Nucleophilic Substitution

SH S

1
I. Nucleophilic Substitution

R X + Y R Y + X substitution
substrate nucleophile product leaving reaction
group

e.g.,

H O CH3 Br CH3 OH + Br
I. Nucleophilic Substitution
A. Functional group transformation
R X + HO R OH alcohol
alkyl
halide R'O R O R' ether
(sp3 only)
O O
R' C O R' C OR ester

HS R SH thiol

R'S R S R' thioether

CN R C N nitrile

R' C C R C C R' alkyne

N3 R N N N azide
I. Nucleophilic Substitution
Question 8-1. Give the products. Click on the arrow to check answers.

CH3Br + NaOH

Br + CH3S-

Br + CN-
I. Nucleophilic Substitution
Answer 8-1. Give the products. Click on the arrow to check answers.

CH3Br + NaOH CH3OH

Br + CH3S- S CH3

Br + CN- C N
I. Nucleophilic Substitution
B. Leaving groups
weaker base = better leaving group
reactivity: R-I > R-Br > R-Cl >> R-F
best L.G. worst L.G.
most reactive least reactive

R X + Y R Y + X K>1
stronger weaker
base base

Br + NaF F + NaBr
SB WB
precipitate
drives rxn
acetone
+ NaI + NaBr (s) (Le Châtelier)
Br I
WB SB
I. Nucleophilic Substitution
C. Two mechanisms

general: Rate = k1[RX] + k2[RX][Y–]

k1 increases
RX = CH3X 1º 2º 3º

k2 increases

k1 ~ 0 k2 ~ 0
Rate = k2[RX][Y–] Rate = k1[RX]
(bimolecular) (unimolecular)
SN2 SN1
II. SN2 Mechanism
A. Kinetics
e.g., CH3I + OH–  CH3OH + I–

find: Rate = k[CH3I][OH–], i.e., bimolecular

 both CH3I and OH– involved in RLS

and recall, reactivity: R-I > R-Br > R-Cl >> R-F

 C-X bond breaking involved in RLS

 concerted, single-step mechanism:

[HO---CH3---I]–

CH3I + OH–

CH3OH + I–
II. SN2 Mechanism
B. Stereochemistry: inversion of configuration

Stereospecific reaction:

H Br HO H
NaOH

(R)-(–)-2-bromooctane (S)-(+)-2-octanol

Reaction proceeds with

inversion of configuration.
 II. SN2 Mechanism
C. Mechanism

Back-side attack: inversion of configuration

H + - H H

HO C I HO C I HO C + I
H H
H HH H

HO C I HO C I HO C I

sp3 sp2 sp3

high energy TS
II. SN2 Mechanism
D. Steric effects
e.g., R–Br + I–  R–I + Br–

1. branching at the  carbon ( X–C–C–C.... )



Compound Rel. Rate

methyl CH3Br 150
1º RX CH3CH2Br 1 increasing
2º RX (CH3)2CHBr 0.008 steric hindrance

3º RX (CH3)3CBr ~0
II. SN2 Mechanism
D. Steric effects
1. branching at the  carbon

H
I C Br minimal steric hindrance
H
H
H H
H C
H
I C Br maximum steric hindrance
H C
H C
H H
H
II. SN2 Mechanism
D. Steric effects
1. branching at the  carbon

Reactivity toward SN2:

CH3X > 1º RX > 2º RX >> 3º RX

react more does not

readily difficult react by
by SN2 S N2
(k2 large) (k2 ~ 0)
II. SN2 Mechanism
D. Steric effects
2. branching at the  carbon

Rel. Rate
 
CH3 CH2 CH2 Br 1
CH3
increasing
CH3 CH CH2 Br 0.003 steric
hindrance
CH3
CH3 C CH2 Br 0.00001
CH3

~ no SN2 with neopentyl substrates

 II. SN2 Mechanism
E. Nucleophiles and nucleophilicity
1. anions

R X + OH R OH + X

R X + CN R CN + X

2. neutral species

R X + H2O R O H + X ROH + HX
solvolysis H hydrolysis
reactions
R X + R'OH R O R' + X ROR' + HX
H alcoholysis
II. SN2 Mechanism
E. Nucleophiles and nucleophilicity
3. nucleophilicity
a. charged species are more nucleophilic than neutral species
HO– > H2O
RO– > ROH
HS– > H2S
b. when nucleophilic atoms are in the same row, nucleophilicity
follows basicity
H2N– > HO– > F–
H3N > H2O
RO– > RCO2–
c. when nucleophilic atoms are in the same column, nucleophilicity
follows ionic radius (polarizability)
I– > Br– > Cl– > F–
HS– > HO–
PH3 > NH3
II. SN2 Mechanism
E. Nucleophiles and nucleophilicity

Summary:
very good Nu: I–, HS–, RS–, H2N–
good Nu: Br–, HO–, RO–, CN–, N3–
fair Nu: NH3, Cl–, F–, RCO2–
poor Nu: H2O, ROH
very poor Nu: RCO2H
II. SN2 Mechanism
Question 8-2. Which reaction will proceed faster in each of the following pairs?
What will be the product?

NaN3 NaOH
Cl I
NaN3 NaOH
I I

Br NaCN NaSH
Br

NaCN NaOH
Br Br