Nucleophilic Substitution
and Elimination Reactions
Self-Study Material
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by Daniel Berger
Nucleophilic Aliphatic Substitution
R
Nu
+ R C X
R
nucleophile
2
R
Nu
C R +
R
leaving group
X
Nucleophilic Aliphatic Substitution
leaving group
nucleophile
R
Nu
+ R
R
C X
Nu
R
R
in reverse
3
C
R +
X
Nucleophilic Substitution
in Synthesis
The nucleophile
attacks the alkyl
halide 180o away
from the halogen
The SN2 Mechanism
H3C
HO
+
H C Br
CH3CH2
(R)-2-bromobutane
δ−
HO
CH3
δ−
Br
C
H CH2CH3
Transition state with
simultaneous bond breaking
and bond forming
5
On the web
The configuration
at carbon is inverted
CH3
HO C H
CH2CH3
(S)-2-butanol
+
Br
1.
H3C
H C Br
CH3CH2
slow ratelimiting step
methanol
CH3
C
+
Br
H CH2CH3
A planar carbocation
The SN1 Mechanism
2.
H3C
CH3
O C H
H
CH2CH3
CH3OH
fast
CH3
C
H CH2CH3
CH3OH
fast
H C O
H
CH2CH3
CH3OH
HOCH3
3.
H3C
CH3
O C H
CH2CH3
(S)-2-methoxybutane
On the web
CH3
H3C
a racemic
mixture
H3C
CH3
H C O
CH2CH3
(R)-2-methoxybutane
Whether a reaction is SN1 or SN2
1. Structure of nucleophile
– Also affects side reactions
2. Structure of alkyl halide substrate
3. Structure of leaving group
7
What makes a good nucleophile
• Negative charge
– OH- > H2O
C N
• Polarizability
– Less electronegative
– Larger
• Basicity
– Brønsted
– Lewis
8
P
O
F
S Cl
nucleophilicity
Bronsted basicity
Br
I
Common nucleophiles and their
electrophilicities
9
Side reactions in the SN1 mechanism
Basicity of nucleophile
NaI
Br
H2O
Br
OH
NaOH
Br
10
I
+
Whether a reaction is SN1 or SN2
1. Structure of nucleophile
– Also affects side reactions
2. Structure of alkyl halide substrate
3. Structure of leaving group
11
Structure of Alkyl Halide
Governed by
electronic factors R
SN1
R
H
R
R
H
R
H
R
H
H
H
Increasing stability of carbocation intermediate
R3CX
R2CHX
RCH2X
CH3X
(tertiary)
(secondary)
(primary)
(methyl)
Increasing ease of access to site of reaction
R
RC
R
12
X
R
C
RH
X
R
C
H
H
H
X
H
H
SN2
Governed by
C X steric factors
Steric Hindrance of SN2
CH3
CH3CH2Br
CH3CCH2Br
CH3
Rate = 1
13
Rate = 10-30
Whether a reaction is SN1 or SN2
1. Structure of nucleophile
– Also affects side reactions
2. Structure of alkyl halide substrate
3. Structure of leaving group
14
Leaving Group Ability
Correlates with Acid Strength
reactivity as a leaving group
O
I
> Br
> Cl
>> F
> CH3CO
> HO
> CH3O
> H2N
strength of conjugate acid
Protonated leaving groups are good, because the conjugate
acids of neutral molecules are more acidic.
(In other words, the leaving groups are less basic.)
15
On the web
Nucleophilic substitution will not
occur with a poor leaving group!
good leaving groups
–
–
–
TsO ≥ X ≈ RS > HOR ≈ HNR2
16
poor leaving groups
–
–
CN > OR > NR2
–
Summary: SN1 vs. SN2 Reactions
Type of Alkyl Halide
SN2
SN1
methyl CH3X
Favored.
Does not occur
because of cation
instability.
primary RCH2X
Favored.
Rarely occurs
because of cation
instability.
secondary R2CHX
Favored in aprotic
solvents with good
nucleophiles
Favored in protic
solvents with poor
nucleophiles
tertiary R3CX
Does not occur
because of sterics.
Favored because of
cation stability.
stereocenter
Inversion
Racemization
β-Elimination
C C
H2 O
H OH2
C C
H
B
C C
+
HB
C C
+
HB
E1
C C
H X
E2
C C
H X
B
18
On the web
X
C C
H
C C
B
+
HB
+
X
E2 Mechanism
E1 Mechanism
SN2 vs. E2
Substitution vs. elimination
22