Chem 232 Fall 2015 UIUC Notes

Understanding Reactivity
Chemistry is the study of change.

Up to this point, the molecular
changes we have studied involved
internal
changes
such
as
conformational rotation about
single bonds of alkanes or ring
flipping of cyclohexane. None of
these changes involved the
breaking and making of covalent
bonds. The chemical change we
will study from this point forward
involves changes in electron
configuration.
Much of the
language that was developed in
previous lessons will apply to
covalent bond changes.
Our
description of these changes will
greatly benefit from the curved
arrow notation that we began to
study
when
we
discussed
resonance.
The discussion of
intermediates and transition
states from the last lesson will be
utilized as well.
Our goal in this course is to learn

and understand the chemical
transformations (i.e., reactions)
common to molecular compounds.
To achieve this goal, we will
analyze reactions by breaking
them down into a sequence of
elementary steps.
This
sequence of steps is called the
reaction mechanism. In order to
write mechanisms, you will need a
working knowledge of the
electronic structure of molecules
and the skill in writing curved
arrow notation. This lesson will
begin to put these skills to use as
we learn to write the mechanism
for a simple reaction - the proton
transfer reaction.
Organizing chemistry around
mechanisms allows the process of
change to be understood, not just
memorized. Once basic principles
of reactivity are understood, youll
learn to reason-by-analogy to
rationalize and predict outcomes
of reactions that youve never
previously seen.
Elementary step?
Elementary steps describe the
process of change between
adjoining minima on the MEP of
an overall reaction. Many
reactions have several minima
(i.e.,
intermediates)
located
between starting and ending
points. Thus, the overall reaction
mechanism requires a sequence of
elementary steps to describe the
entire process.
Each elementary step has:
A reaction arrow () connecting
the starting and ending structures
of that step
Balanced charge
Balanced stoichiometry
Nucleophiles and Electrophiles

We will expand the concept of acids and bases to a related classification scheme known as electrophiles
and nucleophiles. The word nucleophile derives from the Greek nucleo, for nucleus, and philos, for
loving. The word electrophile is derived from the Greek electros, electron, and philos, loving.
Most elementary steps involve a nucleophile reacting with an electrophile. Electrophiles are electron
deficient. They are characterized by partial or fully developed positive charges and by incomplete
octets. Electrophiles have low-lying LUMOs. Nucleophiles are electron rich. They are characterized
by partial or fully developed negative charges, and by electron lone pairs or pi bonds. Nucleophiles have
high-lying HOMOs. It should not surprise you to learn that all acids are electrophiles, and all bases are
nucleophiles.
filled orbital ready to
donate an electron pair
An elementary step between a

generic nucleophile, Nu, and a
generic electrophile, E+
empty orbital able to

accept an electron pair
Nu
a nucleophile
an electrophile
reaction arrow
new bond between

nucleophile and
electrophile
Nu
Notice that charge is balanced (the sum the formal

charges on one side of the reaction arrow is the
same as the sum of the charges on the other side)
The sa
of "ac
used t
Nu
Electron Reconfigurations - the Flow of

Electrons - Usually Involve Electron Pairs
Covalent bond making and breaking are changes in electron configuration. Electron reconfiguration
most often takes place as pairs of electrons, not as single electron entities. In fact, most all of the
chemistry that we will study involves the movement of electrons in pairs. Heterolytic chemistry
is the class of reactions that involves electrons moving in pairs, while homolytic chemistry
describes the less common mode involving single electron reconfiguration. Organic chemists like
to think of the movement of electrons as a flow of electron density from regions of high to
regions of low electron density that is from nucleophiles to electrophiles. The movement of
electron pairs is represented by curved arrows.
Nu
a nucleophile
Nu
an electrophile
The same process takes on a sense

of "action" when curved arrows are
used to illustrate electron flow
Nu
E
Nu
Proton Transfer - A Single-step Mechanism

(building block considerations)
Notice that most of the

atoms remain unchanged.
Focus is given only to
those building blocks that
undergo a change in
electron configuration. !
phenol
water
hydroxide
phenolate
O
OH
hydroxide
phenol
O
water
phenolate
Curved Arrows Describe the Electron

Reconfigurations in a Chemical Reaction
Each double-headed curved arrow symbolizes the
movement of an electron pair thats involved in the
electron reconfiguration. The tail of the first arrow is
placed at the source of electrons. This may be a lone
pair, pi-bond or sigma bond. The head of the last arrow
indicates the destination or sink. The electron sink tends
to either be an electronegative atom that is, an atom
that can stabilize negative charge or an atom with an
empty atom-centered orbital (we symbolize empty, atomcentered orbitals with the letter a).
sink
If, in the process of pushing an electron pair to an

uncharged C, H, N, or O atom, a new bond is formed, then
the electron flow must continue in the same step and
subsequently break one of the existing bonds at the newly
bonded atom. This avoids exceeding the allowed electron
count of that atom (e.g., octet for C, N or O; duet for H).
pushing electrons using

curved arrow notation
OH
source
+
phenol
The hydroxide anion is the source. A lone pair of electrons on the
hydroxide anion forms a new bond with the phenolic hydrogen atom
making water. Simultaneously the O-H bond in phenol breaks and
this electron pair moves onto oxygen to make a phenolate anion.
phenolate
Proton Transfer Reactions Involve Sigma

Bond Breaking and Sigma Bond Making
Empty *
O
This symbol means a

proton transfer step
Filled n
1st arrow
OH
H
2nd arrow
New
bond
[pt]
An n *
-type interaction
Curved Arrows Imply the Frontier Orbitals
Curved arrows indicate the HOMO-LUMO pair (Frontier Orbitals)
involved in an elementary step. The tail of the first arrow implies
the filled orbital (HOMO) is a non-bonded electron pair, n. The
head of the first arrow points to the empty orbital (LUMO, *) that
accepts the electron pair. The empty orbital may not be obvious
until you realize that phenols O-H sigma bond breaks, as implied
by the tail of the second arrow. Sigma bond breaking would result
upon filling * with the electron pair from n. The frontier orbitals
align coaxially (a -type interaction).
empty
filled
"a
"
" a
"
" na
n "
" a
"
LUMO / HOMO Applied to Acid / Base Interactions

Low energy LUMO = strong acid (reactive electrophile)
High energy HOMO = strong base (reactive nucleophile)
Consider the O-H bond in
H3O
H2O
HO
n
n
Energy Changes Accompany Each Elementary Step

coordinate diagram
(b)
(a) reactants
(b) transition state
(c) products
(d) G Gibbs standard free energy change
(e) G free energy of activation
(e)
(a)
free energy
We have already encountered a useful tool

that allows us to track energy changes
along a complex reaction pathway the
tool was the reaction coordinate diagram
used to describe the ring flipping process
of cyclohexane. Although cyclohexanes
reaction did not involve electron
reconfiguration, the minimum energy
pathway (MEP) correlated energy and
progress of change for a complex set of
conformations. Not only does the reaction
coordinate diagram and its MEP serve as a
way to track energy changes for
conformational processes, but it also is a
tool for tracking energy of reactions that
involve electron reconfiguration.
A Reaction Coordinate Diagram

MEP
on a 1-step reaction
for a One-Step
Process
(d)
(c)
progress of the reaction
We are interested only in the

minima and maxima on reaction
coordinate diagrams. By knowing
the energy at these positions, either
qualitatively or quantitatively, we
will be able to judge the
equilibrium position of the reaction,
and how fast each step of the
reaction takes place.
The essential components of a reaction coordinate diagram for a one-step reaction are shown above. Most important is
the MEP on this diagram. The particular MEP on the above diagram might, for example, apply to the proton transfer
from phenol to hydroxide. The reactants (a) are higher in energy than the products (c), so there is a favorable driving
force (d) to promote the change. This driving force is the Gibbs standard free energy and its directly related to the
equilibrium constant (Keq) by G = -RT ln Keq where T is the temperature in Kelvin and R is the gas constant.
The transition state (b) is a transient structure caught in the act of undergoing electron reconfiguration. The
symbol TS represents the transition state structure. Notice that the energy associated with TS is higher than the
reactants. This maximum on the energy profile represents a barrier that resists the transformation of reactants to
products. The higher the barrier is, the slower the rate of the reaction. The coefficient, k, is proportional to the
reaction rate (k and G are related by k = 2.084x1010Te-(G/1.986T)).
Activated-Rate Theory
Getting from reactants to products requires energy, e.g.,
energy to surmount a transition state barrier or energy to
become an unstable intermediate on the MEP. Where
does this energy come from?
In order to surmount barriers on the MEP, reactants
must somehow acquire energy from their surroundings.
This energy might come from heat, light, electrical
potential, or mechanical force. The barrier is thus only
a temporary one, because as soon as the reactants
acquire sufficient energy from their surroundings,
electron reconfiguration can take place. In the case of
proton transfer, the barrier is not very high and is easily
surmounted by the thermal energy (i.e., random,
Brownian motion) available to the reactants at room
temperature.
The energy transduction network (diagram at the right)
reminds us that potential energy of one form (e.g.,
electrical potential) can be converted into another form
(e.g., chemical potential). When molecules acquire
energy from their surroundings, they can surmount the
barriers on an MEP and reactions will proceed. This is
the basic idea behind the activated-rate theory which
describes how fast reactants transform into products.
The theory says that reactants must become activated to
their transition state structures by acquiring energy
from their surroundings.
Structure of the Transition State

The transition state (TS) is a transient species lying on
the reaction pathway that is undergoing the act of
electron reconfiguration. But what does the structure of
the TS look like? We can generate a representation of
the transition state structure using curved arrow notation
as a guide. In representing the TS, lone pairs are not
shown because the number of lone pairs often changes as
part of the electron reconfiguration. Bonds being broken
and bonds being made are represented as dashed lines.
Changes in formal charge are important. In the TS
charges on one particular atom may be growing or
diminishing and such charges are non-integer (i.e., they
are partial charges).
Partial charges, developing or
diminishing, are represented as + (for positive charge)
and (for negative charge).
developing
charge
For the proton transfer reaction shown below, notice the

connection between the curved arrow notation and the
representation of the TS. The tail of each curved arrow
either corresponds to a lone pair whose electron density is
being consumed as the reaction unfolds, or a bond that is
being broken. The head of each arrow either corresponds
to a lone pair being produced, or a bond being made. The
changes in charge are determined by looking at the
location of charge in the reactant and in the product. Each
atom associated with a changing charge is given by a +
or a . The entire structure is placed in square brackets
with a double dagger () in the upper right sided to
signify that the structure is transient.
developing
bond
OH
OH
H
O
diminishing
bond
transition state structure
diminishing charge
signifies transition
state structure
Hammonds Postulate: Transition State Structure & Energy

Activated-rate theory says that the energy of a
TS must be known to predict reaction rates.
Although TS energies can accurately be
calculated with modern computational tools
like WebMO, TSs cannot be studied
experimentally because they only exist
transiently. For building chemical intuition, a
qualitative analysis may be better than
sophisticated computation; thus, it is worthwhile to have some rules to help us rationalize
the relationship between TS energy and
structure. In the TS, bonds are being made
and bonds are being broken. How far along
are the bond-formation and bond-breaking
processes at the point the transition state is
reached? Are bonds nearly fully developed or
just beginning to form? Are bonds fully
broken, or are they just beginning to weaken?
The Hammond postulate helps to answer
these questions. The Hammond postulate tells
us that for any two minima connected via a
TS, the structure of the transition state will
more closely resemble the minimum that it is
closer to in energy.
This might sound
complicated, but in reality there are only two
possibilities to consider. Lets examine them
with reference to the diagram.
Case 1: the beginning state is higher than the ending state In this case
Hammonds postulate tells us that the TS will more closely resemble
the beginning state. The energy of the TS must be closer to the
beginning state. Theres just no other way to draw the diagram. We call
this TS early since the structure of the transition state has not
evolved far from its starting point.
Case 2: the ending state is higher than the beginning state In this case
Hammonds postulate tells us that the TS will more closely resemble
the ending state. The energy of the TS must be closer to the energy of
the ending state. We call this TS late since the structure of the
transition state has nearly evolved to its ending point.
The Reaction Coordinate Diagram

for Proton Transfer
Keq > 1 for this proton transfer
step (soon we will be able to
predict this result, but for now just
accept the fact). Since Keq > 1, the
reaction is thermodynamically
downhill; case 1 of Hammonds
Postulate applies.
The TS is
early, and the TS structure more
closely resembles the reactants.
OH
Keq
OH
free
energy
The complete reaction coordinate

diagram includes the structures of the
reactants,
products
and
a
representation of the TS . The rate of

the reaction in the forward direction
is determined by Gf while the rate
of the reaction in the backwards
direction is determined by Gb.
Based on the relative heights of Gf
and Gb, notice that the forward rate
is faster than the backward rate.
Recall that Keq is given by the ratio of
the forward to backward rate
coefficients.
The driving force for
the reaction is determined by G.
Gf
H
G
Gb
O
H
H
Summary
1.
2.
3.
4.
Curved arrow notation shows the changes in electron configuration for each
step of a reaction mechanism. !
Curved arrows indicate the partial bonds formed or broken in the transition
state (e.g., an arrow tail drawn from a bond represents a bond that is
breaking; an arrow head drawn between two atoms represents a bond being
made).!
The sum of the formal charges on each side of a reaction arrow must
balance. !
The atoms in transition state structures may have developing or diminishing
charge. Developing or diminishing charge in transition states is represented
by the partial charge symbol (e.g., + or ). If the formal charge on a
particular atom changes from one side of the reaction arrow to the other,
that atom is assigned a partial charge in the transition state.
Structure-Reactivity Relationships
A change in structure corresponds to a
chemical reaction. Reactivity is the term we
use to describe the potential of a structure to
undergo chemical change. Some structures
are more prone to react than others. Structures
that are likely to undergo chemical change are
said to be reactive.
Structures that are
resistant to chemical change are said to be
unreactive. We sometimes choose to speak
about the complementary property known as
stability. Structures that are highly reactive
are generally unstable. Structures that are
unreactive are generally stable.
We want to view molecular

structure from the perspective of
potential to undergo chemical
change. A goal is to establish trends
that will allow you to examine a
structure and make predictions
about its chemical characteristics.
Just like a physician diagnoses
patients, chemists learn to associate
certain features of structure with the
tendency to react.
From these
trends emerge the structurereactivity relationships.
Potential energy (specifically, chemical potential) is the link between structure and reactivity.
The greater a structures chemical potential, the greater is its reactivity. Understanding the link
between structure and reactivity will help us decide which, among several possible changes, are
most reasonable (e.g., pathways having intermediates with exceedingly high energies are not
likely to be reasonable and should therefore be avoided, especially if a pathway with lower
energy intermediates is available).
structure
chemical potential
reactivity
Analysis of Chemical Potential

Analysis of Chemical Potential: Chemical potential makes sense in the context of a chemical reaction because we
can compare whats on the two sides of a reaction arrow () and determine the difference in chemical potential.
By comparing whats on one side with whats on the other, it becomes possible to know if the chemical change is
favored or not. Does the left-hand-side or the right-hand-side have greater chemical potential? The favored
direction will be from high to low chemical potential.
An analysis of chemical potential can be done for individual elementary steps, or an overall chemical reaction, as
the problem demands. The things that contribute to chemical potential - the things that need to be compared - are:
Bond energy changes
Strength (reactivity) of electrophiles and /or acids
Strength (reactivity) of nucleophiles and/or bases
free energy
AB
Chemical potential for

the reaction A B
GA
G = GB - GA
GB
What Factors Contribute to High Chemical Potential?

Weak bonds
Low energy LUMO = strong acid (reactive electrophile)
High energy HOMO = strong base (reactive nucleophile)
Permanent charges
Factors Contributing to Charge Stability

Charged species are commonly encountered in chemical reactions, either as starting
components, end products, or as intermediates and TS along a reaction pathway. There
is considerable energy associated with charged species; consequently, the relative
stability of charged atoms often provides important information about chemical
reactivity. The four factors listed below are some of the most important aspects of
structure that contribute to charge stability.
(1) Atom type and periodic table trends

________________________________
- The electronegativity and size
of charged atoms contribute to its ability to stabilize charge.
(2) Delocalization
____________________________
- All other things being equal, greater
charge delocalization leads to greater stability.
(3) Hybridization
________________________________
- All other things being equal, if
negative charge is localized on an atom, the greater the s-character of that
atoms hybrid orbitals, the greater the stability (for negative charge: sp is
more stable than sp2, which in turn is more stable than sp3). Conversely, if
positive charge is localized on an atom, the lesser the s-character of that
atoms hybrid orbitals, the greater the stability (for positive charge: sp3 is
more stable than sp2, which in turn is more stable than sp).
(4) Coulombic
_______________
Like charges repel; opposite charges attract.
Bond Energy Changes

Bond dissociation energies are a useful way to estimate chemical potential. Values for bond dissociation energies are
summarized in the table below. Note that by convention, all bond energies are assigned a negative value. In
working these calculations, be sure to note all bond changes that take place on both sides of the reaction arrow ().
An example is provided on the next slide. Hint: Drawing the implied hydrogen atoms is often VERY helpful!
Average Bond Energies (kcal mole-1)
Si
Cl
Br
104
99
83a
93
73b
39
111
86c
53e
47
135
116d
65
45
37
76
72
83
65
103
81
46
52
87
68
71
52
48
56
91
61
58
74
52
56
C=C 146, C C 200
108
135
53
60
C=N 147, C N 213
In CF4
46
c
C=O 176 (aldehydes)

In nitrites and nitrates
179 (ketones)
All bond energies are assigned a negative value by convention.
36
H
C
N
O
F
Si
S
Cl
Br
I
For a more extensive list see: http://www.jhu.edu/chem/lectka/Bond%20Strengths.html
Bond Energy Changes: Example Calculation

To determine the net change in bond energy, we first must
determine which bonds undergo change. For the reaction:
H
C C
H
H H
H
H Br
H C C Br
H H
the HBr and C=C double bond are broken. The energy of the C=C double bond is
not entirely lost, however, as the double bond becomes a CC single bond. Thus,
we will take this change into account by assuming that a C=C bond is broken and a
CC bond is made. Other new bonds include CH and CBr. The energies of all
bonds broken and all bonds made are then summarized as shown in the table below.
The reaction is favorable by 17 kcal/mol as a result of the increased net bond
strength. Note that this calculation is for bond enthalpies (H), not G.
Bonds changes (reactants)
bond
Energy (kcal/mol)
C=C
-146
H-Br
-87
Bonds changes (products)

bond
Energy (kcal/mol)
C-C
-83
C-H
-99
C-Br
-68
net
-233
net
-250
Overall change = bonds made bonds broken = (-250) (-233) = -17 kcal/mol
Recognizing Nucleophiles and Bases

Nucleophiles donate electrons
from their highest occupied MO
The usual order

of energy levels
The signatures of a nucleophile
energy
an electron rich atom, especially as revealed by negative formal charge

a nonbonded pair of electrons (a lone pair)
an electron pair in a pi bond
a partial negative charge revealed via resonance contributor(s)
strong bases tend to be strong nucleophiles
any species with a high-lying HOMO
*
*
a
n
Typical nucleophiles
HO
Cl
R
C C
H2O
CH3NH2
Nucleophilicity and HOMO Energy Level

Theres a good analogy between nucleophiles and bases. Just as some bases are stronger than others,
some nucleophiles are stronger than others. Whereas we speak of basicity to describe the strength of
bases, we speak of nucleophilicity to describe the strength of nucleophiles.
HOMO Energy Level
LUMO Energy of E+!
Given the LUMO energy

of E+ as indicated above:
Nu 1
Nu 2
Nu 3
Nu 4
Consider the series of

nucleophiles Nu 1 to Nu 4
with HOMO energies as
shown above!
Which frontier orbital

interaction will be the
strongest?
Which electron pair is the
most energized?
Which nucleophile has the
highest nucleophilicity ?
Recognizing Electrophiles and Acids

Electrophiles accept electrons
The usual order
into their lowest unoccupied MO
of energy levels
The signatures of electrophiles and acids
energy
an electron deficient atom especially as revealed by an incomplete octet (duet for

H) of electrons (e.g., carbocation, boron, H+)
a partial positive charge owning to a polarized H-X or C-X bond (polarization
results when H or C is bound to electronegative atom X or an atom X+ that
bears a positive formal charge such as [HNH3]+)
a partial positive charge revealed via resonance contributor(s)
a weak bond usually involving a pair of heteroatoms e.g., XY bonds like BrBr,
ICl, -OO strong acids tend to be strong electrophiles
any species with a low lying LUMO
*
*
a
n
Typical electrophiles
R
O CH3
R C
H
H
H B
H
+
R R
H3C O
Cl Cl
Electrophilicity and LUMO Energy Level
Consider the series of

electrophiles E+ 1 to E+ 4
with LUMO energies as
shown!
E+ 1
HOMO Energy of Nu!
E+ 2
E+ 3
E+ 4
LUMO Energy Level
Theres a good analogy between electrophiles and acids. Just as some acids are stronger than others,
some electrophiles are stronger than others. Whereas we speak of acidity to describe the strength of
acids, we speak of electrophilicity to describe the strength of electrophiles.
Given the HOMO energy
level of Nu as indicated:
Which frontier orbital
interaction will be the
strongest?
Which empty orbital is
most easily accessed?
Which electrophile has the
highest electrophilicity?
REACTIVITY CONCISELY SUMMARIZED: Continuing the acid/base analogy further, strong

nucleophiles will generally react with strong electrophiles just as strong acids and strong bases always
react. Such favorable reactions are expected from small frontier orbital HOMO-LUMO energy gaps.
Weak nucleophiles and weak electrophiles are not likely to react at all; the frontier orbital gap is too
wide in this case. A weak electrophile is likely to react only if it encounters a strong nucleophile; a
weak nucleophile is likely to react only if it encounters a strong electrophile.
Recognizing Acids and Bases

Acids and bases will be one of two types as illustrated by the two
equations below.
Type I
Type II
HX
Ka
acid
HX
acid
proton
Ka
proton
base
X
base
Acids:
Must have a hydrogen atom to donate
The most acidic hydrogen is often bound to a heteroatom (N, O, S, X)
In rare (but important!) cases, the acidic hydrogen is bound to carbon
Will be neutral or positively charged
Bases:
Must have a lone pair to accept a hydrogen
Will be neutral or negatively charged
Acid-Base Equilibria: Concepts & Definitions

Many protonation and deprotonation steps are reversible. The
equilibrium can be expressed in terms of pKa. Lets review the
+][A-]
meaning of pKa:
[H
O
3
Keq
Keq =
HA + H2O
H 3 O + + A[HA][H2O]
Assuming the [H2O] to be constant (55.5 M) i.e., [H2O]>>[H3O+], we
Ka = Keq[H20]
can define a new constant _________________
which allows us to
drop water from the above equilibrium expression. This is the basis
of the widely used pKa convention:
[H+][A-]
Ka
Ka =
+
[HA]
HA
H + A
Or
log Ka = log [H+] + log
[A-]
[HA]
-log Ka = -log [H+] + log

definition
pKa
pH
[HA]
[A-]
Relative conc. vs. pH

pKa = 5.2
HA
A- "
[HA]
+ log
[A-]
Henderson-Hasselbalch eqn.
pH
Determining the Position of Equilibria

Based on the magnitude of Keq, can we conclude that protonated alcohol is a reasonable species?
Keq
Keq can be calculated by analyzing this reaction as a sum of two acid / base equilibria
Relevant
equilibria
_______________
Ka(1)
Ka(2)
1
Keq = Ka(2)
Ka(1)
pKa
____
-2.5
-1.7
pKa = - log Ka
10-(-1.7)
Keq = = 0.16
10-(-2.5)
Acid-Base Equilibria in Organic Chemistry

1.
2.
3.
4.
5.
6.
7.
8.
Each side of the equation will have one proton donor and one proton acceptor (i.e., one acid
and one base will be on each side of the equation).
Charge must be balanced.
Stoichiometry must be balanced.
Draw all electron lone pairs on all structures to see what bonding takes place in the proton
transfer process. In cases where the proton donor is a C-H group, the implied hydrogen
atom must be explicitly drawn.
Some molecules have more than one acidic (or basic) site. Use the rules of charge stability
to determine the location to add (or remove) a proton. If necessary, check your guess with
the pKa calculator.
The position of the equilibrium is predicted (qualitatively) by consideration of charge
stability. If necessary, the pKa calculator can be used to check your guess.
The equilibrium arrows ( ) indicate the reaction is reversible. A longer arrow is drawn
toward the species favored at equilibrium.!
Curved arrows are added to show the flow of electrons.!
circle one
CH3
H
H3C
N
H
H
O
H
or
ACE Organic Requires Arrows to Be Drawn Carefully

STEP 1 - To begin, click on the electron
source. If the source is a lone pair, click
on the atom to which the lone pair
belongs. The cursor is correctly
positioned when you see the blue
STEP 3 - Prior to releasing the

mouse button, blue ( ) will indicate
the implied position of the new
bond. Release the mouse only when
the ( ) are correctly positioned.
STEP 2 - Move the cursor to the
electron pairs new location.
More About ACE Arrow Conventions

STEP 4 - Check each arrow after
releasing the mouse button. Move
the cursor to the arrows head. The
blue rectangle shows the implied
location of the new bond.
STEP 5 - The second arrow begins

from a bond (the electron source is
a bond). In this case, look for the
blue ( ) to signify the position of the
second arrows tail.
Final ACE Arrow Conventions

STEP 6 - The second arrow ends on
an atom. After releasing the mouse,
check that it looks like this. Here
the blue rectangle shows the bond
source.
STEP 7 - Once the arrows are drawn, finish drawing the structures. Take
advantage of ACE shortcuts. For example, double click on the structure
and copy it to the product box. Adjust the structure as required, but
dont draw it from scratch.
Commonly Used Acids and Bases

Proton transfer steps (protonation or deprotonation reactions) are an extremely common way to initiate chemical
reactions. Because of this, chemists frequently add acids or bases (often in sub-stoichiometric quantities) to
execute a variety of useful reactions. What do some commonly used acids and bases look like in practice?
Weve collected the common ones for you on this page.
oxygen bases
strong inorganic acids

HCl
weak nitrogen bases
hydrochloric acid
H2SO4 sulfuric acid

HNO3
Et
Et
Et
pyridine
(Py)
triethylamine
(TEA)
NaOH
sodium hydroxide
NaOMe
sodium methoxide
NaOEt
sodium ethoxide
KOtBu
potassium tert-butoxide
nitric acid
organic acids
strong bases
O
H3C
strong nitrogen bases
OH
sodium hydride
NaNH2
p-toluenesulfonic acid
(PTSA, TsOH)
sodium amide
CH3CH2CH2CH2Li
CH3COOH
acetic acid
O
F3C
S
O
OH
trifluoromethanesulfonic acid
(triflic acid, TfOH)
NaH
CH3
H3C
butyllithium
(nBuLi)
CH3
N
Li
CH3
lithium diisopropylamide
(LDA)
Conventions and Terms Used in Writing Chemical Equations

Chemists have developed a loose style for writing chemical transformations as equations. In a
typical equation, one or more reactants (also called substrates) are combined with a reagent(s),
and compounds are usually dissolved in a solvent. Reactions are often performed under
conditions of heat () or light (h). The conditions (solvent, temperature, etc.) are commonly
listed above or below the reaction arrow. Sometimes reagents are on the left side of the
reaction arrow, while other times reagents are listed above or below the reaction arrow. Very
often the stoichiometry is not balanced. The following example is illustrative.
O
LiI is the reagent. Dimethylformamide

(DMF) is the solvent. Here LiI is
written to the left of the reaction arrow.
O
OCH3
+ LiI
O
DMF ,
O
OCH3
LiI
DMF ,
Sometimes transformations are performed

by subjecting the substrate to a sequence of
reaction conditions. In such a case, the
conditions are listed numerically above and /
or below the reaction arrow, as shown.
Here LiI is written above

the reaction arrow.
Cyclohexanone is first treated with

H2NNH2 followed by KOH and heat.
1) H2N-NH2
2) KOH,
Common organic solvents: http://organicdivision.org/organic_solvents.html
Classes of Chemical Transformations

This page summarizes the main classes of chemical transformations. The purpose of presenting this overview is to
provide an organizational framework as an outline of upcoming studies. In learning new reactions you will benefit
from recognizing to which of the seven classes the new reaction belongs.
1) Acid-Base - hydrogen swap

Y
base
acid
acid
5) Elimination - loss of XY elements

with concomitant pi bond formation
6) Addition - gain of XY elements
with concomitant loss of pi bond
+ X
base
form bond
-XY
2 & 3) Oxidation & Reduction

change in the
H
replaces
number of C-H
X
bonds in relation
X reduction H
to the number of
C oxidation C
C-X bonds
X
replaces
H
4) Substitution - replace Cs
substituent (-X) with another (-Y),
neither being -H
Y
replaces
X
Y
X
C
Y
C
+ X
neither X nor Y being hydrogen
elimination
Z
addition
break bond
+XY
Z = C, N, O
7) Rearrangement - isomerization
process (no atoms lost or gained);
results in new bonding connectivity
(one of many examples shown as
there is no generic representation).
CH3
R
R
R stands for a generic "residue"
Substitution at sp3 Carbon: Examples

Nu + CH3Br
CH3Nu + Br
Substitution at sp3 Carbon: More Examples

Nu + CH3Br
CH3Nu + Br
Two Mechanistic Pathways for Substitution

This symbol means bimolecular
nucleophilic substitution
One step mechanism: [SN2] = [AN] + [DN]

[SN2] involves
-bond making
& breaking
Nu
C L
[SN2]
Nu C
An n *
-type interaction
Here bond making and breaking take place at the same time - a concerted process. Any one-step process is its
own elementary step. So well call the elementary step that results from concerted combination of [AN] + [DN] the
[SN2] step, which stands for nucleophilic, bimolecular substitution. Its bimolecular because two species must
come together. We need to re-consider the frontier orbitals involved in this new elementary step. The tail of the
first arrow implies the filled orbital (HOMO) is a non-bonded electron pair, n. The head of the first arrow points to
the empty orbital (LUMO, *) that accepts the electron pair. The empty orbital may not be obvious until you
realize that the C-L sigma bond breaks, as implied by the tail of the second arrow. Sigma bond breaking would
result upon filling * with the electron pair from n. The frontier orbitals align coaxially (a -type interaction).
Two step mechanism: [SN1] = [DN] then [AN]

The second pathway is a sequential combination of [DN] followed by [AN]. This sequential, two-step
mechanistic pathway is called unimolecular nucleophilic substitution, or [SN1]. The slowest step is the
unimolecular [DN]. process, hence the unimolecular in the name. The most important thing to realize is that the
[SN1] pathway will only be available if a stable carbocation can form.
C L
[DN]
[AN]
Nu
Nu
C
Substitution Mechanisms Require New Elementary Steps:

Nucleophile Dissociation [DN] & the Nature of Leaving Groups
Filled
-L is the
leaving group
C L
This symbol means a

dissociation of a nucleophile
[DN]
Empty a
[DN] involves a a
no-bond interaction
involved in an elementary step. The tail of the arrow implies the
filled orbital (HOMO) is electron pair. The head of the arrow
points to an atom on the leaving group (L) suggesting that an
atom-centered empty orbital (LUMO, a) accepts the electron pair.
The process produces no new bonding interactions. A good
leaving group will have a high energy and low lying a.
[DN] involves
sigma bond
breaking
+ L
empty
filled
#a
# a
# na
n #
# a
Substitution Mechanisms Require New Elementary Steps:

Nucleophile Association [AN]
Nu
is the nucleophile
This symbol means an
association of a nucleophile
Filled n
Nu
[AN]
[AN] involves
sigma bond
making
Nu C
Empty a
[AN] involves an n a
-type interaction
involved in an elementary step. The tail of the arrow implies the
filled orbital (HOMO) is non-bonded electron pair, n. The head of
the arrow points to an empty orbital on the carbocation,
suggesting that an atom-centered empty orbital (LUMO, a)
accepts the electron pair. A good nucleophile will have a high
energy n.
empty
filled
#a
# a
# na
n #
# a
Bimolecular Nucleophilic Substitution:

Simultaneous Bond Making and Bond Breaking
The [S
____
N2] pathway ( Substitution, Nucleophilic, Bimolecular )
HO
Br
HO
Br
HO
The TS of the rate-determining step involves

the association of ___
two molecules (bimolecular)
http://csi.chemie.tu-darmstadt.de/ak/immel/misc/oc-scripts/animations.html?structure=sn2
Unimolecular Nucleophilic Substitution:

Bond Breaking Precedes Bond Making
SN1 pathway ( Substitution, Nucleophilic, Unimolecular )
The ____
CH3
CH3 C+Br
slow
step
CH3
CH3 C
CH3
CH3
H
O
fast
step
CH3
CH3
CH3 C OH
Br
fast
step
CH3
H
H
H3O+
The TS of the rate-determining step involves

just one
___ molecule (unimolecular)
CH3 H
C O
CH3 H
H
Comparison of [SN1] and [SN2] Pathways

first step is the RDS for [SN1]
[SN2] ---[SN1]
http://www.chemtube3d.com/
Structure-Reactivity and the Haloalkane

favors
SN1
Governed by
electronic factors
Carbocation stability
Access to the site of reaction

Governed by
steric factors
favors
SN2
Recognizing Leaving Groups (L)
-7
-9
-10
This general trend holds for [SN2], [SN1] and other reactions that well study
Increasing leaving ability
3.2
Increasing basicity X
pKa
___
Increasing acidity HX
Leaving group reactivity correlates to basicity.

The ______
weaker the base, the ______
better its leaving ability.
From Paula Y. Bruice Organic Chemistry 4th Ed.

Pearson
Why Does L Correlate to Basicity?

In the TS (RDS), the leaving group develops negative
charge; thus, the ability of a group to function as a leaving
group is related to the stability of the corresponding anion
Nu
TS for SN2
+C
TS for SN1
The List of Good Leaving Groups is Short
>
>
>>
>
Increasing reactivity
Not only is it important to recognize what

qualifies as a good -L, but it is equally
important to recognize what is not a good -L
increasing nucleophilicity
Nucleophile Reactivity
good
moderate
poor
Nucleophilicity and Basicity

Increasing Nucleophilicity
nucleophile
<
<
conjugate
acid
pKa
4-5
15.7
17
In a series of nucleophiles with the same nucleophilic atom,

the stronger the base, the greater the nucleophilicity.
Nucleophilicity of Neutrals vs. Anions

<
<
<
In a series of nucleophiles with the same nucleophilic
anionic nucleophiles are stronger than neutrals
atom, _______
Nucleophilicity of Nucleophiles in the Same Row

row 2
<
<
<
basicity
row 3
<
<
Within a row, nucleophilicity increases from right

to left and tracks with________
basicity
(regardless of solvent type)
Solvents Influence Nucleophilicity

Nucleophilicity also depends on the _______
solvent
solvation
The interaction between solvent and nucleophile: ________
In polar _______
aprotic solvents (DMSO, acetone, acetonitrile,
DMF) relative nucleophilicities parallel relative basicities.
DMSO
Reason: Cations are effectively solvated
but anions are poorly solvated and thus
the nucleophile is not shielded by solvent.

Pearson
Nucleophilicity and Solvent

In polar ______
protic solvents, the solvent shell is tightly held
hydrogen bonding
around the nucleophile due to _______________
The smaller the ion, the tighter the

solvent shell. Thus, for nucleophiles
of different size (moving up or down
larger the
in the periodic table) the ______
better the nucleophile
size, the ______
(opposite to base strength).
Modified from Paula Y. Bruice Organic Chemistry 4th Ed.

Pearson
Nucleophilicity of Nucleophiles in Different Rows

solvent
Polar aprotic
<
<
<
basicity
Polar protic
<
<
<
Summary
1.
2.
3.
4.
Substitution reactions at 1 and 2 (but not 3) C(sp3) centers usually

proceed by the SN2 mechanism under basic or neutral conditions.
Substitution at C(sp2) centers rarely (if ever) occurs by the SN2 mechanism.!
Leaving group ability: !
The weaker the base, the better is the leaving ability.!
F, OH, RO (except epoxides), H, and carbanions are almost never

leaving groups in [SN1] or [SN2] reactions.!
Nucleophilicity (an aprotic solvent like DMSO): !
The stronger the base, the stronger the nucleophile.!

Nucleophilicity (in a protic solvent like methanol):!
Neutrals are poorer nucleophiles than anions.!
Comparing nucleophilic atoms that are in the same row, the stronger
the base, the stronger the nucleophile.!
Comparing nucleophilic atoms that are in the same column, the larger
the atom, the stronger the nucleophile.!
Elimination Across sp3 Carbons

Next we examine a class of elimination reactions to produce carbon-carbon multiple bonds. We recently studied
substitution reactions at sp3 carbon atoms. Elimination and substitution are competing reactions; some mechanisms of
elimination and substitution have common intermediates.

Y
base
acid
acid

+ X
base
form bond
-XY

change in the
H
replaces
number of C-H
X
bonds in relation
X reduction H
to the number of
C oxidation C
C-X bonds
X
replaces
H
neither being -H
Y
replaces
X
Y
X
C
Y
C
+ X
elimination
Z
addition
break bond
+XY
Z = C, N, O
CH3
R
R
Elimination Across Carbon-Carbon Bonds:

Three Examples
H
H C H
H C CH2CH3
KOH
Br
CH3
CH3 C Br
CH3
CH3
H2O,
C
C
C
C
KOH
KBr
CH2CH3
CH3
+
H
OH
HOH
HOH
Br
The Relative Stability

of Carbon-Carbon Double Bonds
Alkenes are hydrocarbons that contain the double bond functional group. Alkenes are also called olefins and they
are said to be unsaturated compounds meaning that their carbon atoms do not have the maximum number of
allowed substituents (4 for carbon). As explained on the following page, heats of hydrogenation can be used to
determine stability for alkenes that differ by their degree of alkene substitution. The general conclusion is that
the more alkyl substituents that are bonded to sp2 carbons of an alkene, the more stable is the double bond.
Heats of Hydrogenation and an Experimental

Determination of Alkene Stability
H2 +
CH3
CH3
CH3
The addition of hydrogen to

carbon-carbon double bond is
known as hydrogenation. This
reduction reaction transforms
alkenes into alkanes.
The
conditions and mechanism of the
reaction do not concern us at this
time. We are going to use this
reaction
to
experimentally
determine the relative stability of
alkenes.
H2 +
1.0 kcal/mol
trans
isomer
CH3
cis
isomer
-28.6 kcal/mol
-27.6 kcal/mol
H H
butane
CH3 C C CH3
H H
The heat produced by a reaction is accurately measured by a calorimeter. Lets compare the hydrogenation of cis and
trans 2-butene. Both reactions yield the same product, butane. The enthalpy change for the trans isomer is 27.6 kcal/
mol whereas for the cis isomer the enthalpy change is 28.6 kcal / mol. Since both reactions yield the same product,
we know that the energy difference comes from the difference of the starting alkenes. The diagram illustrates this
result, and shows that the trans isomer is more stable than the cis isomer by about 1.0 kcal/mol. The origin of this
stability difference is a steric interaction between the methyl groups. You can use MarvinSketch to convince yourself
of the close proximity of the methyl groups in the cis isomer.
Elimination Mechanisms Require New Elementary Steps:

Electrophile Dissociation From an Adjacent Carbocation
-E is the electrophile
(-E is often an -H, hydrogen)
Filled E
C C
This symbol means

dissociation of an electrophile
[DE]
C C
Empty a
[DE] is a a
-type interaction
involved in the elementary step. The tail of the arrow implies the
filled orbital (HOMO) is an electron pair in a -bond. The head of
the arrow points between two carbon atoms and suggests a new
-bond. An empty orbital on the carbocation is available to
accommodate this electron pair implying that the LUMO is an
atom-centered, empty orbital (a). The HOMO (-orbital) is beside
(and nearly parallel to) the LUMO (a) allowing for a -type
interaction.
empty
[DE] involves
-bond breaking,
-bond making
filled
$a
$ a
$ na
n $
$ a
Elimination Mechanisms Require New Elementary Steps:

Beta Elimination [E]
-L is a leaving group
Empty * L
Filled n
C C

This symbol means beta elimination
[E]
C C
[E] involves
-bond making
-bond breaking
L (C) is defined as the carbon

The alpha carbon
bearing the leaving
+ L
C Y groups
C group,
Y -L. Many leaving
[E], even poor ones (e.g., -OH).
(-L) participate in
The new -bond is formed across the C-C bond.
involved in this elementary step. The tail of the first arrow implies
that the filled orbital (HOMO) is a nonbonded electron pair, n. The
head of the first arrow points between two carbon atoms
suggesting in a new -bond. An empty, low-lying *-orbital from
the adjacent C-L bond is available to accommodate this electron
pair suggesting the LUMO is *. The HOMO, n, is beside (and
nearly parallel to) the LUMO, *, allowing for a -type interaction.
[E] is an n *
-type interaction
empty
filled
$a
$ a
$ na
n $
$ a
There are Three Mechanistic Pathways for Elimination

H
pathway
[DN]
$
L
BH
[pt]
B:
[DE]
[E1]
[DN] then [DE]
(two-step)
[E]
BH + L
[E1cb]
[pt] then [E]
(two-step)
[E2]
[pt] + [DN]
(concerted)
The three elimination pathways differ in the timing of the leaving groups departure. In the unimolecular elimination,
[E1], the leaving groups departs in the first step via a [DN] process. In the [E1cb] (conjugate base variant of the
unimolecular elimination), the leaving group departs in the second step via a [E]. In the [E1cb] mechanism, a
strong base must be present, the leaving group will generally be poor, and the beta hydrogen must be acidic. In the
bimolecular elimination pathway, [E2], the leaving group leaves at the same time as the beta hydrogen is loss. This is
a one-step, concerted process with [pt] + [DN] happening in unison.
[E2] is a Concerted Elimination Pathway

All bond breaking happens simultaneously with pi-bond
making. The [E2]
___ pathway (Elimination, Bimolecular)
The TS for the rate

determining step involves
2
the association of ___
molecules (bimolecular).
Many frontier orbitals are involved in the [E2]

pathway. Theres an n -type interaction
between ethoxide and the beta hydrogen. Theres
a -type interaction between the beta C
H and the CX bond. Theres a a no-bond
interaction leading to leaving group dissociation.
http://www.chemtube3d.com/index.html
Regiochemistry of [E2] Elimination Reaction

[E2]: Double bond character is _______________
highly developed in the TS so the
relative stability of possible C=C determines the major product.
'
'
'
major
minor
Product Ratios for [E2] Elimination Reactions Generally

Follow Stability of Developing Double Bond in TS
Label the energy
parameter that
determines the
product ratio
[E1] Is a Two-Step Elimination Pathway

Bond breaking precedes bond making. The [E1]
___
pathway (Elimination, Unimolecular )
"
"
The [SN1] and [E1]

mechanisms proceed through
a ________
common intermediate
http://www.chemtube3d.com/Elimination%20-%20E1.html
Regiochemistry of [E1] Elimination Reactions
The major product is the more

substituted alkene. Why?
As before, this has to do with the
stability of the developing double bond
in the TS
Consider the Developing Double Bond Character

in Each TS
+
[E2] Regiochemistry Exceptions

(When the Less Substituted Product is Major)
A bulky base is used
The leaving group is ___
F
A conjugated double bond can form
major
major

F
When the leaving group is a poor one (e.g., -F), deprotonation precedes C-L bond breaking
and negative charge begins to accumulate on carbon. In these cases, the reaction
mechanism resembles the [E1cb] pathway. These reactions follow the pathway of the most
stable carbanion (carbanion stability increases as the number of C-H increases).

F
major
major
http://www.chemtube3d.com/Elimination%20-%20E2.html
Summary
1.
2.
3.
C(sp3)X electrophiles can undergo -elimination reactions as well as

substitution. The -carbon is the carbon adjacent to the electrophilic C atom.
Electrons in the CH bond form a bond with the electrophilic C atom. "
Under basic conditions, elimination proceeds by the [E2] mechanism. Under
neutral or acidic conditions, elimination proceeds by the [E1] mechanism."
Like the [SN2] mechanism, the [E2] mechanism is a concerted process. A
reaction is said to be concerted if bond breaking and bond making occur
simultaneously.
E2 Promoting Factors
Br
check the boxes corresponding to the conditions that favor the E2 mechanism
strong base (CH3O)
CH3
CH3CH2
weak base (CH3OH)
CH3
H
C CH3
CH3
small base (HO)
C CH3
X
large (bulky) base ((CH3)3CO)
heat ( )
no heat
http://wps.prenhall.com/wps/media/objects/725/742549/0044f.html
Stereochemistry of the [SN2] Pathway

Stereospecific Reaction: A reaction in which the stereochemistry of the reactant completely
determines the stereochemistry of the product without any other option.
Stereoselective Reaction: A reaction in which there is a choice of pathway, but the product
stereoisomer is formed preferentially because its reaction pathway is more favorable than
the others available.
The SN2 reactions proceeds with inversion

_______ of configuration.
Stereospecific or Stereoselective?
Stereochemistry of the [SN1] Pathway
Starting with a
single enantiomer
planar
carbocation
(achiral)
The nucleophile will attack both

faces of the planar carbocation
with equal probability resulting in
a racemic mixture.
Stereochemistry of the [E2] Pathway

The [E2] reaction pathway has very specific requirements:
There must be ________________
continuous overlap among the orbitals in
which bonds are made/broken and bonds are made.
Conformational Requirements of [E2] Elimination

(1) X and H oriented anti-periplanar
(2) X and H oriented syn-periplanar

For steric reasons, the preferred pathway for [E2] elimination is
through (1). The double bond geometry depends on which
pathway is followed. Consider the following example:
The carbon atoms smoothly

rehybridize from sp3 to sp2
Heres another example:

http://www.chemtube3d.com/EliminationE2stereospecific.html
[E2] Pathway in Cyclic Compounds
In cyclic compounds, anti-periplanarity demands that

the groups to be eliminated occupy _____
axial positions.
This requirement has important consequences

on rates and regiochemistry of elimination
reactions involving substituted cyclohexanes
[E2] Elimination in Substituted Cyclohexanes

Explain the reason for the difference in relative rates and
regiochemistry in the following examples:
[E2] Reactions in Substituted Cyclohexanes: Example A
Two anti-periplanar pathways are possible

from the most stable chair conformation.
The observed product follows the pathway
leading to the more substituted alkene
http://www.chemtube3d.com/EliminationE2regioselectiveA.html
[E2] in Substituted Cyclohexanes: Example B
nar
a
l
p
eri xists
p
i
t
e
n
No a onship
ti
rela
ring-flip
http://www.chemtube3d.com/EliminationE2regioselectiveB.html
An anti-periplanar arrangement exists only

in an unstable conformation (slow rxn
rate) Only one anti-periplanar pathway
exists (regiochemistry)
[E2] Pathways in Acyclic Compounds
The major product eliminates via a pathway

with the bulky groups on opposite sides.
trans
The carbon atoms
smoothly rehybridize
from sp3 to sp2
Which -H is this?
cis
Stereochemistry and the [E1] Pathway

There is no anti-periplanar requirement for the
[E1] pathway. The carbocation intermediate
undergoes rotation about the single bond.
Summary
Orbital alignment requirements in the [SN2] and [E2] pathways have
stereochemical consequences.
The
* sigma-type interaction of the [SN2] pathway results in
inversion of configuration at carbon.
In the [E2] pathway, the C H bond and the C X bonds break
simultaneously; these bonds must be parallel to one another to allow
the orbitals involved to be properly aligned.
Acyclic compounds can orient the two bonds in two ways:
synperiplanar (eclipsing at a 0 dihedral angle) or antiperiplanar
(staggering at a 180 angle). The antiperiplanar conformation is
generally lower in energy and the reaction usually proceeds
through this conformation.
In cyclic compounds, there are much greater restrictions on
conformational flexibility. In six-membered rings, the
antiperiplanar requirement for [E2] elimination is satisfied
when both the leaving group and the adjacent H atom are axial.
In principle, any lone pair can act as either a base or a nucleophile
toward C(sp3)X. Thus, it is sometimes difficult to decide if a
reaction will follow the [E2] or [SN2] pathway. The competition
between substitution vs. elimination depends on two factors: (1) the
nucleophilicity vs. basicity of the lone-pair and (2) the identity of the
alkyl halide substrate (1, 2, 3). The table summarizes the behavior.
Factors determining substitution vs. elimination under basic conditions

Alkyl halide
good nucleophile poor base good nucleophile good base poor nucleophile good base
1
SN2
SN2
E2
2
SN2
SN2 < E2
E2
3
E2 or no reaction
E2
E2
Examples of good nucleophiles and poor bases: Br, I, RS
Examples of good nucleophiles and good bases: RO, R3N, RCC
Example of poor nucleophile and good base: t-BuO
Carbocation Intermediates
Carbocations are common intermediates in organic chemistry. We have
encountered carbocations in [SN1] substitution and [E1] elimination.
Although carbocations are never present in very high concentrations
(because they are unstable and highly reactive), they do open up a
reaction pathway through which important chemistry ensues.
Carbocations have a carboncentered empty p-orbital
C
carbocation
6-electron species
trigonal planar geometry
sp2 hybridized
empty p orbital on carbon
H
H
methyl cation
least stable carbocation
bonds directly attached to
the carbocation do not
share their electron density
H
H2C
eth
stabilized b
bonds dire
carbocatio
share their
Stability of Carbocation Intermediates

Certain carbocations are more easily formed than others. Only if the carbocation can be formed easily
does it open a viable pathway. We thus need to understand how carbocation stability relates to structure,
and how this structure relates to reactivity. A simple rule predicts stability for carbocations: the more
nonhydrogen substituents attached to a carbocation, the greater is its stability.
Increasing stability
-type a Resonance Interaction Stabilizes Carbocations

Why are substituted carbocations more stable than unsubstituted carbocations? The carbocation is
a 6-electron species; any atom (or bond) that supplies this electron deficient carbon with electron
density increases its stability. Electrons in bonds that are directly attached to the carbocation do
not offer any help because the filled and empty orbitals are perpendicular and incapable of
overlapping. However, electrons in bonds that are one atom away from the carbocation center
are able to donate some of their electron density through a a (-type) interaction.
The a filledempty orbital

interaction of hyperconjugation
H
H
H
H2C
H
H
methyl cation
least stable carbocation
ethyl cation
stabilized by hyperconjugation
bonds directly attached to

the carbocation do not
bonds directly attached to a

carbocation substituent do
http://www.chemtube3d.com/index.html
Carbocation Intermediates Undergo

Rearrangement Reactions via 1,2-Shifts
We have encountered carbocations in [SN1] substitution and [E1] elimination. Any
reaction that proceeds through carbocation intermediates may undergo a type of
rearrangement reaction known as the 1,2-shift (also called 1,2-rearrangement). Recall
from the seven classes of reactions that a rearrangement is a reaction with only a
change in bonding connectivity. Typical groups undergoing 1,2-shifts are hydrogen
(hydride shift), methyl (methyl shift), and C-C bonds in rings (ring expansion).
These reactions are driven by formation of a more stable carbocation. The reactions
may be reversible. It is possible for hydride and methyl migrations to take place over
longer distances. However, when longer migrations do occur, they usually take place
via a sequence of successive 1,2-shifts, not by a single-step, long-distance pathway.
H3C
CH3H
CH3
a long-distance
migration is the result of
successive 1,2-shifts
a secondary
carbocation
CH3H
a tertiary
carbocation
H
1,2-shift
H3C
H3C
H
C
CH3H
a secondary
carbocation
CH3
1,2-shift
CH3
Carbocation Rearrangements Require a New Elementary

Step: The 1,2-Rearrangement [1,2R]
-Y is the group undergoing the 1,2-shift
-Y is typically -H, (hydride shift) or -CH3
Filled
Y
C C
This symbol means a 1,2-rearrangement
[1,2R]
[1,2R] involves
-bond breaking,
-bond making
C C
Empty a
The 1,2-shift involves migration of a sigma bond (its electrons and
the attached atoms to that bond) from a carbon that is adjacent to
the carbocation onto the carbocation. It is illustrated for the
generic group labeled Y. The 1,2-numbering reflects the fact
that the migration takes place from atom labeled 1 to the
adjacent atom labeled 2.
[1,2R] involves a a
-type interaction

involved in the elementary step. The tail of the arrow implies the
filled orbital (HOMO) is an electron pair in a -bond. The head of
the arrow points to the electron deficient carbon. An empty orbital
on the carbocation is available to accommodate this electron pair
implying that the LUMO is an atom-centered, empty orbital (a).
The HOMO (-orbital) is beside (and nearly parallel to) the
LUMO, a, allowing for a -type interaction (-type overlap is not
possible due to bonding constraints).
empty
filled
$a
$ a
$ na
n $
$ a
An Example of Ring Expansion

CH3
C C
[1,2R]
CH3 H
a strained
4-membered ring
CH3
C C
CH3 H
C CH3
C
H
CH3
less strained
5-membered ring
The way it looks in ACE Organic

Step 2
Step 3
Step 1
either way
is fine
Step 4
Step 5
Rearrangements May Intervene in the [SN1] Pathway!
2 carbocation
3 benzylic
carbocation
Encountering New Chemical Reactions

Write mechanisms for the following reactions. Use clear, carefully drawn structures and precise curved
arrow notation for all steps. Provide distinct structures for all intermediates. Show resonance
contributors and electron lone pairs where necessary.!
CH3
H3C CH3
CH3
CH3OH,
Cl
H3C
CH3
CH3
Br
CH3
CH3
CH3OH,
CH3
The steps of writing reaction mechanisms

make sure the overall stoichiometery is balanced
draw implicit hydrogen atoms wherever they might be important (e.g., on carbon atoms of reactants
and products near to where the bond changes takes place)
list the bonds made and broken
identify nucleophiles, bases, electrophiles and acids; repeat for each step of the mechanism
draw curved arrows to show the flow of electrons
make sure charge is balanced for each step of the mechanism
find a reasonable pathway that leads to the products
look for hidden reactivity by drawing resonance contributors for each intermediate
work backwards if you get stuck
Reactions at sp3 Carbon:

Leaving Groups Other Than Halogen
In this lesson we will reason by analogy to predict the outcome
of new reactions (e.g., predictions of leaving group ability)
Breaking CO bonds:
OH is a poor leaving group and does NOT directly
participate in [SN1], [SN2], [E1] or [E2] reactions.
Why is OH a poor leaving group?
Why OH is a Poor LG
-10.0
-9.0
15.7
Protonation of an Alcohol
Improves the Leaving Group Ability
___
LG
_____________
Conjugate Acid
pKa of
____________
Conjugate
Acid
H 2O
H3O+
-1.7
Protonated Alcohol as a Leaving Group
Reactions of Protonated Ethers

[SN2] or [SN1] pathway depending on:
steric accessibility of nucleophile
stability of carbocation
If a stable carbocation can form, the reaction
will follow the [SN1] pathway (otherwise [SN2])
[SN2]
[SN1]
Examples - Nucleophilic Substitution
Examples - Water Elimination (dehydration)
Activated Alcohols Based on PBr3
Nucleophilic attack
on phosphorus by
oxygen
PBr3 is an electrophile
OH,
a poor leaving group

is converted into this good
leaving group
Activated Alcohols Based on SOCl2
Nucleophilic
attack on sulfur
by oxygen
Activated Alcohols Based on Sulfonate Esters
sulfonyl
chloride
sulfonate
ester
-1.0
Common Sulfonyl Chlorides
(tosyl
abbreviated Ts)
(mesyl
abbreviated Ms)
(triflyl
abbreviated Tf)
Ethers and Epoxides

a 3-membered
cyclic ether
Like alcohols, ethers are poor leaving groups. They can be

activated by acids or _______
strain (epoxides are strain-activated ethers)
Protonation
pKa = ?
-3.6
Complete the diagrams

(use the link for help)
Summary:
Converting
Alcohols,
Ethers and
Amines
into Leaving
Groups
http://wps.prenhall.com/wps/media/objects/725/742646/0048f.html!
Leaving Groups
Br
CH3CH2O H
P Br
CH3CH2O P
Br
a bromophosphite
Br
O
CH3O H
Cl
Cl S Cl
CH3O S
a chlorosulfite
Cl
O S O
CH3CH2CH2O H
C N
S
a tosylate
O
O
+
H
OH
H O S OH
H2SO4
Cl P Cl
Cl
O P Cl
Cl
CH3
CH3 O C CH3
H CH3
CH3 O C CH3
CH3
CH3CH2CH2NH2
CH3
CH3I
K2CO3
H H CH3
CH3 C C N CH3
Energetics of Epoxide Reactions

Epoxides are more reactive than ethers because
the strain is released when the ring opens
Epoxides react faster because their ground state is ___________
destabilized
relative to ethers (by about ___
25 kcalmol-1)
G ~ 25 kcalmol-1
G
G
25
Acid-Catalyzed Ring Opening

([pt] then [SN2])
[pt]
+
+
[SN2]
[SN2]-like in that nucleophilic attack follows backside displacement

[SN1]-like in that the regiochemistry places the nucleophile on the
more substituted carbon
Regiochemistry Rationalization
carbocation character in the
Because there is some ____________
TS, attack occurs at the carbon better able to bear a
partial positive charge.
protonated
intermediate
2nd best
resonance contributor
Wheres the Site of Electrophilicity?

Two Pathways NOT Followed
H
Option 1
[AN] at O+
H
O H
CH3
Nu
H
O Nu
CH3
oxygen
exceeds octet
the nucleophile does NOT attack the

positively charged oxygen via [AN] as there
is no empty orbital centered on this atom."
Option 2
[SN2] at O+
H
O H
CH3
Nu
H
O Nu
charges are
CH3 not reasonable
[SN2] at carbon (NOT oxygen) is most reasonable.

Why? On which atom of CO+ is * largest? Draw
an MO diagram to illustrate these differences.
Ring Opening Under

Nucleophilic (Basic) Conditions
[SN2] backside
attack at less
hindered carbon
Many Nucleophiles React with Epoxides
Summary of
Epoxide Reactivity
Complete the diagrams (use the link for help)
http://wps.prenhall.com/wps/media/objects/725/742646/AADFQQH0.html
Ring Opening of Epoxides

OH
acidic conditions
O
OCH3
H2SO4 (cat.)
CH3OH
OCH3
OH
HOSO3H
HOCH3
O
1
OCH3
basic conditions
OH
O
CH3ONa
CH3OH
OH
OCH3
O
O
product
HOCH3
Carbon-Based Nucleophiles
A special class of carbon-centered nucleophiles
organometallic compounds
are _____________
M is less electronegative than C
"
+"
These organometallic compounds are strongly basic
The carbon acts as an

_______
anionic nucleophile
<
<
Increasing stability
<
Preparation and Reactions

of Carbon Nucleophiles
Organolithium
Grignard (Organomagnesium)
New CC bond
Summary
1) Heres an important general rule to be followed in writing all reaction mechanisms. If a reaction is executed
under acidic conditions, no strong bases can be present. Any negatively charged species must be a weak
base (e.g., Cl). If a reaction is executed under basic conditions, no strong acids can be present. Any
positively charged species must be a weak acid.
2) Under basic conditions, a hydroxyl group cannot be substituted directly because HO is too poor of a leaving
group. The hydroxyl group must first be transformed into a derivative that is a suitable leaving group.
3) Under acidic conditions, the R3CX+ bond can ionize spontaneously to give X: and R3C+. The likelihood of
ionization depends on the stability of the carbocation product, the leaving group and the solvent.
4) Under acidic conditions, a lone pair nucleophile bearing a proton (e.g., H2O, ROH, RCO2H, RNH2) is always
deprotonated after it adds to the electrophile (e.g., carbocation).
5) Under acidic conditions, epoxides open by attack of the nucleophile onto the protonated ring. The
nucleophile attacks the most highly substituted carbon.
6) Under basic conditions, epoxides open by nucleophilic attack onto the least substituted carbon (the reaction
resembles an SN2 reaction; the leaving group is a poor one, but the process is driven by the release of ring
strain).
7) If carbocations are intermediates, rearrangement is possible.
Electrophilic Addition Reactions - Adding XY

Across
Unsaturated
Carbon-Carbon
Bonds
This page summarizes the main classes of chemical transformations. Having studied the process of elimination, we are
now set to examine the reverse reaction - addition of the elements XY across carbon-carbon multiple bonds.

Y
base
acid
acid

+ X
base
form bond
-XY

change in the
H
replaces
number of C-H
X
bonds in relation
X reduction H
to the number of
C oxidation C
C-X bonds
X
replaces
H
neither being -H
Y
replaces
X
Y
X
C
Y
C
+ X
elimination
Z
addition
break bond
+XY
Z = C, N, O
CH3
R
R
Examples of Addition Reactions

to Carbon-Carbon Double Bonds
CH3
1
CH3
+ HBr
1
Br
H2C CHCH3
+ H2O
2
H H
H
H2C C CH3
H OH
a non-nucleophilic
solvent (i.e., inert)
Br Br
CH2Cl2
Br
cyclopentene
Br
a nucleophilic solvent
participates in the reaction
+
cyclopentene
Cl Cl
H2O
H
Cl
a vicinal dibromide (or

vic-dibromide for short)
a chlorohydrin
H
OH
+ HCl
Addition Mechanisms Require a New Elementary Step:

Association of an Electrophile with a -bond [AE]
E+ is the
electrophile
Empty a
This symbol means an electrophile

association with a -bond
[AE]
Filled
[AE] involves
-bond breaking and
-bond making
[AE] involves a a
-type interaction
empty

involved in an elementary step. For [AE] the tail of the arrow
implies the filled orbital (HOMO) is an electron pair in a pi-bond.
The head of the arrow points between one carbon atom of the bond and the E+ suggesting that an atom-centered empty orbital
(LUMO, a) accepts the electron pair with -type orbital interaction
(note: the HOMO for [AE] will always be but the LUMO will vary
according to the specific E+ involved).
filled
#a
# a
# na
n #
# a
The Electrophilic Pathways for C=C Addition

(two variations of [AdE2])
Two-step mechanism: [AdE2] = [AE] then [AN]
E
C C
[AE]
E
C C
[AN]
E
C C
Nu
Nu
When E+ has no
lone pair (e.g., H+)
Two step mechanism: [AdE2] = [AE] then [SN2]

E
C C
[AE]
E
C C
[SN2]
Nu
When :E+ has a

lone pair (e.g., :Br+)
E
C C
Nu
Depending on whether or not the electrophile has an electron lone pair will determine the nature of the
intermediate resulting from the [AE] step. If the electrophile has a lone pair, then a 3-membered intermediate
will form in order to satisfy the octet rule. If no lone pair exists on E+, then [AE] results in a carbocation.
[AE] Drawn
in ACE
Addition of H-Br
When the Electrophile Has No Lone Pair,
[AE] Gives a Carbocation Intermediate
H
Draw the
1st arrow
After the
2nd arrow
C C
H
[AE]
Check the
1st arrow
H H
H
H Br
H C C Br
H H
H
H
H
C C
[AN] Drawn
in ACE
Check the
arrow
[AN]
H Br
intermediate
Draw the
arrow
http://aceorganic.pearsoncmg.com/epoch-plugin/public/mechmarvin.jsp
Clean in 2D
Reaction Coordinate Diagram for the [AdE2] of

HBr to Ethylene
Br
free energy
H
H
+ H
C
H
H
H
H
H2C CH2
C C
H
H
H
+ H
C C H
Br
H
H Br
intermediate
HBr
CH3 CH2Br
Unsymmetrical Alkenes
CH3
CH3
HBr
this carbon bears
no hydrogen atoms
an
unsymmetrical
alkene
this carbon bears

one hydrogen atom
CH3
+
Br
H H
major
H Br
minor
The first step of the mechanism involves the formation of a carbocation intermediate. Because
the alkene is unsymmetrical, there are two possible carbocations that can form. The relative
stability of these carbocation intermediates (technically, the transition state leading to these
intermediates) determines which product is formed the fastest. Hammonds postulate allows us
to predict the relative energy of the TSs leading to the two possible intermediates. Draw a
representation of the transition state structures for both modes of reactivity. Your representations
should show that one begins to develop character of a secondary carbocation, while the other
develops character of a tertiary carbocation. The TS leading to the secondary carbocation is a
higher energy species comparied to the TS leading to the tertiary carbocation intermediate.
Thus, the secondary carbocation pathway represents a higher barrier to reaction. In contrast, the
TS leading to the tertiary carbocation is a lower energy species, and thus represents a lower
barrier to the reaction pathway. The reaction coordinate diagram illustrates this logic and helps
explain why the major observed product results from attack of bromide on a tertiary carbocation.
Start from the reactants. Notice the pair of diverging pathways, one leading to the major product
and the other leading to the minor product.
Diverging Reaction Pathways

The relative energies of these TS can be determined because:
1)
Both steps are examples of a late TS
2)
The structure and energy of each TS will track according to
the carbocation intermediate to which it is en route
Acid-Catalyzed Addition of Water or Alcohols to Alkenes
H2O
Balance charge
at every step
Step 1 combines
neutral reactants
and H+. The
charge at the end
of step 1 must be
+1.
CH3
H
C C
H
H
H
step 1
OH
H
CH3
[AE]
H2O
[AN]
step 2
step 3
CH3
[pt]
Step 2 combines
the positively
charged
intermediate
from step 1 and
neutral H2O.
The 2nd
intermediate
must also have a
+1 charge.
Notice first, that the stoichiometry is balanced. Water is probably the solvent of this reaction, and in this case, it
participates in the reaction, too. Such behavior where the solvent gets incorporated into the product is fairly common in
organic chemistry. In contrast to water, the H+ above the equilibrium arrow does not enter into the stoichiometry.
However, H+ does play an important role. If you were to combine water and an alkene without any acid, no change will
take place for a long time, at least not at lower temperatures. These observations point to the notion that the reaction is
catalyzed by H+, meaning that acid enhances the rate of the reaction, but does not show up in the stoichiometry. So, when
you see H+ or HO listed above the arrow, but not enter the stoichiometry, think about acid or base catalyzed reactions.
Complete the mechanism, reasoning by analogy to the [AdE2] mechanism for H-Br addition to an alkene.
Rationalizing Br2 and Cl2 As Electrophiles

Reagents such as Cl2, Br2, I2, and ICl are electrophiles that add to alkenes. We will see that
these reactions follow the [AdE2] mechanism with a slight variation, as a consequence of the
lone pair on these electrophiles.
First, how can these reagents be rationalized as
electrophiles? The answer is that they have weak bonds and low lying empty * orbitals.
The resonance picture below may help build your intuition about structure and reactivity.
Very often the second best resonance contributor provides insight about reactivity.
Addition of Br2 to an Alkene
When the Electrophile Possesses a Lone Pair,

[AE] Gives a Halonium Ion Intermediate
CH2Cl2 (DCM)
a non-nucleophilic solvent
Br Br
Br
[AE]
CH2Cl2
Br
Br
[SN2]
Br
Here bromonium ion

formation is written as
[AE] then [AN]
H
Br
[AN]
H
H
Br
Br
This carbocation does not
satisfy the octet rule, yet
there is a way to do so.
Br
This bromonium ion satisfies the octet rule.
It's true that it is highly strained and has a
positive charge on an electronegative atom;
nonetheless, this is a better structure than
an electron deficient carbocation.
[AE] of Br2 to a Carbon-Carbon - Bond

It is possible to proceed
directly to the bromonium ion
from Br2 and alkene by
combining [AE] and [AN] into
one step. This reflects the fact
that the carbocation may not
be an intermediate on the
MEP for this reaction. The
curved arrow notation might
seem complex, but shows all
of the electron reconfiguration
that accompanies this process.
The overall process is [AE], an
association of the electrophile,
Br2, with C=C -bond. The
curved arrows imply a pair of
filled-empty (frontier) orbitals
for this step:
*
n *
curved arrow notation for direct

formation of bromonium ion
n *
Br Br
[AE]
H
Br
Br
What it looks like in ACE Organic
Draw the
1st arrow
After the
2nd arrow
Expressed in words, weve

combined the alkenes HOMO
with Br2s LUMO ( *),
and weve combined Br2s
HOMO with the alkenes
LUMO (n *).
Draw the
3rd arrow
After the
3rd arrow
Clean in 2D
A Bromonium Ion Behaves Much Like

Reason by
a Protonated Epoxide
analogy
the bromide nucleophile does NOT attack the positively charged Br
H
Br
Br
Br
Br
[AN] at Br+ is not reasonable because theres no low lying

empty atom-centered orbital. [SN2] at carbon (NOT Br+) is
most reasonable.
the electrophilic sites of the bromonium ion are revealed
by the second best resonance contributors
Br
Br
Br
Br
second best contributor
Br
best contributor
Br
second best contributor
Addition Reactions to Alkynes

Alkynes contain carbon-carbon triple bonds. The triple bond is an electron dense region and it
should therefore not be surprising that it has good nucleophilic characteristics. In studying the
reactions of alkynes, we will reason-through new transformations by drawing analogies to the
mechanisms and concepts that we have previously learned. The success of applying
established ways to a new class of compounds illustrates the power of the mechanism-based
approach for studying reactivity.
CH3CH2C CH
[AdE2]
HBr
H
CH3CH2C C
Br
[AE]
H
CH3CH2C C
H
a vinylic cation
intermediate
Br
[AN]
The Vinylic Cation

A two-EPD carbocation
(sp-hybridized)
CH3CH2C CH2
CH3CH2CH CH
more stable
less stable
The vinylic cation possesses a positively charged carbon atom having only two electron pair
domains (EPDs); the carbon bearing the positive charge is thus sp-hybridized. The addition of the
electrophilic H+ takes place so as to place the positive charge on the most highly substituted carbon,
just as for alkenes. As before, the more highly substituted the vinylic cation, the greater its
stability. This preference determines the regioselectivity of the addition. As a consequence, the
bromide is located on the more highly substituted carbon (i.e, the internal carbon). It turns out that
the vinyl cation is much less stable (i.e., much more reactive) than the corresponding alkyl
cation. One reason is because sp hybrid orbitals, consisting of 50% s character, are less well-suited
to stabilize positive charge compared to sp2 hybrid orbitals that have only 33% s character (the s
orbital resides closer to the positively charged nucleus).
primary alkyl cation
primary vinylic cation
R C H
H
RCH CH
3-EPDs
(sp hybridized)
2
2-EPDs
(sp hybridized)
Relative Stability of Various Carbocations

The order of stability for various carbocations is provided in the
chart below. It can be seen that the secondary vinyl cation is
not even as stable as the primary alkyl cation.
Successive Addition
Since the addition product to an alkyne is a vinyl bromide a type of alkene it
should not be surprising that subsequent reaction involving further addition is
possible. In fact, successive addition tends to be the normal mode of reactivity for
alkynes, as addition to the alkene is generally faster than the initial alkyne addition.
H
CH3CH2C C
Br
Br
HBr
CH3CH2C C H
Br H
a geminal dibromide
a vinyl bromide
(an alkene)
One reason why the subsequent reaction is faster is because of the special stability of the carbocation
intermediate that results when an electrophile adds to a vinyl bromide. The lone pairs on the bromo
group can donate to the electron deficient carbocation. Although this places a positive charge on the
electronegative bromo group, all atoms have an octet of electrons making this a very important
resonance contributor.
H
CH3CH2C C H
Br H
n a -type
resonance interaction
H
CH3CH2C C H
Br H
the most important resonance
contributor (each atom has an
octet of electrons)
Addition of Br2 to Alkynes

trans alkene
Br2
CH3CH2C CCH3
CH3CH2
Br
Br
CH3CH2
Br
CH3
a second addition
usually occurs
CH3
Br Br
Br
a bromonium ion
intermediate
CH3CH2C CCH3
a tetrabromide
Br Br
Halogens add to alkenes in a way that is similar to alkenes. An analogous

bromonium ion is formed in this case as well, and the subsequent attack of
bromide anion results in trans addition. However, this initially formed
product usually undergoes a second addition to give a tetrabromoalkane.
The Addition of Water to Alkynes

The complete mechanism is outlined in a
discussion problem.
Try to work
through this on your own.
H3C
CH3
Bonds Made
Bonds Broken
C1=O
C2-H
C2-H
C1C2
H-O
H-O
+ HOH
H3C
H2SO4
O
1 2 CH3
H
The addition of water to an alkyne initially results in an enol. The enol, whose name is derived from alkene + alcohol, is
generally not the form that is most stable. Enols tend to undergo a process known as tautomerization, an equilibrium
reaction which shifts the position of a double bond together with a C-H, N-H or O-H bond (in this case, an O-H). A bond
energy calculation will show why the equilibrium favors the keto form. What we are after right now is not the knowledge
that this reaction is a tautomerization, but to understand the mechanism of how tautomerization occurs.
H O
O
1
CHCH3
H3C
an enol
H
H3C 1
tautomerization
CH3
H H
a ketone
The acid-catalyzed tautomerization mechanism is included with the discussion problem. You can fully
understand this mechanism using elementary steps that you previously learned.
Acid-Catalyzed Tautomerization Mechanism
To begin, it should not be surprising that the enol is a nucleophilic -bond capable of
undergoing [AE]. This -bond nucleophile finds an electrophilic partner in H+ (from H2SO4).
The new C-H bond must be made at carbon atom C2, consistent with the need for a new C2-H
bond. The resulting carbocation is stabilized by resonance with the lone pair of oxygen (Box 4).
This resonance contributor has an octet of electrons on every atom. Moreover, this resonance
contributor has the necessary C=O bonding of the final product. All that remains to realize the
final product is dissociation of a proton, breaking the final O-H bond in our bonds made / bonds
broken list. Notice how H2SO4 is regenerated each time it is used, consistent with its use as a
catalyst.
Addition of Hydrogen to Alkenes and Alkynes

H
The addition of hydrogen to an organic compound is called

hydrogenation. An example is shown. Hydrogenation is an
addition reaction and it is also a reduction reaction (there is
an increase in the number of C-H bonds without an increase
in C-X bonds).
O
oleic acid (an unsaturated fatty acid)
Pd-C
H
H H
H H
hydrogen
OH
The addition of H2 occurs only in the presence of
a metal catalyst (Pd, Pt or Ni) that is adsorbed
onto a finely divided inert solid, such as charcoal.
The catalyst 10% Pd on carbon is common. The
reaction takes place at the metals surface but we
wont study the details.
O
steric acid (an saturated fatty acid)
OH
Alkynes Usually Undergo Successive

Hydrogen Addition
CH3CH2C CH
H2
Pt / C
H
CH3CH2CH C
H
H2
Pt / C
H
CH3CH2CH2 C H
H
Hydrogen adds to alkynes in an analogous way as with alkenes. The initially formed
alkene generally continues on to the saturated alkane under the reaction conditions.
CH3CH2C CCH3
H2
Lindlar's
catalyst
H
CH3CH2
H
CH3
a cis alkene
The addition of H2 to triple bonds is somewhat faster than to alkenes; thus, it is possible to stop
the reaction at the alkene using a type of poisoned or deactivated catalyst known as Lindlars
catalyst. Lindlars catalyst is stereoselective for the formation of the cis alkene.
The Alkynes Terminal Hydrogen Is Acidic

CH3 C C CH3
CH3 C C H
an internal alkyne
a terminal alkyne
Compared to other C-H bonds,

the terminal hydrogen of a
terminal alkyne is acidic. Yes,
it is a weak acid, but
comparatively speaking, it is
acidic. Deprotonation results
in a carbon-centered anion that
is sp hybridized. This anion is
called an acetylide anion. As
stated earlier, sp hybrid orbitals
are
more
effective
at
stabilizing negative charge
than sp2 or sp3 orbitals. It is
the stability of the anion that
makes the C-H of a terminal
alkyne more acidic than other
C-H bonds.
the triple bond ends

in a hydrogen atom
compared to other CH
bonds this one is acidic
CH3 C C H
CH3 C C
an acetylide anion
pKa = 25
H
CH2 C
H
H
H
CH2
a vinylic anion
pKa = 44
Homolytic vs. Heterolytic Fragmentation

Most organic transformations involve the movement of electron pairs (heterolytic reactions). There are a few
important addition reactions, however, in which the electron reconfiguration involves the movement of single
electrons. Whereas heterolytic bond cleavage leads to ion pairs, homolytic bond cleavage results in unpaired
electrons or free radicals. Some weak bonds have a tendency to fragment homolytically (e.g., peroxides,
halogens). Chemists use a slight variation of curved arrow notation to show the movement of single electrons. For
single electron movement, fishhook arrows, i.e., single headed arrows are drawn. The difference in these two
notations is illustrated below for heterolytic vs. homolytic fragmentation of Br2.
The fishhook
arrow tool.
How it looks
in ACE
http://aceorganic.pearsoncmg.com/epoch-plugin/public/mechmarvin.jsp
Comparing Homolytic and Heterolytic Addition

When peroxides are heated, they fragment homolytically. This behavior can be used to initiate
addition reactions that proceed via radical intermediates. A consequence of the different reaction
mechanism is that the regiochemistry of addition varies from that seen for the heterolytic case, as the
comparisons below illustrate.
Stability of Carbon-Centered Radicals

In order to rationalize the reactivity trends seen above, we must first understand how
radical stability depends on structure. The radical is a half-occupied electron pair domain
(open shell). The geometry at carbon is approximately planar, and the single electron
can be assumed to occupy the p-orbital of an sp2-hybridized atom. Since the carbon
atom has 7 electrons, one short of the desired octet, it is electron deficient, and stability
as a function of substitution follows the same trend found for carbocations.
The Radical Chain Mechanism

A chain mechanism has repeating characteristics. Species produced at the end reenter the mechanism to
cause it to start all over. Radical reactions are often of this type. Chain mechanisms have three events in
common: initiation events, propagation events and termination events. For radical chain mechanisms,
initiation events are what create the radicals. Propagation events are what produce products and these are
the steps that repeat in what are known as cycles, (like the links of a chain, hence the name chain
mechanism). A single radical from an initiation event may yield several cycles of propagation. Since
each cycle produces product, a single radical can account for several equivalents of product. The
termination events consume radicals and shut down the propagation cycles.
HBr
tert-Butyl peroxide
heat
Br
n-butyl bromide
The thermally induced bond homolysis of peroxides is a common way to initiate radical reactions.
The oxygen-oxygen bond of peroxides is a weak covalent bond of 47 kcal/mol and hence is readily
susceptible to thermal dissociation. The result is a pair of oxygen-centered radicals.
Initiation
RO OR
RO
a peroxide
Thermal homolysis of peroxides results in a pair of oxygen-centered radicals. The next step in
initiation involves HBr. A newly formed oxygen-centered radical abstracts a hydrogen atom
from H-Br resulting in a bromine-centered radical and a hydroxyl group. The bromine-centered
radical then enters the propagation cycle.
RO
H Br
RO H
Br
Propagation
The first step of the propagation cycle involves the addition of the bromine-centered radical to an alkene. This
step creates a carbon-centered radical, and it determines the isomer that is formed (i.e., n-butyl vs. sec-butyl
bromide). The formation of the most stable carbon-centered radical is what governs the outcome of this crucial
step. By having the bromine-centered radical add to the terminal position of the alkene, a secondary carboncentered radical results. This pathway is lower energy than the addition that leads to a primary radical.
The second half of propagation involves the carbon-centered radical abstracting a hydrogen atom from another
molecule of HBr. This regenerates a bromine-centered radical along with the alkene addition product. The brominecentered radical is ready to reenter a new chain propagation cycle.
H
CH3
Br
H Br
H
CH3
H
Br
Br
Termination
Termination events are the ways that radicals annihilate themselves. All propagation steps involve
a radical combining with a non-radical species. Through combination of a pair of radicals, the
radicals will disappear. Because the concentration of radicals tends to be very low, these events
are relatively rare. Some examples of termination reactions are shown below. All of them involve
the combination of two radicals, and they produce non-radical products.
Br
Br
Br Br
H
Br
CH3
Br
H
CH3
Br
CH3
H
Br
H
Br
CH3
Br
Br
Br
Stereoisomers and Addition Reactions

Many addition reactions have important stereochemical consequences and as we have previously seen, new
details about a reaction mechanism will be unveiled when we examine the stereochemical relationship
between reactants and products. For example, the hydrogenation to alkenes normally results in both
hydrogen atoms adding to the same side, or face of the planar double bond. Same-face addition of atoms to
a double bond is known as syn addition. An example of syn addition is illustrated for the hydrogenation of
cis-2,3-dideuterio-2-pentene (deuterium, D is the nuclear isotope of hydrogen with an atomic mass of 2).
Syn addition can take place from either the bottom or top. Because both top and bottom face addition are
equally possible, an equimolar mixture of an enantiomer pair results. An equamolar mixture of enantiomers
is known as a racemic mixture. Note that different products result from the trans alkene.
Anti vs. Syn Stereoselectivity

Although hydrogenation generally follows syn addition, special conditions exist that favor anti
addition. In anti addition, one hydrogen atom adds to one face while the other adds to the
other.
The hydrogenation conditions shown in the reaction below exhibit anti
stereoselectivity. You should draw the implied hydrogen atoms in the two products, showing
their proper stereochemial orientation. The anti and syn products are diastereomers. The
enantiomer of the anti product is not shown but is produced with equal preference to the anti
isomer that is shown (i.e., of the 73% anti product, half of this amount is one enantiomer and
half is the other). The syn product is a meso molecule. Can you find the plane of symmetry?
CH3
CH3
H2
Pd / Al2O3
CH3CO2H
these specialized reaction

conditions favor the anti
addition product
CH3
CH3
+
CH3
CH3
anti
syn
73%
27%
The specific set of conditions written above and below the reaction arrow describe to a chemist
important details about how the reaction was performed. In this particular case, palladium metal
was deposited on solid aluminum oxide and the reaction was conducted in a solvent of acetic acid
(CH3CO2H) in the presence of gaseous hydrogen. Please note that it is NOT important for you to
memorize these specialized conditions or even understand the mechanistic details of how these
conditions produce anti products. What is important is that you have the ability to examine a
reactant / product pair and determine the mode of addition (syn vs. anti).
Same Face Addition = Syn

Opposite Face Addition = Anti
By comparing the stereochemistry of the products and reactant, it can be seen that the anti
diastereomer arises from the addition of hydrogen atoms to opposite faces of the double bond, while
the syn product results from same face addition.
Hydrogen atoms add

to the opposite faces
of the double bond
Hydrogen atoms add

to the same face of
the double bond
Halogens Add Stereospecifically to Alkenes

A mechanism that constrains the stereochemical outcome of a reaction is said to be stereospecific. Such a close
relationship between mechanism and stereochemistry means that it is often possible to gain valuable insight into
reaction mechanisms by studying their stereochemical features. This kind of a relationship is found for the addition of
halogens to alkenes. In fact, the evidence that a bromonium ion was involved in alkene addition came from studies of
the reaction stereochemistry. Consider the reactions of trans and cis 2-pentene shown below. The product has two
stereocenters so up to four different stereoisomers are possible (there are no meso molecules in this case). Notice,
however, that trans and cis substrates each give rise to unique subsets of the possible stereoisomers. The mechanism
must account for these stereochemical observations.
Br
Br
Br2, CH2Cl2
trans 2-pentene
Br
Br
enantiomeric pair
Br
Br
Br2, CH2Cl2
cis 2-pentene
Br
enantiomeric pair
Br
Rationalizing the Stereoisomers From

Bromine Addition to Trans 2-Pentene
The addition of bromine to alkenes is a stereospecific reaction. In particular, the analysis below will show that this reaction
is stereospecific for anti addition. The fact that the reaction follows anti addition provides important details of how the
reaction mechanism must proceed. Trans 2-pentene gives rise to the bromonium ion shown below. The observed product
is a mixture of enantiomers. These stereoisomers, being the only 2 of all the possible stereoisomeric products, can only
come about if the Br nucleophile always attacks from the opposite side of Br+, as expected for n * interaction of an
[SN2] step involving a bromonium ion intermediate. The different enantiomers arise from Br attack at the two different
carbon atoms. The anti relationship of the bromine atoms can be seen in the Newman projection.
[SN2]
[SN2]
Rationalizing the Stereoisomers From

Bromine Addition to Cis-2-Pentene
Bromine addition to cis-2-pentene produces a different set of enantiomers.
However, the exact same mechanism discussed for the trans case also
accounts for the stereoisomers produced in the cis case.
bromonium ion
from cis-2-pentene!
A Non-Stereospecific Example
Reactions that proceed by non-stereospecific mechanisms will result in a much greater array of
stereoisomers. Consider the reaction of HBr adding to an alkene (recall that the addition of HBr to an
alkene proceeds via either a cationic or radical intermediate). As a specific case, the addition of HBr to
cis-3,4-dimethylhex-3-ene results in all four possible stereoisomers as shown below. Those isomers
related as enantiomers must be formed in equal amounts. Those isomers related as diastereomers may be
present in unequal amounts. Think through the mechanism and decide if trans-3,4-dimethylhex-3-ene
will produce the same stereoisomer mixture as cis (will the proportions of the various isomers be the
same for cis vs. trans?).
CH2CH3
H3C
H3C
Br
CH2CH3
enantiomers
CH3
Br
CH3
CH2CH3
CH3CH2
CH3CH2
CH3
HBr
diastereomers
CH2CH3
diastereomers
diastereomers
CH3
CH2CH3
cis-3,4-dimethylhex-3-ene
H
H3C
CH3
Br
CH2CH3
CH2CH3
enantiomers
H3C
Br
H
CH3
CH2CH3
Pathways Involving Carbocation and Radical

Intermediates Are Not Stereospecific
The uniqueness of the bromonium ion intermediate in its ability to stereospecifically govern the stereochemical outcome
of reactions is appreciated when we compare its behavior to that of pathyways that proceed via carbocation or radical
intermediates. In these cases, there is generally equal probability that the nucleophile or radical will react on either side
as shown. Thus, carbocation and radical intermediates are not-stereospecific and unless there is another stereocenter in
the molecule, non-stereoselective. Only if a stereocenter exists elsewhere in the carbocation or radical intermediate will
there be a stereoselective (not stereospecific) preference. Typically, even when another stereocenter is present, the
stereoselectivity induced from this remote site will only result in a small bias.
Substitution at Aromatic Carbon

We previously studied substitution reactions at sp2 carbonyl carbon and learned that the process goes by variations of
nucleophilic acyl substitution. Here we examine substitution at sp2 aromatic carbon. These substitution reactions
often follow the electrophilic aromatic substitution pathway, although 3 other pathways are possible in certain cases.

Y
base
acid
acid

+ X
base
form bond
-XY

change in the
H
replaces
number of C-H
X
bonds in relation
X reduction H
to the number of
C oxidation C
C-X bonds
X
replaces
H
neither being -H
Y
replaces
X
Y
X
C
Y
C
+ X
elimination
Z
addition
break bond
+XY
Z = C, N, O
CH3
R
R
Aromatic Substitution:
Four Examples
I. Electrophilic Aromatic Substitution
O
OH
HNO3
H2SO4
II. Nucleophilic Aromatic Substitution

H
Cl
NO2
O
NO2
NaOH
H2O, 100 C
NO2
NO2
H OH
Aromatic Substitution:
Four Examples
III. Substitution via arenediazonium ion
IV. Substitution via benzyne intermediate

CH3
CH3
Na
NH2
NH3 (l), -33 C

Cl
CH3
NH2
+
NH2
NaCl
Four Mechanistic Pathways for Aromatic Substitution:
I. Electrophilic Aromatic Susbstitution

H
E
[AE]
H
[DE]
resonance stabilized cationic intermediate

MO pictures of the cationic intermediate
The LUMO shows positions
of electron deficiency
this filled orbital shows a

a -type interaction
II. Nucleophilic Aromatic Susbstitution

LG
Nu
Nu
EWG
EWG
Nu
[AdN]
Nu LG
[E]
Nu LG
LG
LG
MO picture of
the anionic
intermediate
Nu LG
EWG
EWG
EWG
resonance stabilized anionic intermediate
The HOMO shows positions
of surplus electron density
III. Substitution via Arenediazonium Ion

H
H
Nu
Nu
+
H
Two views of the

aryl cations LUMO
top
[AN]
[DN]
N2
H
H
Nu
N N
H
H
H
side
H
an aryl cation
The LUMO shows
positions of
electron deficiency
the unsubstituted carbon of the aryl

cation approaches sp hybridization
and distorts the rings geometry
IV. Substitution via Benzyne Intermediate

H
NaNH2, NH3 (l), -33 C
Cl
NH2
NH2
[E2]
[pt]
NH3 + Cl
H NH2
H
H
benzyne
side
NH2
[AdN]
Two views of the
benzynes LUMO
top
NH2
H
H
NH2
H
The LUMO shows positions

of electron deficiency
NaCl
Substituents Greatly Influence Reactivity and the Stability of

the Various Intermediates on the Substitution Pathways
Does the substituent make benzene a better nucleophile or better electrophile?
Substituents that interact through bonds influence reactivity by what are known as ________
inductive
effects. Withdrawing substituents accept -electron density into an appropriately-aligned, lowenergy * orbital; in contrast, donating substituents contribute electron density from an
appropriately-aligned, high-energy orbital. This behavior is revealed below in the frontier orbital
pictures. For -CF3 (left), the LUMO (but not the HOMO) shows an interaction between the
substituent and the -system.. Thus, -CF3 lowers the LUMO energy and makes the ring more
electrophilic. For -CH3 (right), the HOMO (but not the LUMO) shows an interaction between the
substituent and the -system. Thus, a C-H bond of -CH3 contributes electron density to the
HOMO making the ring a better nucleophile.
LUMO
LUMO
electron
withdrawing
F
F
F
C
reference
HOMO
electron
donating
H
H
H
C
HOMO
Substituents with Non-bonding Pairs Donate Electron Density

Through an n (-type) Resonance Interaction
Substituents adjacent to a benzene ring can donate electron density from an appropriately-aligned,
high-energy n orbital. This behavior is revealed below in the frontier orbital pictures of aniline.
Notice that nitrogen is planar (not pyramidal) for maximum n overlap. The HOMO (but not
the LUMO) shows an interaction between the substituent and the -system (indicated by the block
arrows). Thus, nitrogens lone pair contributes electron density to the HOMO making the ring a
better nucleophile. This is predicted by the resonance contributors. Those atoms sharing the
negative charge contribute most to the HOMO and are the most nucleophilic positions.
HOMO
top
side
LUMO
top
side
Substituents with Low-Lying * Accept Electron Density

Through a (-type) Resonance Interaction
Substituents adjacent to a benzene ring can accept electron density into an appropriately-aligned,
low-energy * orbital. This behavior is revealed below in the frontier orbital pictures of
benzaldehyde. Notice that the carbonyl and ring atoms are coplanar for maximum -type overlap.
The LUMO (but not the HOMO) shows an interaction between the substituent and the -system
(indicated by the block arrows). Thus, the C=O lowers the LUMO energy and makes the ring more
electrophilic. This is predicted by the resonance contributors. Those atoms sharing the positive
charge contribute most to the LUMO and are the most electrophilic positions.
HOMO
top
side
LUMO
top
side
Rationalizing Substituent Effects for Electrophilic

Aromatic Substitution Reactions
RDS
EWG
EWG
RDS
RDS
E
E
EDG
EDG
E
E
A B C
TS resembles
the intermediate
free energy
A B C
starting
products
substrates
progress of reaction
Since the benzene ring is the

nucleophile the reaction is
__________,
accelerated by EDGs
Comparing Intermediates
For Rings with an EWG vs. EDG
EWG
O
E H
EDG
CH3
deactivating
CH3
activating
CH3
E H
CH3
CH3
CH3
E H
E H all atoms have a

complete octet
Substituents and Regiochemistry in

Electrophilic Aromatic Substitution
X
X
H
+ E
or
or
E
X is EWG
or EDG
ortho
meta
All activating substituents (EDG) and weakly

ortho / para directors
deactivating halogens are __________
All substituents more deactivating than the
halogens are meta
____ directors (i.e., the EWGs)
E
para
Substituent - Reactivity Correlation Chart
Ortho / para
directing
From P. Y. Bruice
Organic Chemistry (5th Ed.)
Summary
The bonds in aromatic compounds behave as nucleophiles and are thus reactive toward
electrophiles. In the first step of electrophilic aromatic substitution, the aromatic ring attacks an
electrophile in an [AE] fashion to give a delocalized carbocation intermediate."
In the second step of electrophilic aromatic substitution, the carbocation undergoes [DE] with loss
of H+ from the same carbon to which the electrophile added, re-forming the benzene ring (the net
result is substitution at this C)."
The electronic nature of substituents on an aromatic ring has profound effects on the rate of
reactivity and the regiochemistry of electrophilic aromatic substitution reactions."
Draw your curved arrows correctly. Arrows should not show the H+ flying off into space! If H+ loss
via [DE] bothers you, show a weak base making a new bond to hydrogen at the same time the CH
bond is cleaved (technically now a [pt] step). Often the base is assumed to be present but need not be
shown."
B
[DE]
CORRECT
[pt]
CORRECT
H WRONG
Which best represents the transition state for the first step in the electrophilic aromatic substitution pathway?"
A"
+
+
+
+
+
E
+
E
E
H
E
B"
C"
H
H
+
D!
+
+
Electrophiles for Electrophilic Aromatic Substitution
Bromination
Br
Br Br
Lewis Base
Br2
FeBr3
Br
Fe
Br
Br
Lewis Acid
[AN]
HBr
Br
Br Br Fe Br
Br
Other Halogenations
Chlorine is similar to bromine
Cl
FeCl3
Cl2
HCl
For iodine, the following conditions are used

I
HNO3
I2
HI
OH
Here the active electrophilic
N
O
I
species is presumed to be ________
J.
Chem. Soc. B, 1971, 2264 - 2268, DOI: 10.1039/J29710002264
Nitration by Electrophilic Aromatic Substitution

O
H
O
H2SO4
OH
HNO3
O
H OH
The active electrophilic species is O N O (NO2 )

nitronium
How does it form?
ion
O
H
N
O
H O S O H
[pt]
O
H
N
O
+
H
[E]
H2O
O N O
O S O H
O
Sulfonation
OH
O S O
H2SO4
H2O
O
The active electrophilic species is H O S
O
How does it form?
O
H O S O H+
O
H O S O H
[pt]
[DN]
H O S
O
H O S O
O
O
H2O
O S O H
O
Friedel-Crafts Acylation
O
An acyl group has the structure

R
An alkyl group has the structure
O
R
Cl
acyl chloride
+
H
R
O
R
acid anhydride
1) AlCl3
2) H2O
1) AlCl3
2) H2O
The Acylium Ion is the Electrophile in

Friedel-Crafts Acylation Reactions
The active electrophile for
Friedel-Crafts Acylation is
the acylium ion
R C O
AlCl4
How does it form?

R C O
acylium ion
Cl
O
R C Cl
Cl
Al
For the acylium ion, which resonance

contributor is more important? Why?
[AN] (or
[AdN])
[DN] (or
[E])
[AN]
ion pair
dissociation /
formation
Cl
R C Cl Al
Cl
Cl
Cl
All atoms have

octet of electrons
Friedel-Crafts Alkylation
H
R Cl
AlCl3
HCl
The active electrophilic species is the carbocation R+
Example:
H
Cl
isobutyl
chloride
+
tert-butylbenzene
HCl
Mechanism of Friedel-Crafts Alkylation

CH3
Cl
CH3 CH CH2Cl
Cl
Al
CH3
Cl
[AN]
Cl
CH3 C
CH2Cl Al
Cl
Cl
isobutyl chloride aluminum chloride complex
[1,2R] + [DN]
H
CH3
[AE]
CH3
CH3
AlCl4
General Considerations About Ortho vs. Para Substitution
HNO3
H2SO4
NO2
1:1
HNO3
H2SO4
NO2
NO2
1 : 4.5
NO2
Ortho and para substitution have similar electronic considerations.

Steric factors can have an influence on the ortho / para product ratio.
______
Electrophile Orientation With

Disubstituted Benzenes
With disubstituted benzenes:
First consider the contributions of the individual substitutents and determine if
they direct to a common position to produce a major product.
When substituents are in competition, strongly activating substituents will
dominate weakly activating or deactivating ones.
CH3
CH3
+
NO2
p-nitrotoluene
HNO3
H2SO4
NO2
NO2
2,4-dinitrotoluene
Summary
Electrophiles preferentially attack ortho or para to electron-donating substituents such as
(RO, R2N, RCONH) and halo substituents, whereas electrophiles attack meta to
electron-withdrawing groups such as carbonyl, CN, NO2, and SO3H.!
The directing ability of a group is closely related to its ability to stabilize or destabilize
the intermediate carbocation.!
Give the major product of these reactions.
CH2CH3
+ Br2
CH2CH3
CH2CH3
CH2CH3
Br
Br
CH2CH3
FeBr3
Br
Br
Br
NO2
+ HNO3
Br
B
Br
C
Br
Br
Br
NO2
H2SO4
NO2
OCH3
CH2CH2Br
OCH3
NO2
OCH3
OCH3
Anilines are Prepared by

Reduction of the Nitro Group
Anilines are commonly formed by the reduction of the nitro group. The reaction
is accomplished by the reagents shown below. Given that the nitro group is
easily introduced via electrophilic aromatic substitution, the synthetic sequence:
Nitration reduction diazotization substitution
is a powerful route to many substituted arenes.
NO2
NH2
Sn, HCl
NO2
NH2
Pd/C, H2
Substitution Reactions via

Arenediazonium Salts
Mechanism of Diazotization
O N O
sodium
nitrite
[pt] H
H O N O
nitrous
acid
[pt] H
[pt]
NH2
N N O
[AN] or [AdN]
H
H
[pt] H
N N O
H
H
N N O
[E] or
H2O [DN]
O N O
N O
N O
nitrosonium ion OR
nitrosyl cation
[pt]
H
H
N N O
[pt]
H
H
N N
H2O
[E]
H
H
N N O
H
Mechanistic Considerations:
Substitution of Arenediazonium Ions
In these reactions the leaving group leaves before the Nu adds
(compare to electrophilic aromatic substitution mechanism)
H
H
H
H
N N
[DN]
H
H
H
H
aryl cation
Nu
[AN]
Nu
H
H
Although conveniently thought of as proceeding via nucleophilic capture

of the aryl cation via an [AN] step, evidence suggests that many of these
reactions may involve radical chain mechanisms (for example, see: J. Am.
Chem. Soc. 72, 1950, 3013).
Benzene as an Electrophile:
Nucleophilic Aromatic Substitution
Cl
NO2
O
NO2
NaOH
H2O, 100 C
NO2
NO2
addition / elimination
This reaction goes by an ___________________
pathway,
analogous to nucleophilic acyl substitution (recall that substitution
reactions at sp2 carbon do not follow the [SN2] pathway).
Mechanism of Nucleophilic
Aromatic Substitution
Cl
NO2
Cl OH O
N
OH
[AdN]
addition step
(slow step)
NO2
Cl OH O
N
Cl
O
NO2
Cl OH O
N
O
O
[E]
elimination step
(fast step)
NO2
Cl OH O
N
Substrate Requirements for

Nucleophilic Aromatic Substitution
Cl
NO2
EWG to activate ring (lower LUMO energy)

Good leaving group (F best in these reactions)
NO2
ortho or _____
The EWG must be located ______
para positions.
A variety of nucleophiles can be used. The incoming
group must be a stronger base than the outgoing
leaving group.
Substitution that Involves Elimination at Benzene

OCH3
OCH3
Na
Br
NH2
NH3 (l), -33 C

NH2
OCH3
OCH3
Br
Na
NH2
NH3 (l), -33 C
Na
NaBr
NH2
OCH3
OCH3
NH2
OCH3
NH3 (l), -33 C

Br
NaBr
NH2
+
NH2
This reaction goes by an _________________

elimination - addition pathway and
it involves a high-energy intermediate known as benzyne
_______
NaBr
EliminationAddition (Benzyne) Reactions of Bromoanisole

Isomers with Sodium Amide in Liquid Ammonia
NaNH2 is a very strong base. The elimination

process follows the [E1cb] pathway. [AdN] to
benzyne is favorable because a triple bond in a 6membered ring causes considerable strain.
Published in: John D. Roberts; J. Org. Chem. 2009, 74, 4897-4917.
DOI: 10.1021/jo900641t
Copyright 2009 American Chemical Society
Functional Groups With C=O

and Related Carbon-Heteroatom Multiple Bonds
O
H
aldehyde
ketone
thioketone
The acyl group

N
N
C
imine
O
OH
carboxylic
acid
O
NH2
amide
nitrile
O
O
carboxylic
ester
O
S
thioester
N
H2N
NH2
urea (or guanidine)
O
carboxylic
anhydride
O
Cl
acid chloride
, unsaturated
carbonyls
Chemistry of the Carbonyl Functional Group
Leaving group
(substitution
reactions)
Basic site:
protons add here
Electrophilic site:
nucleophiles
attack here
Acidic hydrogen:
deprotonation creates
a nucleophile
Types of Carbonyl Reactions

I. Addition reactions
Here the carbonyl

serves as an
___________
electrophile
O H
Nu
The elements of Nu-H

add across the C=O
Nu
double bond
II. Substitution reactions

Here the carbonyl
serves as an
electrophile and X
___________
leaving group
is a ____________.
Nu
O
R
III. Reactions at the -carbon

O
Here the carbonyl
serves as a
nucleophile following
___________
deprotonation.
O
R
Nu
H H
H E
The X group is
replaced by the
Nu group. This
is substitution at
an sp2 carbon.
Overall result is
substitution of -H at
the -carbon by -E.
Resonance Contributors and the LUMO Reveal a

Consistent Picture of Carbonyl Polarity
+
2nd best
resonance
contributor
The molecular orbital model is consistent with

the above resonance picture. The LUMO (*)
of formaldehyde is shown; the * lobe on
carbon is much larger than on oxygen. In other
words, carbon contributes more to * than
does oxygen. Nucleophiles will be attracted to
the largest lobe of the LUMO. Conclusion:
Carbon (not oxygen) is the electrophilic site in
carbonyl groups.
O
C
formaldehyde
Structure-Reactivity and the Carbonyl Group

Aldehydes are more reactive than ketones.
Reason:
Steric factors
Better electrophile
Reason:
Electronic factors;
LUMO energy level
better electrophile
The Carbonyl Oxygen is Protonated

Under Acidic Conditions
The carbonyl is converted into a more powerful

protonating the carbonyl oxygen.
electrophile by ___________
* energy is lowered
O
C
add
H+
O
C
Characteristic of a more powerful electrophile, the protonated carbonyl

has a lower lying * (LUMO) energy than the neutral carbonyl.
On the Bascisity of Carbonyl Oxygen

Which carbonyl is the stronger base?
Which of these protonated
forms (A or B) is more
stable? Why?
delocalized charge
__________________
Circle the
stronger base
A pKa = -7.2
(stronger acid)
B pKa = -6.5
(weaker acid)
On the Acidity of -Hydrogen

weaker
acid
Negative charge better

delocalized in B than A
stronger
acid
free energy
O
C C
H
+B
C C C
H
+B
reaction progress
C-H acidity correlates to the

stability of the conjugate base.
The more stable the conjugate
base, the stronger the acid.
pKa Values of Some Carbon Acids
Other Nucleophiles Derived From Carbonyl Groups
The enol is the tautomeric form of the carbonyl group
Mechanism, pH, and Charge:

General Considerations
Under acidic conditions: the carbonyl oxygen will be protonated first.
DONT draw negatively charged intermediates under acidic
conditions (charged intermediates should only bear ___
+ charge).
Under basic conditions: the carbonyl oxygen will become negatively
charged. DONT draw positively charged intermediates under basic
charge).
conditions (charged intermediates should only bear ___
These are good rules to follow when you write any organic reaction,
but they are especially common in carbonyl chemistry (We will see
specific examples in the next several lessons).
Oxidation of Alcohols to Form Carbonyls

1. Oxidation of secondary alcohols to form ketones
Reagents: PCC (pyridinium chlorochromate), PDC (pyridinium dichromate), chromic

acid (seen as H2CrO4 or K2Cr2O7/H2SO4/H2O)
2. Oxidation of primary alcohols to form aldehydes
Reagents: PCC (pyridinium chlorochromate), PDC (pyridinium dichromate)
3. Oxidation of primary alcohols to form carbox. acids
Reagent: Chromic acid (seen as H2CrO4 or K2Cr2O7/H2SO4/H2O)
Mechanism of Chromic Acid Oxidation of 2-Propanol

1. Condensation of alcohol and chromic acid (couple elementary steps)
2. Proton-transfer/beta-elimination
3. A series of redox reactions converts the chromium from the 4+ oxidation state to the 3+
oxidation state
Summary
Tautomers are isomers in which a double bond and a hydrogen atom change their locations. The
most important kinds of tautomers are carbonyl-enol tautomers. Tautomerization is a chemical
equilibrium that occurs very rapidly in acidic or basic media; it should not be confused with
resonance (resonance is not an equilibrium process).
O
OH
CH2
CH3
<1%
C
H2
CH3
> 99 %
An organic acid, HA, is much more acidic when the lone pair of the conjugate base can be
stabilized by resonance (e.g., PhOH is more acidic than EtOH). A C-H bond is acidic when the lone
pair of the conjugate base (a carbanion) can be delocalized into a carbonyl group, and even more so
when it can be delocalized into two carbonyl groups.
Carbonyl compounds are some of the most important organic compounds. To help understand their
behavior, remember these pKa values:
O
H
CH3
N
H
pKa = 5
O
CH3
pKa = 16
H
H
C
H
CH3
pKa = 20
Nucleophilic Addition Reactions - Adding XY Across

Unsaturated C=Z and C=C Bonds
We previously studied the electrophilic addition of XY across carbon-carbon multiple bonds. Here we examine the
nucleophilic variations of addition. We will consider C=C and C=Z -bonds (where Z is a heteroatom such as O or N).

Y
base
acid
acid

+ X
base
form bond
-XY

change in the
H
replaces
number of C-H
X
bonds in relation
X reduction H
to the number of
C oxidation C
C-X bonds
X
replaces
H
neither being -H
Y
replaces
X
Y
X
C
Y
C
+ X
elimination
Z
addition
break bond
+XY
Z = C, N, O
CH3
R
R
Addition Mechanisms Require a New Elementary Step:

Nucleophile Addition to a C=O -bond [AdN]
This symbol means nucleophile
addition to a -bond
Filled n
Nu
C O
[AdN]
Empty *
C O
Nu
[AdN] involves
-bond making and
-bond breaking
[AdN] is a n *
-type interaction
empty

involved in an elementary step. The tail of the first arrow implies
the filled orbital (HOMO) is non-bonded electron pair. The head of
the arrow points between Nu and a carbon atom from the bond. The tail of the second arrow shows that a -bond breaks
suggesting that * accepts the electron pair via -type orbital
interaction.
filled
#a
# a
# na
n #
# a
There are Two Mechanistic Pathways for Nu Addition

Nu
[AdN]
pathway
H
Nu
[pt]
C O
[AdN2]
Nu
C O
H
alkoxide
adduct
[AdN] then [pt]

(two-step, basic
conditions)
O
C
[pt]
[AdN]
C O
C O
H
Nu
Nu
[AdN2]
[pt] then [AdN]
(two-step, acidic
conditions)
The two addition pathways differ in the timing of the proton transfer and nucleophile addition. Both are two-step
mechanisms and both are called [AdN2] (bimolecular nucleophilic addition to a polarized -bond). The
bimolecular [AdN] step is rate-determining for both. In the top case, the two steps are often actually performed
sequentially (i.e., in the laboratory, a proton source is subsequently introduced to quench the initially formed
adduct). For the top case nucleophilic addition is under basic conditions and an acid then neutralizes the initially
formed alkoxide adduct. In the bottom case, reversible proton transfer takes place followed by [AdN]. Unlike the top
case, this two-step process occurs without changing conditions (no intervention on the part of the chemist is needed).
Addition Involving Carbon Nucleophiles

Grignard reagents
Reacts like a
carbanion Nu:
Synthesis of primary alcohols
Acetylide Anions As Carbon Nucleophiles

compared to other CH
bonds this one is acidic
CH3 C C H
CH3 C C
an acetylide anion
pKa = 25
H
CH2 C
H
H
sodium acetylide
H
CH2
a vinylic anion
pKa = 44
Hydride Reduction of Ketones and Aldehydes

hydride
Hydride is a strong base

and nucleophile
Addition of H-CN to a Ketone or Aldehyde:

Cyanohydrin Formation
pKa = 9.3
a cyanohydrin
For aldehydes and most ketones, the position of the equilibrium

favors cyanohydrin formation. For aryl ketones and sterically
hindered aliphatic ketones, starting materials are favored.
Nucleophilic Addition to
, Unsaturated Carbonyl Compounds
1,2-addition is called ______

direct addition
1,4-addition is called conjugate
________ addition
Draw resonance structures that
reveal the two electrophilic sites
[AdN] Also Applies to Polarized C=C -Bonds

EWG is an electron withdrawing
group that polarizes the -bond
and lowers the LUMO energy
Filled n
Nu
EWG
C C
Empty *
[AdN] is a n *
-type interaction
This symbol means nucleophile

addition to a -bond
EWG
[AdN]
C C
Nu
[AdN] involves
-bond making and
-bond breaking
Orbital calculations (see below) show that

C makes a significant contribution to *
H
H
LUMO (side view)
LUMO (top view)
Analogous Pathways for Nu Addition to Polarized C=C

Nu
[AdN]
Nu
[pt]
C C
Nu
C C
C O
C O
enolate anion
C C
C O
Nu
[pt]
[AdN]
C C
[taut]
C C
C O
C O
Nu
Nu
enol
H
C C
C O
Nucleophilic addition to a polarized carbon-carbon -bond takes place by analogous pathways. The top case is just
like carbonyl addition except that [AdN] occurs at the C site. The initially formed enolate anion is resonance
stabilized (via electron donation into the withdrawing group (e.g., C=O)). For the bottom case, the proton first adds to
the carbonyl oxygen. Then, [AdN] occurs at the C site giving rise to an enol. The enol is usually unstable and
undergoes spontaneous tautomerization to produce the addition product.
Direct vs. Conjugate Addition

H CN O
C N
CH3CO2H
H H
HO
Li
Nucleophiles that are weak bases tend

to give conjugate addition products.
Nucleophiles that are strong bases
tend to give direct addition products.
Understanding Direct vs. Conjugate Addition

(Kinetic vs. Thermodynamic Control)
is
Conjugate addition _____
irreversible
may be
Direct addition ___________reversible
Direct addition is _________
than conjugate
faster
OH
C
H
C
H
OH
C
H
Nu
fast
O
C
H
C
H
slow
O
H
C
CH2 C
Nu
C
Nu
fast
C
H
C
H
C
H
kinetic product
slow
O
H
C
CH2 C
Nu
thermodynamic product
Whether or not direct addition is reversible depends on the

leaving group
ability of the -Nu to act as a good ___________________.
(More about this in the next lesson)
Summary
Alkenes and alkynes that are substituted with electron-withdrawing groups such as carbonyl,
nitro, or sulfonyl groups are electrophilic. Many nucleophiles react with these alkenes to give
conjugate addition (i.e., 1,4-addition) products.!
The enol resulting from 1,4-addition undergoes spontaneous tautomerization to give alkene
addition as the net result.!
Nucleophiles that are weak bases such as alcohols, thiols, amines, and halides, add reversibly
to ,-unsaturated carbonyls and tend to give the thermodynamic product (i.e., typically the
product of conjugate addition). Nucleophiles that are strong bases add irreversibly and give
direct addition (i.e., 1,2-addition) products.!
1,2- vs. 1,4-Additions to ,-Unsaturated Carbonyl Compounds
O
nucleophile
CH3CH2 MgBr
H3O+
strong or weak base

(circle one)
C N
H3O+
strong or weak base

(circle one)
H3O+
strong or weak base

(circle one)
Substitution at the Carbonyl Carbon (Acyl Substitution)

We previously studied substitution reactions at sp3 carbon and concluded that they proceed either by the [SN1] or the
[SN2] pathway. Here we examine substitution at the sp2 carbonyl carbon (nucleophilic acyl substitution reactions).
Well see that substitution at sp2 atoms generally proceed by pathways much different than those at sp3 atoms.

Y
base
acid
acid

+ X
base
form bond
-XY

change in the
H
replaces
number of C-H
X
bonds in relation
X reduction H
to the number of
C oxidation C
C-X bonds
X
replaces
H
neither being -H
Y
replaces
X
Y
X
C
Y
C
+ X
elimination
Z
addition
break bond
+XY
Z = C, N, O
CH3
R
R
Nucleophilic Acyl Substitution:

Three Examples
O
CH3 O
CH3 C Cl
CH3 C OCH3
+ Cl
H
CH3 NH2
CH3 NH
H
CH3
CH3 NH2
O
O
CH3
NHCH3
O
CH3
+
O
CH3 OH
CH3 C OH
esterification
H
O
CH3 C OCH3
H OH
CH3
Three Mechanistic Pathways for Acyl Substitution

L
Nu
Nu
Nu
C O
[AdN]
C O
[E]
H
base
Nu
O
C
[AdN]
[pt]
B
H Nu
C O
L
H B
Nu
Nu
C O
[pt]
H
[pt]
H L
[AdN]
C O
L
C O
[E]
Nu H
H Nu
[pt]
C O
L
H
Nu
C O
H L
[E]
Nu
C O
H
All three pathways include [AdN] and subsequently [E] steps (i.e., addition followed by elimination,
proceeding through tetrahedral intermediate [TI]). The three paths differ by the role of [pt]. Which pathway is
best will depend on the pH, the nucleophile strength, and the leaving group quality. A rough generalization is
that the top pathway is for basic, the middle for neutral, and the bottom for acidic conditions. Slight variations
on these pathways will be encountered.
Acyl Substitution Requires a Variation of the [E] Step:

Beta Elimination Across the C-Z: Bond
This symbol means beta elimination
Empty * L
-L is a LG;
Z: is O or N
Filled n
C C

L
C
Z
Y
[E]
[E]
C C
Z
C Y
[E] involves
-bond making
-bond breaking
[E] is an n *
-type interaction
We first encountered [E] when we studied the [E1cb] elimination pathway (top equation). In the second
equation, [E] is now shown for the generalized case where Z: may be an oxygen or nitrogen atom. Many
leaving groups (-L) participate in [E], even poor ones (e.g., -OH). This step is the reverse of [AdN].

involved in this elementary step. The tail of the first arrow implies
that the filled orbital (HOMO) is a nonbonded electron pair, n. The
head of the first arrow points between C-Z: suggesting a new bond. An empty, low-lying *-orbital from the adjacent C-L bond
is available to accommodate this electron pair suggesting the
LUMO is *. The HOMO (n) is beside (and nearly parallel to) the
LUMO (*) allowing for a -type interaction.
empty
filled
%a
% a
% na
n %
% a
Nucleophilic Acyl Substitituon:

Addition-Elimination Through a Tetrahedral Intermediate
O
R
CH3O
Cl
addition
[AdN]
Cl
OCH3
elimination
O
R
OCH3
[E]
Cl
tetrahedral
intermediate
[TI]
Heres a related mechanism on the
formation of amides via acid chlorides.
Equilibrium Position and the RDS

Depend on Relative Basicity of Nu and X
relative basicities:
L > Nu
free energy
free energy
relative basicities:
Nu > L
[TI]
O
R C Nu
R C L
+ L
+ Nu
reaction progress
leaving
group
(conjugate
acid pKa)
R C Nu
+ L
R C L
+ Nu
reaction progress
O
Cl
O C R
(-2.2)
O
derivative
[TI]
R C Cl
acyl chloride
(4.8)
O
OH
(15.7)
R C O C R
R C OH
acid anhydride
acid
O R
(16)
O
NH2
(35)
O
R C O R R C NH2
ester
amide
Base-Catalyzed Ester Hydrolysis

[AdN]
O
CH3 C OCH3
addition
OH
CH3 C OCH3
carboxylic ester
OH
[E]
elimination
O
CH3 C O
carboxylate
CH3OH
CH3 C OH
OCH3
carboxylic acid
Note that under basic conditions, all intermediates are either neutral or negatively
charged. All steps are reversible, but the last step lies very far to the side of the
carboxylate.
This nearly irreversible step makes formation the reverse process
(formation of esters from acids under basic conditions) nearly impossible.
Ester Formation via the Acid Anhydride

(Near Neutral Conditions)
[AdN]
acid anhydride
These reactions are often conducted in

presence of a weak base such a pyridine.
The base assists in proton transfer steps.
ester
[pt]
pyridine
[E]
Acid-Catalyzed Ester Formation via Carboxylic Acid

carboxylic
acid
[AdN]
carboxylic
ester
Note that under acidic conditions,
all intermediates are either neutral
or positively charged. All steps are
reversible so formation and
hydrolysis are related as the
forward and backward directions of
these pathways.
For ways to
manipulate the equilibrium see the
link below.
[E]
Manipulating the Equilibrium

Acid-Catalyzed Amide Hydrolysis

Amides are stable functional groups but under forcing conditions can be made to
hydrolyze to carboxylic acids. The acid-catalyzed process is used to hydrolyze
peptides and proteins for amino acid composition and sequence determination.
O
R C NH2
H OH
R C OH
HCl
+ NH4Cl
H
H
R C NH2
R C NH2
R C OH
R C NH2
H
+ NH3
elimination
addition
H
R C NH2
O
O H
R C N H
H
O H
Interconversion of Carboxylic Acid Derivatives

For the reagents needed to accomplish these
interconversions, see the following link:
Decreasing reactivity!
Mechanism of Acid Chloride Formation
thionyl
chloride
chlorosulfite
Summary
Many carbonyl compounds including esters, acyl chlorides, and acid anhydrides
have leaving groups attached to the carbonyl C, and many reactions proceed with
substitution of this leaving group by a nucleophile.!
Substitutions at the carbonyl C usually occur by an addition-elimination
mechanism. The nucleophile (Nu) adds to the electrophilic C of the carbonyl
group to make a tetrahedral intermediate. The leaving group (L) then leaves in
the elimination step to give a new carbonyl compound. Note that either L or Nu
may be expelled from the tetrahedral intermediate. Which one that is expelled
depends on their relative leaving group abilities and the reaction conditions.
Expulsion of Nu gives back the starting material (which is not very productive!).!
(1) What products are observed from the following reaction (the
oxygen of methanol is labeled with the 18O isotope)?!
A!
B!
C!
D!
E!
F!
Acyl Substitution Followed by Addition

acyl
substitution
Nu
O
C
addition
Nu
Nu
H
Nu
C O
L
L
C O
Nu
The carbonyl product resulting from acyl substitution may be susceptible to further attack by
the nucleophile. These sequential processes follow pathways that have previously been
discussed. Whenever substitution is slower than addition, stopping the reaction at the end of
the substitution reaction can be nearly impossible. The result will be two equivalents of
nucleophile attaching to the carbonyl carbon (the first by substitution, the second by
addition). In general, the substitution-addition sequence takes place for very strong
nucleophiles such as hydrides and Grignard reagents. A source of H+ must intentionally be
added by the chemist to quench the reaction after formation of the addition adduct (i.e., in
chemical equations this is often written in H+ workup).
Examples of Acyl Substitution Followed by Addition

OH
O
CH3 MgBr
+ CH3CH2
CH3CH2 C CH3
C O
following
H+ workup
CH3
HO
OH
O
LiHAlH4
CH3CH2 C H
CH3CH2 C O
CH3
following
H+ workup
HO
CH3
O
NH2
1) LiAlH4
2) H+ workup
H H
NH2
Substitution-Addition Mechanism
for Grignard Nucleophiles
OH
O
CH3 MgBr
CH3CH2 C O
CH3CH2 C CH3
CH3
[AdN]
OH
O
[MgBr]
CH3CH2 C O
[pt]
CH3
[E]
O
CH3CH2 C CH3
[AdN]
CH3 MgBr
add
H
O [MgBr]
CH3CH2 C CH3
CH3
Substitution-Addition Mechanism
for Hydride Nucleophiles & Esters
OH
H
Li
H Al H
H
CH3CH2 C O
CH3CH2 C H
[AdN]
H
OH
O Li
CH3CH2 C O
H
add
H
[pt]
[E]
[AdN]
CH3CH2 C H
H
Li
H Al H
Li
O Li
CH3CH2 C H
H
Substitution-Addition Mechanism:
LiAlH4 with Primary or Secondary Amides
[AdN]
[pt]
[AN]
[E]
[AdN]
Substitution-Addition Mechanism:
LiAlH4 with Tertiary Amides
H
tertiary
amide
H Al H
H
N CH3
[AdN]
R C H
Al
H3O
low temp.
hydrolysis
R C N CH3
[E]
H CH3
This TI is
relatively
stable to [E]
CH3
H
O
Al
R C N
H
H
CH3
an iminium ion
[pt]
[AdN]
CH3
R C N
H Al H
H
H
an aldehyde
[AN]
CH3
CH3
add
H+
H
H Al H
For tertiary amides, the elimination step is not assisted by loss of

H2 (theres no N-H available). Thus, the initial tetrahedral
intermediate is fairly stable. If kept cold, hydrolysis of this TI
yields aldehydes. At higher temperature, elimination takes place
to the iminium ion which undergoes further hydride addition.
Substitution of the Carbonyl Oxygen of Ketones and

Aldehydes by Nitrogen: Imines and Enamines
H
1 amine
R N H
O
O H
C N H
C
addition
C
C
H
addition
O H
N R
C
imine
2 amine
R N H
O
elimination and
[pt] from N
elimination and
[pt] from C
C C N R
O H
C C N R
R
O H
H
enamine
When primary amines are combined with ketone and aldehyde groups, the carbonyl C=O is
replaced by the C=N (imine) group. The mechanistic sequence is addition followed by
elimination of water (the second NH proton is necessary for imine formation). When secondary
amines are combined with aldehydes and ketones, there is no second proton on nitrogen to permit
imine formation. In this case, elimination of water is achieved via proton transfer from a HC
bond (assuming that the aldehyde or ketone substrate has at least one -hydrogen). The functional
group that results is called an enamine.
Examples of Imine and Enamine Formation

O
NH2
H
(cat.)
N
primary
amine
imine
H H
H
(cat.)
O H
N
H
secondary
amine
H
enamine
O H
H
Other Amino Reagents that Produce

Derivatives of Aldehydes and Ketones
Reagent H2N R
Derivative Name
H2N OH
hydroxylamine
oxime
H2N NHR
hydrazine
hydrazone
Structure
N
semicarbazide
NHR
H
H2N N C NH2
OH
semicarbazone
NH
C NH2
Mechanism of Imine Formation

O
NH2
H2O
N
H
O
[pt]
[pt]
[AdN]
HN
H
H2O
H H
HO N
H H
H O N
[E]
[pt]
Mechanism of Enamine Formation

H
N
H
[pt] (or [DE])
[pt]
H
O
H2O
H
H
H H
N
H
H N
H2O
[E]
[AdN]
H
O
[pt]
H
H
H
H
Hydride Reduction of Imines Produces Amines:

Reductive Amination
O
C
H2O
+
H
N
C
H
O
CH3
NH2
CH3
NH3
NaBH(OAc)3
pH 6
H+ + H
N H
C H
hydride
H NH2
CH3
CH3
excess C=O
NaCNBH3
pH 6
CH3
CH3
Imines and iminium ions are reduced by hydride sources to make amines. The process is known as reductive
amination. The hydride reducing reagents in the above equations are carefully chosen so as to remain stable
under the mildly acidic (pH=6) conditions and to selectively react with protonated imines rather than ketones.
Substitution of the Carbonyl Oxygen in Ketones and

Aldehydes with Two CO Bonds: Acetals and Ketals
H
R O
R O
O H
O
C
addition
C O
elimination
then addition
H R
aldehyde
O R
C O
H R
hemiacetal
O H
acetal
H
H
R O
R O
O H
O
C
ketone
addition
C O
elimination
then addition
R
hemiketal
Addition of one molar equiv alcohol (ROH) to aldehydes and

ketones gives hemiacetals and hemiketals, respectively.
Hemiacetals and hemiketals are not usually isolated.
Elimination of water followed by addition of a second molar
equiv of R-OH gives the corresponding acetals and ketals.
Acetal and ketal derivatives are isolable compounds. Note:
several [pt] steps assist the elimination of water.
O R
C O
R
O H
ketal
H
Examples of Acetal and Ketal Formation

O
H3C
O
C
a ketone
H3C
two molar equiv

of an alcohol
an aldehyde
H3C
2 CH3OH
+
H
H3CO
+
CH3
a diol
+ H2O
an acetal
OH
HO
OCH3
H3C
O
CH3
a cyclic ketal
+ H2O
Removal of Water to Shift Equilibria

Reactions such as ester, imine, enamine, and acetal formation are reversible equilibria that
generate water as a byproduct. The equilibria constants for these reactions are near unity,
meaning that at equilibrium approximately equal quantities of reactants and products are present.
To obtain high yields, the reaction must be driven to the right. Le Chatelier's principle suggests
a useful strategy for driving these equilibria is to remove water. The apparatus below is called a
Dean-Stark trap and is a practical device for removing water to shift chemical equilibria.
Benzene is a commonly used solvent for these reactions. When heated to boil, benzene vapor
forms an azeotropic mixture with the water that is generated in the reaction.
The azeotropic vapor phase is relatively rich in
water content.
When this vapor condenses it
separates into immiscible liquid fractions, one rich
in benzene and the other rich in water. In the
receiver arm, the liquid benzene phase floats above
the more dense water fraction. The benzene-rich
fraction spills back into the pot, ready again to
carry over more water. The water-rich phase sinks
to the bottom of the receiver arm, withdrawn as
needed. The Dean-Stark trap works because of the
benzene-water density difference and because
benzene and water are more compatible as vapors
than they are as liquids.
Manipulating the Equilibrium

Mechanism of Ketal (Acetal) Formation

O
+
CH3
CH3O OCH3
2 CH3OH
CH3
CH3
CH3
CH3
addition
CH3 C CH3
CH3 C CH3
[AdN]
O
O
CH3
HOCH
3
CH3
H2O
CH3
HOCH3
addition
[AdN]
H2O
H
[pt]
H
[pt]
O
CH3
elimination
[E]
H
[pt]
H
[pt]
CH3 C CH3
CH3 C CH3
CH3 C CH3
CH3
CH3
CH3
The Wittig Reaction: Substitution of =O by =C

Ph
Ph
Ph
Ph P CH2
P CH2
Ph
a phosphonium ylide
Ph
(carbon nucleophile)
This net substitution proceeds by

an addition-elimination sequence.
This elimination
involves breakdown of
the 4-membered ring
Ph3P O
[AN]
a betaine
CH2
Ph3P CH2
[AdN]
Ph =
O
Ph3P
an oxaphosphetane
Ph3P=O
Phosphonium ylides (powerful nucleophiles)

add to aldehyde or ketone carbonyl groups via
normal [AdN]. This tetrahedral intermediate, a
betaine, (BAY-tah-een) has no leaving group,
yet its not stable. Because phosphorous has a
high affinity for oxygen, the oxyanion attacks
the positively charged P via [AN] to make a 4membered ring (called a phosphaoxetane).
This strained phosphaoxetane reacts further to
split into Ph3P=O and an alkene. This
elimination is a little funky, but you should be
able to draw a reasonable set of curved arrows
(and identify the frontier orbitals).
Formation of Ylides
Ph3P +
CH3
triphenylphosphine
[SN2]
H
Ph3P
C H
H
methyltriphenylphosphonium
iodide
[pt]
Ph3P CH2
LiI
CH3CH2CH2CH3
butane
CH3CH2CH2CH2 Li
butyllithium
(strong base)
Summary
Primary amines (RNH2) add reversibly to ketones or aldehydes to give imines (Schiff
bases) and related compounds via the intermediate hemiaminals. The position of the
equilibrium depends on the structure of the amine and the carbonyl compound. With
alkylamines, the equilibrium favors the carbonyl compound, but it can be driven to the
imine by removal of water.
With hydrazines (R2NNH2) and hydroxyl and
alkoxylamines (RONH2), the equilibrium greatly favors the hydrazone, oxime, or
oxime ether.!
Secondary amines (R2NH) can form hemiaminals and iminium ions, but they cannot
form imines. Removal of the -hydrogen from iminium ions gives enamines. The
equilibrium can be driven to favor the enamine by removal of water from the reaction
mixture.!
Water and alcohols add reversibly to aldehydes and ketones under either acidic or
basic conditions to give hydrates, hemiacetals, or hemiketals. Only under acidic
conditions can further reaction take place to give acetals and ketals. !
Acetals and ketals are usually thermodynamically unfavorable, so these reactions are
usually driven to completion by removing H2O from the reaction mixture.!
The Carbonyls Alpha C-H is Acidic

hydrogens
O
CH3 C
CH2
CH3
Recall, the larger the pKa, the weaker the acid. The
data below shows that of all the CH bonds, the
carbonyl CH is the strongest acid. The unusually
high acidity of this C-H bond gives it some very
important reactivity (e.g., deprotonation of C-H
makes the alpha position a carbon nucleophile).
bond
carbons
CH3CH2O H
pKa
16
Because of the acidity of the -hydrogen,

ketones exist in another, generally less
stable form known as ____________
enol tautomer
O
OH
CH2
CH3
C
H2
CH3
<1%
> 99 %
enol tautomer
keto tautomer
CH2 H
20
CH3 C C H
25
H2C C H
H
44
CH3CH2 H
51
CH3 C
Interconversion Between Tautomeric Forms is

Catalyzed by Acid or Base
Base-catalyzed mechanism of keto-enol interconversion
keto
tautomer O
RCH C R
O
RCH C R
enolate anion
O
O
enol
tautomer
RCH C R
HO
HO
Acid-catalyzed mechanism of keto-enol interconversion

O
RCH C R
H
keto tautomer
+
H
RCH C R
H
RCH C R
H
H
H3O
enol tautomer
LDA is a Base Used to Form Enolate Anions

Strong organic bases such as LDA (Lithium DiisopropylAmide) can be used to drive
the ketone-enolate equilibrium completely to the enolate side. LDA is a strong base
that is useful for this purpose. The steric bulk of its isopropyl groups makes LDA nonnucleophilic. Even so, its a strong base. LDA is prepared by the deprotonation of
diisopropyl amine using a very strong base such as n-butyl lithium as shown.
pKa = 35
H
diisopropyl amine
CH3CH2CH2CH2 Li
n-BuLi
N
Li
LDA
CH3CH2CH2CH3
pKa = 50
Enolate Equilibria are Acid-Base Reactions

To which side does the equilibrium lie?
Keq = 5 x 10-5
O
CH3 C CH3
pKa = 20
NaOH
O Na
CH2 CCH3
H2O
pKa = 15.7
Keq = 1 x 1015
O
CH3 C CH3
pKa = 20
O Li
LDA
CH2 CCH3
N
H
pKa = 35
Using a strong enough base, quantitative enolate formation is feasible.
Thermodynamic vs. Kinetic Control of Enolate Formation

O
H
O
CH3
LDA
slight
excess
0 C
O
H
CH3
B
1%
A
99%
O
H
O
CH3
LDA
0 C
The indicated difference in reaction

conditions determines whether
deprotonation is reversible or irreversible.
A
10%
CH3
+
slight
excess
CH3
CH3
B
90%
Which enolate is more stable? ____

B
Which enolate is formed faster? ____
A
Summary - How the Various Carbonyl Species Interconvert

Under Acidic or Basic Conditions!
hemiacetal / hemiketal
O OR"
HO OR"
R'
R
[pt]
then base
R"OH
[AdN]
base
R'
[pt]
then
+H
H2O [DN]
+
OR"
[AN]
+ R"OH then
H+
[pt]
[AN] + R"OH
then
H+
[pt]
O
R carbonyl
R'
[pt]
+H+
R'
OH
R"O OR"
R'
R'
acetal / ketal
+H+
[AE]
base
OH
O
R
enolate
-H+
[DE]
R'
base
R'
R
enol
COLOR KEY
intermediates generated under
basic conditions are blue
neutral compounds are black
intermediates generated under
acidic conditions are red
pay careful attention to which
side of the equilibrium arrow (i.e.,
forward or backward direction)
the base or acid lies
Enolate and Enol Nucleophiles

The enolate anion is as an ________
ambident nucleophile (two nucleophilic sites, carbon
and oxygen). Electrophiles generally add to carbon rather than oxygen. The net
result of a reaction at C-alpha is substitution (the electrophile, E+, replaces the
carbonyls alpha hydrogen).
O
O
enolate
anion
E
O
O
RCH C R
RCH C R
RCH C R
RCH C R
H
E
substituted
HO
product
The enol is nucleophilic too

O
enol
RCH C R
tautomer
RCH C R
E
H
H
O
RCH C R
E -substituted
product
enolate anion
Under basic conditions, the nucleophilic form will be the ____________
enol
Under acidic conditions, the nucleophilic form will be the ____
Alkylation of Enolate Anions

(Enolates are Ambident Nucleophiles)
O
O
LDA
Li
(CH3)3Si Cl
"O"-alkylation
Si(CH3)3
LiCl
These are
[SN2] reactions
O
CH3 I
"C"-alkylation
CH3
LiI
enolate HOMO
As the HOMO indicates, enolates are ambident nucleophiles, being reactive at
both C and oxygen. Consistent with the largest lobe of the HOMO being on C,
most electrophiles react at carbon; some very powerful electrophiles (and oxophilic
electrophiles) react mainly at oxygen (e.g., silicon is strongly oxophilic).
Alkylation via Enamine Nucleophiles

O
[SN2]
Br
iminium
bromide
Br
an enamine from
cyclohexanone
HCl / H2O
hydrolysis
O
Enamine nucleophiles are more

mild than enolates:
Less basic
More C-alkylation
Mono-alkylation products only
Acylation via Enamine Nucleophiles

N
CH3 C Cl
[AdN] then [E]
Cl
O
CH3
an enamine from
cyclohexanone
Enamine nucleophiles are mild enough
to give high yields of acylation products
without interference from over acylation
or addition products. Hydrolysis of the
iminium ion involves the [AdN] addition of
water, [pt], and [E] elimination.
an
iminium
ion
HCl / H2O
N
H2
O
1
O
2
3 CH
3
a 1,3-dicarbonyl
Halogenation of the -Carbon
The Enol as a Nucleophile; Br2 as an Electrophile

-bromo substituted
O
carbonyl
"
CH2Br + HBr
O
"
CH2
+ Br2
CH3CO2H
H
H
enol
formation
OH
CH2
Br
Br Br
H
CH2Br
[AE]
Because the conditions are acidic, all intermediates

are neutral or positively charged. The [AE] step is
most easily seen by drawing an alternative resonance
contributor. Can you draw it?
-Halogenation Under Basic Conditions

-Halogenation can also be conducted under basic
conditions with the enolate anion as the nucleophile.
H O
C C
OH
C C
+X
C C
X
However, successive halogenation steps are faster than previous ones,

since the electron-attracting halogens increase the acidity at the -carbon
R C CH3
3 Br2
3 OH
R C CBr3
+ 3 Br +
3 H2O
The product is unstable to the reaction conditions. It reacts with

hydroxide to give a carboxylate salt (the Haloform Reaction).
O
R C CBr3
OH
R C O
CHBr3
The Michael Reaction

(Conjugate addition with an -Carbon Nu)
We have seen that nucleophiles can add
across ,-unsaturated double bonds,
(conjugate addition).
When the
nucleophile is an -carbon nucleophile,
this reaction is called _______
Michael addition.
+$ +
O
H
Nu H
H
C
H C
Nu C
O
1
O
2
Nu
Draw a (----) line across the new CC bond in the product
Identify the nucleophilic carbon
Assign partial charges to atoms of the electrophile to indicate their state of polarization
in the reactant
Number the carbonyl carbons in the product and use this to recognize Michael adducts
O
R
Michael Reaction: Example and Mechanism

O
H
H
O
H
O
OH
CH3
CH3
CH3
CH3
H
H H
H
OH
[pt]
OH
[pt]
H2O
H
O
CH3
[AdN]
CH3
CH3
H
CH3
H
For the acid-catalyzed version of this reaction see:
,unsaturated compound
O
Reactants for
the Michael
Reaction
nucleophile
O
aldehyde
CH3
CH3
-diketone
H H
O
O
CH3
ketone
CH3
OCH3
-diketoester
H H
O
OCH3
-diketonitrile
H H
NH2
amide
O
N
CH3
ester
O
-diester
EtO
OEt
nitrile
H H
nitro
O
CH3
enamine
Summary
The conjugate base of a carbonyl compound, an enolate, is generated under
basic conditions. Enolates are nucleophilic at the -carbon (and at oxygen).
Enolates are better nucleophiles than enols. They react with alkyl halides
(alkylation) by the [SN2] mechanism. They react with ,-unsaturated carbonyl
compounds to give conjugate addition products (another version of the Michael
reaction).!
Enolates can be prepared quantitatively by deprotonation with a strong base
such as lithium diisopropylamide (LDA).!
Enols are good nucleophiles that can be generated under acidic conditions.
Under acidic conditions, carbonyl compounds are thus electrophilic at the
carbonyl C and nucleophilic at the -carbon (and also at oxygen).!
Enols react with electrophiles (e.g., bromine) leading to net substitution of one
-hydrogen by the electrophilic atom(s).!
Enols are particularly reactive toward electrophilic alkenes such as ,unsaturated carbonyl compounds to give conjugate addition products (the
Michael reaction). This is one of the mildest, most versatile, and most efficient
methods for forming C-C bonds.!
The Aldol Addition Reaction

In this reaction, two molecules of an _________________
aldehyde or ketone
combine to produce a -hydroxycarbonyl. One molecule
serves as the nucleophile (enol or enolate) and the other is
the electrophile which undergoes carbonyl addition. The
reaction is acid or base catalyzed.
New CC bond
Base-Catalyzed Aldol Addition

O
H C CH2
Na OH
O
H C
H C CH3
[pt]
O
O
H C CH2
H C CH2
enolate anion
H OH
C CH3
OH
OH
CH2
H
a -hydroxyaldehyde
OH
H C CH3
[AdN]
[pt]
O
H C
O
CH2
C CH3
H
Under basic conditions

the intermediates bear
negative charges
Acid-Catalyzed Aldol Addition

H
H O
O
H C CH2
H OH
H C CH2
enol
[pt]
H OH
H
H C CH3
C CH3
H O
H O
[taut]
CH2
[pt]
OH
H C
H C CH3
OH
[AdN]
H C
OH
CH2
C CH3
H
Under acidic conditions

the intermediates bear
positive charges
Dehydration of -Hydroxy Carbonyl

Compounds Is Common in Aldol Reactions
O
OH
CH3 CH
CH
CH3 CH
H
[taut]
OH
CH C H
H
O
OH
CH3 CH CH C H
enol tautomer
H
[pt]
H
H
[pt]
The acid-catalyzed
dehydration is shown.
The base-catalyzed
dehydration follows
the [E1cb] pathway.
+
O
warm
acid or base
C H
H2O
CH3 CH
H2O
H2O
[E]
H
CH3 CH
O
CH
C H
O
CH
C H
Mixed Aldol Reactions

Mixed aldol reactions involve two different carbonyl
compounds. Up to four products are possible (two
self-addition and two crossed-addition products).
Mixed aldol reactions between an aldehyde with no -hydrogens

and a ketone generally give good yields of a single product
Only enolate possible is from the ketone

Aldehydes are better electrophiles than ketones
Possible Products from a Mixed

Aldol Reaction
Under conditions where

enolate formation is reversible,
a complex mixture results.
Crossed-Aldol Using Preformed Enolates
If the enolate is preformed and

added to the aldehyde, the
desired crossed-aldol product
will be obtained in high yield.
Intramolecular Aldol Reaction

Another example of a successful mixed aldol reaction is when both enolate
anion and carbonyl group to which it adds are in the same molecule
Because of the greater stability of 6-membered rings

compared to 4-membered rings, only a single product
is formed in this intramolecular aldol reaction.
The Claisen Condensation

In this reaction, two molar equiv of an ____
ester combine to produce a -ketoester.
One equiv serves as the nucleophile (enolate) and the other is the electrophile
which undergoes addition and elimination. The reaction is driven to product by the
final deprotonation step.
O
O
O
CH2 +
H
EtO
CH3
CH3
H
O
O
CH3
a -ketoester
Mechanism of the Claisen Condensation

O
O
O
CH2
CH3
EtO
O
H
EtO
[pt]
EtOH
O
CH2
toward the starting ester. The

overall reaction is driven to
completion by the acid-base
reaction between the ethoxide
and -ketoester.
CH2
an ester enolate
CH3
H H pK = 10.7
a
[E]
EtO
CH3
[AdN]
CH3
pKa = 15.9 EtOH

[pt]
The position of the equilibrium
EtO
for the first three steps lies
O
O
O
O
O
C OEt
CH3
a tetrahedral intermediate
Mixed Claisen Condensation

Like mixed aldol reactions, mixed Claisen condensations are useful if
differences in reactivity exist between the two esters as for example when
one of the esters has no -hydrogen. Examples of such esters are:
excess
-Ketoacids are Easily Decarboxylated

CO2 from the carboxyl group of an acid.
Decarboxylation is the loss of ____
Most carboxylic acids are quite resistant to moderate heat. Exceptions
are carboxylic acids that have a carbonyl group __
to the carbonyl.
These carboxylic acids are derived from Claisen condensations
(following ester hydrolysis).
warm
CO2
O
3-oxobutanoic acid
keto-enol
tautomerization
O
a cyclic 6-membered TS
C
O
Alkylation of -Dicarboxylic Esters

(Malonic Ester Synthesis)
Other synthetic plans take advantage of the ease at which decarboxylation
occurs when a carbonyl group is in the position relative to the carboxylic
acid. Here is a general synthetic route to carboxylic acids.
O
O
1) CH3CH2O (deprotonation)
O
O
malonic ester
2) RBr (alkylation)
3) H / H2O / heat (hydrolysis
& decarboxylation)
RCH2 COH
heat
CO2
O
1)
HO
O
O
OH
R
2)
O
O
R
hydrolysis
Alkylation of -Ketoesters
(Acetoacetic Ester Synthesis)
Here is a general synthetic route to methyl ketones.
1) EtO Na
OEt 2)
acetoacetic ester
O
OEt
Br
3) NaOH / H2O
4) HCl / H2O
The product of
acetoacetic ester
synthesis is a
substituted acetone.!
CO2
heat
O
OH
Functional Group Relationships and Retrosynthesis

Michael
Aldol
Aldol + dehydration
Claisen
Acetoacetic acid
synthesis
Malonic acid
synthesis
Learning to recognize compounds

as being products of a specific
organic reaction is the process of
retrosynthetic analysis - working a
synthetic plan backwards.

Chem 232 Fall 2015 UIUC Notes

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Understanding Reactivity

Chemistry is the study of change.

Our goal in this course is to learn

Nucleophiles and Electrophiles

An elementary step between a

empty orbital able to

new bond between

Notice that charge is balanced (the sum the formal

Electron Reconfigurations - the Flow of

The same process takes on a sense

Proton Transfer - A Single-step Mechanism

Notice that most of the

Curved Arrows Describe the Electron

If, in the process of pushing an electron pair to an

pushing electrons using

Proton Transfer Reactions Involve Sigma

This symbol means a

LUMO / HOMO Applied to Acid / Base Interactions

Energy Changes Accompany Each Elementary Step

We have already encountered a useful tool

A Reaction Coordinate Diagram

progress of the reaction

We are interested only in the

Structure of the Transition State

For the proton transfer reaction shown below, notice the

transition state structure

Hammonds Postulate: Transition State Structure & Energy

The Reaction Coordinate Diagram

The complete reaction coordinate

representation of the TS . The rate of

We want to view molecular

Analysis of Chemical Potential

Chemical potential for

What Factors Contribute to High Chemical Potential?

Factors Contributing to Charge Stability

(1) Atom type and periodic table trends

Bond Energy Changes

Average Bond Energies (kcal mole-1)

C=C 146, C C 200

C=N 147, C N 213

C=O 176 (aldehydes)

For a more extensive list see: http://www.jhu.edu/chem/lectka/Bond%20Strengths.html

Bond Energy Changes: Example Calculation

Bonds changes (products)

Recognizing Nucleophiles and Bases

The usual order

The signatures of a nucleophile

an electron rich atom, especially as revealed by negative formal charge

Nucleophilicity and HOMO Energy Level

HOMO Energy Level

LUMO Energy of E+!

Given the LUMO energy

Consider the series of

Which frontier orbital

Recognizing Electrophiles and Acids

an electron deficient atom especially as revealed by an incomplete octet (duet for

Electrophilicity and LUMO Energy Level

Consider the series of

HOMO Energy of Nu!

LUMO Energy Level

REACTIVITY CONCISELY SUMMARIZED: Continuing the acid/base analogy further, strong

Recognizing Acids and Bases

Acid-Base Equilibria: Concepts & Definitions