CHEM1920

Lecture 17

1
LiAlH4 reduces esters/acid chlorides all the way to alcohols

The ester is reduced to an

intermediate that readily
converts to an aldehyde
under reaction conditions.

Aldehyde can be further

reduced during the
reaction.

Same process happens

with acid chlorides

2
 Partial reduction of esters/acid chlorides use special
reagents and low temperatures

O
1. LiAlH(OtBu)3, -78oC

R Cl 2. H2O
Acyl chloride

Lithium tert-butoxide Diisobutyl aluminium

O O
1. DIBAL-H, hexane, -78oC aluminium hydride hydride
R OR' 2. H2O R H
Ester
Two derivatives of aluminum hydride that
are less reactive than LAH due to both
1. DIBAL-H, hexane steric and electronic effects
R C N
2. H2O
Nitrile 3
Partial reduction of esters/acid chlorides use special reagents
and low temperatures
LiAlH4

O Al(i-Bu)2
Low temperature and
DiBAl-H steric hindrance as a
R C H
result of the bulky
OR'
groups prevent further
reaction.

LiAlH(OtBu)3 O Al(OtBu)3
During work-up
R C H Li hydrolysis occurs and
Cl the aldehyde is formed 4
 Partial reduction of nitriles to imines (which can
then be hydrolysed to aldehydes)
O
1. LiAlH(OtBu)3, -78oC

R Cl 2. H2O
Acyl chloride

O O
1. DIBAL-H, hexane, -78oC

R OR' 2. H2O R H Lithium tert-butoxide Diisobutyl aluminium

Ester aluminium hydride hydride

1. DIBAL-H, hexane
R C N Two derivatives of aluminum hydride that
2. H2O are less reactive than LAH due to both
Nitrile
steric and electronic effects

5
Reduction of a nitrile to an aldehyde
Activates DIBAl-H by
making Al negative
and makes H more
nucleophilic
R C N Al(i-Bu)2 R C N Al(i-Bu)2
H
H

Hydrolysis.
Water splits
imine O-Al bond.
O
NH H2O N Al(i-Bu)2
R C R C
R HH H
6
 Reduction of a nitrile to an aldehyde

R C N Al(i-Bu)2 R C N Al(i-Bu)2
H
O H

R H
Formation of
C=O and loss
of NH3.
H2N OH H2O O
NH H2O N Al(i-Bu)2
R C R C
R H R HH H
7
 MECHANISM FOR A MECHANISM FOR A
STRONG NUCLEOPHILE MODERATE/WEAK NUCLEOPHILE

8
Formation of cyanohydrins (two ways)

cyanohydrin
Slow reaction with
weak nucleophile

9
 Formation of cyanohydrins (two ways)

cyanohydrin

Faster reaction with strong nucleophile

NC H—Cl NC
NC Cl-

10
Addition of alcohols (weak nucleophiles)

Cl

O H
H3C What would happen if acid
protonates the OH?

H Cl-
H3 C O H3C−O
Cl-

hemiketal 11
Addition of alcohols (weak nucleophiles)

Cl

O H OH becomes good leaving group.

H3C
Substitution reaction with another
molecule of alcohol.
H Cl-
H3 C O H3C−O
Cl- O−CH3

hemiketal ketal 12
Addition of ammonia and other nitrogen nucleophiles

Cl

N H Protonation makes OH good leaving group.

H H C=N bond forms

H Cl-
H N H2 N
H Cl-

aminal 13
Addition of ammonia and other nitrogen nucleophiles

Cl

N H Protonation makes OH good leaving group.

H H C=N bond forms

H Cl-
H N H2 N R'
H + −
Cl- C NH
O + H A
R (or a Lewis ac
aminal imine 14
 Product of this reaction?
H H
– H
O O + OH
N CH N CH
CH3NH2 3 3
H3C C H3C C H3C C
CH2 CH3 Catalytic CH2 CH3 CH2 CH3
HCl

15
 Product of this reaction?
H H
– CHH
OH +CH3 O + 3 OH
N N N CH N CH
CH3NH2 3 3
H3C C H3C C H3C C
HCH H3CCH CCH
3C 2 C 3 Catalytic
CH 2 3 CH2 CH3
CH2 CH3 CH2 CH3
HCl

16
 Grignard Reagents
δ+ δ- δ- δ+
g

Electrophile becomes converted to Strong nucleophile/Base

The reactions between

Grignard reagents ad carbonyl
compounds follow the same
mechanism as their reactions
with LiAlH4

17
 O aldehyde
MECHANISM FOR A
C
STRONG NUCLEOPHILE H3C H

H3C CH2 MgBr

H—Nu

18
 O aldehyde
MECHANISM FOR A
C
STRONG NUCLEOPHILE H3C H

H3C CH2 MgBr

– +MgBr MgBr
O O
OR
C C
H3C CH2 CH3 H3C CH2 CH3
H H

H—Nu

19
 O aldehyde
MECHANISM FOR A
C
STRONG NUCLEOPHILE H3C H

H3C CH2 MgBr

H
– +
O H O
C H
H3C CH2 CH3
H

H3O+ (H+ and H2O during work-up)

H—Nu
H
O
C
H3C CH2 CH3 Secondary alcohol
H 20
 O Ketone
MECHANISM FOR A
C
STRONG NUCLEOPHILE H3C CH3

H3C CH2 MgBr

H
– +
O H O
C H
H3C CH2 CH3
CH3

H3O+ (H+ and H2O during work-up)

H—Nu
H
O
C
H3C CH2 CH3 Tertiary alcohol
CH3
21
 O Acid chloride
H3C
C
Cl Grignard + acid chloride
H3C CH2 MgBr

–
O
C
H3C CH2 CH3
Cl

H H3O+ (H+ and H2O

H3C CH2 MgBr – + during work-up)
O O H O
C C H
H3C CH2 CH3 H3C CH2 CH3
CH2 Tertiary alcohol
+ Cl-
CH3 22
 O Ester
H3C
C
OR Grignard + ester
H3C CH2 MgBr

–
O
C
H3C CH2 CH3
OR

H H3O+ (H+ and H2O

H3C CH2 MgBr – + during work-up)
O O H O
C C H
H3C CH2 CH3 H3C CH2 CH3
CH2 Tertiary alcohol
+ -OR
CH3 23
 MgBr

O3, H2O2 O
Compound Compound
H3C C
W CH2 CH3 X

Compound W could likely be:

A B C D

24
 MgBr

O3, H2O2 O
Compound Compound
H3C C
W CH2 CH3 X

Compound X could likely be:

H CH3 OH
HO CH3
H3C C H3C C
C H CH2 CH3 H3C CH2
HO CH2

A B C
25
Grignard and epoxides

H3C CH2 MgBr ?

Very reactive due to bond angle

strain.

What is the bond angle shown?

What is the usual angle for sp3
carbons?

26
Grignard and epoxides

H3C CH2 MgBr ?

Where are the δ- atoms?

Where are the δ+ atoms?

27
Grignard and epoxides

H3C CH2 MgBr ?

Which existing polar bonds will be broken?

Which atoms will take the electrons?

Which new atoms will the electrons be donated to?

What new bonds will be formed?

28
Grignard and epoxides
1 2 a b c
1 2 a c

What mechanism is this?

a) SN1
b) SN2
c) E1
d) E2

Why did Grignard react with that

particular carbon?
29