11. Reactions of Alkyl Halides:
Nucleophilic Substitutions and
Eliminations
Alkyl Halides React with
Nucleophiles and Bases
 Alkyl halides are polarized at the carbon-halide bond, making
the carbon electrophilic
 Nucleophiles will replace the halide in C-X bonds of many alkyl
halides(reaction as Lewis base)
 Nucleophiles that are Brønsted bases produce elimination
d+
Acts as
Nucleophile
d+
Acts as
Base
2
Why this Chapter?
 Nucleophilic substitution, base induced
elimination are among most widely occurring
and versatile reaction types in organic
chemistry
 Reactions will be examined closely to see:
- How they occur
- What their characteristics are
- How they can be used
3
11.1 The Discovery of Nucleophilic
Substitution Reactions:Walden Inversion
 In 1896, Walden showed
that (-)-malic acid could be
converted to (+)-malic acid
by a series of chemical
steps with achiral reagents
 This established that optical
rotation was directly related
to chirality and that it
changes with chemical
alteration
 Reaction of (-)-malic
acid with PCl5 gives
(+)-chlorosuccinic acid
 Further reaction with
wet silver oxide gives
(+)-malic acid
 The reaction series
starting with (+) malic
acid gives (-) acid
4
Reactions of the Walden Inversion
 The reactions alter the
array at the chirality
center
 The reactions involve
substitution at that
center
 Therefore, nucleophilic
substitution can invert
the configuration at a
chirality center
 The presence of
carboxyl groups in
malic acid led to some
dispute as to the
nature of the reactions
in Walden’s cycle
5
Another
Example:
(+)-1-phenyl-2-propanol
(-)-1-phenyl-2-propanol
•Used Tosylate as an
excellent leaving group
6
Kinetics of Nucleophilic
Substitution
 Rate (V) = change in concentration with time
 Depends on concentration(s), temperature, inherent
nature of reaction (barrier on energy surface)
 A rate law describes relationship between the
concentration of reactants and conversion to products

The rate law is a result of the mechanism
 A rate constant (k) is the proportionality factor between
concentration and rate




Kinetics = The study of rates of reactions
Rates ↓ as concentrations ↓ but k stays same
Rate units: [concentration]/time such as L/(mol x s)
The order of a reaction is sum of the exponents of
the concentrations in the rate law
7
11.2 The SN2 Reaction
 Reaction is with inversion at reacting center
 Follows second order reaction kinetics
 Ingold nomenclature to describe characteristic step:

S=substitution; N (subscript) = nucleophilic; 2 = both
nucleophile and substrate in characteristic step (bimolecular)
Rate is dependant on both
Nucleophile & Substrate
Rate = k [CH3-Br] [HO-]
8
SN2 Process
The reaction involves a transition state in
which both reactants are together
9
SN2 Transition State
 The transition state of an SN2 reaction has a planar
arrangement of the carbon atom and the remaining
three groups
10
11.3 Characteristics of the SN2 Rxn
Reactant and Transition State Energy Levels
Affect Rate
Higher reactant energy
level (red curve) = faster
reaction (smaller G‡).
Higher transition state
energy level (red curve) =
slower reaction (larger G‡).
11
The Substrate: Steric Effects on
SN2 Reactions
 SN2 Sensitive to steric effects
The carbon atom in (a) bromomethane is readily accessible
resulting in a fast SN2 reaction. The carbon atoms in (b) bromoethane (primary),
(c) 2-bromopropane (secondary), and (d) 2-bromo-2-methylpropane (tertiary) are
successively more hindered, resulting in successively slower SN2 reactions.
12
The Substrate: Steric Effects : Order
of Reactivity in SN2
 SN2 Sensitive to steric effects
 No reaction at C=C (vinyl or Aryl halides)
13
The Nucleophile: in SN2
 Neutral or negatively charged Lewis base
 Reaction increases coordination at nucleophile


Neutral nucleophile acquires positive charge
Anionic nucleophile becomes neutral
d+
d+
14
The Nucleophile: Relative Reactivity in S 2
N
 Depends on
Nucleophiles
reaction and
conditions
 More basic
nucleophiles
react faster
 Better
nucleophiles
are lower in a
column of the
periodic table
 Anions(-) are
usually more
reactive than
neutrals
15
The Nucleophile: Examples
16
The Leaving Group: in SN2
 Stable anions that are weak bases are usually excellent
leaving groups and can delocalize charge
 very basic or very small grps are poor leaving groups
.
Alkyl fluorides, alcohols, ethers,
and amines do not typically
undergo SN2 reactions.
17
The Leaving Group: in SN2
-OH needs to
be turned into
a good
leaving group.
So can
convert to a
•Cl
•Br
•Tos
Which are
excellent
leaving
groups.
(p-toluenesufonylchloride
p-TosCl)
18
The Leaving Group: in SN2
O of the epoxide can be turned into a good leaving group so
epoxide can be opened with a weak nucleophile.
Addition of an acid (H+) will make epoxide C’s more electrophilic.
Cl- attacks less hindered site.
(If choice of epoxide C’s is 1o or 2o then major product is from attack at less hindered 1o
If choice of epoxide C’s is 1o vs 3o then major product is from attack at more + 3o)
d+
d+
19
The Solvent: in SN2
 Solvents that can donate hydrogen bonds (protic) (-OH or –NH)
slow SN2 reactions by associating with reactants
 Energy is required to break interactions between reactant and
solvent
Caged nucleophiles can’t
attack so well
H
H
O
O
H
H
H
H
O
O
H
H
20
The Solvent: in SN2
Poor for SN2
Protic solvents (with -OH or –NH)
slow SN2 reactions by complexing
with reactants
Good for SN2
Polar aprotic solvents (no NH, OH,
SH) form weaker interactions with
substrate and permit fast SN2
reactions
21
11.4 The SN1 Reaction
 Tertiary alkyl halides react rapidly in protic solvents by a
mechanism that involves departure of the leaving group prior to
addition of the nucleophile
22
SN1 Reaction
The reaction involves a planar
carbocation intermediate
23
SN1 Energy Diagram
 Called an SN1 reaction
since rate is
dependant only on
substrate
Rate = k [RX]
 SN1 occurs in two
distinct steps while
SN2 occurs with both
events in same step
 The slowest step
(Rate-determining
step) is formation of
the carbocation
intermediate
24
Stereochemistry of SN1 Reaction
 The planar intermediate leads to loss of chirality since a free
carbocation is achiral
Nucleophile can attack either
face of planar carbocation
Product is racemic or has some inversion
25
Stereochemistry of SN1 Reaction
 Carbocation is biased to react on side opposite leaving group
•Suggests reaction occurs with carbocation loosely associated with
leaving group (in an ion pair) during nucleophilic addition
26
Stereochemistry of SN1 Reaction:
Effects of Ion Pair Formation
 If leaving group remains associated, then product has more inversion than
retention
 Product is only partially racemic with more inversion than retention
 Associated carbocation and leaving group is an ion pair
27
Stereochemistry of SN1 Reaction:
Example:
28
Learning Check:
 The optically pure tosylate shown was heated in acetic acid to yield a
product mixture. If complete inversion had occurred the optically pure
acetate product would have [a]D=+53.6o However the product mix has [a]D
=+5.3o. What percentage racemization and what percentage inversion has
occurred?
29
Solution:
 The optically pure tosylate shown was heated in acetic acid to yield a
product mixture. If complete inversion had occurred the optically pure
acetate product would have [a]D=+53.6o However the product mix has [a]D
=+5.3o. What percentage racemization and what percentage inversion has
occurred?
+5.3 x 100 = 9.9 % inverted
+53.6
So: 90.1 % racemic
30
11.5 Characteristics of the SN1 Rxn
Substrate:
in SN1
 Ability to form stable carbocation intermediate best
 Tertiary alkyl halide is most reactive by this mechanism

Remember Hammond postulate,”Any factor that stabilizes a highenergy intermediate stabilizes transition state leading to that
intermediate”
31
Substrate: in SN1
Allylic and Benzylic Halides
Allylic and benzylic intermediates stabilized by delocalization of charge
32
Learning Check:
 Rank the following substances in order of
their expected SN1 reactivity:
33
Solution:
 Rank the following substances in order of
their expected SN1 reactivity:
3
1
4
2
34
Leaving Group: in SN1
 Critically dependent on leaving group

the larger halides ions are better leaving groups

H2O, formed when OH of an alcohol is protonated in acid
p-Toluensulfonate (TosO-) is excellent leaving group

A leaving group won’t leave unless it’s stable on its own.
(Weak conjugate bases of strong acids make great leaving groups).
35
Leaving Group: in SN1
H2O leaving group formed when
OH of alcohol is protonated in acid
rds
Nucleophile attacks after rds
36
Nucleophiles: in SN1
 SN1 Reaction rate is not normally affected by nature or
concentration of nucleophile since nucleophilic addition
occurs after formation of carbocation.
Once the carbocation is formed the rest is quick and easy
regardless of nature of nucleophile.
37
The Solvent: in SN1
 Solvents that
stabilize the
carbocation
intermediate and
also transition
state and speeds
rate
 SN1 reactions go
faster with polar
protic solvents
that cage the
carbocation
intermediate.
38
The Solvent: in SN1
Polar Solvents Promote Ionization
 Polar, protic and unreactive Lewis base solvents facilitate R+ formation
39
Learning Check:
 Predict whether the following reactions is more likely to be SN1 or SN2.
40
Solution:
 Predict whether the following reactions is more likely to be SN1 or SN2.
2o benzylic; forms stable carbocations or can be attacked from behind
Good leaving group
Good nucleophile
SN1
Polar protic solvent
1o; easily attacked from behind; wouldn’t give stable carbocation
Good leaving group
Good nucleophile
SN2
Polar aprotic solvent
41
Learning Check:
 Predict whether the following reactions is more likely to be SN1 or SN2.
42
Solution:
 Predict whether the following reactions is more likely to be SN1 or SN2.
SN1
SN2
2o allylic; forms stable
carbocations or can be
attacked from behind
1o allylic; forms stable
carbocations or can be
attacked from behind
Good leaving group after
protonation with H+
Good leaving group
Strong nucleophile
Weak nucleophile
Polar protic solvent
Stabilizes carbocation
intermediate
Polar aprotic solvent
Would not stabilize a
carbocation intermediate
43
11.6 Biological Substitution Rxns
 SN1 and SN2 reactions are common in biochemistry
 Unlike in the laboratory, substrate in biological substitutions is often
organodiphosphate rather than an alkyl halide
44
Biological Substitution: Examples
SN1
E1
SN1
Biosynthesis of Geraniol in Roses
45
Biological Substitution: Examples
SN2
Biosynthesis of Adrenaline
46
11.7 Elimination Reactions:
of Alkyl Halides
 Opposite of addition
 Generates an alkene
 Can compete with substitution and decrease yield, especially
for SN1 processes
47
Elimination Reactions: E1
•Competes with SN1
•Favored over SN1 when have poor Nu- that can still be a base
48
Elimination Reactions: E1 Example
•Competes with SN1
•Favored over SN1 when have poor Nu- that can still be a base
SN1
E1
H CH3
H C C
H CH3
49
Elimination Rxns: Zaitsev’s Rule
 In the elimination of HX from an alkyl halide, the more
highly substituted alkene product predominates
50
Elimination Reactions: E2
•Competes with SN2
•Favored over SN2 when have strong base and steric hinderance
51
11.8 The E2 Reaction: Mechanism
Base grabs H that is anti-periplanar
to leaving group
Transition state combines
leaving of X and transfer of H
Product alkene forms stereospecifically
52
The E2 Rxn: Deuterium Isotope Effect
 In RDS Breaking of C-H bond is slower than
breaking of C-D bond.
53
Elimination Rxns: E2 Stereochemistry
Overlap of the developing  orbital in the transition state requires antiperiplanar geometry so electrons can give back-side SN2 type attack.
54
Elimination Rxns: Predicting E2
Products
 E2 is stereospecific
 Meso-1,2-dibromo-1,2-diphenylethane with base gives cis 1,2-
diphenyl
cis 1,2-diphenyl product
55
Elimination Rxns: Predicting E2
Products
 E2 is stereospecific
 RR or SS 1,2-dibromo-1,2-diphenylethane gives trans 1,2-diphenyl
S
S
Trans 1,2 diphenyl product
56
11.9 The E2 Rxn: Cyclohexene Formation
 Abstracted proton and leaving group should align trans-diaxial to be
anti periplanar in approaching transition state
 Equatorial groups are not in proper alignment
57
The E2 Rxn: Cyclohexene Formation Example
Fast
=
CH3
Cl
=
CH3
Cl
200 x’s slower since
Ring must flip to less stable
ring conformation in order
to get anti-periplanar E2
58
Comparing E1 and E2
Strong base is needed for E2 but not for E1
E2 is stereospecifc, E1 is not
E1 gives Zaitsev orientation
CH3
H
H
H
59
11.10 The E1cB Reactions
60
E1cB Reaction
 Takes place through a carbanion intermediate
61
11.11 Biological Elimination Rxns
 All three elimination reactions occur in biological pathways
 E1cB very common
 Typical example occurs during biosynthesis of fats when 3-
hydroxybutyryl thioester is dehydrated to corresponding thioester
E1cB
62
11.12 Summary of Reactivity:
SN1, SN1, E1,E1cB, E2
63
Summary of Reactivity:
SN1, SN1, E1,E1cB, E2
Strongly basic nucleophiles give more elimination as steric bulk increases.
Primary halides with strongly
basic nucleophiles give
mostly SN2 products.
Branched halides with
strongly basic nucleophiles
give about 50/50 SN2 and E2
products.
Tertiary halides with strongly
basic nucleophiles give
exclusive E2 products. With
neutral or weakly basic
nucleophiles SN1 and E1
pathways compete.
64
Summary of Reactivity:
SN1, SN1, E1,E1cB, E2
65
Important Concepts
1. Unimolecular Substitution in Polar Media •
•
•
Secondary haloalkanes: slow
Tertiary haloalkanes: fast
When the solvent is the nucleophile, the process is
called solvolysis.
2. Rate Determining Step in Unimolecular
Substitution •
•
Dissociation of the C-X bond to form a carbocation
intermediate.
Added strong nucleophile changes the product but not the
reaction rate.
3. Carbocation Stabilization by
Hyperconjugation: Tertiary > Secondary. Primary
and methyl unstable.
Important Concepts
4. Racemization - Often occurs upon unimolecular
substitution at a chiral carbon.
5. Unimolecular Elimination – Alkene formation
6.
7.
8.
accompanies substitution in secondary and tertiary
system.
Bimolecular Elimination - May result from high
concentrations of strong base. The elimination
involves the anti conformational arrangement of the
leaving group and the extracted hydrogen.
Substitution Favored - by unhindered substrates
and small, less basic nucleophiles
Elimination Favored - by hindered substrates
and bulky, more basic nucleophiles.
Which of the following is the product of the SN2 reaction
between the hydroxide ion (HO–) and (R)-CH3–CHDI?
D = 2H (deuterium)
20%
1.
20%
20%
20%
3
4
20%
2.
3.
4.
5.
1
2
5
I
+
Consider the reaction of (S)-(–)-1iodo-2-methylbutane to produce
(+)-2-methyl-1-butanol. What is the
absolute configuration of the
product?
1.
2.
3.
4.
5.
OH
HO
20%
20%
+
I
20%
20%
3
4
20%
R
S
R and S (racemic mixture)
R and S (unequal amounts)
There is no chiral center in
the product
1
2
5
Which of the following SN2 reactions is expected to
have the highest rate?
20%
1.
2.
3.
4.
5.
20%
20%
20%
3
4
20%
methyl bromide with water in
DMSO
ethyl bromide with chloride in
methanol
ethyl bromide with hydroxide
in HMPA
ethyl chloride with ammonia
in acetonitrile
methyl bromide with
hydrosulfide (HS–) in HMPA
1
2
5
-d[A]/dt = k[A][B]
When A and B react in t-BuOH, the
above rate expression is observed.
What is the most likely mechanism
of this reaction?
1.
2.
3.
4.
5.
OTos
A:
20%
B:
20%
OK
20%
20%
3
4
20%
E2
SN2
E1
SN1
It cannot be determined.
1
2
5
What is the main reason that polar aprotic solvents are
favored over polar protic solvents for SN2 reactions?
1.
2.
3.
4.
5.
Polar aprotic solvents
dissolve nucleophiles more
readily than polar protic
solvents.
Polar aprotic solvents
destabilize anions.
Polar aprotic solvents
stabilize cations, including
carbocations.
Polar aprotic solvents form
stabilizing hydrogen bonds.
Polar aprotic solvents
prevent rearrangements from
occurring.
20%
1
20%
2
20%
20%
3
4
20%
5
What statement about the SN2 reaction of methyl
bromide with hydroxide is incorrect?
1.
2.
3.
4.
5.
The reaction kinetics is
first-order in hydroxide.
In the transition state
the carbon is sp2
hybridized.
Absolute configuration
is inverted from R to S.
The reaction is faster in
HMPA than in water.
The reaction can be
catalyzed by I–.
20%
1
20%
2
20%
20%
3
4
20%
5
Select the substrate which would react fastest in the
substitution reaction.
20%
CH3NH2
?
20%
20%
20%
3
4
20%
CH3CN
1.
2.
3.
4.
5.
1
2
5
Which electrophile will react the fastest by the SN2
mechanism with cyanide (NC–) in DMF?
1.
2.
3.
4.
5.
phenyl iodide (Ph–I)
vinyl tosylate (H2C=CH–
OTos)
ethyl bromide
cyclohexyl bromide
benzyl tosylate (PhCH2-OTos)
20%
1
20%
2
20%
20%
3
4
20%
5
Which of the following reagents is the best
nucleophile for an SN2 reaction?
20%
1.
2.
3.
4.
5.
20%
20%
20%
3
4
20%
methanol
methoxide
acetate
hydroxide
water
1
2
5
Which set of reaction conditions represents the best way
to carry out the following transformation?
20%
Br
1.
2.
3.
4.
5.
20%
20%
20%
3
4
20%
OAc
AcOH
NaOAc in AcOH
NaOAc in H2O
NaOAc in DMSO
AcOH in HMPA
1
2
5
Which of the following will give the fastest SN1
reaction?
20%
1.
20%
20%
20%
3
4
20%
2.
3.
4.
5.
1
2
5
In a reaction between an alkyl halide and methoxide, doubling the
alkyl halide concentration doubles the rate of the reaction. Which
of the following is a reasonable conclusion?
20%
1.
2.
3.
4.
5.
20%
20%
20%
3
4
20%
The reaction is an SN2
process.
The reaction proceeds
by the SN1 mechanism.
The observation
indicates an E2
process.
This is a reaction with
E1 mechanism.
None of these
1
2
5
Which compound would serve as the best starting
material for the transformation shown below?
?
NaNH2
1.
20%
20%
20%
20%
3
4
20%
2.
3.
4.
5.
1
2
5
Including stereoisomers, how many products are
possible from the following reaction?
Br
H
NaOCH2CH3
20%
20%
20%
20%
3
4
20%
HOCH2CH3
1.
2.
3.
4.
5.
1
2
3
4
5
1
2
5
What mechanism is most likely to operate for the
following reaction?
CH3
Br
20%
20%
20%
20%
3
4
20%
CH3
O
H
1.
2.
3.
4.
5.
O
SN1
SN2
E1
E2
E1cB
1
2
5
Select the reagent and solvent combination which would
result in the fastest rate of substitution
(R = CH3 in all cases).
25 oC
20%
20%
20%
20%
3
4
20%
I
?
1.
2.
3.
4.
5.
ROH, HMPA
RS–, H2O
RO–, H2O
RS–, DMSO
RSH, H2O
1
2
5
Which of the following is the best nucleophile?
20%
1.
2.
3.
4.
5.
20%
20%
20%
3
4
20%
H2O
(CH3)3N
(CH3)2P–
(CH3)2O
CH3O–
1
2
5
What is the major product of the following
reaction?
H
TosO
20%
Ph
20%
20%
20%
3
4
20%
NaOH
Cl
H3C
H
1.
2.
3.
4.
5.
1
2
5
What is the most likely product of the following reaction?
Cl
20%
tBuOK
20%
20%
20%
3
4
20%
2.
1.
3.
4.
5.
1
2
5
Which of the two stereoisomers of 4-t-butylcyclohexyl iodide (127I) will
undergo SN2 substitution with 128I– faster, and why?
I127
I127
20%
A
1.
2.
3.
4.
5.
20%
20%
20%
3
4
20%
B
A will react faster because it is more
stable
B will react faster because it gives a
more stable product.
A will react faster because nucleophile’s
approach from the bottom face of the
molecule is easier for steric reasons.
A and B will react with the same rate
because the transition states for both
reactions are the same.
B will react faster because it is less
stable than A, and the transition state
for both reactions is of the same
energy.
1
2
5