Chapter 4

Functional Group
Interconversion (FGI)
 Nucleophilic
Substitution and
Elimination
Nucleophilic Substitution
nucleophilic
- substitution
Nu: + C Lv C Nu + Lv

Nucleophile Leaving
group

 Nucleophile: a molecule or ion that donates a pair of

electrons to another molecule or ion to form a new covalent
bond; a Lewis base.
o Nucleophiles are species with the following characteristics
o a species with lone pairs,
o a species with negatively charged or
o a species with pi bond
 Nucleophilic substitution: any reaction in which one

nucleophile substitutes for another at a tetravalent carbon

 Some nucleophilic substitution reactions
Mechanisms of nucleophilic substitution Rxn
 Chemists propose two limiting mechanisms for nucleophilic
substitution. These are
1. SN1 mechanism and
2. SN2 mechanism
• a fundamental difference between them is the timing of
bond-breaking and bond-forming steps
 At one extreme, the two processes take place
simultaneously; designated SN2
S = substitution
N = nucleophilic
2 = bimolecular (two species are involved in the rate-
determining step)
 Mechanism - SN2

• Both reactants are involved in the transition state of the

rate-determining step.
• SN2 is a one-step reaction

H
H H
- -
:

:
:

: :

: :
-
HO: + C Br : HO C Br: HO C + : Br :
:

:
:

H
H H
H H H
Transition state with simultaneous
bond breaking and bond forming
Mechanism - SN2

Rate = k[Nuc: ][R-X]

Second Order Rate Kinetics
SN2 Reaction

 Occurs with inversion of chiral center

 Requires strong nucleophillic species
 Sensitive to steric effects
 Methyl halides are most reactive
 Primary are next most reactive
 Secondary might react
 Tertiary are unreactive by this path
 No reaction at C=C (vinyl halides)
Steric Effects on SN2 Reactions

 The carbon atom in (a) bromomethane is readily accessible resulting in a

fast SN2 reaction.
 The carbon atoms in (b) bromoethane (primary),
 The carbon atom in (c) 2-bromopropane (secondary), and
 The carbon atom in (d) 2-bromo-2-methylpropane (tertiary) are
successively more hindered, resulting in successively slower or no SN2
reactions.
Mechanism - SN1

 SN1 is a two-step reaction

 This mechanism is designated SN1 where
• S = substitution
• N = nucleophilic
• 1 = unimolecular (only one species is involved in the rate-
determining step)
 Bond breaking between carbon and the leaving group is
entirely completed before bond forming with the nucleophile
begins.
Mechanism - SN1
• Step 1: Ionization of the C-X H3 C slow, rate CH3
bond gives a carbocation C Br
determining
C+ + Br
intermediate H3 C
H3 C H3 C CH3
• Step 2: A carbocation intermediate;
its shape is trigonal planar
o Reaction of the
carbocation (an
electrophile) with CH3 H3 C CH 3 H3 C CH3
methanol (a nucleophile) fast
+

:
C+ + : OCH3 :O C C O:

gives an oxonium ion. H3 C CH3

H H CH3
CH3
H3 C
H3 C
H

o Followed by proton Electrophile Nucleophile Oxonium ions

transfer completes the

reaction

H3 C CH3 H3 C CH3 H
+ H +
C O: + :O : fast C O: + H O:
:
H3 C H CH3 H3 C CH3
H3 C H3 C
Mechanism - SN1
Evidence of SN reactions

1. What is relationship between the rate of an SN

reaction and:
• the structure of Nu?
• the structure of R?
• the structure of the leaving group?
• the solvent?
2. What is the stereochemical outcome if the leaving
group is displaced from a chiral center?
3. Under what conditions are skeletal rearrangements
observed?
 For an SN1 reaction (kinetics)
• reaction occurs in two steps
• the reaction leading to formation transition state for the
carbocation intermediate involves only the haloalkane and
not the nucleophile
• the result is a first-order reaction
CH3 CH3
CH3 CBr + CH3 OH CH3 COCH3 + HBr
CH3 CH3
2-Bromo-2- Methanol 2-Methoxy-2-
methylpropane methylpropane

Rate = - d[ (CH3 ) 3 CBr] = k[( CH3 ) 3 CBr]

dt
Kinetics
 For an SN2 reaction,
• reaction occurs in one-step
• the reaction leading to the transition state involves the
haloalkane and the nucleophile
• the result is a second-order reaction; first order in
haloalkane and first order in nucleophile

CH3 Br + N a + OH- CH3 OH + N a + Br-

Bromomethane Methanol
d [ CH 3 Br] -
rate = = k[ CH3 Br] [ OH ]
dt
Nucleophilicity
 Nucleophilicity: a kinetic property measured by the
rate at which a Nu causes a nucleophilic substitution
under a standardized set of experimental conditions

 Basicity: a equilibrium property measured by the

position of equilibrium in an acid-base reaction

 Because all nucleophiles are also bases, we study

correlations between nucleophilicity and basicity
Nucleophilicity
Effectiveness Nucleophile
- -
Br , I
- -
Good CH3 S , RS
- - -
HO , CH3 O , RO
- -
CN , N3

- -
Cl , F
- -
CH3 COO , RCOO
Moderate
CH3 S H, RSH, R2 S
NH3 , RNH2 , R2 NH, R3 N

H2 O
Poor CH3 OH, ROH
CH3 COOH, RCOOH
Nucleophilicity
 Relative Nucleophilicities of halide ions in polar
aprotic solvents are quite different from those in
polar protic solvents

 How do we account for these differences?

Solvents
 Protic solvent: a solvent that is a hydrogen bond
donor
o the most common protic solvents contain -OH
groups
 Aprotic solvent: a solvent that cannot serve as a
hydrogen bond donor
o nowhere in the molecule is there a hydrogen
bonded to an atom of high electronegativity
Solvation of nucleophile by polar protic solvent
 Solvation by protic solvent weakens the nucleophile, having the
greatest effect on smaller anions.
 In effect, when using protic solvents, nucleophilicity does not follow
basicity when moving up and down a column. In fact, it's the exact
opposite: when basicity decreases, nucleophilicity increases and
when basicity increases, nucleophilicity decreases.
26
27
Strong Bases/Strong Nucleophiles
o A good base is usually a good nucleophile. So, strong bases
— substances with negatively charged O, N, and C atoms
— are strong nucleophiles.
Examples are: RO⁻, OH⁻, RLi, RC≡C:⁻, and NH₂⁻.

Strong Bases/Poor Nucleophiles

o Some strong bases are poor nucleophiles because of steric
hindrance.
Examples are t-BuO⁻, t-BuLi, and LiN[CH(CH₃)₂]

Weak Bases/Good Nucleophiles

o I⁻ is a weak base, but it is a good nucleophile because the
large electron cloud is highly polarizable
Dielectric Constant
 Solvents are classified as polar and nonpolar
• the most common measure of solvent polarity is
dielectric constant
 Dielectric constant: a measure of a solvent’s
ability to insulate opposite charges from one
another
• the greater the value of the dielectric constant of a
solvent, the smaller the interaction between ions of
opposite charge dissolved in that solvent
– polar solvent: dielectric constant > 15
– nonpolar solvent: dielectric constant < 15
Protic Solvents

Dielectric
Constant
Solvent Structure (25°C)
Water H2 O 79
Formic acid HCOOH 59
Methanol CH3 OH 33
Ethanol CH3 CH2 OH 24
Acetic acid CH3 COOH 6
Aprotic Solvents
Dielectric
Solvent Structure Constant
Polar
Dimethyl sulfoxide (DMSO) ( CH3 ) 2 S=O 48.9
Acetonitrile CH3 C N 37.5
N,N-Dimethylformamide (DMF) ( CH3 ) 2 NCHO 36.7
Acetone ( CH3 ) 2 C=O 20.7

Nonpolar
Dichloromethane CH2 Cl2 9.1
Diethyl ether CH3 CH2 OCH2 CH3 4.3
Toluene C6 H5 CH3 2.3
Hexane CH3 ( CH2 ) 4 CH3 1.9
Nucleophilicity

 A guiding principle is the freer the nucleophile, the

greater its nucleophilicity

In polar aprotic solvents (e.g DMSO, acetone, acetonitrile, DMF)

 are not effective in solvating anions.
 because anions are only poorly solvated, they participate
readily in SN reactions, and nucleophilicity parallels
basicity: F- > Cl- > Br- > I-
Nucleophilicity

 In polar protic solvents (e.g., water, methanol)

• anions are highly solvated by hydrogen bonding with the
solvent.
• the more concentrated the negative charge of the anion,
the more tightly it is held in a solvent shell.
• the nucleophile must be at least partially removed from its
solvent shell to participate in SN reactions
• because F- is most tightly solvated and I- the least,
nucleophilicity is I- > Br- > Cl- > F-
Nucleophilicity

 Generalization
• within a row of the Periodic Table, nucleophilicity
increases from left to right; that is, it increases with
basicity.
Nucleophilicity
 Generalization
• in a series of reagents with the same nucleophilic atom,
anionic reagents are stronger nucleophiles than neutral
reagents; this trend parallels the basicity of the nucleophile
Nucleophilicity
 Generalization
• when comparing groups of reagents in which the
nucleophilic atom is the same, the stronger the base, the
greater the nucleophilicity.

- - -
Nucleophile RCOO HO RO
Carboxylate Hydroxide Alkoxide
ion ion ion
Increasing Nucleophilicity

Conjugate acid RCOOH HOH ROH

pKa 4-5 15.7 16-18
Increasing Acidity
Stereochemistry
 For an SN1 reaction at a chiral center, the R and S
enantiomers are formed in equal amounts, and the
product is a racemic mixture
Stereochemistry
 For SN1 reactions at a chiral center
• examples of complete racemization have been observed,
but
• partial racemization with a slight excess of inversion is
more common
Approach of the
R1 nucleophile from
Approach of the this side is partially
nucleophile from C+ - blocked by leaving
this side is less Cl group, which remains
hindered H associated with the
R2 carbocation as an
ion pair
Stereochemistry
 For SN2 reactions at a chiral center, there is inversion
of configuration at the chiral center
 Experiment of Hughes and Ingold

131
I I
- SN 2 -
+ 131 I + I
acetone
2-Iodooctane
Hughes-Ingold Expt
• the reaction is 2nd order, therefore, SN2
• the rate of racemization of enantiomerically pure 2-
iodooctane is twice the rate of incorporation of I-131

C6 H1 3 C6 H1 3
131
S N2 131
-
I: + C I I C + I
H acetone H
H3 C CH3
(S)-2-Iodooctane (R)-2-Iodooctane
Structure of RX
 SN1 reactions: governed by electronic factors
• the relative stabilities of carbocation intermediates
 SN2 reactions: governed by steric factors
• the relative ease of approach of a nucleophile to the
reaction site
Allylic Halides
 Allylic cations are stabilized by resonance
delocalization of the positive charge
• a 1° allylic cation is about as stable as a 2° alkyl cation
Allylic Cations
The Leaving Group
 The more stable the anion, the better the leaving
ability
• the most stable anions are the conjugate bases of strong
acids

rarely function as
leaving groups
Reactivity as a leaving group O
I- > Br- > Cl- > H2 O >> F- > CH3 CO- > HO- > CH3 O- > NH2 -

Stability of anion; strength of conjugate acid

The Solvent - SN2
 The most common type of SN2 reaction involves a negative
Nu and a negative leaving group
negative charge dispersed negatively charged
negatively charged
in the transition state leaving group
nucleophile

 
Nu:- + C Lv Nu C Lv Nu C + Lv

Transition state

• the weaker the solvation of Nu, the less the energy

required to remove it from its solvation shell and the
greater the rate of SN2.
The Solvent - SN2
The Solvent - SN1

 SN1 reactions involve creation and separation of

unlike charge in the transition state of the rate-
determining step.
 Rate depends on the ability of the solvent to keep
these charges separated and to solvate both the
anion and the cation.
 Polar protic solvents (formic acid, water, methanol)
are the most effective solvents for SN1 reactions.
The Solvent - SN1
CH3 CH3
solvolysis
CH3 CCl + ROH CH3 COR + HCl
CH3 CH3

k(solvent)
Solvent k(ethanol)
water 100,000
80% water: 20% ethanol 14,000
40% water: 60% ethanol 100
ethanol 1
Rearrangements in SN1

 Rearrangements are common in SN1 reactions if

the initial carbocation can rearrange to a more
stable one.

+ -
+ CH3 OH OCH3 + CH3 OH + Cl
Cl CH3 OH
H
2-Chloro-3- 2-Methoxy-2-phenylbutane
phenylbutane
Rearrangements in SN1
 Mechanism of a carbocation rearrangement

(1) + : Cl
Cl +

A 2° carbocation

(2) H +
+ H

A 3° benzylic carbocation

H H
+
(3) + + : O-CH3 O
CH3

An oxonium ion
Summary of SN1 & SN2
Type of
Alkyl Halide SN 2 SN 1
Methyl SN 2 is favored. SN 1 does not occur. The methyl cation
CH3 X is so unstable, it is never observed
in solution.
Primary SN 2 is favored. SN 1 rarely occurs. Primary
RCH2 X cations are so unstable, that they are
never observed in solution.
Secondary SN 2 is favored in aprotic SN 1 is favored in protic solvents with
R2 CHX solvents with good poor nucleophiles. Carbocation
nucleophiles. rearrangements may occur.
Tertiary SN 2 does not occur because SN 1 is favored because of the ease of
R3 CX of steric hindrance around formation of tertiary carbocations.
the reaction center.
Substitution Inversion of configuration. Racemization is favored. The carbocation
at a The nucleophile attacks intermediate is planar, and attack of the
stereocenter the stereocenter from the nucleophile occurs with equal
side opposite the leaving probability from either side. There is
group. often some net inversion of
configuration.
Predicting SN1 vs. SN2 mechanisms
We really need to consider three factors:

1) The electrophile: when the leaving group is attached to a methyl group or a primary carbon, an
SN2 mechanism is favored (here the electrophile is unhindered by surrounded groups, and any
carbocation intermediate would be high-energy and thus unlikely). When the leaving group is
attached to a tertiary, allylic, or benzylic carbon, a carbocation intermediate will be relatively
stable and thus an SN1 mechanism is favored.  These patterns of reactivity of summarized
below.

2) The nucleophile: powerful nucleophiles, especially those with negative charges, favor the S N2
mechanism. Weaker nucleophiles such as water or alcohols favor the S N1 mechanism.

3) The solvent:  Polar aprotic solvents favor the SN2 mechanism by enhancing the reactivity of the
nucleophile. Polar protic solvents favor the S N1 mechanism by stabilizing the transition state and
 The reaction below has a tertiary alkyl bromide as the electrophile,
o a weak nucleophile, and a polar protic solvent (methanol is the solvent). Thus
we’d confidently predict an SN1 reaction mechanism. 
o Because substitution occurs at a chiral carbon, we can also predict that the
reaction will proceed with racemization.

 In the reaction below, on the other hand, the electrophile is a secondary alkyl
bromide
o with these, both SN1 and SN2 mechanisms are possible, depending on the
nucleophile and the solvent. 
o the nucleophile (a thiolate anion) is strong, and a polar aprotic solvent is used
– so the SN2 mechanism is heavily favored. 
o The reaction is expected to proceed with inversion of configuration.
Exercise 
1.    Determine whether each substitution reaction shown below is likely to
proceed by an SN1 or SN2 mechanism and explain your reasoning.

Answer
a)    SN2 b/c primary alkyl halide with a strong nucleophile in a polar aprotic solvent.
b)    SN1 b/c tertiary alkyl halide with a weak nucleophile that is also the solvent
(solvolysis).
c)    SN2 b/c secondary alkyl halides favor this mechanism when reacted with a
strong nucleophile (and weak base) in a polar aprotic solvent.
SN1/SN2 Problems
• Problem 1: predict the mechanism for this reaction,
and the stereochemistry of each product
Cl OH OCH3
+ CH3 OH/ H2 O + + HCl
(R)-2-Chlorobutane

• Problem 2: predict the mechanism of this reaction

Br + Na + CN- CN + Na + Br -
DMSO
SN1/SN2 Problems
• Problem 3: predict the mechanism of this reaction and
the configuration of product
Br SCH3
+ CH3 S- Na + acetone
+ Na+ Br-
(R)-2- Bromobutane

• Problem 4: predict the mechanism of this reaction and

the configuration of the product

O O
Br + CH3 COH acetic acid OCCH3 + HBr

(R)-3-Bromo-
cyclohexene
SN1/SN2 Problems
• Problem 5: predict the mechanism of this reaction
+
Br + ( CH3 ) 3 P P( CH3 ) 3 Br -
toluene
Elimination Reaction
-Elimination
 -Elimination: a reaction in which a molecule,
such as HCl, HBr, HI, or HOH, is split out or
eliminated from adjacent carbons.
-Elimination

 Zaitsev rule: the major product of a -elimination is

the more stable (the more highly substituted) alkene.
-Elimination
 There are two limiting mechanisms for -
elimination reactions
1. E1 mechanism: at one extreme, breaking of the R-Lv
bond to give a carbocation is complete before reaction
with base to break the C-H bond
o Only R-Lv is involved in the rate-determining step
2. E2 mechanism: at the other extreme, breaking of the
R-Lv and C-H bonds is concerted
o Both R-Lv and base are involved in the rate-determining step
Zaitsev’s Rule for Elimination Reactions
 In the elimination of HX from an alkyl halide, the more
highly substituted alkene product predominates

 Mechanisms of Elimination Reactions

 E1: two steps reaction
o X- leaves first to generate a carbocation
o a base abstracts a proton from the adjust carbon
 E2: concerted (one step) reaction
 Concerted transfer of a proton to a base and departure
of leaving group
6
E1 Mechanism
E1 reaction is a two-step reaction
Step 1: Ionization of C-Lv gives a carbocation intermediate

slow, rate
CH3 CH3
determining
CH3 -C-CH3 CH3 -C-CH3 + Br
+
Br
(A carbocation
intermediate)

Step 2: Proton transfer from the carbocation intermediate to

the base (in this case, the solvent) gives the alkene

H CH3 H CH3
fast +
O: + H-CH2 -C-CH3 O H + CH2 =C-CH3
+
H3 C H3 C
E1 Mechanism
E2 bimolecular elimination reaction
o Rate of reaction depends on both reactants (base and
substrate)
o One-step reaction
o A strong base to initiate the reaction

67
E2 Mechanism
The E2 Reaction
 A proton is transferred to
base as leaving group begins
to depart

 Transition state combines

leaving of X and transfer of H

 Product alkene forms

stereospecifically

 Rate = k[RX][B]

69
Kinetics of E1 and E2
 E1 mechanism
• reaction occurs in two steps
• the rate-determining step is carbocation formation
• the reaction is 1st order in RLv
d[RLv]
Rate = = k[ RLv]
dt

 E2 mechanism
• reaction occurs in one step
• reaction is 2nd order; first order in RLv

d[RLv]
Rate = = k[ RLv][ Base ]
dt
Regioselectivity of E1/E2
 E1: major product is the more stable alkene
 E2: with strong base, the major product is the more stable
(more substituted) alkene
• double bond character is highly developed in the transition
state
• thus, the transition state of lowest energy is that leading to
the most stable (the most highly substituted) alkene
 E2: with a strong, sterically hindered base such as tert-
butoxide, the major product is often the less stable (less
substituted) alkene
Regioselectivity of E2
Stereoselectivity of E2

 E2 is most favorable (lowest activation energy) when

H and Lv are oriented anti and coplanar

-
CH3 O: CH3 O
H H
C C
C C
Lv
-H and -Lv are anti and coplanar Lv
(dihedral angle 180°)
Stereochemistry of E2
 Consider E2 of these stereoisomers

CH3 O- Na+
+
Cl CH3 OH
cis-1-Chloro-2- 1-Isopropyl- (R)-3-Isopropyl-
isopropyl- cyclohexene cyclohexene
cyclohexane (major product)

CH3 O- Na +

Cl CH3 OH
trans-1-Chloro-2- (R)-3-Isopropyl-
isopropyl- cyclohexene
cyclohexane
Stereochemistry of E2
• in the more stable chair of the cis isomer, the larger
isopropyl is equatorial and chlorine is axial
-
CH3 O:
H
H 2
E2
6
H + CH3 OH + :Cl
1
H
Cl 1-Isopropyl-
cyclohexene
Stereochemistry of E2
• in the more stable chair of the trans isomer, there is no
H anti and coplanar with Lv, but there is one in the less
stable chair

H
H 2 Cl
6 Cl H 6 2 H
1
1 H
H
H H
More stable chair Less stable chair
(no H is anti and (H on carbon 6 is
coplanar to Cl) anti and coplanar to Cl)
Stereochemistry of E2
• it is only the less stable chair conformation of this isomer
that can undergo an E2 reaction

Cl
E2
H 6 2 H + CH3 OH + Cl
1
H
H
- (R)-3-Isopropyl-
CH3 O:
cyclohexene
Stereochemistry of E2

Problem: account for the fact that E2 reaction of the

meso-dibromide gives only the E alkene

C6 H5 C6 H5
Br Br - +
CH3 O Na C C
C6 H5 CH-CHC6 H5
CH3 OH Br H
meso-1,2-Dibromo- (E)-1-Bromo-1,2-
1,2-diphenylethane diphenylethylene
Summary of E2 vs E1
 SN vs E
 Many nucleophiles are also strong bases (OH- and
RO-) and SN and E reactions often compete
 The ratio of SN/E products depends on the relative
rates of the two reactions

nucleophilic
substitution H C C Nu + Lv
H C C Lv + Nu-
-elimination
C C + H-Nu + Lv
 SN vs E
Halide Reaction Comments
Methyl S N2 SN 1 reactions of methyl halides are never observed.
CH3 X The methyl cation is so unstable that it is never
formed in solution.

Primary SN2 The main reaction with good nucleophiles/weak

RCH2 X bases such as I- and CH3 COO- .
E2 The main reaction with strong, bulky bases such as
potassium tert-butoxide.

Primary cations are never observeded in solution and,

therefore, SN1 and E1 reactions of primary halides
are never observed.
 SN vs E (cont’d)

 Charged bases/nucleophiles will tend to perform SN2/E2 reactions.

 Reactions where neutral bases/nucleophiles are involved tend to
go through carbocations (i.e. they tend to be SN1/E1).
Comparing E1 and E2
 Strong base is needed for E2 but not for E1
 E2 is stereospecifc, E1 is not
 E1 gives Zaitsev orientation

83
Substitution versus Elimination

84
Summary of Reactivity: SN2, SN1, E1, E2
 Alkyl halides undergo different reactions in competition, depending on the
reacting molecule and the conditions
 Based on patterns, we can predict likely outcomes
Good L.G.
2o alkyl halide
Polar Protic Solvent
SN1 and E1 products

 Primary Haloalkanes
SN2 with any fairly good nucleophile
E2 only if Bulky, strong base
 Secondary Haloalkanes
SN2 with good nucleophiles, weak base, Polar Aprotic Solvent
SN1/E1 with good LG, weak Nu, Polar Protic Solvent
E2 with strong base
 Tertiary Haloalkane
SN1/E1 with good LG, no base (solvolysis)
E2 with strong base
The E1 Reaction
 Competes with SN1
 Rarely have “clean” SN1 or E1 single products
 Rate = k [RX], same as SN1

86
Neighboring Groups

 In an SN2 reaction, departure of the leaving group is

assisted by Nu; in an SN1 reaction, it is not

 These two types of reactions are distinguished by
their order of reaction; SN2 reactions are 2nd order,

and SN1 reactions are 1st order

 But some substitution reactions are 1st order and yet
involve two successive SN2 reactions
Mustard Gases
 Mustard gases
• contain either S-C-C-X or N-C-C-X

• what is unusual about the mustard gases is that they

undergo hydrolysis so rapidly in water, a very poor
nucleophile
Cl
S
Cl + 2 H O HO
S
OH + 2 HCl
2
Mustard Gases
• the reason is neighboring group participation by the
adjacent heteroatom
slow, rate +
determining
:
S S + Cl
Cl Cl Cl
an internal
SN 2 reaction A cyclic
sulfonium ion

:
fast S H
S + : O-H Cl
Cl a second +O
H S N2 reaction H

• proton transfer to solvent completes the reaction

Phase-Transfer Catalysis
 A substance that transfers ions from an aqueous
phase to an organic phase
 An effective phase-transfer catalyst must have
sufficient
• hydrophilic character to dissolve in water and form an
ion pair with the ion to be transported
• hydrophobic character to dissolve in the organic
phase and transport the ion into it
 The following salt is an effective phase-transfer
catalysts for the transport of anions
(CH 3 CH 2 CH 2 CH 2 ) 4 N + Cl -
Tetrabutylammonium chloride
(Bu4N + Cl- )
Phase-Transfer Catalysis