Chapter 10

Nucleophilic
Substitution:
The SN1 and SN2
Mechanisms

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 Assignment for Chapter 10
• We will cover all the sections in this
chapter, except Sections 10.12 and
10.13

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 Problem Assignment for
Chapter 10
In-Text Problems
1 - 15 17, 18 19 (SN2 react)
20 (SN1 reaction), 21, 22, 24, 25, 26,
27, 28
End-of-Chapter Problems
30 - 37 39 - 42 44 – 49
51 - 55

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Sect. 10.1: Nomenclature of
alkyl halides -- common
names
methylene chloride CH2Cl2
chloroform CHCl3
carbon tetrachloride CCl4

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More common and IUPAC names
isopropyl chloride (2-chloropropane)
sec-butyl chloride (2-chlorobutane)
isobutyl chloride (1-chloro-2-methylpropane)
tert-butyl chloride (2-chloro-2-methylpropane)
allyl chloride (3-chloro-1-propene)
vinyl chloride (chloroethene)

benzyl chloride (chloromethylbenzene)

phenyl chloride (chlorobenzene)

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 Sect. 10.2: Overview of
nucleophilic substitution
• The substitution reaction: SN1 and SN2
• Primary halides = SN2
• Secondary halides = both mechanisms!
• Tertiary halides = SN1
• Leaving groups: halogens most
common
• There are a number of different
nucleophiles!!
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Nucleophilic Substitution (SN2)
Oxygen Nucleophiles (SN2)
_ _
R-CH2-X + Nu R-CH2-Nu + X
substrate nucleophile product leaving group
_ _
R-CH2-X + O-H R-CH2-O-H + X
hydroxide alcohol
_ _
R-CH2-X + O-R R-CH2-O-R + X
alkoxide ether
_ _
R-CH2-X + O-C-R R-CH2-O-C-R + X
O O
carboxylate ester
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Nitrogen as a nucleophile (SN2)
_ _
R-CH2-X + Nu R-CH2-Nu + X
substrate nucleophile product leaving group

+ _
R-CH2-X + NH3 R-CH2-NH3 X
ammonia

_
+
R-CH2-NH3 X R-CH2-NH2 + H-X
primary
amine

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 Carbon as a nucleophile (SN2)
_ _
R-CH2-X + Nu R-CH2-Nu + X
substrate nucleophile product leaving group

_ _
R-CH2-X + C N R-CH2 C N + X
cyanide nitrile
_ _
R-CH2-X + C C-H R-CH2- C C-H + X
alkyne
_ _
R-CH2-X + CH2-C-R R-CH2 CH2-C-R + X
O O
ketone
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 d-
H O
H
R C
H
Br
d-

energy

.. __
H O:
..
H OH
R C H
R C H
H
-
Br Br

Reaction coordinate

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 The SN1 Mechanism
1) CH3 CH3
slow .. _
CH3 C CH3 CH3 C CH3 + : Br :
+ ..
: Br: carbocation
..

2)
CH3 CH3
_ fast
CH3 C CH3 + : Nu CH3 C CH3
+
Nu

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 d+R
R C R
d+
Br R C R
d- Nu
R

d-

+R
R C
energy R

intermediate

R
R C R
R
Nu
R C R
Br

Reaction coordinate
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 Sect. 10.3: SN2 Mechanism
• reaction and mechanism
• kinetics
• stereochemistry
• substrate structure
• nucleophiles
• leaving groups
• solvents
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 The SN2 Reaction
Sterically accessible compounds react
by this mechanism!!
_
.. .. .. _
CH3 Br :O H CH3 OH + : Br :
+ .. .. ..

Methyl group is small

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 SN2 Mechanism: kinetics

• The reactions follows second

order (bimolecular) kinetics

• Rate = k [R-Br]1 -
[OH ]1

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 d-
H O
H
R C
H
Br
d-

energy

.. __
H O:
..
H OH
R C H
R C H
H
-
Br Br

Reaction coordinate

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 SN2 Reaction: stereochemistry
CH3
.. _ CH3
H O: d- d-
C Br H O C
.. Br
H
Et
H Et
(R)- enantiomer

Inversion of configuration CH3

.. _

H O C + Br
.. H
Et
(S) enantiomer
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 For an SN2 Reaction:

EVERY REACTION EVENT

ALWAYS LEADS TO
INVERSION OF CONFIGURATION

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 SN2 Reaction: substrate
structure (Table 10-5)
krel

CH3 Br 150

CH3 CH2 Br 1

CH3 CH Br 0.008
CH3

CH3
unreactive! KI in Acetone at 25°
CH3 C Br

CH3
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Chloromethane + Iodide as
the Nucleophile

Fast

I-

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tert-Butyl Chloride + Iodide
as the Nucleophile

No
reaction

I-

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 SN2 Reaction: substrate
structure
CH3

CH3-Br > CH3-CH2-Br > CH3 CH Br > CH3 C Br

CH3
CH3

primary secondary tertiary

Reactivity order---- fastest to slowest!

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 SN2 Reaction:
nucleophilicity
Basicity Nucleophilicity

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Predict which is more
nucleophilic
- -
CH3-O or CH3-S

-
CH3-S is more nucleophilic!

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 Relative Nucleophilicity

_ _
OH
CH3OH O SH
_ _ _ _ _
CH3 C O O OCH3 I C N
H2O

Increasing Nucleophilicty

1) In general, stronger bases are better nucleophiles

2) However, iodide doesn’t fit that pattern (weak base, but
great nucleophile!)
3) Cyanide is an excellent nucleophile because of its linear
structure
4) Sulfur is better than oxygen as a nucleophile
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 SN2 Reaction: Leaving
Groups
• Best leaving groups leave to form weak Lewis
bases.

• Good leaving groups:

– Br, I, Cl, OTs, OH2+

• “Lousy” leaving groups:

– OH, OR, NH2,, F

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Sulfonate Leaving Groups
O

R O S CH3 R OTs
O
para-Toluenesulfonate Tosylate

R O S Br R OBs

O
para-Bromobenzenesulfonate Brosylate

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 Tosylate leaving group
CH3 CH3
H O
C OH H
C O Ts
CH2 CH3 S Cl
CH2
O [Ts-Cl]
+ H-Cl
Retention of configuration

(S)-(+)-1-Phenyl-2-propanol (S)-(+)-1-Methyl-2-phenylethyl
tosylate

CH3
H
C O Ts
CH2
_ CH3
C2H5O
CH2 CH O CH2 CH3
Retention or inversion?

2-Ethoxy-1-phenylpropane
Is this ether (R) or (S)?

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Inversion of Configuration
CH3 CH2 CH3 O
H
O_ C O S CH3
CH2
O

(S)

CH3
H
CH3 CH2 O C
O
CH2 _
+ CH3 S O

(R) O

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 SN2 Reaction: solvents
SN2 reactions are accelerated in polar,
aprotic solvents. Consider Na+ -OEt as an
example of a nucleophile.
Why are reactions accelerated? The Na+
cation is complexed by the negative part of
the aprotic solvent molecule pulling it
away from –OEt.
Now that the sodium ion is complexed, the
oxygen in the nucleophile –OEt is more
available for attack.

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 Aprotic solvents
• These solvents do not have OH bonds in them.
They complex the cation through the lone pairs on
oxygen or nitrogen:
O
Acetone
H3 C CH3

O
Dimethyl sulfoxide (DMSO) S
H3 C CH3

O
Dimethylf ormamide (DMF) CH 3
H N
CH 3

Acetonitrile H3 C C N

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How cations are complexed
with aprotic solvents
H3C S CH3
O

Na

O
S
H3C CH3
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 Now that the Na+ is complexed,
the –OEt can react more easily

Et O H3C Br Et O CH3 Br

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 SN2 Reaction: solvents
SN2 reactions are retarded (slowed) in polar,
protic solvents. Protic solvents have O-H
groups.
Why are reactions retarded? Nucleophile is
hydrogen bonded to solvent!

Et O H O The nucleophile is
hydrogen bonded
Et to ethanol - reduces
nucleophilicity

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 Protic solvents
Typical protic solvents:
Water
H
O
H
abbreviations
O HOMe
Methanol H CH3

O HOEt
Ethanol H CH2 CH3

Acetic acid O HOAc

H C CH3
O

Formic acid O
H C H
O

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Sect. 10.4: SN1 Mechanism
• reaction and mechanism
• kinetics
• stereochemistry
• substrate structure
• nucleophiles
• leaving groups
• solvents
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 Solvolysis of tert-Butyl
Bromide
Acetone is used to dissolve everything! Water is the
solvent and nucleophile (solvolysis).

CH3 CH3
acetone
CH3 C CH3 + H2O CH3 C CH3 + H Br

Br OH
+ other products

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 The SN1 Mechanism
1) CH3 CH3
slow .. _
CH3 C CH3 CH3 C CH3 + : Br :
+ ..
: Br:
.. carbocation

2)
CH3 CH3
H
fast
CH3 C CH3 + :O: CH3 C CH3
+ H +
:O H

H
3) CH3 CH3
fast +
CH3 C CH3 CH3 C CH3 + H
+
:O H :O H
..
H 1935: Hughes & Ingold
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 d+R
R C R

Br
d-
R
R C R
O
H intermediate
H
+ R
R C
energy R

intermediate
R
R C R
R
OH
R C R
Br

Reaction coordinate
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 SN1 Reaction: kinetics

• The reactions follows first

order (unimolecular) kinetics

• Rate = k [R-Br]1

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 SN1 Reaction:
stereochemistry
With chiral R-X compounds, the
product will be racemic (50% of each
enantiomer).

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 Stereochemistry in SN1
reactions – racemic product
Slow
CH3-O-H Pr
Pr
C Br C
H3C polar
Et protic H3C Et
o
3 substrate solvent!
planar carbocation
(S) enantiomer

Pr CH3 Pr CH3
CH3-O-H C O H
C O
front side H3C H H
attack fast
Pr Et Et 50% (S)
C
H3C Et back side Pr
attack Pr H3C
CH3-O-H H3C H
O O
H CH3 CH3
Fast fast Et
Et
50% (R)
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 d+R
R C R

Br
d-
R
R C R
O
H intermediate
H3C
+ R
R C
energy R

intermediate
R
R C R

O-CH3
R
R C R
Br

Reaction coordinate
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 SN1 Reaction: substrate
structure
krel
CH3 Br no reaction

CH3 CH2 Br 1.00

CH3 CH Br
11.6
CH3

CH3
6
CH3 C Br
1.2 x 10
CH3
Solvolysis in water at 50°C

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 SN1 Reaction: substrate
structure

tertiary>secondary>primary > methyl

Primary and methyl halides are

very unreactive! They don’t go by
SN1 reactions.

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 CH3

CH3 C Br > CH3 CH Br > CH3-CH2-Br > CH3-Br

CH3
CH3

tertiary secondary primary

CH3
+ + +
CH3 CH CH3 CH 2 CH3
CH3 C+
CH3
CH3

tertiary secondary primary very unstable

carbocation carbocation carboc
carbocation carbocation
(very stable) (unstable)

three methyl two methyl one methyl no methyl

groups groups group groups

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 Nucleophiles
• Usually SN1 reactions are run in polar
protic solvents; compounds with O-H
groups.
• The polar protic solvent acts as BOTH
nucleophile as well as the solvent.
• Common solvent/nucleophiles include:
water, ethanol, methanol, acetic acid,
and formic acid.

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A protic solvent acts as both a solvent and
nucleophile in SN1 reactions - solvolysis:
Water O abbreviations
H H

O HOMe
Methanol H CH3

O HOEt
Ethanol H CH2 CH3

Acetic acid O HOAc

H C CH3
O

Formic acid O
H C H
O

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 Typical solvolysis reaction
Slow
Pr CH3-O-H Pr
C Br C Polar solvent stabilizes
H3C polar
Et protic H3C Et the carbocation!
3o substrate solvent!
planar carbocation
(S) enantiomer
Solvent is the
nucleophile CH3-O-H Pr CH3 Pr CH3
C O H
front side C O
H3C H fast H
Pr attack Et Et 50% (S)
C
H3C Et back side Pr
attack Pr H3C
CH3-O-H H3C H
O O
H CH3 CH3
Fast fast Et
Et
50% (R)
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 Leaving groups
• Leaving groups are the same as in SN2
reactions:

• Cl, Br, I, OTs are the usual ones.

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 SN1 Reaction: solvent
polarity
• SN1 solvolysis reactions go much
faster in trifluoroacetic acid and
water (high ionizing power).

• SN1 solvolysis reactions go slower

in ethanol and acetic acid (lower
ionizing power).

• See table 10-9.

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 SN2 versus SN1 Reactions
• A primary alkyl halide or a methyl halide
should react by an SN2 process. Look for a
good nucleophile, such as hydroxide,
methoxide, etc. in an polar aprotic solvent.
• A tertiary alkyl halide should react by an SN1
mechanism. Make sure to run the reaction
under solvolysis (polar protic solvent)
conditions! Don’t use strong base conditions
-- it will give you nothing but E2 elimination!
• A secondary alkyl halide can go by either
mechanism. Look at the solvent/nucleophile
conditions!!
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 SN2 versus SN1 Reactions
(continued)
• If the reaction medium is KI or NaI in acetone,
this demands an SN2 mechanism.

• If the reaction medium is AgNO3 in ethanol,

this demands an SN1 mechanism.

• If the medium is basic, look for SN2.

• If the medium is acidic or neutral, expect SN1.

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Comparison of SN1 and SN2
Reactions
• See Table 10-10 on page 936.
Great table!!

• Section 10-5: Solvent effects; been

there done that!!

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 Sect. 10.6: classification
tests
• Sodium iodide and potassium
iodide in acetone are typical SN2
reagents!!

• Silver nitrate in ethanol is a typical

SN1 reagent!!

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Sect. 10.7: Special Cases
Neopentyl compounds are very
unreactive in SN2 reactions.

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 Effect of b-substitution
on SN2 reactivity (Table 10-11)
krel

b
H CH2 CH2 Br 1.0
b
CH3 CH2 CH2 Br
0.65
CH3

CH3 CH CH2 Br
0.15
b
CH3

CH3 C CH2 Br Neopentyl bromide 0.000026

b
CH3

KI in Acetone
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-- Chemistry
Neopentyl Transition State

Y R1
Y
R1

H
C C
H R2

R3

Nu
Nu

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 Allylic and Benzylic
compounds
Allylic and benzylic compounds are especially
reactive in SN1 reactions.
Even though they are primary substrates, they are
more reactive most other halides! They form
resonance stabilized carbocations.

CH2-Br CH2=CH-CH2-Br

benzyl bromide allyl bromide

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Solvolysis Rates: SN1
Table 10-13
krel
Ethyl chloride very small
Isopropyl chloride 1
Allyl chloride 74
Benzyl chloride 140
tert-Butyl chloride 12,000

80% Ethanol-water at 50°

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 Allylic and Benzylic
compounds
Allylic and benzylic compounds are especially
reactive in SN2 reactions.
They are more reactive than typical primary
compounds!

CH2-Br CH2=CH-CH2-Br

benzyl bromide allyl bromide

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Reaction with KI in Acetone:
SN2
Table 10-14
krel
Ethyl chloride 1
Allyl chloride 33
Methyl chloride 93
Benzyl chloride 93

60° C
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 Vinyl and Phenyl
Compounds
Vinyl and Phenyl compounds are completely inert in both
SN1 and SN2 reactions!!

H Cl

CH2 C
Cl

vinyl phenyl

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 Reactivity order for SN1

CH2
Br
R Br R
C > > CH Br >> R CH2 Br >> CH3-Br >> Br
R R R H
H
R C
3o H C C
CH2 Br 2o 1o methyl Br
H R
Benzyl phenyl
Allyl vinyl

Inert!!
No reaction

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 Reactivity order for SN2
About same reactivity

CH2
Br R R
= CH3-Br R CH2 Br Br
> > CH Br >>> C >>> Br
R R R
H H
o
H C C methyl 1 2o 3o R C
Br
CH2 Br
H Can not R
Benzyl undergo phenyl
Allyl SN2 vinyl

Inert!!
No reaction!!

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 Sect. 10.8: Cyclic Systems
• Cyclopropyl and cyclobutyl halides
are very unreactive in both SN1 and
SN2 reactions

• Cyclopentyl halides are more

reactive than cyclohexyl halides in
SN1 and SN2 reactions.

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Bicyclic systems: Bredt’s Rule
You can’t have p orbitals on a bridgehead
position in a rigid bicyclic molecule.

-- You cannot form a carbocation

at a bridgehead position.

bridgehead

+
bridgehead
--You cannot have a double bond
at a bridgehead position.

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 AgNO 3
No reaction!
Ethanol
Cl

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 Sect. 10.9: Carbocation
Rearrangement
1) CH3 CH3
slow _
CH3 C CH CH3 CH3 C CH CH3 + Br
+
CH3 Br CH3
a carbocation

2) CH3 CH3

CH3 C CH CH3 CH3 C CH CH3

+ +
CH3 CH3

3) CH3 CH3
+
CH3 C CH CH3 + ROH CH3 C CH CH3 + H
+
CH3 OR CH3

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 A Closer Look...
CH3 CH3
CH3 C CH CH3 CH3 C CH CH3
+ +
CH3 CH3

CH3

CH3 C CH CH3
+
CH3

transition state

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Carbocation Rearrangement

CH3

CH3 C CH CH3

CH3
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Carbocation Rearrangement

CH3

CH3 C CH CH3

CH3
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Carbocation Rearrangement

CH3

CH3 C CH CH3

CH3
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Carbocation Rearrangement

CH3

CH3 C CH CH3

CH3
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Carbocation Rearrangement

CH3

CH3 C CH CH3

CH3
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Carbocation Rearrangement

CH3

CH3 C CH CH3

CH3
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Carbocation Rearrangement

CH3

CH3 C CH CH3

CH3
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Carbocation Rearrangement

CH3

CH3 C CH CH3

CH3
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 Sir Christopher Ingold

Source: Michigan State University, Department of Chemistry

http://www.chemistry.msu.edu/Portraits/PortraitsHH_collection.shtml

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 Saul Winstein

Source: Michigan State University, Department of Chemistry

http://www.chemistry.msu.edu/Portraits/PortraitsHH_collection.shtml

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 Sect. 10.10 Competing
Reactions: Elimination --
Table 10-16
• Lower temperatures favor substitution; higher
temperatures give more elimination.
• Highly branched compounds (secondary and tertiary
compounds) give mostly elimination with strong
bases. Weaker bases give more substitution. A
basic medium favors E2; a more nucleophilic medium
favors SN2.
• Primary compounds give mostly substitution with
non-bulky nucleophiles. A bulky base (tert-butoxide)
gives elimination.
• Tertiary compounds should be reacted under
solvolysis conditions to give substitution!!!
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 Sect. 10.11: Neighboring
group participation
O O
_ _ CH3OH _ _
CH3 CH C O + CH3O CH3 CH C O + Br
inversion
Br > 0.5 M OCH3

(R)-(+) (S)-(-)

O O
_ _ CH3OH _ _
CH3 CH C O + CH3O CH3 CH C O + Br
retention
Br < 0.1 M OCH3

(R)-(+) !!!
(R)-(+)

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 Under SN2 Conditions
_ CH3 CH3
..
CH3 O : d- d-
.. C Br
H CH3 O C Br
C
H C
_O O
O
_O
(R)

CH3
_
CH3 O C + Br
Inversion of configuration H
C
O
_O

(S)

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 Internal SN2 reaction
followed by an external SN2
reaction
CH3 H CH3
C Br C CH3
slow O
_ H ..
.. C O CH3
:O C C _ ..
.. H
+ Br
O _ .. C
O :O +
(R) :O: .. O + H
CH3 H
(R)

Retention of Configuration

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 Neighboring Group
Participation
1)
G: G
.. _
slow
C C C C + :X:
..
X

2) G: G:
G
fast
C C C C

Nu

Nu :
X

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 Neighboring group
participation: Summary
• Retention of configuration
• Enhanced rate of reaction

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 Mustard gas
• Mustard gas is a substance that causes tissue blistering (a vesicant). It is
highly reactive compound that combines with proteins and DNA and results
in cellular changes immediately after exposure. Mustard gas was used as a
chemical warfare agent in World War I by both sides.

Cl Cl Cl
Cl
S S
Neighboring
group participation
Mustard gas Internal S N2

Cl O-E nzyme
Cl Cl O-Enzyme Cl
S S
E xternal S N2

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 Sect. 10.13: Ion-pair
mechanisms (skip!!)
• SN1 reactions are “expected” to give a 50-50
(racemic) mixture of the two enantiomers!!
• But, if the leaving group doesn’t get out of the
way, you will get more inversion than
retention, which makes it “look like” SN2.
• In the extreme, you could have a carbocation
give only inversion of configuration by an SN1
mechanism!!

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 In-Class Problem
For the following reaction,

H2O
CH3 CH CH CH2 OTs
acetone

A) Identify the mechanism of this reaction.

B) Predict the product(s) of this reaction, and identify

them as major or minor, if appropriate.

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The following table may be
helpful as a review

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 Substitution versus Elimination
SN1 SN2 E1 E2

Substrate Strong effect; reaction Strong effect; reaction Strong effect; reaction Strong effect; reaction
favored by tertiary favored by methyl or favored by tertiary favored by tertiary
halide primary halide halide halide
Reactivity – primary Does not occur Highly favored Does not occur Occurs with strong
base!

Reactivity – tertiary Favored when Does not occur Occurs under Highly favored when
nucleophile is the solvolysis conditions strong bases (OH-,
solvent – solvolysis or with strong acids OR-) are used
Reactivity – Can occur in polar, Favored by good Can occur in polar, Favored when strong
secondary protic solvents nucleophile in polar, protic solvents bases are used
aprotic solvents
Solvent Very strong effect; Strong effect; Very strong effect; Strong effect; reaction
reaction favored by reaction favored by reaction favored by favored by polar,
polar, protic solvents polar, aprotic solvents polar, protic solvents aprotic solvent
Nucleophile/Base Weak effect; reaction Strong effect; reaction Weak effect; reaction Strong effect; reaction
favored by good favored by good favored by weak base favored by strong
nucleophile/weak nucleophile/weak base
base base
Leaving Group Strong effect; reaction Strong effect; reaction Strong effect; reaction Strong effect; reaction
favored by good favored by good favored by good favored by good
leaving group leaving group leaving group leaving group

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