ORGANIC REACTIONS

• During organic reactions bonds can be broken in a way

that one of the fragments retains both bonding electrons
called heterolytic cleavage or heterolysis.
• But if the fragment retains a single electron each, the
type of cleavage is called homolytic cleavage or
homolysis. Consider cleavage of A-B bond below:

1
 Chapter four
Substitution Reactions

• Substitution reactions involve the exchange of one

functional group for another:

• In every substitution reaction, there is an electrophile

and a nucleophile:

• In SN reactions, the electrophile is usually referred as

substrate 2
 Substitution Reactions cont’d
• A substrate contain a leaving group serving two critical
functions:
1. The leaving group withdraws electron density via
induction, creating electrophilicity difference

2. The leaving group can stabilize any negative charge that

may develop as the result of the leaving group
separating from the substrate:

Halogens (Cl, Br, and I) are very common leaving groups.

3
Possible Mechanisms for Substitution Reactions

• There are only two possible mechanisms for a

substitution reaction:
• Concerted process: nucleophilic attack and loss
of the leaving group occur simultaneously.
• Stepwise process: loss of the leaving group occurs
first followed by nucleophilic attack.

4
 4.1. The SN2 Mechanism

• This mechanism is investigated Based on kinetic and

stereochemical observations:

• Kinetics: the rate of the reaction depends on both

substrate and nucleophile. It is bimolecular

• SN2 to refer

5
 The SN2 Mechanism cont’d

• The experimental observations for SN2

reactions are consistent with a concerted
mechanism, because a concerted mechanism
exhibits only one mechanistic step, involving
both the nucleophile and the substrate:

6
 The SN2 Mechanism cont’d

• Stereospecificity of SN2 Reactions: When the  position is

a chirality center, a change in configuration is generally
observed, as illustrated in the following example:

• The reactant exhibits the S configuration, while the

product exhibits the R configuration.
• That is, this reaction is said to proceed with inversion of
configuration .
7
 The SN2 Mechanism cont’d

• The requirement for inversion of configuration

means that the nucleophile can only attack from
the back side (the side opposite the leaving
group), and never from the front side.

8
 The SN2 Mechanism cont’d

There are two ways to explain why the reaction proceeds

through back-side attack:

1. The lone pairs of the leaving group create regions

of high electron density that effectively block the
front side of the substrate, so the nucleophile can only
approach from the back side.

2. According to MO theory, the electron density flows

from the HOMO of the nucleophile into the LUMO
of the electrophile. 9
 The SN2 Mechanism cont’d

• The requirement for inversion of configuration

means that the nucleophile can only attack from
the back side (the side opposite the leaving
group), and never from the front side.

10
 The SN2 Mechanism cont’d
• The observed stereochemical outcome for an SN2 process
(inversion of configuration) is consistent with a concerted
mechanism.
• The nucleophile attacks with simultaneous loss of the LG.
• This causes the chirality center to behave like an umbrella
flipping in the wind:

• It is stereospecific reaction b/c the configuration of the

product is dependent on the configuration of the starting
material.
11
 Structure of the Substrate
• For SN2 reactions, the rate to be sensitive to the
nature of the starting alkyl halide.
• In particular, methyl halides and primary alkyl
halides react most quickly with nucleophiles.
• Secondary alkyl halides react more slowly, and
tertiary alkyl halides are essentially unreactive
toward SN2.
• This trend is consistent with a concerted process
in which the nucleophile is expected to encounter
steric hindrance as it approaches the substrate. 12
 Structure of the Substrate cont’d
• The relative reactivity of various substrates
toward SN2.

13
 Structure of the Substrate cont’d
• Energy diagrams comparing SN2 processes
for methyl, primary, and secondary substrates.

14
 Structure of the Substrate cont’d
• If the hydrogen atoms in figure below are replaced with
alkyl groups, steric interactions cause the transition
state to be higher in energy, raising Ea for the reaction.

• TS contain partially formed and partially cleaved/broken

bonds
15
 4.2. The SN1 Mechanism
• The second possible mechanism for a substitution reaction
is a stepwise process in which there is (1) loss of the
leaving group to form a carbocation intermediate followed
by (2) nucleophilic attack on the carbocation intermediate:

• Many reactions appear to follow this stepwise mechanism.

Once again, there are several pieces of evidence that
support this stepwise mechanism in those cases. 16
 Kinetics
• Many substitution reactions do not exhibit second-order
kinetics. Rather

• Increasing or decreasing the concentration of the

nucleophile has no measurable effect on the rate.

• The rate equation is first order. The rate determining

(slowest step) step involves only one chemical entity
implying to be unimolecular

17
 The SN1 Mechanism cont’d

• The term SN1 refer to

• The term unimolecular is not mean that the

nucleophile is completely irrelevant.

18
An energy diagram of an SN1 process.

19
 Structure of Substrate

• The rate of an SN1 reaction is highly dependent

on the nature of the substrate, but the trend is
the reverse of the trend we saw for SN2 reactions.
• With SN1 reactions, tertiary substrates react most
quickly, while methyl and primary substrates
are mostly unreactive.
• Why? With SN2 reactions, steric hindrance was
the issue because the nucleophile was directly
attacking the substrate.
20
 Structure of Substrate cont’d

• In contrast, in SN1 reactions the nucleophile does not attack

the substrate directly.
• Instead, the leaving group leaves first, resulting in the
formation of a carbocation, and that step is the rate-
determining step.
• Once the carbocation forms, the nucleophile captures it very
quickly.

• The rate is only dependent on how quickly the leaving

group leaves to form a carbocation.
• Steric hindrance is not at play, because the rate-
determining step does not involve nucleophilic attack.
• The dominant factor now becomes carbocation stability. 21
The relative reactivity of various substrates
toward SN1.

22
Stability of respective carbocations

23
• Energy diagrams comparing SN1 processes for
secondary and tertiary substrates

24
 Stereochemistry of SN1 Reactions

• In contrast, SN1 reactions involve formation of an

intermediate carbocation, which can then be attacked
from either side, leading to both inversion of
configuration and retention of configuration. Example,

25
 Chapter Five
Elimination Reactions
• In an elimination reaction, a proton from the beta (β)
position is removed together with the leaving group,
forming a double bond.

• This type of reaction is called a beta elimination, or 1,2-

elimination, and can be accomplished with any good
leaving group.

• The product of an elimination reaction possesses a C=C

double bond and is called an alkene .
26
 5.1. The E2 Mechanism
• It is a concerted process or pathway
• It involves base and substrate

Kinetic Evidence for a Concerted Mechanism

• Kinetic studies show that many elimination reactions exhibit
second-order kinetics with a rate equation that has the
following form:

27
 The E2 Mechanism cont’d

• Much like the SN2 reaction, the rate is linearly

dependent on the concentrations of two different
compounds (the substrate and the base).
• B/c the rate determining step involves two chemical
entities, it is said to be bimolecular. Bimolecular
elimination reactions are called E2 reactions:

28
 Effect of Substrate
• Steric effects in SN2 and E2 reactions: With a tertiary substrate,
steric hindrance prevents the reagent from functioning as a
nucleophile at an appreciable rate, but the reagent can still
function as a base without encountering much steric hindrance

29
 The E2 Mechanism cont’d

• Relative rates of reactivity for substrates in

an E2 reaction.

30
• The energy diagram of an E2 reaction

31
• Energy diagrams for E2 reactions with various substrates

32
 Regioselectivity of E2 Reactions
• In many cases, an elimination reaction can produce
more than one possible product.
• In the example below, the β positions are not identical,
so the double bond can form in two different regions of
the molecule.

• This consideration is an example of regiochemistry,

and the reaction is said to produce two different
regiochemical outcomes.

33
 Regioselectivity of E2 Reactions cont’d
• Both products are formed, but the more
substituted alkene is generally observed to be the
major product. For example:

• The reaction is said to be regioselective.

• The more substituted alkene is called the Zaitsev
product.
• However, many exceptions have been observed in
which the Zaitsev product is the minor product 34
 Regioselectivity of E2 Reactions cont’d
• The regiochemical outcome of an E2 reaction can often be
controlled by carefully choosing the base.
• For example, the product distribution for the reaction
above is highly dependent on the choice of base

35
 Stereoselectivity of E2 Reactions
• When deprotonation of either β position produces the
same result.
• Cis/trans or E/Z two possible stereoisomeric alkenes can
be obtained:

• Both stereoisomers (cis and trans) are produced, but

the trans product predominates. The substrate produces
two stereoisomers in unequal amounts is stereoselctive.
36
 Stereospecificity of E2 Reactions
• Consider a case where the β position contains
only one proton.
• For example, consider performing an elimination
with the following substrate:

37
 Stereospecificity of E2 Reactions cont’d
• In this example, there are two β positions. One of
these positions has no protons at all, and the
other position has only one proton. In such a
case, a mixture of stereoisomers is not obtained.
• In this case, there will only be one stereoisomeric
product:

38
 Stereospecificity of E2 Reactions cont’d
• Why is the other possible stereoisomer not
obtained? To understand the answer to this
question, we must explore the alignment of
orbitals in the transition state.
• In the transition state, a π bond is forming. Recall
that a π bond is comprised of overlapping p
orbitals.
• Therefore, the transition state must involve the
formation of p orbitals that are positioned such
that they can overlap with each other as they are
forming. 39
 Stereospecificity of E2 Reactions cont’d
• In order to achieve this kind of orbital overlap,
the following four atoms must all lie in the same
plane: the proton at the β position, the leaving
group, and the two carbon atoms that will
ultimately bear the π bond.
• These four atoms must all be coplanar:

40
 Stereospecificity of E2 Reactions cont’d
• Recall that the C—C single bond is free to rotate before
the reaction occurs. If we imagine rotating this bond, we
see that there are two ways to achieve a coplanar
arrangement:

• the terms anti and syn refer to the relative positions of

the proton and the leaving group 41
 Stereospecificity of E2 Reactions cont’d
• The term periplanar (rather than coplanar) is
used to describe a situation in which the proton
and leaving group are nearly coplanar (for
example, a dihedral angle of 178° or 179°).

• The requirement for an anti-periplanar (in E2)

arrangement will determine the stereoisomerism
of the product.
• In other words, the stereoisomeric product of an
E2 process depends on the configuration of the
starting alkyl halide: 42
Stereospecificity of E2 Reactions cont’d

43
Examples of Stereoselective E2 reaction.

44
 Stereospecificity of E2 Reactions cont’d

• If, however, the β position has two protons, then

either of these two protons can be arranged so
that it is anti-periplanar to the leaving group.
• As a result, both stereoisomeric products will be
obtained:

45
 5.2. The E1 Mechanism
• It is stepwise mechanism or pathway

Kinetic Evidence for a Stepwise Mechanism

• Kinetic studies show that many elimination reactions
exhibit first-order kinetics, with a rate equation that
has the following form:

46
 E1 Mechanism cont’d

• Much like the SN1 reaction, the rate is linearly

dependent on the concentration of only one
compound (the substrate).
• B/c the rate determining step involves only one chemical
entity, it is unimolecular.
• Unimolecular elimination reactions are called E1
reactions:

47
 Effect of Substrate
• For E1 reactions, the rate is found to be very sensitive to
the nature of the starting alkyl halide, with tertiary
halides reacting most readily.
• A stepwise mechanism involves formation of a
carbocation intermediate, and the rate of reaction will
be dependent on the stability of the carbocation.
• The rate of reactivity of various substrates in an E1
reaction.

48
 Effect of Substrate cont’d

• Relative stability of primary, secondary, and

tertiary carbocations.

49
 Effect of Substrate cont’d

• A comparison of energy diagrams for the E1

reactions of secondary and tertiary substrates.

50
 Regioselectivity of E1 Reactions
• E1 processes exhibit a regiochemical preference
for the Zaitsev product, as was observed for E2
reactions.
• The more substituted alkene (Zaitsev product)
is the major product.

• For example:

51
 Stereoselectivity of E1 Reactions
• E1 reactions are not stereospecific—that is, they do not
require anti-periplanarity in order for the reaction to
occur.
• Nevertheless, E1 reactions are stereoselective. When
cis and trans products are possible, we generally
observe a preference for formation of the trans
stereoisomer:

52
 Elimination vs substitution
• Substitution and elimination reactions are almost
always in competition with each other. In order to
predict the products of a reaction, it is necessary to
determine which mechanisms are likely to occur.
In some cases, only one mechanism will
predominate:

53
• In other cases, two or more mechanisms will compete; for
example:

Three steps are required to predict the product:

1. Determine the function of the reagent.

2. Analyze the substrate and determine the expected mechanism(s).
3. Consider any relevant regiochemical and stereochemical
requirements.

54
 Identifying the Reagent: (Nucleophilicity vs. Basicity)
• The first category contains reagents that function only as
nucleophiles. That is, they are strong nucleophiles because they
are highly polarizable, but they are weak bases because their
conjugate acids are fairly acidic. The use of a reagent from this
category signifies that a substitution reaction is occurring (not
elimination).

55
• The second category contains reagents that function only as
bases, not as nucleophiles. The first reagent on this list is the
hydride ion, usually shown as NaH, where Na+ is the counterion.

56
• The third category contains reagents that are both strong
nucleophiles and strong bases. These reagents include
hydroxide (HO ) and alkoxide ions (RO ). Such reagents
- -

are generally used for bimolecular processes (S N2 and

E2).

• The fourth and final category contains reagents that are

weak nucleophiles and weak bases.
These reagents include water (H2O) and alcohols (ROH).
Such reagents are generally used for unimolecular
processes (SN1 and E1).

57
 Identifying the Mechanism(s)
• Possible Outcomes for Reagents That Function Only as Nucleophiles

• When the reagent functions exclusively as a nucleophile

(and not as a base), only substitution reactions occur (not
elimination). The substrate determines which mechanism
operates. S 2 predominates for primary substrates, and
N

S1
N

predominates for tertiary substrates. For secondary

substrates, both S 2 and S 1 can occur, although S 2 is
N N N

generally favored (especially when a polar aprotic solvent

is
used).

58
• Possible Outcomes for Reagents That Function Only as Bases

• When the reagent functions exclusively as a base (and

not as a nucleophile), only elimination reactions occur.
Such reagents are generally strong bases, resulting in
an E2 process. This mechanism is not sensitive to
steric hindrance and can occur for primary, secondary,
and tertiary substrates 59
• Possible Outcomes for Reagents That Are Strong Bases and Strong Nucleophiles

• When the reagent is both a strong nucleophile and a strong

base, bimolecular reactions (SN2 and E2) are favored.For primary
substrates, SN2 predominates over E2, unless t-BuOK is used
as the reagent, in which case E2 predominates. For secondary
substrates, E2 predominates, because E2 is not sterically
hindered, while SN2 exhibits some steric hindrance.
For tertiary substrates, only E2 is observed, because the SN2
pathway is too sterically hindered to occur.

60
• Possible Outcomes for Reagents That Are Weak Bases and Weak
Nucleophiles

• 1=NOT PRACTICAL, because the reactions are too slow.

• 2=NOT PRACTICAL, because the reactions are too slow, and too
many products are formed. A secondary alcohol will undergo an
E1 reaction when treated with concentrated sulfuric acid and
heat.
• 3=Under these conditions, unimolecular reactions (SN1 and E1)
are favored. High temperature favors E1. 61
 Saytzef and Hoffmann rules
• Saytzef Rule: Says the more substituted
alkene product is obtained when a proton is
removed from the β-carbon that is bonded to the
fewest hydrogens. This is called Zaitsev’s rule.
Example,

62
• The reaction of a quaternary ammonium ion with hydroxide ion is
known as a Hofmann elimination reaction. The leaving group in
a Hofmann elimination reaction is a tertiary amine. Because a
tertiary amine is only a moderately good leaving group, the
reaction requires heat.

63
• A Hofmann elimination reaction is an E2 reaction.
Recall that an E2 reaction is a
concerted, one-step reaction—the proton and the
tertiary amine are removed in the same step. Very
little substitution product is formed.

64
• In a Hofmann elimination reaction, the
hydrogen is removed from the α-carbon
bonded to the most hydrogens.

65