ALKYL HALIDES

Ch. 6 - 1
 1. Organic Halides

+ -
d d
C X
X = Cl, Br, I

v Halogens are more electronegative than carbon

Ch. 6 - 2
 Carbon-Halogen Bond Lengths
and Bond Strength

H H H H
H C F H C Cl H C Br H C I
H H H H
C–X Bond
Length (Å)
1.39 1.78 1.93 2.14
increase

C–X Bond
Strength 472 350 293 239
(kJ/mol)
decrease
Ch. 6 - 3
 1A. Physical Properties of Organic Halides:
Boiling Point (bp/oC)
Group Fluoride Chloride Bromide Iodide

Me -78.4 -23.8 3.6 42.5

Et -37.7 13.1 38.4 72

Bu 32 78.4 101 130

s
Bu - 68 91.2 120
i
Bu - 69 91 119
t
Bu 12 51 73.3 100(dec)
Ch. 6 - 4
 Different Types of Organic Halides
v Alkyl halides (haloalkanes)

sp3
C X

Attached to Attached to Attached to

1 carbon atom 2 carbon atoms 3 carbon atoms
C C C

C Cl C Br C I
a 1o chloride a 2o bromide a 3o iodide
Ch. 6 - 5
 v Vinyl halides (Alkenyl halides)

sp2

X
v Aryl halides

sp2
X

benzene or aromatic ring

v Acetylenic halides (Alkynyl halides)

sp
Ch. 6 - 6 X
 Prone to undergo Nucleophilic Substitutions (SN) and
Elimination Reactions (E)
sp3

d+ C d-
X

Alkyl halides

sp2
sp2 sp
X X X
v Different reactivity than alkyl halides, and do not undergo SN or E reactions

Ch. 6 - 7
 2. Nucleophilic Substitution Reactions

d+ d-
Nu + C X Nu C + X
(nucleophile) (substrate) (product) (leaving
group)

The Nu⊖ The Nu⊖ uses

The bond The LG
donates its e⊖ pair to
between gains the
an e⊖ pair form a new
C and LG pair of e⊖
to the covalent bond
breaks, originally
substrate with the
giving both bonded
substrate C
e⊖ from the in the
bond to LG substrate
Ch. 6 - 8
 Timing of The Bond Breaking & Bond Making Process

v Two types of mechanisms

● 1st type: SN2 (concerted mechanism)

R
R -
R
-
d+ d- d d
HO C Br HO C Br HO C
R R
R R
R R
transition state (T.S.)
+ Br -
Ch. 6 - 9
 ● 2nd type: SN1 (stepwise mechanism)

Step (1):
R (k 1 ) R
R C Br R C + Br
slow
R r.d.s. R
k1 << k2 and k3
Step (2)
R (k 2 ) R H
R C + H 2O R C O
R
fast R H
Step (3)
R H (k3) R
+
R C O + H2O +
R C OH H3O
H fast
Ch. 6 - 10
R R
 3. Nucleophiles
v A reagent that seeks a positive center
v Has an unshared pair of e⊖
e.g.:

HO , CH3O , H2N (negative charge)

H2O, NH3 (neutral)

+ -
d d
This is the positive
center that the C X
Nu⊖ seeks
Ch. 6 - 11
 v Examples:

H H H H
HO + C C + Cl
CH3 Cl CH3 OH
(Nu ) (substrate) (product) (L.G.)

H H H H

H
O
H
+ C C H + Cl
CH3 Cl CH3 O
(Nu ) (substrate) H (L.G.)

H H
(product)
C + H 3O
Ch. 6 - 12
CH3 OH
 4. Leaving Groups
v To be a good leaving group, the substituent
must be able to leave as a relatively stable,
weakly basic molecule or ion
e.g.: I⊖, Br⊖, Cl⊖, TsO⊖, MsO⊖, H2O, NH3

O
OTs = O S CH3 (Tosylate)
O
O
OMs = O S CH3 (Mesylate)
Ch. 6 - 13 O
 5. Kine(cs of a Nucleophilic Subs(tu(on
Reac(on: An SN2 Reac(on
HO + CH3 Br HO CH3 + Br
-
Rate = k[CH3Br][OH ]
v The rate of the substitution reaction is linearly dependent on the concentration of
OH⊖ and CH3Br
v Overall, a second-order reaction Þ bimolecular

Ch. 6 - 14
 5A. How Do We Measure the Rate of This Reaction?

e.g.:
H H
HO + C Cl HO C + Cl
H H
(Nu ) H H (leaving
(substrate) (product) group)
v The rate of reaction can be measured by
● The consumption of the reactants
(HO or CH3Cl) or
⊖

● The appearance of the products

Ch. 6 - 15
(CH3OH or Cl ) over time
⊖
 Graphically…

Concentration, M
[CH3Cl] ↓
[CH3OH] ↑

Time, t

Δ[CH3Cl] [CH3Cl]t=t − [CH3Cl]t=0

Rate = =−
Δt Time in seconds
Ch. 6 - 16
 Initial Rate

[CH3Cl]t=0

Concentration, M
[CH3Cl]t=t

[CH3Cl]

Time, t

Initial Rate [CH3Cl]t=t − [CH3Cl]t=0

=−
(from slope) Δt
Ch. 6 - 17
 v Example:

60oC
HO + Cl CH 3 H2O
HO CH 3 + Cl

Initial rate
[OH⊖] t=0 [CH3Cl]t=0 Result
mole L-1, s-1
1.0 M 0.0010 M 4.9 × 10-7

1.0 M 0.0020 M 9.8 × 10-7 Doubled

2.0 M 0.0010 M 9.8 × 10-7 Doubled

2.0 M 0.0020 M 19.6 × 10-7 Quadrupled

Ch. 6 - 18
 v Conclusion:

60oC
HO + Cl CH 3 H2O
HO CH 3 + Cl

● The rate of reaction is directly proportional to the concentration of either

reactant.

● When the concentration of either reactant is doubled, the rate of reaction

doubles.

Ch. 6 - 19
 6. A Mechanism for the SN2 Reaction
H
H -
H
+ - -
d d d d
HO C Br HO C Br HO C
H H
H H
H H
transition state (T.S.)
negative OH ⊖ + Br -
brings an e⊖ pair O–C bond partially
formed; C–Br bond O–C bond
to δ+ C; δ– Br formed; Br⊖
begins to move partially broken.
Configuration of C departed.
away with an e⊖ Configuration
pair begins to invert
of C inverted
Ch. 6 - 20
 8.The Stereochemistry of SN2 Reactions
v Inversion of configuration

CH3
HO + C Br (inversion)
H
CH2CH3
CH3
(R)

HO C + Br
H
(S) CH2CH3
Ch. 6 - 21
 v Example:

Nu⊖ attacks from the TOP face.

CH3 I +
OCH3

(inversion of configuration)

CH3 OCH3
+I
Ch. 6 - 22
 v Example:

Nu⊖ attacks from the BACK face.

+ CN + Br
Br CN
(inversion of
configuration)

Ch. 6 - 23
 9. The Reaction of tert-Butyl Chloride
with Hydroxide Ion: An SN1 Reaction
CH3 CH3
CH3 C Br + H2O CH3 C OH + HBr
CH3 CH3
l The rate of SN1 reactions depends only on
concentration of the alkyl halide and is
independent on concentration of the Nu⊖
Rate = k[RX]
In other words, it is a first-order reaction
Þ unimolecular nucleophilic substitution
Ch. 6 - 24
 9A. Multistep Reactions & the Rate-
Determining Step

l In a multistep reaction, the rate of the overall reaction is the same as the rate of the
SLOWEST step, known as the rate-determining step (r.d.s)
l For example:

k1 << k2 or k3
Ch. 6 - 25
 • The opening A is much
smaller than openings
B and C
• The overall rate at
A which sand reaches to
the bottom of the
hourglass is limited by
B the rate at which sand
falls through opening
C A
• Opening A is
analogous to the rate-
determining step of a
multistep reaction Ch. 6 - 26
 10. A Mechanism for the SN1 Reaction

v A multistep process

Step (1):

CH3 (k 1 ) CH3
CH3 C Br slow
CH3 C + Br
CH3 r.d. step
CH3
(ionization
of alkyl
halide)
Ch. 6 - 27
 Step (2)

CH3 (k 2 ) CH3 H
CH3 C + H2O fast CH3 C O
CH3 CH3 H

Ch. 6 - 28
 Step (2)

CH3 (k 2 ) CH3 H
CH3 C + H2O fast CH3 C O
CH3 CH3 H

Step (3)

CH3 H (k3) CH3

CH3 C O + H2O fast CH3 C OH
CH3 H CH3
Ch. 6 - 29 + H3O+
 Step (2)

CH3 (k 2 ) CH3 H
CH3 C + H2O fast CH3 C O
CH3 CH3 H
k1 << k2 and k3
Step (3)

CH3 H (k3) CH3

CH3 C O + H2O fast CH3 C OH
CH3 H CH3
Ch. 6 - 30 + H3O+
 11. Carbocations
11A. The Structure of Carbocations

• Carbocations are trigonal

planar
• The central carbon atom in
a carbocation is electron
H3C deficient; it has only six e⊖
C CH3 in its valence shell
H3C • The p orbital of a
carbocation contains no
electrons, but it can accept
an electron pair when the
sp2-sp3 p bond carbocation undergoes
further reaction
Ch. 6 - 31
 11B. The Relative Stabilities of
Carbocations

v General order of reactivity (towards SN1 reaction)

● 3o > 2o >> 1o > methyl

v The more stable the carbocation formed, the faster the SN1 reaction

Ch. 6 - 32
 v Stability of cations

most stable (positive inductive effect)

R R R H
> > >
C C C C
R R R H H H H H
v Resonance stabilization of allylic and benzylic cations

CH2 CH2
etc.
Ch. 6 - 33
 12. The Stereochemistry of SN1 Reactions
Ph Ph Ph
CH3OH CH3OH
C CH3 C OCH3
CH3 Br
CH2CH3 CH3 CH2CH3 CH2CH3
(S ) (trigonal planar) (R) and ( S)
racemic mixture

CH 3OH CH3OH
attack from left 50:50 attack from right
chance
Ph Ph

CH3O CH3 CH3 OCH3

CH2CH3 (1 : 1) CH2CH3
Ch. 6 - 34 (R) ( S)
 v Example: racemic mixture
( 1 : 1 )
(R) H2O (R) (S)
+
(SN1)
Br OH OH
(one enantiomer)
attack from H2O
slow TOP face H2O
r.d.s.
H 2O O
H H

H2O attack from O

H H
Ch. 6 - 35
(carbocation) BOTTOM face
 13. Factors Affecting the Rates of
SN1 and SN2 Reactions
v The structure of the substrate

v The concentration and reactivity of the nucleophile (for SN2 reactions only)

v The effect of the solvent

Ch. 6 - 36
 13A. The Effect of the Structure of the Substrate

v General order of reactivity (towards SN2 reaction)

● Methyl > 1o > 2o >> 3o > vinyl or aryl

DO NOT undergo
SN2 reactions

Ch. 6 - 37
 v For example:

R Br + HO R OH + Br
Relative Rate (towards SN2)
CH3 CH3
CH3 Br CH3CH2 Br CH3CH Br CH3 C CH2Br CH3 C Br
CH3 CH3 CH3
o o o
methyl 1 2 neopentyl 3
6 4
2 ´ 10 4 ´ 10 500 1 <1
Most Least
reactive reactive
Ch. 6 - 38
 v Compare

H d +
d - H
HO C Br HO C + Br
faster
H H
H H

H +
d d- H
HO C Br HO C + Br
slower
CH3 CH3
CH3 CH3
Ch. 6 - 39
 H d +
d - H
HO C Br HO C + Br
t very t
Bu Bu
slow
H CH3

CH 3 d +
d- CH3
HO C Br HO C + Br
extremely
CH 3 CH3
slow
CH 3 CH3
Ch. 6 - 40
 v Note NO SN2 reaction on sp2 or sp carbons

e.g. sp2
H I
+ Nu No reaction
H H
sp2
I
+ Nu No reaction
sp

I + Nu No reaction
Ch. 6 - 41
 Reactivity of the Substrate in SN1 Reactions

v General order of reactivity (towards SN1 reaction)

● 3o > 2o >> 1o > methyl

v The more stable the carbocation formed, the faster the SN1 reaction

Ch. 6 - 42
 v Stability of cations

most stable (positive inductive effect)

R R R H
> > >
C C C C
R R R H H H H H

v Allylic halides and benzylic halides also undergo SN1 reactions at reasonable rates

I
Br
Ch. 6 - 43 an allylic bromide a benzylic iodide
 v Resonance stabilization for allylic and benzylic cations

CH2 CH2
etc.

Ch. 6 - 44
 13B. The Effect of the Concentration
& Strength of the Nucleophile

v For SN1 reaction

Recall: Rate = k[RX]
● The Nu⊖ does NOT participate in the r.d.s.
● Rate of SN1 reactions are NOT affected by either the concentration or the
identity of the Nu⊖

Ch. 6 - 45
 v For SN2 reaction
Recall: Rate = k[RX][Nu]
● The rate of SN2 reactions depends on both the concentration and the identity
of the attacking Nu⊖

Ch. 6 - 46
 v Identity of the Nu⊖
● The relative strength of a Nu⊖ (its nucleophilicity) is measured in terms of the
relative rate of its SN2 reaction with a given substrate

rapid

CH3O + CH3I CH3OCH3 + I

Good Nu
⊖
Very
slow
CH 3OH + CH 3I CH 3OCH 3 + I
Poor Nu
⊖
Ch. 6 - 47
 v The relative strength of a Nu⊖ can be correlated with 3 structural features

● A negatively charged Nu⊖ is always a more

reactive Nu⊖ than its conjugated acid
t e.g. HO⊖ is a better Nu⊖ than H2O and
RO⊖ is better than ROH
● In a group of Nu⊖s in which the
nucleophilic atom is the same,
nucleophilicities parallel basicities
t e.g. for O compounds,
RO⊖ > HO⊖ >> RCO2⊖ > ROH > H2O

Ch. 6 - 48
 ● When the nucleophilic atoms are different, then nucleophilicities may not
parallel basicities
t e.g. in protic solvents HS⊖, CN⊖, and I⊖ are all weaker bases than HO⊖,
yet they are stronger Nu⊖s than HO⊖
HS⊖ > CN⊖ > I⊖ > HO⊖

Ch. 6 - 49
 13C. Solvent Effects on SN2 Reactions:
Polar Protic & Aprotic Solvents

v Classification of solvents

Non-polar solvents
(e.g. hexane, benzene)

Solvents Polar protic solvents

(e.g. H2O, MeOH)
Polar
solvents
Polar aprotic solvents
(e.g. DMSO, HMPA)
Ch. 6 - 50
 v SN2 Reactions in Polar Aprotic Solvents
● The best solvents for SN2 reactions are
t Polar aprotic solvents, which have strong dipoles but do not have OH or
NH groups
t Examples

O
CH3 O
O
H N P NMe
S Me2N NMe2 2
CH3 CH3 CH3 CH3CN
(DMSO) (DMF) (HMPA) (Acetonitrile)
Ch. 6 - 51
 t Polar aprotic solvents tend to solvate metal cations rather than
nucleophilic anions, and this results in “naked” anions of the Nu⊖ and
makes the e⊖ pair of the Nu⊖ more available

DMSO
CH3O Na CH3O + DMSO Na
"naked anion"

Ch. 6 - 52
 t Tremendous acceleration in SN2 reactions with polar aprotic solvent

CH3Br + NaI CH3I + NaBr

Solvent Relative Rate

MeOH 1

DMF 106

Ch. 6 - 53
 v SN2 Reactions in Polar Protic Solvents
● In polar protic solvents, the Nu⊖ anion is solvated by the surrounding protic
solvent which makes the e⊖ pair of the Nu⊖ less available and thus less
reactive in SN2 reactions

OR
H
RO H Nu H OR
H
Ch. 6 - 54
OR
 v Halide Nucleophilicity in Protic Solvents
● I⊖ > Br⊖ > Cl⊖ > F⊖

+ + OR OR
RO d d H
H H
d+ - d+ -
RO H F H OR RO H I
+ +
d d
H H
RO OR H
OR
(strongly solvated) (weakly solvated)
F Thus, I⊖ is a stronger Nu⊖ in protic solvents,
as its e⊖ pair is more available to attack the
substrate in the SN2 reaction.
Ch. 6 - 55
 v Halide Nucleophilicity in Polar Aprotic Solvents (e.g. in DMSO)
● F⊖ > Cl⊖ > Br⊖ > I⊖

t Polar aprotic solvents do not solvate

anions but solvate the cations

t The “naked” anions act as the Nu⊖

t Since F⊖ is smaller in size and the

charge per surface area is larger than I⊖,
the nucleophilicity of F⊖ in this
environment is greater than I⊖

Ch. 6 - 56
 13D. Solvent Effects on SN1 Reactions:
The Ionizing Ability of the Solvent
v Solvent plays an important role in SN1 reactions, but the reasons are different from
those in SN2 reactions

v Solvent effects in SN1 reactions are due largely to stabilization or destabilization of the
transition state

Ch. 6 - 57
 • Polar protic solvents stabilize the development of the
polar transition state and thus accelerate this rate-
determining step (r.d.s.):

d+ OR
H
CH3 H3C + -
slow d d
CH3 C Cl CH3 C Cl
r.d.s.
CH3 d- CH3 d+
R O H
H OR
CH2
-
Cl + CH3 C
Ch. 6 - 58 CH3
 14. Organic Synthesis: Functional Group
Transformation Using SN2 Reactions

OH

CN CN HO Me

MeO
Br
MeS
HS

Ch. 6 - 59
SMe SH
 Me

I Me C C O Me
I
MeCOO
Br

N3
Me3N

N3 NMe3 Br
Ch. 6 - 60
 • Examples:

NaOEt, DMSO
??
Br O

I NaSMe, DMSO
SMe
??

Ch. 6 - 61
 • Examples:
??

I CN
(optically active, chiral) (optically active, chiral)

● Need SN2 reactions to control

stereochemistry
● But SN2 reactions give the inversion of
configurations, so how do you get the
“retention” of configuration here??
● Solution:
“double inversion” Þ “retention”
Ch. 6 - 62
 ??

I CN
(optically active, chiral) (optically active, chiral)

NaBr NaCN
DMSO DMSO
(SN2 with Br (SN2 with
inversion) inversion)
(Note: Br⊖ is a stronger Nu than
I⊖ in polar aprotic solvent.)

Ch. 6 - 63
 15. Elimination Reactions of Alkyl
Halides
v Substitution

H OCH 3 H OCH 3
-
C C C C + Br
(acts as a
Br Nu )
v Elimination

H OCH3 -
C C (acts as a C C + CH3OH + Br
H
Ch. 6 - 64
Br base)
 • Substitution reaction (SN) and elimination reaction (E)
are processes in competition with each other

e.g.
t
BuOK t
I O Bu +
t
BuOH
SN2: 15% E2: 85%

Ch. 6 - 65
 15A. Dehydrohalogenation

β hydrogen
H α carbon
C C
β carbon
X halide as LG

Br
LG t
BuOK t
β α t o + KBr + BuOH
BuOH, 60 C
H
β hydrogen
⊖OtBu
Ch. 6 - 66
 15B. Bases Used in Dehydrohalogenation
• Conjugate base of alcohols is often used as the base in
dehydrohalogenations

Na
R−O⊖ + Na⊕ + H2

R−O−H
NaH
R−O⊖ + Na⊕ + H2

e.g.
t
EtO Na BuO K
Ch. 6 - 67 sodium ethoxide potassium tert-butoxide
 16. The E2 Reaction
Br
EtO + + EtOH + Br
H
v Rate = k[CH3CHBrCH3][EtO⊖]

v Rate determining step involves both the alkyl halide and the alkoxide anion

v A bimolecular reaction

Ch. 6 - 68
 Mechanism for an E2 Reaction

Et O Et O
H CH3 H CH3
α d- H CH3
Cβ C H C C H C C
H H d- H H
H Br H Br +

EtO⊖ removes a Et OH + Br
Partial bonds in
b proton; C−H the transition C=C is fully
breaks; new p state: C−H and formed and the
bond forms and C−Br bonds break, other products
Br begins to new p C−C bond are EtOH and
depart forms Br⊖
Ch. 6 - 69
 17. The E1 Reaction
• E1: Unimolecular elimination

CH3 CH3 CH
H2O 3
CH3 C Cl CH3 C OH + CH2 C
CH3 CH3 CH3
slow (major (SN1)) (minor (E1))
r.d.s
CH3 H2O as H2O as
CH C nucleophile base
3
Ch. 6 - 70
CH3
 Mechanism of an E1 Reaction

α carbon
β hydrogen
H
H2O H2O
Cl + H3O
slow fast
r.d.s. (E1 product)
fast H2O

H HO
2
O OH + H3O
H
Ch. 6 - 71 (SN1 product)
 Step (1):

CH3 H 2O CH3
CH3 C Cl CH3 C + Cl
(k 1 )
CH3 slow
CH3
r.d. step
Aided by the polar Produces relatively
solvent, a chlorine stable 3o carbocation
departs with the and a Cl⊖. The ions
e⊖ pair that are solvated (and
bonded it to the stabilized) by
carbon surrounding H2O
molecules
Ch. 6 - 72
 Step (2)
H 3C H H 3C
(k 2)
C C H + H 2O fast CH2
H 3C H H 3C
H
H2O molecule removes one of
the b hydrogens which are + H O
acidic due to the adjacent H
positive charge. An e⊖ pair
moves in to form a double bond Produces alkene and
between the b and a carbon hydronium ion
atoms
Ch. 6 - 73
 18. How To Determine Whether
Substitution or Elimination Is Favoured
v All nucleophiles are potential bases and all bases are potential nucleophiles

v Substitution reactions are always in competition with elimination reactions

v Different factors can affect which type of reaction is favoured

Ch. 6 - 74
 18A. SN2 vs. E2

(a) H C
+X
(b) SN 2 Nu C
H C
Nu
C X
(a) (b) C
+ Nu H + X
E2 C

Ch. 6 - 75
 Primary Substrate

• With a strong base, e.g. EtO⊖

• Favor SN2

OEt
SN2: 90%
NaOEt
Br EtOH +

E2: (10%)
Ch. 6 - 76
 Secondary Substrate

• With a strong base, e.g. EtO⊖

• Favor E2
+

E2: 80%
NaOEt
+
Br EtOH

OEt
Ch. 6 - 77
SN2: 20%
 Tertiary Substrate

• With a strong base, e.g. EtO⊖

• E2 is highly favored

NaOEt
+
EtOH
Br OEt
E2: 91% SN1: 9%

Ch. 6 - 78
 Base/Nu⊖: Small vs. Bulky

• Unhindered “small” base/Nu⊖

NaOMe +
Br MeOH OMe
SN2: 99% E2: 1%

v Hindered “bulky” base/Nu⊖

t
KO Bu +
t
Br t O Bu
BuOH SN2: 15% E2: 85%
Ch. 6 - 79
 Basicity vs. Polarizability

O
O
O CH3
CH3 C O
+
(weak base)
Br SN2: 100% E2: 0%

OEt
EtO +
(strong base)
SN2: 20% E2: 80%
Ch. 6 - 80
 Tertiary Halides: SN1 vs. E1 & E2

EtO OEt
+
(strong
base) E2: 99% SN1: 1%
Br

EtOH OEt
+
heat
E1 + E2: 20% SN1: 80%
Ch. 6 - 81
 Review Problems

(1) Br
Na CN CN
t DMF, 25oC
Bu t
SN2 with inversion Bu

(2)
O
H NaH
I O Et2O

H⊖

I O
Ch. 6 - 82 Intramolecular SN2
 (3) CH3 CH3 Cl
OH HCl Cl CH3
+
t t t
Bu Bu Bu
( 50 : 50)

Cl⊖ attacks Cl⊖ attacks

from top face from bottom
CH3 face
H CH3
O
H
t t
Bu Bu sp2 hybridized
carbocation
SN1 with racemization
Ch. 6 - 83
 5. Synthesis of Alkenes via
Elimination Reactions
v Dehydrohalogenation of Alkyl Halides

H
H H H H
base
C C
H -HX
X H H
H

Ch. 7 - 84
 6. Dehydrohalogenation of Alkyl
Halides
v The best reaction conditions to use when synthesizing an alkene by
dehydrohalogenation are those that promote an E2 mechanism

H
E2
B: C C C C + B:H + X
X
Ch. 7 - 85
 6A. How to Favor an E2 Mechanism

v Use a secondary or tertiary alkyl halide if possible. (Because steric hinderance in the
substrate will inhibit substitution)
v When a synthesis must begin with a primary alkyl halide, use a bulky base. (Because
the steric bulk of the base will inhibit substitution)

Ch. 7 - 86
 v Use a high concentration of a strong and non-polarizable base, such as an alkoxide.
(Because a weak and polarizable base would not drive the reaction toward a
bimolecular reaction, thereby allowing unimolecular processes (such as SN1 or E1
reactions) to compete.

Ch. 7 - 87
 v Sodium ethoxide in ethanol (EtONa/EtOH) and potassium tert-butoxide in tertbutyl
alcohol (t-BuOK/t-BuOH) are bases typically used to promote E2 reactions

v Use elevated temperature because heat generally favors elimination over

substitution. (Because elimination reactions are entropically favored over substitution
reactions)

Ch. 7 - 88
 6B. Zaitsev’s Rule

v Examples of dehydrohalogenations where only a single elimination product is possible

EtONa
(1) o
(79%)
Br EtOH, 55 C

EtONa
(2) o
(91%)
Br EtOH, 55 C

t -BuOK
(3) ( )
Br ( ) (85%)
Ch. 7 - 89 n t -BuOH, 40 C o n
 v Rate = H
k H3C C CH3 EtO
Br (2nd order overall)
Þ bimolecular
a
̶ H

B Ha Hb
2-methyl-2-butene

Br
b
̶ H

2-methyl-1-butene
Ch. 7 - 90
 ⊖ ⊖
v When a small base is used (e.g. EtO or HO ) the major product will be the more
highly substituted alkene (the more stable alkene)
v Examples:

Ha Hb NaOEt
(1) +
EtOH
70oC
Br 69% 31%
(eliminate Ha) (eliminate Hb)
Br KOEt
(2) + +
EtOH
51% 18% 31%

Ch. 7 - 91 69%
 v Zaitsev’s Rule
● In elimination reactions, the more highly substituted alkene product
predominates
v Stability of alkenes

Me Me Me Me Me H
C C > C C > C C
Me Me Me H H Me

Me Me Me H
> C C > C C
Ch. 7 - 92 H H H H
 6C. Forma`on of the Less Subs`tuted
Alkene Using a Bulky Base

v Hofmann’s Rule
● Most eliminafon reacfons follow Zaitsev’s rule in which the most stable
alkenes are the major products. However, under some circumstances, the
major eliminafon product is the less subsftuted, less stable alkene

Ch. 7 - 93
 ● Case 1: using a bulky base

EtO CH3CH CHCH3 (80%)

+
(small) CH3CH2CH CH2 (20%)

CH3CH2CHCH3
Br t CH3CH CHCH3 (30%)
BuO
+
(bulky) CH3CH2CH CH2 (70%)
⊖
EtO
(small base)
H H H H tBuO⊖

H C C C C H (bulky base)
Ch. 7 - 94 H H Br H
 ● Case 2: with a bulky group next
to the leaving halide

less crowded β-H

Me H Br H Me H
EtO
H3C C C C C H H3C C C C CH2
Me H Me H Me H Me

(mainly)
more crowded β-H

Ch. 7 - 95
 v Zaitsev Rule vs. Hofmann Rule

● Examples

Ha Hb
(1) +

Br
(eliminate Ha) (eliminate Hb)
NaOEt, EtOH, 70oC 69% 31%

KOtBu, tBuOH, 75oC 28% 72%

Ch. 7 - 96
 ● Examples

Hb Br
Ha
(2) +

(eliminate Ha) (eliminate Hb)

NaOEt, EtOH, 70oC 91% 9%

KOtBu, tBuOH, 75oC 7% 93%

Ch. 7 - 97
 10. Synthesis of Alkynes by
Elimination Reactions
v Synthesis of Alkynes by Dehydrohalogenafon of Vicinal Dihalides

H H
NaNH2
C C C C
heat
Br Br

Ch. 7 - 98
 v Mechanism

H
H H
NH2
R
R C C R R
E2
Br Br Br

NH2

R R

Ch. 7 - 99
 v Examples

Br
H NaNH2
(1)
heat
H Br (78%)

Br H
Ph Br2 Ph
(2)
Ph CCl4 Ph NaNH2
H Br
heat

Ph Ph

Ch. 7 - 100
 v Synthesis of Alkynes by Dehydrohalogenation of Geminal Dihalides

O PCl5 Cl Cl

R CH3 0oC R CH3

gem-dichloride

1. NaNH2 (3 equiv.), heat

2. HA

Ph H
Ch. 7 - 101
 Addition Reactions of Alkyl Halides

Ch. 6 - 102
 1A. How To Understand Additions
to Alkenes
v This is an addition reaction: E–Nu added across the double bond

E
C C + E Nu C C
Nu
p-bond s-bond 2 s-bonds

Bonds broken Bonds formed

Ch. 8 - 103
 v Since pi bonds are formed from the overlapping of p orbitals, p electron clouds are
above and below the plane of the double bond

p electron clouds

C C

Ch. 8 - 104
 v Electrophilic
● electron seeking
● C=C and C≡C p bonds are particularly susceptible to electrophilic reagents
(electrophiles)

v Common electrophile
● H+, X+ (X = Cl, Br, I), Hg2+, etc.

Ch. 8 - 105
 v In an electrophilic addition, the p electrons seek an electrophile, breaking the p bond,
forming a s bond and leaving a positive charge on the vacant p orbital on the
adjacent carbon. Addition of B– to form a s bond provides an addition product

Ch. 8 - 106
 + -
d d
E Nu E
C C C C + Nu

Nu E
C C

Ch. 8 - 107
 2. Electrophilic Addition of
Hydrogen Halides to Alkenes:
Mechanism and Markovnikov’s
Rule
v Mechanism

d+ d- A Nu E
E Nu Nu
C C C C C C

Ch. 8 - 108
 v Mechanism
● Sometimes do not go through a “free carbocation”, may go via

C C

Ch. 8 - 109
 v Markovnikov’s Rule
● For symmetrical substrates, no problem for regiochemistry

H H E E
E Nu same
C C H C C H as H C C H
H H H H H H

Nu

E Nu Nu E
same
H C C H as H C C H

Ch. 8 - 110
H H H H
 v Markovnikov’s Rule
● But for unsymmetrical substrates, two regioisomers are possible

H3C H E E
E Nu
C C CH3 C C H or CH3 C C H
H H H H H H

Nu Nu

E Nu different Nu E
CH3 C C H from CH3 C C H
H H H H
Ch. 8 - 111
 v Markovnikov’s Rule
● In the electrophilic addition of an unsymmetrical electrophile across a double
bond of an alkene, the more highly substituted and more stabilized
carbocation is formed as the intermediate in preference to the less highly
substituted and less stable one

Ch. 8 - 112
 v Markovnikov’s Rule
● Thus

+
d d- E Nu E
E Nu

E
NOT

o o o
Note: carbocation stability Þ 3 > 2 > 1

Ch. 8 - 113
 v Addifon of Hydrogen Halides
● Addifon of HCl, HBr and HI across a C=C bond
● H+ is the electrophile

+ - Br
d d slow Br
+ H Br
r.d.s fast

Br
NO

Ch. 8 - 114
 2A. Theoretical Explanation of
Markovnikov’s Rule

d+ d-
H3C H H H
H X
C C CH3 C C H or CH3 C C H
step 1
H H H H H H
(slow
r.d.s.) 2o carbocation 1o carbocation
(more stable) (more stable)
v One way to state Markovnikov’s rule is to say
that in the addition of HX to an alkene, the
hydrogen atom adds to the carbon atom of the
double bond that already has the greater
Ch. 8 - 115 number of hydrogen atoms
 H H

☓
Br

(1o cation) fast Br

(minor)
H Br
slow
(r.d.s.)
H H
Br

(2o cation) fast

Br
(major)

Step 1 Step 2
Ch. 8 - 116
 v Examples

Cl H
H Cl
(1) +
H Cl

(95 : 5)

H Br
H Br
(2) +

Br H
(98 : 2)
Ch. 8 - 117
 2C. Regioselective Reactions
v When a reaction that can potentially yield two
or more constitutional isomers actually
produces only one (or a predominance of one),
the reaction is said to be regioselective

Cl H
H Cl
+
H Cl
(major) (minor)

regioisomers
Ch. 8 - 118
Regioselectivity: 95 : 5
 2D. An Exception to Markovnikov’s Rule
Br
H Br (anti-Markovnikov's
RO OR product)
heat H

v Via a radical mechanism

v This anti-Markovnikov addition does not take

place with HI, HCl, and HF, even when peroxides
are present
Ch. 8 - 119
 3. Stereochemistry of the Ionic
AddiSon to an Alkene
X
attack from top X
H C CH3
Bu
(S)-2-Halohexane

racemate
H H
H X H (50%)
C C C CH2 H
Bu
Bu H
achiral
trigonal planar H
carbocation Bu C CH3
X X
attack from bottom (R)-2-Halohexane
Ch. 8 - 120
(50%)
 12. Electrophilic Addition of Bromine
and Chlorine to Alkenes

v Addifon of X–X (X = Cl, Br) across a C=C bond

Br
Br2
C C C C
CCl4
Br
(vicinal
dibromide)

Ch. 8 - 121
 12A. Mechanism of Halogen Addition

C C + Br Br C C
Br–Br bond becomes
polarized when close d+ Br
to alkene
d- Br

Br
+ Br
Br Br
(vincinal
Ch. 8 - 122 Dibromide) (bromonium)
 18. Electrophilic Addition of
Bromine & Chlorine to Alkynes
X X
X2 (excess)
R C C H R C C H
CH2Cl2
(X = Cl, Br, I) X X

X H X X
X2 X2
R C C H C C R C C H
H X X X
Ch. 8 - 123 (anti-addition)
 19. AddiSon of Hydrogen Halides
to Alkynes
X H
H X (excess)
R C C H R C C H
(X = Cl, Br, I)
X H
v Regioselectivity
● Follow Markovnikov’s rule

Br H Br H
HBr HBr
H3C C C H C C CH3 C C H
CH3 H Br H
gem-dibromide
Ch. 8 - 124
 v Mechanism

H
H Br Br
CH3 C C H CH3 C C
H
Br H
C C
CH3 H

Br H H
Br Br H Br
CH3 C C H C C H
CH3
Br H H
Ch. 8 - 125
 v Anti-Markovnikov addition of hydrogen bromide to alkynes occurs when peroxides are
present in the reaction mixture

H Br
Br
peroxides
H

(E) and (Z)

(74%)

Ch. 8 - 126