REACTIONS OF ALKYL HALIDES
Alkyl halides (R-X) undergo two types of reactions :
substitution reactions and elimination reactions.
In a substitution reaction, the X group in R-X is
replaced by a different group, e.g. R-XR-OH +XӨ
In an elimination reaction, the elements of H-X are
eliminated from R-X; the product is very often an
alkene.
H
CH3
CH2
C Br
CH3
base
CH2
CH3 C
+ HBr
CH3
1
ALKYL HALIDES – Substitution reactions
H H
HC C
H H

Br + OH
HH
H C C OH + Br
HH
This is a nucleophilic substitution or nucleophilic
displacement reaction on which OH displaces Br.
The C-Br bond is polar, and the carbon (⊕) is
susceptible to attack by an anion or any other
nucleophile.
ӨOH
is the nucleophile (species which “loves nuclei”
or has an affinity for positive charges).
BrӨ is the leaving group
2
ALKYL HALIDES – Substitution reactions
CH3-CH2—Br +
ӨOH
 CH3-CH2—OH + BrӨ
The general reaction is:
R-X + NuӨ  R-Nu + XӨ
These are ionic reactions.
There are two possible ionic mechanisms for nucleophilic
substitution, SN1 and SN2.
S – substitution; N – nucleophilic;
1 – unimolecular (the rate determining, r.d.s., step entails
one molecule);
2 – bimolecular (the rate determining step entails two
species).
3
ALKYL HALIDES
The unimolecular (SN1) reaction
R
X
(a)
R +
X
In the first step, R-X dissociates, forming a carbocation,
R⊕, and the leaving group XӨ.
This is a slow, rate determining step (r.d.s.) and
entails only one species, R-X.
(b)
R⊕+ NuӨ  R-Nu
In the second step the carbocation and the nucleophile
combine. This occurs rapidly.
The overall reaction is R-X + NuӨ  R-Nu + XӨ
The rate of the reaction = k[R-X]
4
ALKYL HALIDES: The bimolecular (SN2) reaction
(a) NuӨ + R-X ⇋ ӨNu---R---XӨ
The nucleophile and the alkyl halide combine to form a
pentacoordinate transition state. This is the slow rate
determining step (r.d.s); it entails two species, R-X and
NuӨ . The dotted lines indicate partially formed or
partially broken covalent bonds.
(b) ӨNu---R---XӨ  Nu-R + XӨ
The pentacoordinate transition state dissociates to form
the product, Nu-R, and the halide ion (the leaving
group).
The rate of the reaction = k[R-X][NuӨ]
The rate is dependent of the concentration of two species;
higher concentrations increase the frequency of molecular
collisions.
5
ALKYL HALIDES
The unimolecular (SN1) reaction
R
X
(a)
R +
X
In the first step, R-X dissociates, forming a carbocation,
R⊕, and the leaving group XӨ.
This is a slow, rate determining step (r.d.s.) and
entails only one species, R-X.
(b)
R⊕+ NuӨ  R-Nu
In the second step the carbocation and the nucleophile
combine. This occurs rapidly.
The overall reaction is R-X + NuӨ  R-Nu + XӨ
The rate of the reaction = k[R-X]
6
ALKYL HALIDES: SN1 reactions in more detail
(a) 2-bromo-2-methylpropane, a 3o alkyl halide dissociates, in
a slow r.d.s. to a 3o carbocation and BrӨ.
Br
CH3
CH3 C CH3
C
CH3
CH3
+ Br
CH3
The positively charged carbon in a carbocation is sp2
hybridized and carbocations have trigonal geometry.
This is a very important point.
(b) A nucleophile, ӨOH, adds to the carbocation to give the
product, 2-methylpropanol. This is a fast process.
OH
CH3
C
CH3
CH3
OH
CH3 C CH3
CH3
7
The Stereochemistry of SN1 Reactions
A 3o alkyl halide with three different alkyl groups
X
attached to the head carbon is chiral.
R1
There are two enantiomers of such a
compound, e.g. 3-bromo-3-methylhexane.
(1)
Br
(2)
CH3CH2CH2 C
C* R3
R2
(1)
Br
(4)
CH3
CH2CH3
(3)
(S)-enantiomer
(3)
CH3CH2 C
(4)
CH3
(2) CH2CH2CH3
(R)-enantiomer
8
The Stereochemistry of SN1 Reactions
Br
CH3CH2CH2 C
CH3CH2CH2
C
CH3
CH3
+ Br
CH2CH3
CH2CH3
CH3
Pr
(S)-enantiomer
C
Et
CH3
Et
C
Pr
9
The Stereochemistry of SN1 Reactions
The initially formed carbocation is planar.
Br
CH3CH2CH2 C
CH3CH2CH2
C
CH3
CH3
+ Br
CH2CH3
CH2CH3
(S)-enantiomer
In the second step, the nucleophile will add from either face
of the carbocation.
OH
OH
Pr
C
Et
CH3
Et
+ OH
CH3CH2CH2 C
CH3
CH2CH3
(S)-enantiomer
C
Pr
CH3
+ OH
CH3CH2 C
CH3
CH2CH2CH3
(R)-enantiomer
Both enantiomers of the product are formed in equal amounts.
The same result is obtained starting with the R enantiomer of the
alkyl halide, because exactly the same carbocation is formed. 10
Other Aspects of SN1 Reactions
X
(a) R1
C R3
2
R
1
R
slow
R3
C
+
R2
carbocation
X
R1
(b)
Nu
R3
C
R2
fast
Nu
R1
C R3
R2
The most important feature of SN1 reactions is
the carbocation intermediate.
A.
Alkyl halides which form stable carbocations
will undergo SN1 reactions.
3o alkyl halides form 3o carbocations (stable) and will
 undergo SN1 reactions.
11
Other Aspects of SN1 Reactions
X
(a) R1
C R3
2
R
1
R
slow
R3
C
+
R2
carbocation
X
R1
(b)
Nu
R3
C
R2
fast
Nu
R1
C R3
R2
Alkyl halides which form stable carbocations will undergo
SN1 reactions.
2o alkyl halides form 2o carbocations (fairly stable) and
 undergo SN1reactions.
1o carbocations are unstable, 1o alkyl halides will not undergo
SN1 reactions.
Substitution reactions of 1o alkyl halides proceed via the
SN2 mechanism.
12
Other Aspects of SN1 Reactions
B.
The RATE of SN1 reactions increases with increasing
stability of the carbocation.
OH
Br
1.
CH3
C CH3
slow
CH3
C
CH3
OH
CH3
fast
CH3
C CH3
CH3
CH3
3o carbocation
+
Br
OH
Br
2.
CH3
C CH3
H
slow
CH3
C
OH
CH3
fast
H
CH3
C CH3
H
2o carbocation
+
Br
The carbocation formed in reaction 1 is more stable than that
formed in reaction 2,  reaction 1 is faster than reaction 2.
13
Other Aspects of SN1 Reactions
C.
Polar solvents STABILIZE carbocations, and accelerate
SN1 reactions.
The first step of an SN1 reaction is
R
X
R
+
X
If R⊕ is stabilized via interactions with the solvent, the
equilibrium is pulled to the RIGHT, and the overall process
is accelerated.
The DIELECTRIC CONSTANT (, “epsilon”) is an index of
solvent polarity.
H2O ( 79) is a polar, protic solvent.
CH3CH2OH (ethanol,  25) is also protic, but much less
polar than H2O.
14
Other Aspects of SN1 Reactions
C.
Polar solvents STABILIZE carbocations, and
accelerate SN1 reactions.
R
X
R
+
X
H2O ( 79) interacts with R⊕ and XӨ as shown here.
The rate of an SN1 reaction of (CH3)3C-Br in pure
H2O ( 79) is approximately 12,000 times the rate in
pure CH3CH2OH (ethanol,  25).
15
Other Aspects of SN1 Reactions
When some 2o alkyl halides undergo the SN1 reaction,
products of rearrangement are observed.
D.
Br
CH3
CH3
slow, r.d.s.
CH3 C
CH3
C
H
CH3 C
CH3
C
CH3 H
CH3
+ Br
2o carbocation
CH3
CH3 C
CH3
CH3
CH3
CH
CH3
+ CH3OH
2o carbocation
CH3
(CH3 shift)
H
C
H
+ CH3OH
CH3
3o carbocation
-H
CH3
C
CH3
C
H
OCH3
CH3
CH
CH3
yield 4%
OCH3 CH3
CH3
C
CH3
C
H
CH3
3o carbocation
3-methoxy-2,2-dimethyl...
CH3
C
CH3 C
-H
CH3
CH3
rearrangement
2o carbocation
CH3
CH3 C
CH3
C
CH3
2-methoxy-2,3-dimethyl... yield 41%
16
ALKYL HALIDES: The bimolecular (SN2) reaction
(a) NuӨ + R-X ⇋ ӨNu---R---XӨ
The nucleophile and the alkyl halide combine to form a
pentacoordinate transition state. This is the slow rate
determining step (r.d.s); it entails two species, R-X and
NuӨ . The dotted lines indicate partially formed or
partially broken covalent bonds.
(b) ӨNu---R---XӨ  Nu-R + XӨ
The pentacoordinate transition state dissociates to form
the product, Nu-R, and the halide ion (the leaving
group).
The rate of the reaction = k[R-X][NuӨ]
The rate is dependent of the concentration of two species;
higher concentrations increase the frequency of molecular
collisions.
17
The Stereochemistry of SN2 Reactions
(a) NuӨ + R-X ⇋ ӨNu---R---XӨ (slow, r.d.s)
(b) ӨNu---R---XӨ  Nu-R + XӨ (fast)
Let us consider a chiral substrate undergoing an
SN2 reaction.
(2)
CH3
(4)
H
C
Br (1)
D (3)
(S)-1-bromo-1deuterioethane
18
The Stereochemistry of SN2 Reactions
CH3
H
HO
C
+
Br

slow, r.d.s
H
HO
CH3
C

Br
(nucleophile)
D
(S)-1-bromo-1deuterioethane

H
HO
CH3
C
D

Br
D
fast
(2)
(4) CH
3
H
HO
(1)
C
D (3)
(R)-1-deuterioethanol
19
The Stereochemistry of SN2 Reactions
NuӨ + R-X ⇋ ӨNu---R---XӨ (slow, r.d.s)
ӨNu---R---XӨ  Nu-R + XӨ (fast)
(a)
(b)
CH3
H
HO
+
C
Br

slow, r.d.s
H
HO
CH3
C

Br
(nucleophile)
D
(S)-1-bromo-1-deuterioethane
D
The pentacoordinate transition state formed at the end of the
first, slow, rate-determining step is a trigonal bipyramid:
a three-sided plane perpendicular to the screen;
the OH and Br groups form apices on either side of the
pentacoordinate carbon, in the plane of the screen.
20
The Stereochemistry of SN2 Reactions
The nucleophile attacks the substrate from the side
opposite to the leaving group.
The stereochemistry of the product is INVERTED,
relative to that of the starting material.
D
H
HO
C
+
D
Br

slow, r.d.s
H
HO
C

Br
(nucleophile)
CH3
(R)-1-bromo-1-deuterioethane
D
H


fast
Br
HO
C
H3C
H3C
(3)
D
(4)
H
HO
(1)
C
CH
(2) 3
(S)-1-deuterioethanol
21
The Stereochemistry of SN2 Reactions
For chiral substrates, reactions proceeding via the
SN2 mechanism result in inversion of configuration.
This is a consequence of the “back side” attack by
the nucleophile.
CH3
H
HO
C
+
Br

slow, r.d.s
H
HO
CH3
C

Br
(nucleophile)
D
(S)-1-bromo-1deuterioethane

H
HO
CH3
C
D

Br
D
fast
(2)
(4) CH
3
H
HO
(1)
C
D (3)
(R)-1-deuterioethanol
22
Other Aspects of SN2 Reactions
SUBSTRATE
The SN2 reaction involves a transition state with
pentacoordinate carbon, so sterically hindered alkyl
halides do not react via this mechanism.
The RATE of the SN2 reaction for the following
substrates therefore follow the trend:
CH3 Br > CH3CH2 Br >>
CH3
CH3
CH Br
Tertiary alkyl halides do not undergo the SN2 reaction.
23
Other Aspects of SN2 Reactions
NUCLEOPHILE
The SN2 reaction is bimolecular, and more
effective nucleophiles will react faster.
Order of nucleophilicity: ӨCN > ӨOR > ӨOH.
Therefore,
CH3Br + ӨCN  CH3CN + Br Ө is a faster
reaction than
CH3Br + ӨOR  CH3OR + Br Ө , and this in
turn is faster than
CH3Br + ӨOH  CH3OH+ Br Ө .
24
Other Aspects of SN2 Reactions
POSSIBILITY OF REARRANGEMENT
When an alkyl halide undergoes
substitution via the SN2 mechanism, the
product has the same carbon skeleton as
the starting material. No rearrangement
takes place.
25
Other Aspects of SN2 Reactions
SOLVENT
The rate of SN2 reactions (involving negatively
charged nucleophiles) increases when the
reactions are carried out in polar APROTIC
solvents.
Dimethyl sulfoxide (DMSO,  37) is an example of
a polar aprotic solvent.
CH3

S O

CH3
26
Other Aspects of SN2 Reactions
SOLVENT: Dimethyl sulfoxide (DMSO,  37) is an
CH3
example of a polar aprotic solvent.

S O

CH3
If, for example, the nucleophile is ӨCN, and the
source is KCN (potassium cyanide) DMSO will
solvate the K⊕ ion, thus making ӨCN readily
available for reaction.
27