A little organic chemistry
SH
S
1
Nucleophilic Substitution
R X + Y
substrate nucleophile
R Y + X
product leaving
group
e.g.,
H O
CH3 Br
CH3
OH + Br
substitution
reaction
Nucleophilic Substitution
Question. Identify the substrate, nucleophile, leaving group
and product for each.
CH3Br + NaOH
CH3S-
Br
+
Br
+ CN-
Nucleophilic Substitution
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–]
(bimolecular)
Rate = k1[RX]
(unimolecular)
SN2
SN1
SN2 Mechanism
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–
SN2 Mechanism
SN2 Mechanism
Steric effects
e.g., R–Br + I–  R–I + Br–
1. branching at the a carbon
( X–C–C–C.... )
a b g
Compound
Rel. Rate
methyl
CH3Br
150
1º RX
CH3CH2Br
1
2º RX
(CH3)2CHBr
0.008
3º RX
(CH3)3CBr
~0
increasing
steric hindrance
SN2 Mechanism
Steric effects
1. branching at the a carbon
H
I
I
H
C
Br
minimal steric hindrance
H
H H
H C
H
C Br
C
H
H C
H
H
H
maximum steric hindrance
SN2 Mechanism
Steric effects
branching at the a carbon
Reactivity toward SN2:
CH3X > 1º RX > 2º RX >> 3º RX
react
readily
by SN2
(k2 large)
more
difficult
does not
react by
SN2
(k2 ~ 0)
SN2 Mechanism
Steric effects
branching at the b carbon
Rel. Rate
CH3
b
CH2
a
CH2 Br
1
CH3
CH3
CH CH2 Br
0.003
CH3
CH3
C
CH2 Br
increasing
steric
hindrance
0.00001
CH3
~ no SN2 with very hindered substrates
SN2 Mechanism
Nucleophiles and nucleophilicity
Summary:
very good Nu:
good Nu:
fair Nu:
poor Nu:
very poor Nu:
I–, HS–, RS–, H2N–
Br–, HO–, RO–, CN–, N3–
NH3, Cl–, F–, RCO2–
H2O, ROH
RCO2H
Nucleophilic Substitution
Leaving groups
reactivity: R-I > R-Br > R-Cl >> R-F
best L.G.
most reactive
worst L.G.
least reactive
R X + Y
stronger
base
R Y + X
weaker
base
Br + NaF
SB
Br
+ NaI
WB
K>1
F + NaBr
WB
acetone
I
+ NaBr (s)
SB
precipitate
drives rxn
(Le Châtelier)
SN2 Mechanism
Question. Which reaction will proceed faster in each of the following pairs?
What will be the product?
NaN3
Cl
NaOH
I
NaN3
I
I
Br NaCN
NaOH
NaSH
Br
NaCN
Br
NaOH
Br
SN1 Mechanism
Kinetics
e.g.,
CH3
H3C C Br + CH3OH
CH3
3º, no SN2
Find: Rate = k[(CH3)3CBr]

CH3
H3C C O CH3 + HBr
CH3
unimolecular
 RLS depends only on (CH3)3CBr
SN1 Mechanism
Kinetics
CH3
CH3
RLS: H3C C Br
H3C C
CH3
CH3
CH3
H3C C
+ Br
HOCH3
CH3
CH3 H
H3C C O
CH3 CH3
-H+
CH3 H
H3C C O
CH3 CH3
CH3
H3C C O CH3 + HBr
CH3
SN1 Mechanism
Kinetics
Two-step mechanism:
R+
RBr + CH3OH
ROCH3 + HBr
SN1 Mechanism
Carbocation stability
R+ stability: 3º > 2º >> 1º > CH3+
R-X reactivity toward SN1: 3º > 2º >> 1º > CH3X
CH3+
1º R+
2º R+
3º R+
SN1 Mechanism
Question. Which of the following compounds will react fastest by SN1? Which
by SN2?
A.
Br
Br
B.
Br
Br
Br
Br
SN1 vs SN2
Solvent effects
nonpolar:
moderately polar:
polar protic:
polar aprotic:
hexane, benzene
ether, acetone, ethyl acetate
H2O, ROH, RCO2H
DMSO
DMF
O
O
CH3
S
CH3
H
C
acetonitrile
CH3
C N
N(CH3)2
SN1 mechanism promoted by polar protic solvents
stabilize R+, X– relative to RX
R+X–
RX
in less polar solvents
in more polar solvents
SN1 vs SN2
Solvent effects
SN2 mechanism promoted by moderately polar & polar aprotic solvents
destabilize Nu–, make
them more nucleophilic
e.g., OH– in H2O: strong H-bonding to water makes OH– less reactive
OH– in DMSO: weaker solvation makes OH– more reactive (nucleophilic)
in DMSO
in H2O
RX + OH–
ROH + X–
SN1 vs SN2
Rate = k1[RX] + k2[RX][Nu]
Summary
rate of SN1 increases
RX = CH3X
1º
2º
rate of SN2 increases
(carbocation stability)
3º
(steric hindrance)
react
may go
reacts
primarily
by either
primarily
by SN2
mechanism
by SN1
(k1 ~ 0, k2 large)
(k2 ~ 0, k1 large)
SN2 promoted good nucleophile (Rate = k2[RX][Nu])
-usually in polar aprotic solvent
SN1 occurs in absence of good nucleophile (Rate = k1[RX])
-usually in polar protic solvent (solvolysis)
SN1 vs SN2
Question. What would be the predominant mechanism in each of the following
reactions? What would be the product?
KCN
Br DMSO
Br
H2O

Br CH3OH

Br
NaSCH3
DMF