1

SUBSTITUTION AND ELIMINATION

REACTIONS OF ALKYL HALIDES
S
N
1, S
N
2, E1 & E2 REACTIONS
2
Reactions of Alkyl Halides (R-X): [SN1, SN2, E1, & E2 reactions]
The o-carbon in an alkyl halide is electrophilic (electron accepting) for either
or both of two reasons

a) the C to X (F, Cl, Br) bond is polar making carbon o+

(4.0 2.5) = 1.5
(3.0 2.5) = 0.5
(2.8 2.5) = 0.3
F H
3
C
o
+
o

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]
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
2) elimination
C C
H
X
Nu:
-
+
C C
H
Nu
+
X
-
+ 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.
Br R
..
..
:
..
..
: :
Br
Nu:
o
o
|
4
There are two kinds of substitution reactions, called S
N
1 and S
N
2.
As well as two kinds of elimination reactions, called E1 and E2.
Lets study S
N
2 reactions first. S
N
2 stands for Substitution,
Nucleophilic, bimolecular. Another word for bimolecular is 2
nd

order.
Bimolecular (or 2
nd
order) means that the rate of an S
N
2 reaction is
directly proportional to the molar concentration of two reacting
molecules, the alkyl halide substrate and the nucleophile:
Rate = k [RX] [Nu:
-
] (This is a rate equation and k is a constant).
The mechanism of an S
N
2 reaction is the one shown on slide #2:


2nd Order Nucleophilic Substitution Reactions, i.e., S
N
2 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. An example is shown on the next slide.


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, those in which the back side of the o-carbon is
not blocked, 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
1alkyl halide is
slightly hindered.
Back side of o-C of a
2alkyl halide is
mostly hindered.
Back side of o-C of a
3alkyl halide is
completely blocked.
decreasing rate of S
N
2 reactions
SPACE FILLING MODELS SHOW ACTUAL SHAPES AND RELATIVE SIZES
7
The o-carbon in vinyl and aryl halides, as in 3 carbocations, is completely
hindered and these alkyl halides do not undergo S
N
2 reactions.
Effect of the nucleophile on rate of 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 t-bonds in vinyl and aryl halides
completely block the access of a nucleophile to the back side of the
o-carbon.
Nu:
-
Nu:
-
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.





Effect of nature substrate on rate of S
N
2 reactions:
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

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.
Examples include acetonitrile (CH
3
CN), acetone (CH
3
COCH
3
),
dimethylformamide (DMF) [(CH
3
)
2
NC=OH], dimethyl sulfoxide, DMSO
[(CH
3
)
2
SO], hexamethylphosphoramide, HMPA {[(CH
3
)
2
N]
3
PO} and
dimethylacetamide (DMA).
Effect of the solvent on rate of S
N
2 reactions:
DMF
C
O
H N
CH
3
CH
3
C
O
N
CH
3
CH
3
DMSO
S
O
CH
3 H
3
C
HMPA
[(CH
3
)
2
N]
3
P O
H
3
C
DMA
: : : : : :
.. .. ..
..
..
..
CH
3 C N
:
acetonitrile
C
O
CH
3 H
3
C
: :
acetone
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
13
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
14
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
+
3C
+
rapid
Na
+
I
-
..
..
: :
2.
Note that the nucleophile is not involved in the slower, rate-limiting step.
15
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
16
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
17
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
+ +
+
18
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 1allylic and 1benzylic C+s are about as stable as 2alkyl C+s.
Note that 2allylic and 2benzylic C+s are about as stable as 3alkyl C+s.
Note that 3allylic and 3benzlic C+s are more stable than 3alkyl 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
19
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.
20
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

21
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

22
Consider the nature of the Nucleophile:
Recall again that 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
-
23
We have seen that alkyl halides may react with basic nucleophiles such as
NaOH via substitution reactions.





Also recall our study of the preparation of alkenes. When a 2or 3alkyl halide
is treated with a strong base such as NaOH, dehydrohalogenation occurs
producing an alkene an elimination (E2) reaction.




bromocyclohexane + KOH cyclohexene (80 % yield)

Substitution and elimination reactions are often in competition. We shall
consider the determining factors after studying the mechanisms of elimination.
Elimination Reactions, E1 and E2:
Br
KOH in ethanol
+ KBr +
H
2
O
-HBr
O H
..
..
: C Br
..
..
:
H
H
H
+
transition state
C Br
..
..
:
H
H
H
O H
..
..
+
..
..
: Br :
C
H
H
H
O H
..
..
24
+ C C
H
Br
OH
- C C + Br
-
+
HO H
There are 2 kinds of elimination reactions, E1 and E2.
E2 = Elimination, Bimolecular (2nd order). Rate = k [RX] [Nu:
-
]
E2 reactions occur when a 2 or 3 alkyl halide is treated with a strong
base such as OH
-
, OR
-
, NH
2
-
, H
-
, etc.











E2 Reaction Mechanism
The Nu:
-
removes an H
+
from a |-carbon &
the halogen leaves forming an alkene.
o
|
All strong bases, like OH
-
, are good nucleophiles. In 2 and 3 alkyl halides
the o-carbon in the alkyl halide is hindered. In such cases, a strong base
will abstract (remove) a hydrogen ion (H+) from a |-carbon, before it hits
the o-carbon. Thus strong bases cause elimination (E2) in 2 and 3 alkyl
halides and cause substitution (S
N
2) in unhindered methyl and 1 alkyl
halides.
25
In E2 reactions, the Base to H o bond formation, the C to H o bond breaking,
the C to C t bond formation, and the C to Br o bond breaking all occur
simultaneously. No carbocation intermediate forms.






Reactions in which several steps occur simultaneously are called concerted
reactions.
Zaitsevs Rule:
Recall that in elimination of HX from alkenes, the more highly substituted
(more stable) alkene product predominates.
E2 Reaction Mechanism
B:
-
C
H
C
R
R
X
B
R
R
H
C C R
R
R
R
X
o
+
-
o
C C
R R
R
R
+ B H
+
X
-
CH
3
CH
2
CHCH
3
Br
CH
3
CH
2
O
-
Na
+
EtOH
CH
3
CH CHCH
3
+ CH
3
CH
2
CH CH
2
2-butene
1-butene
major product
( > 80%)
minor product
( < 20%)
26
E2 reactions, do not always follow Zaitsevs rule.
E2 eliminations occur with anti-periplanar geometry, i.e., periplanar
means that all 4 reacting atoms - H, C, C, & X - all lie in the same
plane. Anti means that H and X (the eliminated atoms) are on opposite
sides of the molecules.
Look at the mechanism again and note the opposite side & same plane
orientation of the mechanism:








E2 Reactions are antiperiplanar
B:
-
C
H
C
R
R
X
B
R
R
H
C C R
R
R
R
X
o
+
-
o
C C
R R
R
R
+ B H
+
X
-
27
Antiperiplanar E2 Reactions in Cyclic Alkyl Halides
When E2 reactions occur in open chain alkyl halides, the Zaitsev
product is usually the major product. Single bonds can rotate to the
proper alignment to allow the antiperiplanar elimination.
In cyclic structures, however, single bonds cannot rotate. We need to
be mindful of the stereochemistry in cyclic alkyl halides undergoing E2
reactions.
See the following example.

Trans 1-chloro-2-methylcyclopentane undergoes E2 elimination with
NaOH. Draw and name the major product.








H
Cl
H
3
C
H
H
H
Na
+
OH
-
E2
H
3
C
H
H
H
Non Zaitsev product
is major product.
H
H
H
3
C
H
Little or no Zaitsev (more stable)
product is formed.
HOH
NaCl
+
+
3-methylcyclopentene 1-methylcyclopentene
28
Just as S
N
2 reactions are analogous to E
2
reactions, so S
N
1 reactions have
an analog, E1 reaction.
E1 = Elimination, unimolecular (1st order); Rate = k [RX]






E1 eliminations, like S
N
1 substitutions, begin with unimolecular
dissociation, but the dissociation is followed by loss of a proton from the
|-carbon (attached to the C
+
) rather than by substitution.
E1 & S
N
1 normally occur in competition, whenever an alkyl halide is
treated in a protic solvent with a nonbasic, poor nucleophile.
Note: The best E1 substrates are also the best S
N
1 substrates, and
mixtures of products are usually obtained.
E1 Reactions
C CH
3
CH
3
CH
3
Br
slow
B:
-
C CH
3
CH
3
C H
H
H
+
rapid
C C
CH
3
H
CH
3
H
+ B H +
Br
-
Br
- -
29
As with E2 reactions, E1 reactions also produce the more highly
substituted alkene (Zaitsevs rule). However, unlike E2 reactions where no
C
+
is produced, C
+
rearrangements can occur in E1 reactions.
e.g., t-butyl chloride + H
2
O (in EtOH) at 65 C t-butanol + 2-methylpropene








In most unimolecular reactions, S
N
1 is favored over E1, especially at low
temperature. Such reactions with mixed products are not often used in
synthetic chemistry.
If the E1 product is desired, it is better to use a strong base and force the
E2 reaction.
Note that increasing the strength of the nucleophile favors S
N
1 over E1.
Can you postulate an explanation?
E1 Reactions
C CH
3
CH
3
CH
3
Cl +
H
2
O, EtOH
65C
C CH
3
CH
3
CH
3
OH
C C
CH
3
H
CH
3
H
64%
36%
S
N
1
product
E1
product
30
1. Non basic, good nucleophiles, like Br
-
and I
-
will cause substitution not
elimination. In 3 substrates, only S
N
1 is possible. In Me and 1
substrates, S
N
2 is faster. For 2 substrates, the mechanism of
substitution depends upon the solvent.
2. Strong bases, like OH
-
and OR
-
, are also good nucleophiles.
Substitution and elimination compete. In 3 and 2 alkyl halides, E2 is
faster. In 1 and Me alkyl halides, S
N
2 occurs.
3. Weakly basic, weak nucleophiles, like H
2
O, EtOH, CH
3
COOH, etc.,
cannot react unless a C+ forms. This only occurs with 2 or 3
substrates. Once the C+ forms, both S
N
1 and E1 occur in competition.
The substitution product is usually predominant.
4. High temperatures increase the yield of elimination product over
substitution product. (AG = AH TAS) Elimination produces more
products than substitution, hence creates greater entropy (disorder).
5. Polar solvents, both protic and aprotic, like H
2
O and CH
3
CN,
respectively, favor unimolecular reactions (S
N
1 and E1) by stabilizing
the C+ intermediate. Polar aprotic solvents enhance bimolecular
reactions (S
N
2 and E2) by activating the nucleophile.
Predicting Reaction Mechanisms
31
Predicting Reaction Mechanisms

alkyl
halide
(substrate)
good Nu
-

nonbasic
e.g., bromide
Br
-

good Nu
-

strong base
e.g., ethoxide
C
2
H
5
O
-

good Nu
-

strong bulky base
e.g., t-butoxide
(CH
3
)
3
CO
-

very poor Nu
-

nonbasic
e.g., acetic acid
CH
3
COOH
Me
1
2

3


S
N
1, E1
S
N
2
E2
S
N
2
S
N
2
S
N
1
S
N
2
S
N
2
E2
E2
S
N
2
E2 (S
N
2)
E2
no reaction
no reaction
S
N
1, E1
Strong bulky bases like t-butoxide are hindered. They have difficulty hitting
the o-carbon in a 1alkyl halide. As a result, they favor E2 over S
N
2
products.
32
The nucleophiles in the table on slide 30 are extremes. Some
nucleophiles have basicity and nucleophilicity in between these extremes.
The reaction mechanisms that they will predominate can be interpolated
with good success.
Predict the predominant reaction mechanisms the following table.










Predicting Reaction Mechanisms

alkyl
halide
(substrate)
.. Nu
-

. .base
e.g., cyanide
CN
-
pkb =
.. Nu
-

.. base
e.g., alkyl sulfide
RS
-
, also HS
-
pkb =
.. Nu
-

.. base
e.g., carboxylate
RCOO
-
pkb =

alcohol
(substrate)
HI
HBr
HCl
Me Me
1 1
2 2
3 3

4.7
v. gd.

moderate

S
N
2
S
N
2
S
N
2
E2
6.0 / 7.0
moderate

v. gd.

S
N
2
S
N
2
E2
S
N
2
9
weak

fair

S
N
2
S
N
2
E2
E2
S
N
2
S
N
2
S
N
1
S
N
1
HCl, HBr and HI are assumed to be in aqueous solution, a protic solvent.
33
Recall the preparation of long alkynes.
1. A terminal alkyne (pKa = 25) is deprotonated with a very strong base

R-C C-H + NaNH
2
R-C C:
-
Na
+
+ NH
3


2. An alkynide anion is a good Nu:
-
which can substitute (replace) halogen
atoms in methyl or 1 alkyl halides producing longer terminal alkynes .

R-C C:
-
Na
+
+ CH
3
CH
2
-X R-C C-CH
2
CH
3
+ NaX

The reaction is straightforward with Me and 1 alkyl halides and proceeds
via an S
N
2 mechanism

Alkynide anions are also strong bases (pKb = -11) as well as good Nu:
-
s,
so E2 competes with S
N
2 for 2 and 3 alkyl halides
CH
3
(CH
2
)
3
CC:
-
Na+ + CH
3
-CH(Br)-CH
3
CH
3
(CH
2
)
3
CCCH(CH
3
)
2
(7% S
N
2)
+ CH
3
(CH
2
)
3
CCH + CH
3
CH=CH
2
(93% E2)

Alkylation of Alkynides
34
Alkyl halides can be prepared from alcohols by reaction with HX, i.e., the
substitution of a halide on a protonated alcohol.















Preparation of Alkyl Halides from Alcohols
+ H Cl (CH
3
)
3
C OH
..
..
(CH
3
)
3
C OH
2
..
+
H
2
O
-
(CH
3
)
3
C+ (CH
3
)
3
C
..
: H
2
O +
:
-
..
..
: Cl
Cl
..
S
N
1
(Lucas Test)
3
..
1
CH
3
CH
2
OH
..
+
H Cl
CH
3
CH
2 OH
2
+
:
-
..
..
: Cl
CH
3
CH
2
Cl + H
2
O
S
N
2
A
Very slow. Protic solvent inhibits the nucleophile.
Rapid. 3C+ is stabilized by protic sovent (H
2
O)
Draw the mechanism of the reaction of isopropyl alcohol with HBr.
What products form if concentrated H
2
SO
4
is used in place of aq. HCl?
OH
-
is a poor leaving group, i.e., is not displaced directly by nucleophiles.
Reaction in acid media protonates the OH group producing a better leaving
group (H
2
O). 2 and 3 alcohols react by S
N
1 but Me and 1 alcohols react
by S
N
2.

35
Alternative to using hydrohalic acids (HCl, HBr, HI), alcohols can be
converted to alkyl halides by reaction with PBr
3
which transforms OH
-
into
a better leaving group allowing substitution (S
N
2) to occur without
rearrangement.











Preparation of Alkyl Halides from Alcohols
S
N
2
CH
3
(CH
2
)
4
CH
2
OH
P
Br
Br
Br
:
ether
CH
3
(CH
2
)
4
CH
2
O
PBr
2
..
..
..
+
H
Br
-
CH
3
(CH
2
)
4
CH
2
Br
1
36
On Slide 22 we noted that 2and 3alkyl halides can be dehydrohalogenated
with a strong base such as OH
-
producing an alkene.




bromocyclohexane + KOH cyclohexene (80 % yield)


Clearly, this is an E2 reaction.


Preparation of Alkenes from Alkyl Halides
Br
KOH in ethanol
+ KBr +
H
2
O
-HBr
Predict the mechanism that occurs with a Meor 1alkyl halide.

Predict the products and mechanism that occur with isopentyl chloride and
KOH

37
Alkyl Halide Substrate Reactivity:



Summary of S
N
/Elimination Reactions
unhindered substrates favor S
N
2
do not form a stable C
+
do not react by S
N
1 or E1
hindered substrates. S
N
2 increasingly unfavorable, E2 is OK
form increasingly stable C
+

favors S
N
1 and E1. E2 is OK
C H
H
H
Br
C CH
3
H
H
Br C CH
3
CH
3
H
Br C CH
3
CH
3
CH
3
Br
E2 reactions possible with strong bases
E2 reactions possible with strong bulky bases (t-butoxide)
methyl
1 2 3
38
Reactivity of Nucleophiles:





Note that poor nucleophiles that are also weak bases (H
2
O, ROH, CH
3
COOH,
etc.) do not undergo any reaction unless a C
+
is formed first. If a C
+
can form
(as with a 2, 3, any benzylic, or any allylic halides), then E1 and S
N
1
generally occur together.
Leaving Group Activity:



Summary of S
N
/Elimination Reactions
HS
-
CN
-
I
-
CH
3
O
-
HO
-

NH
3

Cl
-

H
2
O
125,000 125,000 100,000 25,000 16,000 1000 700 1

good nucleophiles which are good nucleophiles which are
weak bases favor S
N
reactions also strong bases favor elimination
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

good leaving groups favor both poor leaving groups make both
substitution and elimination reactions substitution and elimination
reactions unfavorable