Substitution and Elimination

Reactions of Alkyl Halides

 Substitution, Nucleophilic,
Bimolecular – SN2
   
Nuc : C X Nuc C X Nuc C + X

transition state

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

Second Order Rate Kinetics
Reaction Profile for SN2
Reaction (Wade)
Stereochemistry of SN2 Reaction
Inversion of Configuration

Br CN
+ KCN + KBr

(S) (R)
 Proof of Inversion of
Configuration at a Chiral Center
O
CH2 OH OTs
OCCH3
TsCl
benzyl (Bz) -OAc, acetate H CH3 H CH3
Bz Bz
(S)(-) (S)
[]D = -33o
CH3 SO 2Cl KOAc

p-toluenesulfonyl chloride RO-H

(Ts-Cl) H CH3 H CH3
Bz H 2O Bz
O
CH3 S O R OH OAc
O (R)(+) (R)
a tosylate (ROTs) []D = +33o
 Acetate Approaches from 180 o

Behind Leaving Group

Bz Bz
- - Bz
 
OTs AcO OTs
AcO H AcO OTs
CH3 H
CH3 H CH3
(S) (R)
 Inversion on a Ring is often
more Obvious: Cis Trans
 Substrate Reactivity
Since the energy of the transition state is significant in determining
the rate of the reaction, a primary substrate will react more rapidly
than secondary (which is much more rapid than tertiary).

R Br + Cl R Cl + Br
6
Rate: ~0 1 500 40,000 2 x 10
(CH3)3CBr (CH3)3CCH2Br (CH3)2CHBr CH3CH2Br CH3Br
tertiary neopentyl secondary primary methyl
 1 > 2 >> 3
o o o

Bulkiness of Substrate
 Polar, Aprotic Solvents
Solvents should be able to "cage" the metal cation
O O O
CH3SCH3 CH3CN HCN(CH3)2 CH3CCH3
DMSO acetonitrile DMF acetone

Polar, protic solvents lower energy of nucleophile

HOCH3 by solvation

CH3OH Br HOCH3

CH3OH
 Nucleophilicity
Nucleophile strength roughly parallels basicity
- - - -
CH3 > NH2 > OH > F

Nucleophile strength increases going down a group

- -
OH < SH
- - - -
F < Cl < Br < I
NH3 < PH3

A base is always a stronger nucleophile than its conjugate acid

-
NH2 > NH3
-
OCH3 > CH3OH
Iodide vs. Fluoride as
Nucleophiles
 Nucleophiles
(preferably non-basic)

basic non-basic

- - - - - - - -
HS > :P(CH3)3 > CN > I > OCH3 > OH > Br > Cl > NH3 > OAc
Good Leaving Groups are
Weak Bases
C LG bond is broken during RDS
Quality of leaving groups is crucial

Sulfonates are excellent leaving groups

O O
CH3 SO CH3SO
O O
tosylate mesylate
TsO- MsO-
 Common Leaving Groups

TsO- = MsO- > NH 3- > I- > H2O- = Br- > Cl- >> F-
Sulfonates are easily prepared from alcohols
O O
in pyridine
CH3OH + ClSR CH3OSR + HCl
O O

tosylate R = CH3

mesylate R = CH3
 SN2 and E2
S N2
H H Nuc
Nuc:
R1 C C R1 C C + Br
R2 Br R2

E2
H
B: R1
R1 C C C C + B-H + Br
R2 R2
Br
rate = k[R-Br][B -]
 Bimolecular Elimination - E2
Nucleophile acts as Bronsted Base

Base: H
C C C C + base-H
 
Br + Br
-Elimination


Base H

C C
 

Br
 SN2 Competes with E2
Depends on the Nature of the Nucleophile
Substitution Elimination
CH3CO2 OAc
wk. base CH3CHCH 3 CH2=CHCH 3
Br 100% 0%
CH3CHCH 3
OEt
CH3CH2O
CH3CHCH 3 CH2=CHCH 3
str. base
20% 80%
 SN2 Competes with E2

Depends on the Size of the Base

CH3CH2O
CH3CH2CH2CH2OEt CH3CH2CH=CH2
str. base
90% 10%
CH3CH2CH2CH2Br
(CH3)3CO
CH3CH2CH2CH2OtBu CH3CH2CH=CH2
str. bulky base 15% 85%
 SN2 Competes with E2
Depends on the Nature of the Substrate

CN
CH3CH2CH2CH2Br CH3CH2CH2CH2CN
str. nuc.; wk. base
1 o 100% SN2

CN
(CH3)3CBr CH2=C(CH3)2
3o 100% E2
 Stereochemistry of E2

rate = k[R-X][base]
second order rate kinetics

CH3O H
C C C C + CH3OH

Br + Br

H on  carbon is anti to leaving group

Anti-Coplanar Conformation
 3(R),4(R) 3-Bromo-3,4-
dimethylhexane
CH2CH3
Br CH3 NaOCH3
H CH3 in CH3OH
heat
CH2CH3
 H and Br Anti-coplanar
orientation
CH3O H Me Et
Et Me
C C C C
Et  Me Et
Me (R) (R) Br

OCH3
H
Me Et Me Et
Et Me
Et Me
Br
 In a Cyclohexane,
Leaving Group must be Axial
KOC(CH 3)3
OTs + KOTs
in t-BuOH / 

OTs
OTs

OtBu
has no anti-coplanar H H
H
 Zaitsev’s Rule

NaOCH3
+
in CH3OH
Br 85% 15%
Zaitsev's Rule: In an elimination reaction, the
more highly substituted alkene (usually) predominate
More Stable Alkene
Predominates
 Hyperconjugation
 bond associates with adjacent C-H  bond

1-butene trans 2-butene

C
C C
C

mono-substituted disubstituted
 With Bulky Base,
Hofmann Product Forms
Which will react more rapidly?
CH3

NaOEt in EtOH
Cl heat
CH(CH3)2
Menthyl chloride
CH3

NaOEt in EtOH
Cl heat
CH(CH3)2
Neomenthyl chloride
 Reactive Conformations
Menthyl chloride Neomenthyl chloride

Cl
CH3
(CH3)2CH CH3
(CH3)2CH
Cl
stable H H
stable and reactive
flip NaOEt

CH(CH3)2 CH3 CH3

H
NaOEt

Cl
CH3 CH(CH3)2 CH(CH3)2
reactive
 E2 Reaction of
(R,R) 2-iodo-3-methylpentane
I
NaOCH2CH3 H CH3
CH3CHCHCH2CH3 C C
in ethanol 
CH3 CH3 CH2CH3
(R,R) OR
CH2=CHCHCH 2CH3 H CH2CH3
OR C C
CH3 CH3 CH3
 Stereochemistry is Important
reactive conformation
I
CH2CH3 H CH3CH2
H C CH3
CH3 C C=C
H CH3 CH3
(R,R) OEt

I
CH3CH2 CH3

H CH3
H
 E2 Reaction of a Vicinal
Dibromide using Zn dust or Iodide

Br H CH3 Br
H CH3 CH3 CH3
C C Zn
H (R) (R) C C
CH3 Br H CH3 HOAc
H H
Br
anti conformation only cis forms
Unimolecular Substitution and
Elimination – SN1 and E1

CH3 CH3 CH3

in warm CH3OH
CH3 C Br CH3 C OCH3 + C=CH2
CH3 CH3 CH3 + HBr

SN1 E1
Rate = k[R-Br]
1st order rate kinetics
 SN1 mechanism (Wade)
1 step is rate determining
st
Reaction Profiles (Wade)
SN 1 S N2
 Hammond’s Postulate
• Related species that are close in energy are close in
structure.
• In an endothermic reaction, the transition state is
similar to the product in structure and stability.
• In an exothermic reaction, the transition state is
similar to the reactant in structure and stability.
• i.e. the structure of the transition state resembles
the structure of the most stable species.
Endo- transition state looks like product
Exo- transition state looks like reactant
SN1 Transition State
 SN1 Solvent Effects

CH3 CH3
ROH
CH3 C Cl CH3 C OR + HCl
CH3 CH3

EtOH 40% H2O / 60% EtOH 80% H2O / 20% EtOH H2O

react.: 1 100 14,000 100,000

Transition state energy is lowered by polar protic solvents
Partial Racemization in SN1
 Carbocation Stability
more highly substituted, lower energy
 Carbocation Stability

CH3 H
CH3 C > CH3 C = CH2=CH CH2 = CH2 > CH3CH2
CH3 CH3
tertiary > secondary = primary allylic = primary benzylic > primar

resonance stabilized
 Carbocations can Rearrange
1,2-Hydride Shift
Br H H OH
H2O
CH3 C C CH3 CH3 C C CH3 + HBr
H CH3 H CH3
Carbocations can Rearrange
1,2-Methide Shift
 Hydride shift

Hydride
H
shift
H

o o
2 3
 Ring Expansion

a
a
c
c
b
b
o o
2 2
Rings Contract, too

hydride
a
shift
b
H
ring
contraction a
b
E1 Mechanism
 E1 and SN1 Compete
a) b)
OTs
CH3OH /  OCH3
+
CH3 CH3 CH3
Zaitsev
a) CH3OH
H

H
CH3
CH3
b) CH3OH
 Synthetic Chemist’s Nightmare
Br

CH3OH

CH3O
CH3O CH3O
CH3O
 Ring Expansion to a More
Stable 6-membered Ring
H

via
Br hydride shift
c
H
b CH3OH
a
b c
a via
ring expansion

 hydride shift

Dehydration of Alcohols – E1
OH
H
H2SO4 (aq) cat.
+ H2O

H
regenerated
H H HSO4
O or H2O
-H2O H
 Methide Shift is Faster than
Loss of H +

OH CH3
CH3 CH3
H2SO4 (aq) CH3
CH3 + CH3
distill
+ H2 O
major minor
 Provide a Mechanism

H OCH3 CH3O H
Br
OCH3
CH3OH, warm
+ +

+ HBr
(or CH3OH2)
 H OCH3 CH3O H
Br
OCH3
CH3OH, warm
+ +
a) b) c)
CH3OH a) Br H + HBr
b) OCH3 (or CH3OH2)

ring expansion
(squiggly bond = both isomers)
CH3OH CH3OH
H H
H OCH3

hydride shift
 Can R-X form a good LG?
No Yes

no reaction classification of  carbon

o o
1 3
o
2
nuc. hindered, strong base? strong base? Yes E2
nuc. a strong base?
Yes No
No
Yes No
Yes SN1*
polar solvent?
E2 good nuc., non-basic? E1
E2 good nuc., nonbasic?
Yes No
(some SN2) Yes
No

SN2 (slow SN2) solvent polar? Yes

SN1*
SN2 E1
* SN1 is favored over E1 unless high temp. and trace amounts of base are used.
Give the Major Product &
Predict the Mechanism

OH
6M H2SO4
120oC, distill
CH3
 OH
6M H2SO4
120oC, distill
CH3 E1 CH3
 NaNH2 in liq. NH3

OTs
 NaNH2 in liq. NH3
E2
OTs
 H
KBr
CH3 CH2CH3
OTs in acetone, 20oC
 H
KBr Br
CH3 CH2CH3 CH3 CH2CH3
OTs in acetone, 20oC H
SN2
Br 1% AgNO3
in CH3CH2OH
Br 1% AgNO3 CH3CH2O
in CH3CH2OH + AgBr
SN1
 CH3CH2CH2OH
Br warm
 CH3CH2CH2OH
Br warm OCH2CH2CH3
SN1/E1

+
CH3
NaSCH2CH3
in CH3CN
Br
CH3
NaSCH2CH3 CH3

in CH3CN
Br SCH2CH3
SN2
I
H 2O
(phase transfer cat.)
I OH
H 2O
(phase transfer cat.)
SN1 (E1) +
I
NaOCH2CH3
CH3
in refluxing ethanol
CH3
I
NaOCH2CH3
CH3 CH3
in refluxing ethanol
CH3 E2 CH3
 NaOCH3
CH3CH2CH2CH2CH2Cl
in methanol, room temp.
 NaOCH3
CH3CH2CH2CH2CH2Cl
in methanol, room temp. O
SN2
Which Reacts More Rapidly in
E2 Reaction?

(CH3)2CH I (CH3)2CH I

A B
 Cis Reacts more Rapidly
trans I

(CH3)2CH I
reactive stable
CH(CH3)2

cis I

(CH3)2CH reacts more rapidly

reactive & stable H