1

SUBSTI TUTI ON REACTI ONS OF ALKYL

AEN (F-C) =
AEN (Cl-C) =
AEN (Br-C) =
AEN (I-C) = (2.5 2.5) = 0.0
b) X (Cl, Br, I) is a leaving group

pKb = 23 pKb = 22 pKb = 21 pKb = 11 pKb = -1.7
I
-
Br
-
Cl
-
F
-
HO
-
30,000 10,000 200 1 0
decreasing basicity, increasing stability

increasing leaving ability

Br H
3
C
o
+
o

Cl H
3
C
o
+
o

I H
3
C
The best
leaving
groups are
the weakest
bases.
The poorest
leaving groups
are the
strongest
bases.
3
Reactions of Alkyl Halides (R-X): [S
N
1, S
N
2, E1, & E2 reactions]
There are two kinds of substitution reactions, called S
N
1 and S
N
2.
When a nucleophile (electron donor, e.g., OH
-
) reacts with an alkyl halide,
the halogen leaves as a halide
There are two competing reactions of alkyl halides with nucleophiles.
1) substitution
C C
H
X
Nu:
-
+
C C
H
Nu
+
X
-
Br R
..
..
:
..
..
: :
Br
Nu:
o
2) elimination
+ C C
H
X
Nu:
- C C +
X
-
+ Nu H
The Nu:
-
replaces the halogen on the o-carbon.
The Nu:
-
removes an H
+
from a |-carbon &
the halogen leaves forming an alkene.
o
|
4
S
N
2 stands for Substitution, Nucleophilic, bimolecular. Another
word for bimolecular is 2
nd
order.
Bimolecular (or 2
nd
order) means Rate = k [RX] [Nu:
-
] (This
is a rate equation and k is a constant).
The mechanism of an S
N
2 reaction is


S
N
2 reactions, i.e. 2
nd
Order Nucleophilic Substitution Reactions
C C
H
X
Nu:
-
+
C C
H
Nu
+
X
-
o
Note that the nucleophile must hit the back side of the o-carbon.
The nucleophile to C bond forms as the C to X bond breaks.
No C
+
intermediate forms.

Sn2 Mechnism
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GIF for Sn2
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5
2nd Order Nucleophilic Substitution Reactions, i.e., S
N
2 reactions
The rate of an S
N
2 reaction depends upon 4 factors:
1. The nature of the substrate (the alkyl halide)
2. The power of the nucleophile
3. The ability of the leaving group to leave
4. The nature of the solvent
1. Consider the nature of the substrate:
Unhindered alkyl halides will react fastest in S
N
2 reactions, that is:
Me >> 1 >> 2 >> 3
While a methyl halides reacts quickly in S
N
2 reactions, a 3 does not react.
The back side of an o-carbon in a 3 alkyl halide is completely blocked.


O H
..
..
: C Br
..
..
:
H
H
H
+
transition state
C Br
..
..
:
H
H
H
O H
..
..
+
..
..
: Br :
C
H
H
H
O H
..
..
6
Me >> 1 >> 2 >> 3
Effect of nature of substrate on rate of S
N
2 reactions:
C H
3
Br C H
3
CH
2
Br
CH Br
C H
3
C H
3
C Br
C H
3
C H
3
C H
3
t-butyl bromide methyl bromide ethyl bromide isopropyl bromide
Back side of o-C
of a methyl halide
is unhindered.
Back side of o-C of a
1 alkyl halide is
slightly hindered.
Back side of o-C of a
2 alkyl halide is
mostly hindered.
Back side of o-C of a
3 alkyl halide is
completely blocked.
decreasing rate of S
N
2 reactions
SPACE FILLING MODELS SHOW ACTUAL SHAPES AND RELATIVE SIZES
7
The a-carbon in vinyl and aryl halides, as in 3 carbocations, are
completely hindered and these alkyl halides do not undergo S
N
2
reactions.
C H
2
CH Br
H
2
C CH
Br
Br
Br
vinyl bromide
bromobenzene
The overlapping p-orbitals that form the p-bonds in vinyl and aryl halides
completely block the access of a nucleophile to the back side of the alpha
carbon.
Nu:
-
Nu:
-
Effect of nature substrate on rate of S
N
2 reactions:
8
2. Consider the power of the nucleophile:
The better the nucleophile, the faster the rate of S
N
2 reactions.
The table below show the relative power or various nucleophiles.
The best nucleophiles are the best electron donors.





Reactivity Nu:
-
Relative
Reactivity
very weak HSO
4
-
, H
2
PO
4
-
, RCOOH < 0.01
weak ROH 1
HOH, NO
3
-
100
fair F
-
500
Cl
-
, RCOO
-
20 10
3

NH
3
, CH
3
SCH
3
300 10
3

good N
3
-
, Br
-
600 10
3

OH
-
, CH
3
O
-
2 10
6

very good CN
-
, HS
-
, RS
-
, (CH
3
)
3
P:, NH
2
-
,RMgX,
I
-
, H
-
> 100 10
6



i
n
c
r
e
a
s
i
n
g

Effect of the nucleophile on rate of S
N
2 reactions:
9
3. Consider the nature of the leaving group:
The leaving group usually has a negative charge
Groups which best stabilize a negative charge are the best leaving groups,
i.e., the weakest bases are stable as anions and are the best leaving groups.
Weak bases are readily identified. They have high pKb values.









Iodine (-I) is a good leaving group because iodide (I
-
) is non basic.
The hydroxyl group (-OH) is a poor leaving group because hydroxide (OH
-
)
is a strong base.

Effect of nature of the leaving group on rate of S
N
2 reactions:
pKb = 23 pKb = 22 pKb = 21 pKb = 11
pKb = -1.7
pKb = -2 pKb = -21
I
-
Br
-
Cl
-
F
-
HO
-
RO
-
H
2
N
-

30,000 10,000 200 1 0 0 0

Increasing leaving ability
10
4. Consider the nature of the solvent:
There are 3 classes of organic solvents:
Protic solvents, which contain OH or NH
2
groups. Protic solvents slow
down S
N
2 reactions.
Polar aprotic solvents like acetone, which contain strong dipoles but no OH
or NH
2
groups. Polar aprotic solvents speed up S
N
2 reactions.
Non polar solvents, e.g., hydrocarbons. S
N
2 reactions are relatively slow in
non polar solvents.


Effect of the solvent on rate of S
N
2 reactions:
Protic solvents (e.g., H
2
O, MeOH, EtOH, CH
3
COOH, etc.) cluster around the Nu:-
(solvate it) and lower its energy (stabilize it) and reduce its reactivity via H-bonding.

X:
-
H
H
H
H
OR
OR
OR
RO
o
+
o
+
o
+
o
+
-
o
-
o
-
o
-
o
A solvated anion (Nu:-) has reduced nucleophilicity,
reduced reactivity and increased stability
A solvated nucleophile has difficulty hitting the o-carbon.
11
Polar Aprotic Solvents solvate the cation counterion of the nucleophile but
not the nucleophile
Effect of the solvent on rate of S
N
2 reactions:
Polar aprotic solvents solvate metal cations
leaving the anion counterion (Nu:
-
) bare and
thus more reactive
CH
3
C O
O
: :
..
..
:
_
Na
+
Na
+
N C CH
3
N C CH
3
N C CH
3 N C H
3
C
-
o
-
o
-
o
-
o
o
+
o
+
o
+
o
+
+ CH
3
C O
O
: :
..
..
:
_
CH
3
CN
: :
..
..
:
12

Non polar solvents (benzene, carbon tetrachloride, hexane, etc.) do
not solvate or stabilize nucleophiles.

S
N
2 reactions are relatively slow in non polar solvents similar
to that in protic solvents.
Effect of the solvent on rate of S
N
2 reactions:
benzene
C
Cl
Cl
Cl
Cl
carbon
tetrachloride
CH
3
CH
2
CH
2
CH
2
CH
2
CH
3
n-hexane
Stereochemistry of S
N
2 Reaction
Cl
R
1
R
3
R
2
Nu
Transition State
Energy Maxima
Bond
Forming
2
1

2
1

sp
2
Bond
Breaking
R
1
R
2
R
3
Nu
Cl
Inversion
of Configuration
Nucleophile attacks from behind the C-Cl o-
bond.
This is where the o*-antibonding orbital of
the C-Cl bond is situated.
Hence inversion of configuration takes place.
This inversion is called Walden Inversion

Rate = k [R-Hal][Nu]
R
1
R
2
R
3
C l Nu
sp
3
Bimolecular
Process
Rate
Determinig
Step
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Transition States
A + B
E
n
e
r
g
y
Reaction Coordinate
A + B
C + D
[A
.
B]

Transition
State
Energy
Maxima
Rate = k[A][B]
AG

AG
o
E
n
e
r
g
y
Reaction Coordinate
R
1
R
2
R
3
Cl Nu
R
1
R
2
R
3
Nu
Cl
Cl
R
1
R
3
R
2
Nu
Transition State
Energy Maxima
Bond
Forming
2
1

2
1

sp
2
Bond
Breaking
19
1st Order Nucleophilic Substitution Reactions, i.e.,
S
N
1 reactions
C
CH
3
H
3
C
CH
3
Br
+
Na
+
I
-
C
CH
3
H
3
C
CH
3
I
+
Na
+
Br
- 3
rapid
3 alkyl halides are essentially inert to substitution by the S
N
2
mechanism because of steric hindrance at the back side of the o-
carbon.
Despite this, 3 alkyl halides do undergo nucleophilic substitution
reactions quite rapidly , but by a different mechanism, i.e., the S
N
1
mechanism.
S
N
1 = Substitution, Nucleophilic, 1st order (unimolecular).
S
N
1 reactions obey 1st order kinetics, i.e., Rate = k[RX].
The rate depends upon the concentration of only 1 reactant, the
alkyl halide-not the nucleophile
The order of reactivity of substrates for S
N
1 reactions is the reverse
of S
N
2
3 > 2 > 1 > vinyl > phenyl > Me
R
3
C-Br R
2
HC-Br RH
2
C-Br CH
2
=CH-Br |-Br H
3
C-Br
increasing rate of S
N
1 reactions
20
The mechanism of an S
N
1 reaction occurs in 2 steps:






Reaction Steps
1. the slower, rate-limiting dissociation of the alkyl halide forming a C+
intermediate
2. a rapid Nucleophilic attack on the C+








Mechanism of S
N
1 reactions
C
CH
3
H
3
C
CH
3
3
Br
..
..
:
+
Na
+
Br
-
C
CH
3
H
3
C
CH
3
I
..
..
:
1.
Br
-
-
C
CH
3
H
3
C
CH
3
+
3 C
+
rapid
Na
+
I
-
..
..
: :
2.
Note that the nucleophile is not involved in the slower, rate-limiting step.
Sn1 Mechanism
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GIF Sn1
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21
The rate of an S
N
1 reaction depends upon 3 factors:
1. The nature of the substrate (the alkyl halide)
2. The ability of the leaving group to leave
3. The nature of the solvent
The rate is independent of the power of the nucleophile.
1. Consider the nature of the substrate:
Highly substituted alkyl halides (substrates) form a more stable C+.
The Rate of S
N
1 reactions
C
H
H
H
+
C
CH
3
H
H
+
C
CH
3
H
H
3
C
+
C
CH
3
CH
3
H
3
C
+
tertiary
3
secondary
2
primary
1
methyl
more
stable
less
stable
>
> >
increasing rate of S
N
1 reactions
22
Alkyl groups are weak electron donors.
They stabilize carbocations by donating electron density by
induction (through o bonds)





They stabilize carbocations by hyperconjugation (by partial overlap of
the alkyl C-to-H bonds with the empty p-orbital of the carbocation).
Stability of Carbocations
C
CH
3
CH
3
H
3
C +
Inductive effects:
Alkyl groups donate (shift) electron
density through sigma bonds to
electron deficient atoms.
This stabilizes the carbocation.
vacant p orbital
of a carbocation
sp
2
hybridized
carbocation
Csp
3
-Hs
sigma bond
orbital
overlap (hyperconjugation)
HYPERCONJUGATION
+
C
C
..
H
H
H
23
Allyl and benzyl halides also react quickly by S
N
1 reactions
because their carbocations are unusually stable due to their
resonance forms which delocalize charge over an extended t
system







Stability of Carbocations
H
2
C CH
+
CH
2
CH
2
HC
H
2
C
+
1 allyl carbocation
H
2
C CH
+
CHR
CHR HC
H
2
C
+
2 allyl carbocation
2 benzylic
1 benzylic
C
H
R
+ C
H
H
+
C
H
H
C
H
H
C
H
H
+ +
+
24
Relative Stability of All Types of Carbocations
2 allylic
>
>
3 allylic
>
>
>
3 C
+
C CH
3
CH
3
CH
3
+
CH
2
CH CHR
+
CH
2
CH CR
2
+
C R
2
+
3 benzylic
C HR
+
2 benzylic
1 allylic
C CH
3
CH
3
H
+
2 C
+
CH
2
CH CH
2
+
C H
2
+
1 benzylic
1 C
+
C CH
3
H
H
+
+
+
C H
H
H
methyl C
+
phenyl
>
CH
2
CH
+
+
vinyl C
Increasing C+ stability and rate of S
N
1 reaction
Note that 1 allylic and 1 benzylic C+s are about as stable as 2alkyl C+s.
Note that 2 allylic and 2 benzylic C+s are about as stable as 3 alkyl C+s.
Note that 3 allylic and 3 benzlic C+s are more stable than 3 alkyl C+s
Note that phenyl and vinyl C+s are unstable. Phenyl and vinyl halides do not
usually react by S
N
1 or S
N
2 reactions
25
2. Consider the nature of the leaving group:
The nature of the leaving group has the same effect on both S
N
1 and S
N
2
reactions.
The better the leaving group, the faster a C+ can form and hence the faster will
be the S
N
1 reaction.
The leaving group usually has a negative charge
Groups which best stabilize a negative charge are the best leaving groups,
i.e., the weakest bases are stable as anions and are the best leaving groups.
Weak bases are readily identified. They have high pKb values.









Effect of nature of the leaving group on rate of S
N
1 reactions:
pKb = 23 pKb = 22 pKb = 21 pKb = 11
pKb = -1.7
pKb = -2 pKb = -21
I
-
Br
-
Cl
-
F
-
HO
-
RO
-
H
2
N
-

30,000 10,000 200 1 0 0 0

Increasing leaving ability
Iodine (-I) is a good leaving group because iodide (I
-
) is non basic.
The hydroxyl group (-OH) is a poor leaving group because hydroxide
(OH
-
) is a strong base.
26
3. Consider the nature of the solvent:
For S
N
1 reactions, the solvent affects the rate only if it influences the
stability of the charged transition state, i.e., the C+. The Nu:
-
is not
involved in the rate determining step so solvent effects on the Nu:
-
do not
affect the rate of S
N
1 reactions.
Polar solvents, both protic and aprotic, will solvate and stabilize the
charged transition state (C+ intermediate), lowering the activation energy
and accelerating S
N
1 reactions.
Nonpolar solvents do not lower the activation energy and thus make S
N
1
reactions relatively slower


Effect of the solvent on rate of S
N
1 reactions:
reaction rate increases with polarity of solvent
The relative rates of an S
N
1 reaction due to solvent effects are given

(CH
3
)
3
C-Cl + ROH (CH
3
)
3
C-OR + HCl

H
2
O 20% EtOH (aq) 40% EtOH (aq) EtOH
100,000 14,000 100 1

27
Solvent polarity is usually expressed by the dielectric constant, c, which is a
measure of the ability of a solvent to act as an electric insulator.
Polar solvents are good electric insulators because their dipoles surround and
associate with charged species.
Dielectric constants of some common solvents are given in the following table










Effect of the solvent on rate of S
N
1 reactions:
Name dielectric constant Name dielectric constant
aprotic solvents protic solvents
hexane 1.9 acetic acid 6.2
benzene 2.3 acetone 20.7
diethyl ether 4.3 ethanol 24.3
chloroform 4.8 methanol 33.6
HMPA 30 formic acid 58.0
DMF 38 water 80.4
DMSO 48

28
Consider the nature of the Nucleophile:
The nature of the nucleophile has no effect on the rate of S
N
1 reactions
because the slowest (rate-determining) step of an S
N
1 reaction is the
dissociation of the leaving group and formation of the carbocation.
All carbocations are very good electrophiles (electron acceptors) and even
weak nucleophiles, like H
2
O and methanol, will react quickly with them.
The two S
N
1 reactions will proceed at essentially the same rate since the
only difference is the nucleophile.
Effect of the nucleophile on rate of S
N
1 reactions:
C
CH
3
H
3
C
CH
3
Br
+
Na
+
I
-
C
CH
3
H
3
C
CH
3
I
+
Na
+
Br
- 3
C
CH
3
H
3
C
CH
3
Br
+
C
CH
3
H
3
C
CH
3
F
+
K
+
Br
- 3
K
+
F
-
R
1
R
2
R
3
Nu
R
1
R
2
R
3
Nu
Racemisation
of
Configuration
R
1
R
2
R
3
Cl
sp
3
Unimolecular
Process
Rate = k[R-Hal]
Rate
Determining
State
R
1
R
3
R
2
Nu
Cl
Reactive Intermediate
Energy Minima
sp
2
Nucleophile attacks from either side
of the carbocationic intermediate.
Stereochemistry of S
N
1 Reaction
30
Stereochemistry of S
N
1 Reaction
AG
o
E
n
e
r
g
y
AG

AG

E
n
e
r
g
y
Reaction Coordinate
A + B
D + E
C + B
Reactive
Intermediate
Energy
Minima
Rate = k[A]
Reactive Intermediates
E
n
e
r
g
y
Reaction Coordinate
R
1
R
2
R
3
Cl
R
1
R
3
R
2
R
1
R
2
R
3
Nu
R
1
R
2
R
3
Nu
Reactive Intermediate
Racemisation takes place after intermediate formation