.)
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
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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)-
138
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.
.
1,2-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.
139
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.
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.
140
Chapter 8. Alkenes
Substituents that contain a triple bond are ethynyl and propargyl. Ethynyl is a triple bond
equivalent of vinyl group and propargyl of allyl.
5-hepten-1-yne 3-propyl-4-hexen-1-yne
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
___________________________________________________________________________
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
147
Veljko Dragojlovic
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
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.
HF
mixture of products
148
Chapter 9. Reactions of Alkenes
149
Veljko Dragojlovic
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
150
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
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.
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
154
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
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.
155
Veljko Dragojlovic
H Cl
H
(2°) Cl
minor
methyl
shift
Cl
Cl H
major (3°)
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
156
Chapter 9. Reactions of Alkenes
+ Br Br Br + Br
H
H Br
Termination Steps:
Br
Br + Br
Br
Br + Br Br
Br
Br + Br Br2
157
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.
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.
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
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
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.
159
Veljko Dragojlovic
Addition of Bromine
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
Fluorine is extremely reactive. It even reacts with C-H bonds. Therefore, the reaction is not
synthetically useful. Iodine does not react (ΔGº > 0).
161
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
162
Chapter 9. Reactions of Alkenes
Hg HgOAc H
HgOAc NaBH4
HO HO
H2O
OH
1) Hg(CH3CO2)2, H2O, THF
2) NaBH4, KOH, H2O
OH
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
163
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
165
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
H
H H H
H H
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.
H°
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.
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
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
R4 R3 H O R4 R3 H O
O O +
O R O R
R1 R2 R1 R2
168
Chapter 9. Reactions of Alkenes
cis-2-butene cis-2,3-dimethyloxirane
O
H O H O
H3C O H
H H
trans-2-butene trans-2,3-dimethyloxirane
OH
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
169
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
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
O
KMnO4, OH, H2O
+ CO2
heat
O
KMnO4, OH, H2O OH
HO
heat
O
O
KMnO4, NaOH
OH + CO2
H2O, heat
O
KMnO4, H3O
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
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.
RC CH + NH2 RC C + NH3
RC CH + OH RC C + H2O
182
Chapter 10. Reactions of Alkynes
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
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.
hν
RO OR 2 RO
RO + H Br ROH + Br
184
Chapter 10. Reactions of Alkynes
Br R Br
Br Br
R C C H
R H Br H
Br
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
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
186
Chapter 10. Reactions of Alkynes
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
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
188
Chapter 10. Reactions of Alkynes
H
Na H NH2
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.
___________________________________________________________________________
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.
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.
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.
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.
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Chapter 11. Stereochemistry
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
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
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.
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Veljko Dragojlovic
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
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
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
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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).
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.
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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
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
D T T D
T T
R R
D D R R
3 1
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
CH2OCH3 CH2OCH3
(S)-
2 4
4 3 3 2
1 1
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Veljko Dragojlovic
graduated
scale
sodium
lamp polarizer
α
tube with an
optically active
compound
analyzer
eyepiece
Schematic of a polarimeter
208
Chapter 11. Stereochemistry
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.
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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.
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:
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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.
n=2; 2n = 22 = 4
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Veljko Dragojlovic
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
Br H H Br H Br Br H
H Cl Cl H H Cl Cl H
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").
Cl Cl Cl Cl
erythro pair threo pair
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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.
H Br Br H H Br Br H
H Cl Cl H Cl H H Cl
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
H OH HO H H OH HO H plane of
symmetry
HO H H OH H OH HO H
Br H H Br H Br Br H
H Br Br H H Br Br H
H OH HO H H OH HO H
HO H H OH H OH HO H
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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)
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Chapter 11. Stereochemistry
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.
H OH HO H H OH
H OH H OH HO H
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.
CO2H
H CH3
O O O O
NH2 NH3 NH3
+ + +
CO2H
H3C H
1) separation of
diastereomers
2) HCl hydrolysis
of salts
CO2H CO2H
racemic mixture
H3C H H CH3
pure enantiomers
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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
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.
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Veljko Dragojlovic
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.
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
230
Chapter 12. Substitution Reactions of Alkyl Halides
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
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Veljko Dragojlovic
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.
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Chapter 12. Substitution Reactions of Alkyl Halides
(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)
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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
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
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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
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
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Veljko Dragojlovic
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
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Chapter 12. Substitution Reactions of Alkyl Halides
CH3Cl + OH CH3OH + Cl
CH3Br + I CH3I + Br
+-
CH3I + NH3 CH3NH3 I
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
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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
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
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
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
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.
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
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
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
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:
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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 H CH3 H
H3C CH3 H3C CH3
OH CH3 -H OH2 CH3
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.
acetone
H3C CH2 CH2 Br + I H3C CH2 CH2 I + Br
nucleophile
substrate
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Veljko Dragojlovic
strong
244
Chapter 12. Substitution Reactions of Alkyl Halides
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
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Veljko Dragojlovic
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
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
2 CH3CH2OH + 2 Na 2 CH3CH2O Na + H2
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
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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
Br
Br
+ H3CC CH H3C C C: H3C C C CH2 CH3
248