Chapter 11: Reactions of Alkyl Halides

Coverage:
1. Substitution Reactions, SN1 and SN2
2. Elimination Reactions, E1 and E2

Problems:25-39, 43,47,54

Goals:
1. Know the detailed mechanisms of SN1, SN2, E1 and E2
2. Know what is a good nucleophile and what is a poor nucleophile
3. Understand the concept of inversion of configuration (SN2)
4. Know the kinetics associated with each reaction
5. Know Zaitzev’s Rule and how it applies to the elimination reactions.
6. Know what is a good leaving group in a reaction.
 There are two fundamental types of reaction mechanisms to be covered:

Substitution SN2 and SN2

Elimination E1 and E2

Definitions

Nucleophile – electron-rich species that attacks a nucleus which is positively charged

Electrophile – electron-poor species that is attacked by a nucleophile.

SN2

S – substitution
N – nucleophilic
2 - bimolecular reaction
H
HH H
Nu- C X Nu C + X-
H H

Backside attack
Inversion of Configuration: As the nucleophile attacks, the three groups attached
to the carbon undergo inversion, that is, they flip to the opposite side of the carbon.

Kinetics

Rate = k [Nu-] [RX] 2nd order reaction

k – rate constant characteristic of the reaction.

The larger the k, the faster the reaction.

Effect of Substrate Structure

Alkyl Halide Type Relative

Rate

CH3X methyl 3 x 106

CH3CH2X 10 1 x 105
CH3CH2CH2X 10 4 x 104
(CH3)2CH-X 20 2.5 x 103
(CH3)3CCH2-X 10 1
(CH3)3C-X 30 ~0
 Reaction Energy Diagram for SN2 Mechanism

TS

Ea
E

R-X + Nu R-Nu + X

Reaction Coordinate
 Why this order of reactivity? What controls the relative rate of reaction of the
various substrates?

Answer: Steric Hindrance to nucleophilic attack.

H3C
H3 C
Nu- No Reaction
C X
H3 C

The bulky methyl groups prevent backside attack by sterically hindering the
nucleophile from attacking the electrophilic carbons. Contrast this situation to
that of the CH3X group.

Nucleophiles

Nu: + R-X  Nu-R+ + X-

neutral

Nu:- + R-X  Nu-R + X-

charged
Reaction:

Nu- + CH3Br Nu-CH3+ + Br-

Nu- Relative Rate pKa (conjugate

acid)

HS- 125,000 7.04

CN- 125,000 9.31 Strongest base
I- 100,000 0.77
CH3CH2O- 25,000 16
OH- 16,000 15.7
Ph-O- 8,000 10
-
CH 3CO2
Conclusion: 500 base is not the best nucleophile.
The strongest 4.8 In other words,
Hbasicity
2O
does not control nucleophilicity.
1

What controls nucleophilicity?

1. Polarizability.
HH
HH
F- C X F- C X
H
H
Electrons tightly held by
the nucleus and not easily Transition state – not good
distorted bonding between carbon
and fluorine atom. High energy

HH
HH
I- C X I- C X
H
H
Electrons loosely held by
the nucleus and easily Transition state – very good
distorted bonding between carbon
and iodine atom. Lower energy
 2. Solvation

F- has a high charge density due to small size

..
H O
• Highly solvated by water
H • Very stabilized

-
.. • Less reactive in Sn2 reaction
F H O

H-bond H
H

H
..O
Generally, the larger nucleophile is the better one in a given group.

Halogen Nucleophiles:

I- > Br- > Cl- > F- HS- > HO-

Best Worst NH3 > H2O

 3. Charge on Nucleophile

Charged nucleophiles are better than neutral nucleophiles in the same

group.

HS- > H2S OH- > H2O NH2- > NH3

Table of Nucleophilic Strengths

Strong Nucleophile Moderate Weak

Strongest (CH3CH2)2P Br- F-

HS- NH3 H2 O
I- CH3SCH3 CH3OH
(CH3CH2)2NH Cl-
CN- CH3CO2-
Weakest OH-
CH3O-
4. Bulky Nucleophiles

CH3CH2O- > (CH3)3CO-

Not Bulky Bulky
Unhindered Hindered

Alkoxides Ions

Effect of Leaving Group

N C X
N C + X

Leaving Group
 • The LG is usually displaced with a negative charge. LGs that best stabilize the
negative charge are best.

• Electronegative LGs, which polarize the C atom are also good.

• LGs should be polarizable to stabilize the Transition State

• In general, the weaker the base, the better the LG.

LG Rel. Reactivity pK a (conjugate acid)

O
H3C S O 60,000 -6.5
O

I- 30,000 -9.5 Weakest base

Br- 10,000 -9
F- 1 3.2
OH- ~0 15.7
NH2- ~0 35 Strongest base
 O
H3C S O Symbolized as -OTs
O

tosylate group

O
H3C O S CH3
:N C
O

O
-O S CH3
:N C-CH3
O

Halogens as Leaving Groups

I- > Br- > Cl- > F-

Stereochemistry of SN2

Recall that the nucleophile attacks from the backside.

What happens when a single enantiomer with a reactive chiral carbon undergoes
SN2 reaction???

Answer: It undergoes inversion of configuration

CH3 CH3
H3C H
H H
HO- C Br HO C X + X
HO C
CH3CH2
CH2CH3
CH2CH3
(S)-2-bromobutane (R)-2-butanol

SN2 reaction proceeds with 100% inversion of configuration – termed

Walden inversion.
SN1 Mechanism 1- Unimolecular

CH3 CH3
H3C C Br + H2O H3C C OH + H Br
CH3 CH3

30 Halide Solvent 30 alcohol

Solvolysis: Solvent acts as nucleophile and reacts with substrate.
What is the mechanism? Not SN2! Remember, a 30 substrate is unreactive in SN2
Answer: SN1
CH3 CH3
slow
H3C C Br H3C C+ + Br
CH3 CH3

CH3 CH3
H3C C+ + H2O H3C C OH2+
CH3 CH3
CH3
CH3
H3C C OH2+ Br
CH3
H3C C OH + H Br
CH3
 Reaction Energy Diagram for SN1

TS#1 TS#2

R+ + X-
E
NuH TS#3

R-X
R-NuH+ + X-
R-Nu + H-X

Reaction Coordinate

First step is rate-determining (highest activation energy).

Rate = k [R-X] First order reaction

Rate-determining Step is Unimolecular
 Effect of Substrate Structure on SN1 Reactivity

30 > 20 > 10 > CH3X

Most Least Reactive

Why this order

• 30 substrates form stable 30 carbocations in rate-determining step. They

form faster with a lower Energy of Activation

E 10 carbocation  less stable  higher Ea  forms slower

30 carbocation  more stable  lower Ea  forms faster

Reaction Coordinate
 Allylic and Benzylic Substrates are very reactive in SN1 reactions.

Why so??

They form resonance-stabilized carbocations.

Br
+ +

Allyl bromide
H2O

OH OH2+
Br

H Br

What about benzyl bromide? Write a mechanism showing its reaction

with water. CH2Br

?
+ H2O
 Leaving Groups: The same factors that favor SN2 leaving groups also
Favor SN1 leaving groups, i.e. if a LG is good for SN2, it is good for SN1.

Stereochemistry of SN1 OCH3

CH3OH
H3C C
CH2CH3
B (CH3)2CH
Br
+ S isomer
H3C C H3C C CH2CH3
(CH3)2CH ~50%
CH2CH3
(CH3)2CH
A
S isomer

CH3OH H3C CH2CH3

(CH3)2CH
Planar, symmetric C

carbocation OCH3

The carbocation is attacked both from the top and the bottom by R isomer
the nucleophilic methanol, resulting in a near racemic mixture of ~50%
enantiomers as products
Reactions that proceed by the SN1 reaction often undergo rearrangements.
Why?

Carbocations are intermediates and may undergo 1,2 ~H or 1,2 ~CH 3 shifts.

Br OCH2CH3 OCH2CH3
CH3CH2OH
CH3CHCHCH3 CH3CHCHCH3 + CH3CHCHCH3
CH3 CH3 CH3

+ H Br

Practice: Write a mechanism for this reaction to account for both products.
 Solvents in SN1 and SN2 Reactions

SN2 Polar, aprotic solvents are best.

Aprotic - no OH or NH group present

These solvents cannot H-bond to nucleophile and therefore
the nucleophile is more reactive.
O
O
CH3CCH3 CH3C N
CH3SCH3
Acetone Acetonitrile Dimethylsulfoxide (DMSO)
SN1 Polar, protic solvents are best.

Protic – possess OH or NH group

These solvents promote formation of ions through H-bonding.
H2O CH3OH CH3CH2OH

Water Methanol Ethanol

 Summary of SN1 and SN2

Topic SN 2 SN1

Kinetics Rate=k[R-X][Nu] Rate=k[RX]

Nucleophile Strong Nu required Weak Nu required,

usually solvent

Substrate Polar, aprotic Polar, protic

Stereochemistry 100% inversion Racemization

Rearrangements No Yes
E2 Elimination

Requirements: Alkyl substrate with a good leaving group possessing

ß-hydrogen

Hß
Cß C
X
The ß-hydrogen is bonded to the ß-carbon, which is bonded to the -carbon
which is bonded to the leaving group X!

A strong base is also required. Any of these will do:

OH- < CH3O- < CH3CH2O- < (CH3)3CO- < NH2-

Weakest Strongest
Mechanism: The E2 mechanism is a one-step mechanism with bond-breaking and
Bond-making taking place at the same time; termed a concerted mechansim. In
Addition, the Hß and the leaving group X must be anti-coplanar for rapid reaction.

OH-

X
+ H2O + X

Notice that H and X are anti to each other and the four atoms, H-C-C-X,
are coplanar in the reactant. This situation stabilizes the transition state
leading to the alkene.
CH 3 .. :
O Overlap develops in the T.S. if the
H anti-coplanar relationship is maintained.
.. R
H The overlap stabilizes the T.S. and the
H C C
reaction takes place faster.
R
..
:Br
.. :

Kinetics
..
CH 3 O
.. H Rate = k [B-][R-X] 2nd Order Reaction
. .
H C C R
R H
.. E2 Ball and Stick Movie
:Br
.. :
Substrate Reactivity

30 > 20 > 10

Why this order of reactivity?

30 substrates yield more stable alkenes and therefore react faster.

10 substrates yield unstable alkenes and react more slowly.

Recall: Alkene Stability

R R H R H R H R H H

R R R R R H H H H H

tetrasubstituted > trisubstituted > disubstituted > monosubstituted > unsubstituted

 OH-
H CH3
H CH3 H CH3
H X CH3
+ H2O + X
H

30 substrate Disubstituted Alkene - more stable

OH-
H H
H3C H H3C H
H X H
+ H2O + X
H

10 substrate Monosubstituted alkene – less stable

What about substrates that can yield more than one possible product such as
2-bromobutane.

HO-
a
b a
H H H H3C H H H
H3C C C C H
C C + C C
H CH3 H3C CH3
H Br H
b 81%
+ H2O + Br

CH3CH2 H
C C
H H

19%
The more stable alkene predominates in the product mixture.

Zaitzev’s Rule: In elimination reactions, the more highly substituted, more

stable alkene is usually the major product. This product is referred to as the
Zaitzev Product
 E2 reactions with Diastereomers

Ph
Br
s H Ph H
Ph H
OH-
H3C s H
or
Ph H3C Ph Ph CH3

(1S,2S)-1-bromo-1,2-diphenylpropane trans cis

In the above reaction, only 1 product forms. Which one?

Ph
H3C Br Ph Br
Br H rotate
 H H H3C
H3C H Ph
Ph Ph H H
Ph
Note: H and Br are
anti-coplanar in a staggered
conformation.
 Ph Br
H3C Ph Ph
Ph H3C H
H H

100% cis isomer

OH-

The E2 reaction is an example of a stereospecific reaction.

Stereospecific Reaction: a reaction in which different stereoisomers

of a given reactant yield different stereoisomeric products.

(1S,2S)-1-bromo-1,2-diphenylpropane  100% cis product

(1S,2R)-1-bromo-1,2-diphenylpropane  100% trans product

Homework Problem: Show that the (1R,2R) yields the cis and the (1R,2S)
yields only the trans.
E2 in Cyclohexane Systems

Br

OH-

Recall that there are two possible conformations of bromocyclohexane

H
Br Anti, coplanar
H H and Br
H
H Br

The equatorial conformation if favored, but it does not provide the necessary
anti, coplanar relationship of the H and Br.

But the axial conformation does! So it reacts.

 OH-

+ H2O + Br-
H
Br

Conclusion: In order for the H and Br to be anti-coplanar, both must be in

axial positions. This geometry is referred to as trans-diaxial.

Homework: The following two geometric isomers yield different alkenes as

products. Why? Write mechanisms to account for each product.

CH3 base, E2 CH3

Br

trans

CH3 CH3
base, E2

Br
cis
E1 Mechanism

CH3 CH3
CH3OH
H3C C Br H2C C + HBr
CH3 CH3

This reaction cannot be E2 because there is no strong base present

CH3
slow CH3
H3C C Br H3C C + Br
CH3 CH3
CH3OH

H
CH3 CH3
H2C C + H2C C + CH3OH2+
CH3 CH3

Kinetics Rate = k [R-X] 1st order

Substrate Reactivity 30 > 20 > 10 (parallels carbocation stability!)

E1 always competes with SN1

CH3 CH3
H3C C Br H3C C + Br
CH3 CH3

CH3OH as CH3OH as base

nucleophile
CH3 CH3
H3C C OCH3 H2C C
CH3 CH3

SN1 E1

Mixture of Products
 Summary of E1 and E2

Topic E2 E1

Kinetics 2nd order 1st order

Base Strong required Weak required

Substrate 30 > 20 > 10 30 > 20 > 10

Solvent Type not critical Polar, aprotic for

ionization

Orientation Zaitzev rule Zaitzev Rule

Conformation Anti-coplanar None required

Requirements H and X

Rearrangements No Yes