HOFMANN REACTION

E2 gone astray
 HOFMANN RULE
When you have a bulky leaving group like
-N(CH3)3+ the least-substituted alkene will
be the major product.
Big is not
BULKY = Branched at the first atom the same
attached to the chain as bulky.

chain chain

+ +
H3 C N CH 3 H3 C S CH3
trimethyl CH3 dimethyl
ammonium sulfonium

OTHER GROUPS FOLLOW THE ZAITSEV RULE

 HOFMANN ELIMINATION
Hofmann found that when the leaving group was -N(CH3)3+
E2 elimination reactions gave the least-substituted alkene.

Hofmann
KOH
CH3 CH2 CH CH3 CH3 CH2 CH CH2 95%
+  EtOH
H3 C N CH3 +
CH3 CH3 CH CH CH3 5%

Zaitsev
KOH
CH3 CH2 CH CH3 CH3 CH2 CH CH2 31%
 EtOH
Br +
CH3 CH CH CH3 69%
EFFECT OF INCREASING SUBSTITUENT BULK
KOH
CH3 CH2 CH2 CHCH3
 EtOH
E2 X
HOFMANN ZAITSEV (cis + trans)
X CH3 CH2 CH2 CH CH2 CH3 CH2 CH CHCH 3

Br 31% 69%
I 30% 70%
O
O S CH3 48% 52%
O Big is not
CH3 the same
+ 87% 13% as bulky.
S
CH3

CH3
+
N CH3 98% 2%
CH3
ANALYSIS OF 2-SUBSTITUTED PENTANE ELIMINATIONS

ZAITSEV less crowding in

cis this area of the
molecule
trans H
C C C C CH 3
H X

bulky groups HOFMANN

cause crowding ( all H equivalent )
and give Hofmann
products
 H
most steric
H CH3 crowding
less steric
crowding
H
H CH2CH3 no steric
H CH3
crowding
N(CH3)3
H
CH3CH2 H
H CH2CH2CH3
N(CH3)3

H H

N(CH3)3

WOULD MAKE WOULD MAKE

cis ZAITSEV trans
PRODUCTS HOFMANN
FORMED
NOT FORMED PRODUCT
 BULKY BASES ALSO INCREASE HOFMANN PRODUCT

H ZAITSEV HOFMANN
H3 C CH2 C CH3 H3 C CH CH CH 3 CH 3 CH 2 CH CH 2
Br

CH 3 O
-
methoxide 81% 19%
CH3
H3 C C O
-
t -butoxide 47% 53%
CH3

bulky
base
 BULKY -SUBSTITUENTS What constitutes bulky?

a methyl group
ZAITSEV HOFMANN
  is not bulky
NO CH3 CH 3 CH 3
NaOEt
H3 C CH2 C CH 3 H3 C CH C CH3 CH3 CH2 C CH2
Br
even two or three 80% 20%
 are not bulky
NO CH3 CH3 CH3
NaOEt
H3 C CH C CH3 H3 C C C CH 3 H3 C CH C CH 2
CH3 Br CH3 CH3
YES 79% 21%
CH3 CH 3 CH3 CH3 CH 3 CH3
NaOEt
H3 C C CH2 C CH3 H3 C C CH C CH 3 H3 C C CH2 C CH2
CH3 Br CH3 CH 3

14% 86%

t-butyl is bulky !
 THE ELIMINATION MOVES TO A LESS CROWDED REGION

less
crowded
crowded crowding
H3 C CH3
CH3 CH3 H3 C
C CH3
H3 C C CH2 C CH3 H3 C + CH3 CH2
CH3 Br H CH3 H3 C C CH2
CH3
14% 86%
REACTIVE CONFORMATIONS CH3
CH3 C CH3
H H
CH3 CH3 crowding CH2 CH3
CH3
spacer
H C H H
CH3
Br CH3 Br
EXAMPLES
 HOW THE VARIOUS FACTORS AFFECT THE OUTCOME

CH3
NORMAL CH3
NaOEt Zaitsev
Br
EtOH /  ~90%
Bromine is big, not bulky
BULKY
LEAVING CH3 CH2
GROUP Hofmann
KOH
+ ~90%
N(CH3)3 EtOH / 
-
I
Prototypical “Hofmann” elimination
BULKY CH3
BASE CH2 CH3
NaOtBu
Br +
tBuOH / 

Bulky base alone not as

effective as bulky leaving group
~60/40%
 HOW THE VARIOUS FACTORS AFFECT THE OUTCOME
( CONTINUED )

BULKY BASE
& LEAVING CH3 CH2
GROUP NaOtBu Hofmann
+
N(CH3)3 tBuOH /  ~100%
-
I Double Whammy !
Bulky base + bulky leaving group
BULKY
-SUBSTITUENT
CH3
CH3 CH2
Br NaOEt
+
EtOH / 
tBu tBu tBu
H no double
bond here
either cis or trans
Favors Hofmann products
to Br - same result
Use a bulky base here and ...
E2 REACTIONS DEVIATE FROM THE ZAITSEV RULE

1. If the favored -hydrogen can’t achieve

anti-coplanar geometry.

2. If the double bond would form at a bridgehead.

(see next slides)
3. If there is a bulky leaving group.

4. If there is a bulky base.

5. If there is a bulky -substituent.

 BREDT’S RULE

A double bond cannot form at a bridgehead.

 BREDT’S RULE
A double bond cannot form at a bridgehead in a
bicyclic system with small rings.

no way !

Cl

p orbitals cannot
become coplanar

y y Try a model !

z
 SYN ELIMINATION

More difficult than anti-coplanar elimination,

but does occur in some circumstances.

( Usually requires forced conditions

- heat and pressure. )
COPLANAR ARRANGEMENTS
E2
H
~ ~ ~
~ ~ ~ not coplanar
( very difficult )
180o C C other
angles
anti-coplanar
BEST SITUATION syn-
X coplanar
(difficult)

H X syn- 0o
coplanar
SECOND-BEST anti-
SITUATION coplanar
C C 0o (easiest)

Difficulty Order 180o

SYN-COPLANAR ELIMINATIONS
REQUIRE FORCED CONDITIONS

H X syn-coplanar (0o)

C C
C C

This often requires heating above the boiling point

of the solvent in a sealed tube (next slide).

Temperatures above 100 oC are common.

 SEALED TUBE
Glass tube sealed at both ends.
glass
tube
1.25” D alkyl halide +
0.25” wall NaOEt / EtOH (bp 78 oC) REACTANTS
inside tube

Carried out in a hood

behind a glass shield.

Allows reactants
heated oil to be heated to a
(bp > 250 oC) high temperature
(above bp) without
boiling away.
hot plate
 A CASE OF SYN ELIMINATION
SYN ELIMINATION OCCURS BECAUSE
THERE ARE NO ANTI-COPLANAR -H
Bredt’s
Rule
H NaOEt H
Br EtOH +
H 110 oC
H
H 100% H 0% H

D NaOEt
same products
Br EtOH
D
NO DEUTERIUM
110 Co
H
H
H not this one
proves the syn hydrogen H
is the one removed
 SYN ELIMINATION IS SEEN WHEN ANTI-COPLANAR DOES NOT EXIST

not H
coplanar H Cl hydrogens
are not
Cl NaOH anti-coplanar
H Cl
110o to chlorines
very slow

difficult
reaction
H H
coplanar
Cl
Cl
H NaOH Cl
110o

faster syn-
elimination
 -ELIMINATION

C
occurs when the substrate has
NO -HYDROGENS C C H
on these carbon atoms
X
  -ELIMINATION
Cl Cl
KOH -
Cl C H CHCl3
Cl C :
Cl Cl
no  -hydrogens

-elimination

very
reactive Cl
..
Cl C : + : Cl
.. :
a carbene
CARBENES ARE ELECTROPHILES !
Because of an incomplete octet carbenes are
electrophilic (need electrons to complete their
valence shell).
Cl missing a pair
of electrons
Cl C :

Carbenes will react with an alkene (electron pair donor).

Cl
Cl C : : nucleophile
electrophile
CARBENES ADD TO DOUBLE BONDS
CHCl3 alkene + carbene =
cyclopropane ring
KOH
2 H
Cl Cl
+ : C Cl
Cl
1 H
syn addition
Probably
concerted : steps 1,2 for visualization only
ANALYSIS OF THE ADDITION
2p

H
: C SP2 hybrid
..
H

stepwise analysis of the concerted process syn addition

Cl Cl
: C Cl + .. - Cl
Cl
Cl
the intermediate does not exist
 SYN ADDITION

H CHCl3 H BOTH NEW RING

KOH Cl BONDS FORM ON
THE SAME SIDE
EtOH Cl OF THE DOUBLE
H H
BOND

H
Stereospecific
H C
Cl
Cl
 STEREOSPECIFICITY PROVES
THE REACTION IS CONCERTED

CHCl3 SUBSTITUENTS
H CH3 H CH3 ON THE DOUBLE
KOH Cl
cis cis BOND RETAIN
EtOH Cl THEIR ORIGINAL
H CH3 H CH3 CIS OR TRANS
RELATIONSHIPS
IN THE NEW RING

H CH3 CHCl3 H CH3

KOH Cl
trans trans
EtOH Cl
H3C H H3C H
 STEREOSPECIFIC = CONCERTED

YES ! H Concerted.

H Both bonds form on the

CH3 same side.
CH3 C Stereospecific!
Cl
Cl

H
NO ! An intermediate
H would allow rotation.
+ CH3
.. This does not happen.
CH3 C
Cl Would not be stereospecific.
Cl
COMPOUNDS WITHOUT -HYDROGENS
Not a common type of compound !

Ph Ph
Ph C H H C H
Cl Cl

Cl Cl
Cl C H H C H
Cl Cl
ELIMINATIONS SUMMARY
 K.I.S.S. THE MOST BASIC STUFF

alkyl halide + strong base + heat = E2

alkyl halide + solvent + heat (solvolysis) = E1

alcohol + strong acid + heat = E1 (acid assisted)

O X
typical situation for E1cb
C C C
H next to C=O (easy to remove)
H X = strong base (difficult to break bond)

Only E1 reactions have rearrangements (carbocations)

Only E2 reactions require anti-coplanar -hydrogens

 THE BIG PICTURE
special alkyl halides alcohols

E1cb E2 E1 E1 E1 acid
assisted

strong strong weak acidic

neutral
base base base

stepwise - concerted stepwise - carbocation

carbanion
stereospecific
anti-coplanar “solvolysis”
special case -
not common Zaitsev if not stereospecific
stereochem
requires:
allows
acidic H and Zaitsev Zaitsev Zaitsev
poor leaving Hofmann if
bulky groups
group

-elim. if no -H carbocation rearrangements