REDUCTION OF CARBONYL GROUPS 531

negative charge on oxygen is protonated by the alcohol, and resulting alkoxide adds to the
boron during or immediately after the reduction. The by-product, an alkoxyborohydride
anion, is itself a reducing agent, and can go on to reduce three more molecules of carbonyl
compound, transferring step-by-step all of its hydrogen atoms. O H H

R1 OR2 R1 OH
How to reduce esters to alcohols ester
primary
alcohol
LiAlH4 is often the best reagent, and gives alcohols by the mechanism we discussed in Chapter + R2OH
10 (p. 217). As a milder alternative (needed because LiAlH4 has caused countless fi res through
careless handling), lithium borohydride in alcoholic solution will reduce esters—in fact, it has ■ Why not try writing the
useful selectivity for esters over acids or amides that LiAlH4 does not have. Sodium boro- mechanism out now for this
hydride reduces most esters only very slowly. reaction to make sure you
understand it, before checking
back to p. 217. In a moment,
LiBH4 H H
we will show you a slightly more
MeO2C CO2H CO2H
HO sophisticated version, in which
EtOH
we account for the fate of the Li
and Al species.
How to reduce amides to amines
O H H
Again, LiAlH4 is a good reagent for this transformation. The mechanism follows a similar
course to the reduction of esters: both are written out in detail below, and there is a key differ- R1 NR22 R1 NR22
amide amine
ence at the steps boxed in orange and in green. In the orange box, loss of alkoxide from the
tetrahedral intermediate forms an aldehyde, which is reduced further. This doesn’t happen ■ The mechanism for ester
with amides; instead the anionic oxygen is lost—assisted by coordination to aluminium—to reduction here has rather more
form an iminium ion. A good alternative for the reduction of amides to amines is borane detail than the simplified one we
(BH3), described in the next section. presented to you in Chapter 10.

LiAlH4 reduction of esters

Li
Li Li Li AlH3 AlH3 H
O O O O OH
quench
O
R OR R H R H R H R H
R OR H H H H

H3Al H
H3Al H tetrahedral intermediate
collapses to give an aldehyde

LiAlH4 reduction of amides

Li
Li AlH3 AlH3 NR2
O O O NR2

R NR2 R NR2 R NR2 R H R H

H H H

H3Al H H3Al H
tetrahedral intermediate collapses
to give an iminium ion O H H

R OH R OH
How to reduce carboxylic acids to alcohols carboxylic primary
acid alcohol
The best reagent for this is borane, BH3. Borane is, in fact, a gas with the structure B2H6, but
it can be ‘tamed’ as a liquid by complexing it with ether (Et2O), THF, or dimethyl sulfide These complexes are formed
(DMS, Me2S). when BH3, a Lewis acid, accepts
a lone pair of electrons from the
Although borane appears superficially similar to borohydride, it is not charged, and that
ether or sulfide—a Lewis base.
makes all the difference to its reactivity. Whereas borohydride reacts best with the most
Lewis acids and bases were
electrophilic carbonyl groups, borane’s reactivity is dominated by its desire to accept an elec- described on p. 180.
tron pair into the boron’s empty p orbital. In the context of carbonyl group reductions, this
means that borane reduces electron-rich carbonyl groups fastest. The carbonyl groups of
532 CHAPTER 23 CHEMOSELECTIVITY AND PROTECTING GROUPS

acyl chlorides and esters are relatively electron-poor (Cl and OR are very electronegative);
borane will not touch acyl chlorides and reduces esters only slowly. But it will reduce very
effectively both carboxylic acids and amides.
Borane reacts with carboxylic acids fi rst of all to form triacylborates, with evolution of
■ This ‘sharing’ of lone pair hydrogen gas. Esters are usually less electrophilic than ketones because of conjugation
between two conjugating
between the carbonyl group and the lone pair of the sp3 hybridized oxygen atom—but, in
groups is also the reason why
these boron esters, the oxygen next to the boron has to share its lone pair between the carbonyl
anhydrides are more reactive
than esters (see p. 206). group and the boron’s empty p orbital, so they are considerably more reactive than normal
esters.

O O O
BH3 BH3 RO
B B OR
R OH R O fast
R OH R O
3
reactive triacylborate carbonyl group more reactive
+ 3 x H2 as a result of boron's
electrophilicity

Borane is a highly chemoselective reagent for the reduction of carboxylic acids in the pres-
ence of other reducible functional groups such as esters, and even ketones.

HO2C CO2Me BH3 HO O BH3 O

CO2Me
OH
Ph CO2H Ph
H H

Borane and lithium borohydride are a most useful pair of reducing agents, with opposite
selectivities. Japanese chemists used an enzyme to make a single enantiomer of the acid
below, and were able to reduce either the ester or the carboxylic acid by choosing lithium
borohydride or borane as their reagent. Check for yourself that the lactones (cyclic esters) in
black frames are enantiomers.

enantiomer single enantiomer enantiomer

of other lactone made using enzyme of other lactone
H Me H Me H Me H Me H Me
H LiBH4 BH3 H

CO2H EtO C CO2H CO2Et

O O HO 2 OH O O

Because borane reacts well with electron-rich carbonyl groups, it is also a good alterna-
tive to LiAlH4 for reducing amides to amines, and is chemoselective even in the presence
of an ester:

CO2Me CO2Me
O H H
BH3 BH3
Me Me H
N N O
THF N THF N
Me Me H
79% yield
Ph Ph

The carbonyl group of an amide is electron-rich because it receives electron density from
the delocalized N lone pair. It therefore complexes well with the empty p orbital of the Lewis
acidic borane. Hydride transfer is then possible from anionic boron to electrophilic carbon.
The resulting tetrahedral intermediate collapses to an iminium ion that is reduced again by
the borane.
 REDUCTION OF CARBONYL GROUPS 533

empty p orbital
tetrahedral intermediate collapses
H H to give an iminium ion
H B
H B H BH2 H H2O
O O H H B BH2
O H H quench Me
Me Me R N
Me Me R N
Me R N R N R N
R N H Me
Me Me
Me Me
Me
O O
How to reduce esters or amides to aldehydes
R1 OR2 R1 H
The step boxed in orange in the ester reduction scheme on p. 531 gave an aldehyde. The alde- ester aldehyde
hyde is more readily reduced than the ester, so the reduction doesn’t stop there, but carries on O O
to the alcohol oxidation level. How, then, can you reduce an ester to an aldehyde? This is a real
problem in synthetic chemistry—the ester below, for example, is easy to make by methods R1 NR 22 R1 H
amide aldehyde
you will meet in Chapter 25, but an important synthesis of the antibiotic monensin requires
the aldehyde.

O LiAlH4 O OH Cr(VI) O
CO2Et CHO
H H
required for synthesis of
readily available antibiotic monensin

In this case, the chemists decided simply to put up with the fact that LiAlH4 gives the alco-
hol, and oxidize the alcohol back to the aldehyde using chromium(VI), the oxidant you met
in Chapter 9 (p. 194). There is, however, a reagent that will sometimes do the job in a single Al H
step, although you must bear in mind that this is not at all a general reaction. The reagent is
known as DIBAL or DIBALH—diisobutyl aluminium hydride, i-Bu2AlH. DIBAL
DIBAL is an alane: its structure is shown in the margin. Its chemistry is in many ways like
borane—it exists as a bridged dimer, and it becomes a reducing agent only after it has formed
H
a Lewis acid–base complex, so like borane it too reduces electron-rich carbonyl groups most
Al Al
rapidly. DIBAL will reduce esters even at –70 °C, and at this temperature the tetrahedral inter-
H
mediate, formed by the transfer of hydride from aluminium to carbon (and shown below),
may be stable. Only in the aqueous work-up does it collapse to the aldehyde. This step also bridged dimer
destroys any excess DIBAL so no further reduction is possible.

i-Bu2 Ali-Bu2
O O O
DIBAL Al H3O
O
H
R OEt R OEt R H
hexane, H
–70 °C R OEt 88% yield
tetrahedral intermediate (R = n -C11H23)
stable at –70 °C
unreactive towards further reduction

Lactols from lactones

A stable tetrahedral intermediate is more likely in the reduction of lactones, for the same reasons that cyclic hemiacetals
are more stable than acyclic ones. DIBAL is most reliable in the reduction of lactones to cyclic hemiacetals (also known
as lactols), as in this reaction from E. J. Corey’s synthesis of the prostaglandins.

lactone O lactol OH
OH
O O H
H DIBAL H
CHO
–70 °C H
H H
RO R
RO R RO R
534 CHAPTER 23 CHEMOSELECTIVITY AND PROTECTING GROUPS

In the amide reduction scheme on p. 533, the step framed in green gives an iminium ion.
■ Higher temperatures are
Stopping the reaction before the iminium ion forms would therefore provide a way of making
needed to promote collapse to
the iminium. aldehydes from amides because in the absence of the aluminium, this tetrahedral intermedi-
ate collapses to an aldehyde. Because tetrahedral intermediates like these formed during
amide reduction are rather more stable than those from ester reduction, this can often be
achieved simply by carrying out the amide reduction and quenching with water, all at 0 °C.

AlH3
O Li O O
LiAlH4 H3O
NMe2 NMe2 H
THF, 0 °C H

tetrahedral intermediate 80% yield

stable at 0 °C

DIBAL is also good for reducing nitriles to aldehydes. Indeed, this reaction and the reduc-
tion of lactones to lactols (see box above) are the best things that DIBAL does.

■ Carboxylic acids can be H H

reduced to aldehydes via their CN CHO
acyl chlorides using the 1. DIBAL, –70 °C
Rosenmund reaction—see
below. 2. H2O, H
H H 96% yield

The box below summarizes the chemoselectivity of all of these reagents.

■ Also included is sodium

● Summary of reducing agents for carbonyl groups
cyanoborohydride, which as you
saw in Chapter 11 reduces O O O
Key
imines but not carbonyl
reduced
compounds. reduced slowly R H R H R H
not usually reduced

via acyl
via alcohol LiAlH4, 0 °C chloride
or DIBAL
(see later)

most reactive
least reactive
NHR O O O O O

R H R H R R R OR R NR2 R OH
imine aldehyde ketone ester amide carboxylic acid
NaCNBH3

NaBH4
LiBH4
LiAlH4

BH3
OH
R NHR R OH R OH R NR2 R OH
R R

Hydrogen as a reducing agent: catalytic hydrogenation

You will meet some The simplest reducing agent is hydrogen itself, H 2. Hydrogen can’t generally be used as a
exceptions in Chapter 41. reducing agent for carbonyl compounds—it isn’t nucleophilic enough. However, it can act as