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.

BULKY =
chain

Branched at the first atom attached to the chain

chain

Big is not the same as bulky.

H3C N CH3
trimethyl ammonium

H3C S CH3
dimethyl sulfonium

CH3

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
CH3 CH2 CH CH3 + H3C N CH3 CH3
KOH

EtOH

CH3CH2 CH CH2 + CH3 CH CH CH3

95%

5%

Zaitsev
CH3 CH2 CH CH3 Br
KOH

EtOH

CH3CH2 CH CH2 + CH3 CH CH CH3

31%
69%

EFFECT OF INCREASING SUBSTITUENT BULK

E2

CH 3CH 2CH 2CHCH3 X X Br I O

KOH

EtOH

HOFMANN
CH3CH2CH 2CH CH2

ZAITSEV (cis + trans)

CH3CH2CH CHCH3

31% 30%
CH3

69% 70% 52% 13%

Big is not the same as bulky.

O S O CH3 + S CH3

48% 87%

CH3 + N CH3 CH3

98%

2%

ANALYSIS OF 2-SUBSTITUTED PENTANE ELIMINATIONS

ZAITSEV

cis trans

less crowding in this area of the molecule

C C C C C H3

H X
bulky groups cause crowding and give Hofmann products

( all H equivalent )

HOFMANN

H H CH3

most steric crowding H H less steric crowding CH3 H CH3CH2 H H CH2CH2CH3 no steric crowding

CH2CH3 N(CH3)3

N(CH3)3
H H N(CH3)3
WOULD MAKE WOULD MAKE

cis

ZAITSEV PRODUCTS NOT FORMED

trans

HOFMANN PRODUCT

FORMED

BULKY BASES ALSO INCREASE HOFMANN PRODUCT

H H3C CH2 C CH3 Br

ZAITSEV
H3C CH CH CH3

HOFMANN
CH3CH2 CH CH2

methoxide

CH3 O CH3

81% 47%

19% 53%

t -butoxide

H 3C C O CH3

bulky base

BULKY b-SUBSTITUENTS
NO

What constitutes bulky?

b a
CH3 Br

a methyl group is not bulky

NaOEt

ZAITSEV
CH3

HOFMANN
CH3 CH3CH2 C CH2

H3C CH2 C CH3

H3C CH

C CH3

NO

b
CH3 H3C CH CH3 Br

even two or three are not bulky

NaOEt

80%
CH3

20%
CH3 H3C CH CH3 C CH2

C CH3

H 3C C CH3

C CH3

YES
CH3 H3C C CH3 CH3 CH2 C CH3 Br
NaOEt

79%
CH3 H3C C CH CH3 CH3 C CH3 CH3 H3C C CH2 CH3

21%
CH3 C CH2

b
t-butyl is bulky !

14%

86%

THE ELIMINATION MOVES TO A LESS CROWDED REGION

crowded less crowded

crowding

CH3 H3C C CH3

CH3 CH2 C CH3 Br

H3C H3C C H

CH3

CH3 + CH3

H3C CH3 H3C C CH2 CH3 CH2

14%
REACTIVE CONFORMATIONS

86%

CH3
CH3 C CH2
spacer

H CH3 CH3 crowding

CH3

H
CH3

CH3
H C Br CH3 CH3

H
Br

EXAMPLES

HOW THE VARIOUS FACTORS AFFECT THE OUTCOME

NORMAL

CH3 Br NaOEt EtOH /

Bromine is big, not bulky

CH3

Zaitsev

~90%

BULKY LEAVING GROUP

CH3
+ N(CH3)3 I KOH

CH2

Hofmann
~90%

EtOH /
Prototypical Hofmann elimination

BULKY BASE

CH3 NaOtBu Br tBuOH /

CH2 + ~60/40%

CH3

Bulky base alone not as effective as bulky leaving group

HOW THE VARIOUS FACTORS AFFECT THE OUTCOME

( CONTINUED )
BULKY BASE & LEAVING GROUP

CH3

+ N(CH3)3 tBuOH / I
BULKY b-SUBSTITUENT

NaOtBu

CH2

Hofmann

~100%
Double Whammy ! Bulky base + bulky leaving group

CH3
Br tBu H
either cis or trans to Br - same result

NaOEt EtOH /

CH3 + tBu

CH2

tBu

no double bond here Favors Hofmann products Use a bulky base here and ...

E2 REACTIONS DEVIATE FROM THE ZAITSEV RULE

1. If the favored b-hydrogen cant 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 b-substituent.

BREDTS RULE
A double bond cannot form at a bridgehead.

BREDTS RULE
A double bond cannot form at a bridgehead in a bicyclic system with small rings. no way !

Cl
z

p orbitals cannot become coplanar

y y z Try a model !

SYN ELIMINATION
More difficult than anti-coplanar elimination, but does occur in some circumstances. ( Usually requires forced conditions - heat and pressure. )

COPLANAR ARRANGEMENTS

E2
~ ~ ~ ~ ~ ~
not coplanar
( very difficult ) other angles

180o

anti-coplanar
BEST SITUATION

syncoplanar
(difficult)

H
C

X
C

syncoplanar
SECOND-BEST SITUATION

0o

anticoplanar
(easiest)

0o

Difficulty Order

180o

SYN-COPLANAR ELIMINATIONS REQUIRE FORCED CONDITIONS

H
C

X
C

syn-coplanar (0o)

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 0.25 wall alkyl halide + NaOEt / EtOH (bp 78 oC) inside tube

REACTANTS

Carried out in a hood behind a glass shield. Allows reactants to be heated to a high temperature (above bp) without boiling away.

heated oil (bp > 250 oC) hot plate

A CASE OF SYN ELIMINATION

SYN ELIMINATION OCCURS BECAUSE THERE ARE NO ANTI-COPLANAR

b-H

H Br H

Bredts Rule
NaOEt EtOH

H +
100%

H H
D Br

110 oC

0%

NaOEt

EtOH

same products
NO DEUTERIUM proves the syn hydrogen is the one removed

H H

110

oC

not this one

SYN ELIMINATION IS SEEN WHEN ANTI-COPLANAR DOES NOT EXIST

not coplanar

Cl Cl
NaOH 110o

H Cl

hydrogens are not anti-coplanar to chlorines

very slow difficult reaction

coplanar

Cl H

H Cl
NaOH 110o

H Cl

faster

synelimination

a-ELIMINATION
C C C H X

occurs when the substrate has

NO b-HYDROGENS on these carbon atoms

a -ELIMINATION
Cl Cl C H Cl
no b -hydrogens KOH CHCl3

Cl Cl C : Cl
a -elimination
very reactive

Cl
+

Cl C :
a carbene

.. : Cl : ..

CARBENES ARE ELECTROPHILES !

Because of an incomplete octet carbenes are electrophilic (need electrons to complete their valence shell).

Cl

Cl C :

missing a pair of electrons

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

Cl Cl C :
electrophile

nucleophile

CARBENES ADD TO DOUBLE BONDS

CHCl3 KOH
2

alkene + carbene = cyclopropane ring

Cl +
1

Cl Cl
H

: C Cl

syn addition
Probably concerted
: steps 1,2 for visualization only

ANALYSIS OF THE ADDITION

2p

H .. :

SP2 hybrid

H
syn addition
Cl

stepwise analysis of the concerted process

Cl

: C Cl

..- Cl
Cl Cl

the intermediate does not exist

SYN ADDITION
CHCl3 KOH
EtOH
BOTH NEW RING BONDS FORM ON THE SAME SIDE OF THE DOUBLE BOND

H H

H H

Cl Cl

H
H Cl

Stereospecific
Cl

STEREOSPECIFICITY PROVES THE REACTION IS CONCERTED

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

H
cis

CH3 CH3

H
cis

CH3 Cl Cl CH3

H
trans

CH3 H

CHCl3 KOH EtOH

H
trans

H3C

H3C

CH3 Cl Cl H

STEREOSPECIFIC = CONCERTED
YES !
H CH3 Cl C H CH3 Cl H + CH3 Cl CH3 Cl An intermediate would allow rotation. Concerted.

Both bonds form on the same side.

Stereospecific!

NO !
H

..
C

This does not happen.

Would not be stereospecific.

COMPOUNDS WITHOUT b-HYDROGENS

Not a common type of compound !

Ph
Ph C H Cl Cl Cl C H Cl

Ph
H C H Cl Cl H C H Cl

ELIMINATIONS SUMMARY

K.I.S.S.

THE MOST BASIC STUFF E2

alkyl halide + strong base + heat =

alkyl halide + solvent + heat (solvolysis)

alcohol + strong acid + heat =
O H X

= E1

E1

(acid assisted)

C C C

typical situation for E1cb

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

Only E1 reactions have rearrangements (carbocations) Only E2 reactions require anti-coplanar b-hydrogens

THE BIG PICTURE

special E1cb strong base stepwise carbanion alkyl halides E2 strong base concerted E1 weak base E1 alcohols E1 acid assisted acidic

neutral

stepwise - carbocation

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

a-elim. if no b-H

carbocation rearrangements