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Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Page 1 of 20
Nucleophilic Substitution Reactions
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There are several different kinds with different mechanisms
They are polar and involve nucleophiles
Substrates are usually alkyl halides, alcohols or esters of alcohols
They can be used to prepare a wide variety of useful functional groups (p.267)
Leaving Groups
- good leaving groups are usually weak bases.
d+
X
C
d-
Br
X
C
X
C
Br
d+ d-
X
C
OH
HO
O
X
C
O
O
S
CH3
X
C
O
O
S
CH3
O
Sulfonate Esters
O
C
+ Cl
OH
S
O
N
R
C
O
S
O
O
O
S
O
O
CH3
O
S
O
O
O
CF3
O
>
SO3
>
Br
>
S
O
Order of "Leavibility"
I
R
Cl
>
RCO2
CH3
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
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Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
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Nucleophilicity - What makes a good nucleophile?
- Basicity, polarizability or both
Useful generalizations:
1) Bases are more nucleophilic than their conjugate acids.
2) When comparing the same atom type, the more basic are the better
nucleophiles:
3) Going down a group of the periodic table, bigger atoms are better
nucleophiles because their orbitals are more polarizable.
Note: Iodide and bromide are good leaving groups and good nucleophiles.
Two mechanisms apply to most substitution reactions: SN1 and SN2
SN1: Substitution, nucleophilic, unimolecular
SN2: Substitution, nucleophilic, bimolecular
Which mechanism applies depends on the structure of your substrate.
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Page 4 of 20
Classifying the Substrate
CH3Br
CH3CH2Br
CH3CH2OH
Cl
H
C
H3C
Cl
Br
OH
H
Br
OH
CH3
Cl
OH
H3C
C
H3C CH3
H3C
H3C
OH
H
OH
Good substrates for SN1:
Good substrates for SN2:
Notice: Aryl and vinyl substrates do not undergo SN1 or SN2 reactions.
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Page 5 of 20
The SN1 Reaction
1)
CH3
CH3
H3C
C
Br
H3C
CH3
2)
+ Br-
C
CH3
CH3
H3C
CH3
:Nu
C
H3C
CH3
C
Nu
CH3
The first step is the rate determining step.
Note: Nucleophile concentration or nucleophile strength...
Solvolysis reactions are SN1 reactions in which the solvent acts as the
nucleophile.
CH3
CH3
H2O/CH3CH2OH
+ ClH3C C
H3C C Cl
1)
CH3
CH3
CH3
H3C
2)
CH3
H
C
CH3
H3C
O
H
C
H
O
CH3
H
H
H
CH3
3)
H3C
C
H
O
CH3
CH3
O
H
H
H3C
C
O
CH3
H
O
H
H
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Page 6 of 20
SN1 reaction involve carbocation intermediates. So, the only substrates that
undergo SN1 reactions are those that form stabilized carbocations.
So - What makes a relatively stable carbocation?
Br
Br
O
Br
Alkyl carbocations are stabilized by hyperconjugation.
H
H
H
H
C
H
C
H
H
C
H
H
1° Carbocation
3° Carbocation
Vinyl and aryl carbocations...
Cl
C
H
H
C
C
H
C
C
H
H
C
C
H
The order of stability for carbocations is...
Cl
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
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Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Page 8 of 20
The Hammond Postulate - widely used to rationalize differences in reaction rate
"The structure of a transition state resembles that species to which it is closest
in energy."
Early T.S.
Late T.S.
For endothermic reactions, the T.S. is closer
in energy to products. The T.S. is said to be
product-like in structure. It's also referred to
as a "late" T.S.
For exothermic reactions, the T.S. is closer
in energy to reactants. The T.S. is said to be
reactant-like in structure. It's also referred to
as an "early" T.S.
In the SN1 reaction, the rate determining step involving the formation of the
carbocation intermediate is endothermic. The transition state
CH3
CH3
Br
CH3
H3C C
CH3
+ Br - + I -
Energy
+I
-
H3C C
I
H3C C
CH3
CH3
+ Br
Br
-
+I
-
H3C C
CH3
+ Br - + I -
Energy
H3C C
H
H
CH3
Reaction Coordinate
Reaction Coordinate
H
H3C C
I
CH3
+ Br -
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Reactions Involving Carbocations
Substitution
:Nu
H3C
C
Nu
C
H3C
H3C
CH3
H3C
CH3
Elimination
H3C
C
H 3C
CH2
H3C
OH3
OH2
H
C
CH2
H 3C
Addition
H2C C
H3C
C
H3C
CH3
H
H3C
H3C
C
H
CH3
H3C
C
H2
C CH
3
Rearrangement
H3C
H 3C
C
H
Cl
H3C
H3C
C
AlCl3
C
H2
Cl
C
H2
H
Cl AlCl3
H3C
H3C
C
CH3
H3C
H3C
C
H3C
H3C
H3C
C
H3C
Cl
AlCl3
AlCl3
Cl
AlCl3
Page 9 of 20
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Page 10 of 20
Rearrangments are often a problem when carbocation intermediates are present.
CH3
H3C
C
H
C
H3C
H 3C
C
H
H
and
H
C
C
H3C C CH(CH )
3
C CH3
3 2
CH3
Cl
60%
Cl 40%
HCl
-78°
CH2
CH3
H
C
CH3
CH3
CH3
H2O, CH3OH, ∆
I
CH3
H3C
C
HO
H
C
H
CH3
C
H H
C
CH3
H
C
CH3
CH3
H3C
C
H
CH3
CH3
C
H
H
C
HO
CH3
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Page 11 of 20
Stereochemical Consequences of the SN1 Reaction
Br
C
CH3
CH2CH3
Ph
NaI/Acetone
H 3C
C
CH2CH3
Ph
S enantiomer
I
H3C
C
CH2CH3
Ph
Sometimes, Racemization is not complete
I
I
Br
CH3
Br
CH3
C
C
S
CH2CH3
Ph
H3C
C
CH2CH3
Ph
R
CH3
I
C
I
CH2CH3
Ph
Ph
CH2CH3
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Page 12 of 20
The Mechanism of the Sn2 Reaction - one step
With a charged nucleophile (i.e. Nu: = HO or NC ) and a leaving group, LG
H
dNu
C
d-
LG
HH
+
+
Activated
Complex
H
I
H
C
H
Br
I
C
H
H
Br
H
H
Nu:-
C
H
LG
H
H
Nu
C
H
:LG-
H
The Stereochemical Consequences of the Sn2 Reaction
NC-
H3C
CH3CH2
C
Br
H
(S)-(+)-2-bromobutane
dNC
CH3
C
CH3CH2 H
+
+
dBr
CH3
NC
C
CH2CH3
Br-
H
(R)-(-)-2-cyanobutane
(In contrast, those reactions in which the stereocenter's configuration is unchanged are said to occur with retention of
configuration.)
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Page 13 of 20
Why backside attack?
Br
C
Br
C
C-Br s bonding orbital
(from the overlap of sp3 orbitals on each)
C-Br s* antibonding orbital
Steric Effects in Sn2 Reactions
-
CH3
H 3C
*Br
CH3CH2
dd*Br C Br
C Br
H
+
+
CH3
*Br
CH3CH2 H
H3C
Methyl>1°>2°>>3°
H3C Br
Relative Rates
100
of reaction
(label incorporation)
C CH CH Br
2
3
H
H3CH2C Br
1° Bromide
1.31
H3CH2CH2C Br
1° Bromide
0.81
C Br
H
H3C
2° Bromide
0.015
H3C
C Br
H 3C
H3C
3° Bromide
0.004
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Solvent effects in substitution reactions
O
O
Polar aprotic
Polar protic
C
H 3C
O
H 2O
CH3OH
CH3CN
H 3C
CH3
H3CO
OCH3
O
O
CH3CH2OH
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S
H
CH3
C
N(CH3)2
Polar, protic solvents facilitate SN1 reactions because they stabilize the
transition state (which involves developing charges) ...
d
--
H
Br
H3C
C
H3C
H
H
O
H
d++
H
CH3
H
O
H
Br
H
O
H
O
H O
H
H 3C
H
H3C
H O
H
Polar aprotic solvents facilitate SN2
because they destabilize the reactants
(usually the charged nucleophile)...
-
H3C
NC
CH3CH2
C
Br
H
d-
NC
CH3
C
+
+
d-
Br
CH3CH2 H
The transition state involves a diminishment of
charge in the SN2 reaction.
The Finkelstein always use the same solvent...
Cl
C
H H
O H
H O
H
O
+ NaI
Cl
+ NaCl
H
O
H
CH3
O H
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
The Effects of b-Branching in SN2 Reactions
H
H
ddCH3CH2O C Br
CH3CH2O H C Br
H
H H
H3C Br
Relative Rates
of reaction
34.3
H3CH2C Br
b
a
1.95
+
+
H
Br-
CH3CH2O C H
H
H3CH2CH2C Br
b
Page 15 of 20
a
H3CH2CH2CH2C Br H3CH2CH2CH2CH2C Br
0.60
0.44
CH3
b
0.41
CH3
a
H3C C C Br
H H2
0.058
b
a
H3C C C Br
H2
CH3
0.0000083
Some SN2 reactions are complicated by the fact that the product may itself act as a nucleophile...
H3N:
Br
Br
NH2
NH3 Br + NH3
+ NH4+
N
H2
NaOH
16 eq. H3N:
Br
NH2
34%
N
H
57%
N(CH2CH3)3
1%
N
H
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Page 16 of 20
Alcohols are common substrates for substitution reactions but ...
H3C
H3C C
H
Br
H 3C
H3C C
Br
OH
H3C
OH2
H3C
Br
CH3
H3C C
CH3
H 3C
H3C C
OH2
H3C
Br
H OSO3H
OH
OH2
NaBr
ZnCl2
OH
HCl
Br
Br
OH2
Cl
O
H
ZnCl2
Cl
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Page 17 of 20
Other reagents useful in preparing alkyl halides from alcohols are
SOCl2, SOBr2, PCl5 and PBr3
SOCl2, ∆
OH
Cl
O
S
Cl + SO2 + HCl
Cl
Cl
O
H
OH
Cl
O
O
S
O
H
Cl
HCl
Cl
Cl
O
S
O
S
78%
Cl
Cl
+ SO2 + Cl
PBr3, ∆
Br
OH
60%
Br
PBr2
OH
O
H
PBr2
Br
O
PBr2
HBr
Br
H
Br
O
P[OCH(CH3)2]2
H
O
P[OCH(CH3)2]2
H
O
Br
P[OCH(CH3)2]2
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Page 18 of 20
The Mitsonobu Reaction
...couples alcohols with weakly acidic species.
CO2Et
EtO2C
:PPh3
RX + OPPh3
ROH + HX
O O
H3CH2CO
N N
H
H
OCH2CH3
N N
Diethyl Azodicarboxylate
X-
R
O
RX + OPPh3
PPh3
O
OH
Ph
O
O
OCH3
HN3, PPh3, DEAD
65%
PhCO2H
O
HO
OCH3 HN , PPh , DEAD
3
3
HO
O
HN
O
N
O
HO
N3
HO
N3
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Page 19 of 20
Ethers...
are usually formed by an SN2 process - the "Williamson Ether Synthesis"
NaH, DMF
OH
Br
O
O
Ethers can be cleaved by treatment with H-I or TMSI: (CH3)3SiÑI
2 HI
O
H
O
OH
CH3
I
2
Br
H
O
OH
Br
CH3
+ H 2O
H
O
CH3Br
OH
Chemistry 2500 Lecture Notes
Chapter 7 Nucleophilic Substitution Reactions
Page 20 of 20
Epoxides are cyclic ethers...
The OÑ is a good leaving group due to...
O
:Nu
N3
NaN3
O
O
EtOH, H2O
OH
Nu
The nucleophile must attack the face opposite the O atom.
Inversion is the rule.
Under anionic conditions (Nu: ) the reaction is SN2
O
O
H
H 3C
HO
H3C
SPh
H
H3C
SPh
SPh
Under acidic conditions the reaction is SN1-like...
H
O
H+
H
O
H
H3C
H
H3C
H3C
O
H
Nu
:Nu
H
HO
Cl , H2O
pH = 7
H3C
H
H3C
91
O
9
H
H3C
O
H
Cl
H
Cl
Cl
H
H3C
Cl , H2O
pH = 3.8
O
68
HO
H
H3C
32
Cl