II

Reduction Reactions

Objectives

By the end of this section you will:

1)

be able to exploit the differences in reactivity of various reducing agents (hydride vs

neutral reductants) in chemoselective reductions and be able to provide a mechanistic
rationale to account for their differing reactivities;

2)

be able to use the inherent chirality in a substrate to control the outcome of a reduction of
proximal ketones to generate selectively syn and anti 1,3- and 1,2-diols;

3)

be able to rationalise the outcome of these diastereoselective reactions using T.S.

diagrams;

4)

have gained an appreciation of the versatility of transition metals in reduction reactions;

5)

have gained an appreciation of the synthetic utility of dissolving metal reductions;

6)

be able to use radical chemistry for deoxygenation and reduction of halides.

II.A

Reduction of Carboxylic Acid Derivatives and Related Functionality

OR'
R

carboxylic acid
derivatives

aldehyde

primary alcohol

NO2

OH

NH2

Issues of Reactivity and Selectivity

Similar issues of selectivity and reactivity to those we encountered in the case of oxidation
reactions also arise in reduction reactions.

1. Chemoselectivity. Many different functional groups can be reduced in a variety of ways. We

often need to selectively reduce one functional group whilst leaving others intact (remember year
1 practical!).

O 2N

OH

NaBH 4
O 2N

Sn, HCl
H 2N

Chemoselective reductions from a practical in CHM1C3

2. In the case of carboxylic acid derivatives there are two possible reduction products:

an

aldehyde and an alcohol. Ideally we need methods for selectively accessing either product.

Q? Why is it often difficult to stop the reduction of an ester at the aldehyde (consider the relative
electrophilicities of the starting material and intermediate product.

3.

Stereoselectivity.

Asymmetrically substituted ketones provide secondary alcohols on

reduction, which introduces a new stereogenic centre into the molecule. We need methods for
controlling the stereochemical outcome (relative and absolute) of this reduction using substrateor reagent- (or both) control.

In this course we will only consider substrate-controlled

diastereoselective reductions.
4. Regioselectivity. Ambident electrophiles such as ,-unsaturated ketones can give a variety
of reduction products. We need methods for obtaining only the one that we want.

II.A.1 Hydride Reducing Agents

Some of the most important reducing agents are hydrides derived from aluminium and boron.
There are numerous varieties differing principally in their reactivity. They all act as sources of
nucleophilic hydride and therefore are most reactive towards electrophilic species. Some of the
most widely used hydride reagents are discussed below:

II.A.1.i Lithium Aluminium Hydride (LiAlH4)

one of the most powerful reductants

highly flammable reagent and therefore must be used with care

reactions are normally carried out in ethereal solvents (e.g. THF, Et2O); LiAlH4 reacts
violently with protic solvents (c.f. NaBH4)

The extremely high reactivity of LiAlH4 imparts relatively low levels of chemoselectivity on
this reagent. However it is most reactive towards strong electrophiles.
Ease of Reduction of some Functional Groups with LiAlH4
substrate

product

aldehyde RCHO

RCH2OH

ketone RC(O)R'

RCH(OH)R'

acid chloride RC(O)Cl

RCH2OH

lactone

diol

ease of reduction

most readily reduced

epoxide

O
R

RCH2CH(OH)R

ester RC(O)OR'

RCH2OH + R'OH

carboxylic acid RCO2H

RCH2OH

carboxylate salt RCO2

RCH2OH

amide RC(O)NR'2

RCH2NR'2

nitrile RCN

RCH2NH2

nitro RNO2

RN=NR

isolated alkene RCH=CHR

most difficult to reduce

unreactive

In addition to being capable of reducing virtually every carboxylic acid derivative, the high
reactivity of LiAlH4 makes it useful for reducing other functional groups:

Reduction of halides and sulfonates:

LiAlH4

X = I, Br, Cl, OTs, OMs, OTf

Reduction of propargylic alcohols to (E)-allylic alcohols:

LiAlH4

OH

OH

In this case the proximal alcohol is essential. The reaction proceeds through a trans-selective
hydrometallation of the triple bond releasing the alkene on protolytic work-up:

H
HO

O Al

LiAlH4

H
H
OMe

OMe

OMe

H2

HO

Epoxide Ring-Opening

In the case of unsymmetrically substituted epoxides, issues of regioselectivity arise. In acyclic

-

systems the nucleophile (H ) tends to react in an SN2 fashion at the less hindered end of the
epoxide.

O
R

OH

LiAlH4
R

In cyclic systems there is a strong preference for axial attack (trans diaxial ring-opening)

Hax
Heq

H
LiAlH4
Et2 O

90%
OH

OH
Heq

Hax

LiAlH4

81%

Et2 O
H

II.A.1.ii Sodium Borohydride (NaBH4)

much milder than LiAlH4

frequently used to chemoselectively reduce aldehydes and ketones in the presence of esters
(esters are reduced with NaBH4 but usually at a much lower rate (less electrophilic))

reactions are carried out in protic solvents (including H2O). NaBH4 is insoluble in most
common aprotic solvents

Related Borohydride Reagents

Lithium and Calcium borohydride

Although the reactive component of sodium borohydride is the hydride anion, the counterion can
also be used to modulate the reactivity of the reagent system. A number of other borohydride
reagents are available including LiBH4 and Ca(BH4)2. Both these reagents are more reactive
than NaBH4 and readily reduce esters in addition to aldehydes and ketones. The increased
reactivity of these reagents can be attributed to the increased Lewis acidity of the cations which
confers increased electrophilicity on the carbonyl group (by Lewis acid-Lewis base formation).

II.A.1.iii Sodium Borohydride-Cerium(III) Chloride

Problem 1: Regioselective reduction of ,-unsaturated carbonyl groups (ambident electrophiles).

1,2-reduction

good route to allylic alcohols (very important functional groups)

use a 1:1 ratio of NaBH4 and CeCl3 - Luche reduction

OH
NaBH 4
100%

OH

OH

NaBH 4
CeCl36H2O
97 : 3
100%

A. L. Gemal, J.-L. Luche, J. Am. Chem. Soc., 1981, 103, 5454-5459.

Example from Isobe's synthesis of ()-5,11-dideoxytetrodotoxin.

This reaction is not only

completely regioselective for the 1,2-reduction product but is also highly stereoselective.

O
O

O
NHCOCCl3

NaBH 4, CeCl3

OH
20:1 stereoselectivity

To obtain selective 1,4-reduction

NHCOCCl3

Angew. Chem. Int. Ed ., 1999, 38, 3081

a) catalytic hydrogenation
b) 'copper hydride' [PPh3CuH]6 Stryker's reagent

Chemoselective reduction of aldehydes in the presence of ketones can usually be achieved

by exploiting their increased reactivity towards nucleophilic hydride sources.

Q? Why are aldehydes more electrophilic than ketones?

Problem 2:

How might we chemoselectively reduce a ketone in the presence of a more

electrophilic aldehyde:

The increased electrophilicity of aldehydes over ketones, however, renders them much more
prone to hydration/acetal formation.

Acetals are not reduced by borohydride reagents.

Ce(III) is a good Lewis acid and strongly oxophilic - it promotes hydration of carbonyl groups
especially aldehydes.

Therefore it should be possible to temporarily mask an aldehyde as its acetal/hydrate to allow

selective reduction of the ketone. Unmask the aldehyde in the work-up.

Solution: use 1:1 NaBH4-CeCl3 in wet EtOH:

HO

NaBH 4 - CeCl3
OMe

OMe

EtOH, H2O, -15 C

O

O
H

A. L. Gemal, J.-L. Luche, J. Org. Chem., 1979, 44, 4187-4189.

II.A.1.iv Sodium Cyanoborohydride (NaCNBH3)

C. F. Lane, Synthesis, 1975, 135-146.

a very useful borohydride reagent

milder than NaBH4 at pH 7

reactivity is strongly pH dependent - it is one of the few borohydrides which tolerates acidic
conditions (down to ~pH 3)

at pH 3-4: NaCNBH3 readily reduces aldehdyes and ketones

at pH 6-7: NaCNBH3 readily reduces iminium ions but NOT C=O groups - this property is
responsible for its most important use - REDUCTIVE AMINATION:

a very useful method for synthesising secondary and tertiary amines by coupling a secondary
or primary amine with an aldehyde or ketone.

O
R'NHR"
R

R'

NaCNBH3
MeCN
pH 6

R"

R'

R"
H

R, R', R" = H, alkyl, aryl

Q? An alternative method for amine formation is to alkylate a primary or secondary amine with
an alkyl halide? What are the problems with this approach? Hint - is the product amine more or
less nucleophilic than the starting material?
Example 1

a source of NH 3

NH4 Br
R

NaCNBH3
MeOH

Q? Account for the stereoselectivity of this reaction.

H
N

Example 2

NH2

EtO 2C CO2Et

NH
O

N
NaCNBH3

EtO 2C CO2Et

HN

N
H

87%

N
H

NH
O

Example 3 from Cha's synthesis of clavepictine A:

TIPSO

TIPSO
NaCNBH3, H
N

BnO

N
O

OAc

BnO

OAc

J. Am. Chem. Soc., 1999, 121, 10014

Q? What is the mechanism of this reaction? Account for the stereoselectivity.

II.A.1.v Other Hydridic Reducing Agents

There are many other hydride reducing agents. The following have been developed as sterically
very bulky hydride sources for use in stereoselective reduction:

Reducing Agent
t

LiHAl(O Bu)3

Red-Al

Comment

Li

Na

H
H

Na[H2Al(OCH2CH2OMe)2]

O
Al
O O

Al

good for converting carboxylic

acid derivatives to aldehydes

similar reactivity to LiAlH4

Li
L-selectride

B
LiHB(CH(CH3)CH2CH3)3

similar reactivity to LiBH4

Stereoselective Reduction of 4-tert-Butyl-Cyclohexanone

tBu

reducing agent

OH
H

tBu

H
OH

tBu

H
equatorial attack

axial attack

reducing agent

equatorial attack

axial attack

LiAlH4 (unhindered)

10

90

10

90

93 (RT)

7 (RT)

96.5 (-78 C)

3.5 (-78 C)

100

LiAlH(O Bu)3 (more hindered)

s

LiBH( Bu)3 (very hindered)

Lithium trisamylborohydride

Li

BH

(very very hindered)

What factors might affect the stereochemical outcome of this reduction? Hint: consider such
factors as the approach trajectory of the incoming nucleophile and the size of the nucleophile.
Draw Newman projections of the starting ketone and the two products and consider how the
molecule reorganises on proceeding from starting material to product; remember that eclipsing
interactions are unfavourable.

II.A.2 Neutral Reducing Agents

The reagents discussed above are all hydridic and behave as nucleophiles - they react most
readily with good electrophiles.

Another class of reducing agents involves those that are neutral. They react through a different
mechanism and as a result have quite different selectivities which are often complementary to the
hydride reagents discussed earlier.

basic mechanism

H
O
R

BH3
R'

H
O

R'

Lewis acid-Lewis base

complex

BH2
H

R
H
R'
intramolecular hydride
transfer

OH
R
R'

Comparison between BH4 and BH3

BH4

BH3

negatively charged

neutral

nucleophilic

electrophilic

Valence shell of the central boron is a complete

6 electrons in the valence shell of the central

octet

boron - vacant pAO confers Lewis acidity

hydride transfer proceeds intermolecularly

hydride transfer is often intramolecular via a

Lewis acid-Lewis base complex

II.A.2.i Borane (BH3)

Borane is too unstable to be isolated (exists either as the dimer B2H6 or a Lewis acid-Lewis base
complex e.g. BH3THF or BH3Me2S both of which are commercially available).

very useful reagent for selectively reducing carboxylic acids to alcohols in the presence of
esters

amides are also readily reduced to the corresponding alcohols

O
OH

EtO

BH3THF
-10 C to RT
8-10 h, 67%

OH

EtO

Thus it seems that the more electron rich carboxylic acid derivatives appear to be reduced most
readily - complete opposite reactivity to hydridic reducing agents.

Q? Why are carboxylic acids reduced so fast relative to esters?

Key:

borane first reacts with the carboxylic acid to generate a triacyloxyborane (protonolysis).

This is essentially a mixed anhydride and therefore very reactive. Esters cannot react in this way
and are therefore reduced at a slower rate.

O
O

B[OC(O)R]2

B[OC(O)R]2

reactive species
3 RCO 2H

BH3

[RC(O)O]3B
BH3

RCH 2OH

3 H2

A note of caution!

Borane is a good reducing agent but it is also very useful for hydroborating unsaturated systems
(triple and double bonds) - chemoselectivity may be a problem.

Ease of Reduction of some Functional Groups with Borane

substrate

product

ease of reduction

carboxylic acid RCO2H

RCH2OH

most readily reduced

isolated alkene RCH=CHR

(RCH2CHR)3B

ketone RC(O)R'

RCH(OH)R'

nitrile RCN

RCH2NH2

epoxide

O
R

RCH2CH(OH)R

ester RC(O)OR'
acid chloride RC(O)Cl

RCH2OH + R'OH

most difficult to reduce

inert

II.A.2.ii

Diisobutylaluminium Hydride (DIBALH)

Al
H

very widely used reducing agent especially for reducing esters

esters can be reduced to either the aldehyde or the alcohol depending on the stoichiometry
and reaction conditions:

OH

2 eq. DIBALH

O
R

1eq. DIBALH
OR'

-78 C, toluene

aldehyde only
released on work-up
OAlR2
OR'

R
H

stable at low temperature

Nitriles are also reduced to aldehydes. In this case reaction proceeds via the imine which is
hydrolysed on acidic work-up to afford the aldehyde product:

1eq. DIBALH
R

AlR2

H
H

Lactones provide a useful method for preventing over-reduction of the aldehyde product. In these
cases the lactone is reduced to a lactol, the hemiacetal functionality essentially masking the
aldehyde and preventing over-reduction:

OH
O

1eq. DIBALH

Esters with proximal alcohols can also be partially reduced by exploiting lactol formation.

O
O

MeO
HO

DIBALH
-78 C
98%

HO

O
O

Tetrahedron , 1993, 49, 6669

II.A.2.iii

Meerwein-Ponndorf-Verley Reduction with Al(O Pr)3

a relatively old method of reducing carbonyl groups (principally aldehydes and ketones)

isopropanol behaves as the hydride donor

the by-product is acetone

the reaction is reversible - the reverse oxidation is known as the Oppenauer Oxidation.

the mechanism is typical of a range of reagents proceeding through a well-defined chair-like

T.S. (Zimmerman-Traxler) in which the beta-hydride is transferred intramolecularly to the
carbonyl group.

Al(OiPr)3

O
R"

R'

i PrOH

O
"R
R'

OR
Al O
H
RO

OH
R"

R'

Zimmerman-Traxler
chair T.S.

Compare this reaction mechanism with methods for directed reduction of -hydroxy ketones
(Me4NHB(OAc)3 and the Evans-Tischenko reduction) later - the mechanism is very similar CHAIR-LIKE ZIMMERMAN-TRAXLER transition states are very commonly used to
rationalise the stereochemical outcome of reactions which can proceed through 6membered transition states.

II.B

Stereoselective Reduction of Prochiral Ketones

The addition of a hydride nucleophile to a chiral ketone provides diastereoisomers - when the
stereogenic centres are close to the carbonyl group (1,2- or 1,3-disposed (i.e. - or -hydroxy
ketones)) then by careful choice of protecting group, reaction conditions and reducing agent, a
high degree of stereoselectivity can often be obtained in the reduction.

1,2-Diols and 1,3-diols are widespread in natural products (see erythromycin and related
polyketide macrolides). Stereoselective reduction of hydroxyketones provides a reliable route for
incorporating such functionality.

Diastereoselective 1,3-reduction:

OP

OP

H
R'

OH

R'

OP
R

syn

P = H or protecting group

OH
R'

anti

Diastereoselective 1,2-reduction:

O
R

OH

H
R'

OP
P = H or protecting group

R'

OH
R

R'

OP

OP

syn

anti

We will consider each reduction in turn. While some of the reagents may be new to you, you
should already be aware of the underlying concepts and models; if you are not then REVISE this
area of Chemistry - it will be cropping up time and time again in this lecture course.
for example see:

F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry: Volume B, Plenum Press, New

York, 1990 (3rd Edition), pp 241-244.

M. B. Smith, Organic Synthesis, McGraw-Hill, New York, 1994, pp 400-417.

E. L. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds, Wiley, New York, 1994, pp

858-938 for an indepth discussion of this area of Chemistry

II.B.1

Diastereoselective Formation of Anti-1,3-Diols

A number of methods have been developed for forming the anti-1,3-diol from the corresponding
-hydroxy-ketone. All rely on a so-called DIRECTED REDUCTION which takes advantage of an
intramolecular hydride transfer proceeding through a well-defined 6-membered chair-like
transition state (c.f. Meerwein-Ponndorf-Verley reduction earlier).

II.B.1.i Davis' Intramolecular Hydrosilylation

S. Anwar, A. P. Davis, Tetrahedron, 1984, 40, 2233-2238.

iPr

iPr

Si
OH

i Pr

2SiHCl

Et3N
cat. DMAP

H
O

nucleophilic substitution

Lewis acid
or Brnsted acid

iPr

OH OH
R

i Pr

Si

HF, MeCN

O
R

O
R

anti

Step 1: form silyl ether

Step 2: Treat silane with Lewis or Brnsted acid to induce hydride transfer. Levels of
diastereoselectivity are good to excellent anti:syn 320:1 to 120:1 (BF3OEt2 and SnCl4 give
particularly good results).

the silyl acetal product is stable and the isopropyl groups make this functionality a suitable
diol protecting group.

Fluoride-induced deprotection of the silyl acetal provides the free diol.

Intramolecular hydride transfer through a chair-like T.S. accounts for the stereochemical outcome
of the reaction.

Si

R'

iPr

iPr

O
i Pr

Si

i Pr

R'

syn

O
LA

R'

LA

Si

O
R

iPr

iPr

O
iPr

i Pr

Si

R'

anti

II.B.1.ii Tetramethylammonium Triacetoxyborohydride (Evans)

Evans has introduced an alternative reagent Me4NHB(OAc)3 for carrying out directed reductions.
D. A. Evans, K. T. Chapman, E. M. Carreira, J. Am. Chem. Soc., 1988, 110, 3560-3578.

Although the levels of selectivity are not as high as Davis' method the reaction is easier to
perform and generally higher yielding (a pay-off):

OH

NMe4BH(OAc)3
OR

MeCN / AcOH
-40 C, 5 h
completely chemoselective
and highly diastereoselective

OH

OH

O
OR

92%
anti:syn = 95:5

Note in this example that only the -ketone is reduced; the ester remains intact (chemoselective)

Draw a T.S. which satisfies the stereochemical outcome of the reaction (hint: the AcOH cosolvent acts as a Brnsted acid and activates the ketone electrophile).

II.B.1.iii Evans-Tischenko Reduction

D. A. Evans, A. H. Hoveyda, J. Am. Chem. Soc., 1990, 112, 6447-6449.

provides anti-1,3-diol with high levels of stereocontrol

one potential advantage is that the directing hydroxyl group is protected as an ester (the
choice of aldehyde determines the type of ester PG)

this ensures that the two secondary alcohols are differentiated (one is protected in situ as an
ester). Selective monofunctionalisation of a 1,3-diol can be difficult to achieve.

The mechanism involves the reaction of a -hydroxy ketone with an aldehyde (source of acyl
protecting group) and is mediated by samarium(II) iodide (SmI2). The samarium ensures the
formation of a well-defined transition state (by coordination - recall that lanthanides are strongly
oxophilic) and directs the transfer of hydride from the aldehyde to the ketone.

Ph
OH

>4 eq. PhCHO

OH

15 mol % SmI2
THF, -10 C
99%

O
Ph

anti : syn >99:1

Sm(II)
H

H O Sm(III)
Ph

Ph

H
O
formation of
hemiacetal

Sm

well-defined T.S. in which all

substituents are equatorially oriented
around a chair-like reactive conformation

Another example:

OH

OTBS

OH

OTBS

MeCHO
40mol% SmI 2
1.5 h
89%

anti:syn >99:1

II.B.2

Diastereoselective Formation of Syn-1,3-Diols

Chelation-Controlled Intermolecular Hydride Delivery

Metals capable of forming a chelate between a -hydroxyl group and a ketone provide a
molecular conformation which resembles that of cyclohexene:

R' adopts a pseudoequatorial

position (dictates half-chair conformation)

OH

R'

MgBr2
R

O
R'

Mg

R'

X
O M
X
O H

INTERmolecular hydride delivery on the chelate would then be expected to provide the syn1,3-diol products. This is indeed the case.

The most reliable reaction conditions are Et2B(OMe)-NaBH4 at low temperature:

K.-M. Chen, G. E. Hardtmann, K. Prasad, O. Repic, M. J. Shapiro, Tetrahedron Lett., 1987, 28,
155-158.

OH O
Bu

OH

Et2B(OMe)
Bu

THF-MeOH (4:1)
-70 C, NaBH4

Bu

OH

OH

Bu

syn

Bu
99:1

OH
Bu

anti

99%

Make sure that you can rationalise the stereochemical outcome of this reaction using clear
conformational diagrams.

other reagents which also give good syn selectivity are Zn(BH4)2 and DIBALH

K. Narasaka, F.-C. Pai, Tetrahedron, 1984, 40, 2233-2238.

There are numerous variants on this theme (chelation followed by intermolecular hydride
delivery). For an example in which an ester is used to form the chelate:

OBn
O

Zn(BH4)2
Et2O, 0 C
85%

OBn
OH O

syn : anti

>99:1

Draw a T.S. diagram which accounts for the observed stereochemical outcome of this reaction.

II.B.3

Diastereoselective Formation of Anti-1,2-Diols

Exploit chelation control; we therefore require:

i)

a free alcohol or a protected alcohol in which the protecting group can still form a chelate
(alkyl ethers) i.e. the oxygen must still be able to behave as a Lewis base.

ii)

a metal which can form a chelate (typical metals include Zn(II), Mg(II), Ti(IV) etc.)

Once again the chelated intermediate is much more conformationally rigid and sterically
differentiates the two diastereotopic faces of the carbonyl group [This is Cram chelation].
M
RO

O OR

RO OH

O
R'

R'

(nucleophile approaches along the

Brgi-Dunitz trajectory on the face
containing the smaller group (H))

R'

H
H

R'

RO

OH

Examples:

OH
Zn(BH4)2

THPO

OBn

Et2 O, -30 C

THPO

OBn

anti : syn
O

Bu

Zn(BH4)2
Et2O, -50 C

OH

90%

OH

Bu

OH

anti : syn
OH

Zn(BH4)2

98.5:1.5

OH

Et2 O, -78 C
N

75%

95:5

HN

anti : syn

97:3

II.B.4

Diastereoselective Formation of Syn-1,2-Diols

This requires

i) careful choice of a protecting group which suppresses chelate formation and is

very bulky (large silyl protecting groups are ideal).
ii) use Felkin-Anh T.S. analysis to account for the stereocontrol.

TBDPS protecting group

is very bulky
Na
O

Si

H2Al

OTBDPS
2

C5H 11

-78 C, toluene

O
O CH
5 11

OTBDPS
C5H11

C5H 11
OH

anti

OH
2:98

syn

SiO
H

Make sure you understand the steric AND stereoelectronic arguments behind the Felkin-Anh T.S.

For other examples:

T. Takahashi, M. Miyazawa, J. Tsuji, Tetrahedron Lett., 1985, 26, 5139-5142.

L. E. Overman, R. J. McCready, Tetrahedron Lett., 1982, 23, 2355-2358.

II.C

Other Methods of Reduction

II.C.1

Raney-Nickel

most widely used in the hydrogenolysis of CS bonds.

Examples:

S
S

O
O

Ra-Ni
H2, EtOH

Ra-Ni
EtOH
95%

Ph

also used in the hydrogenation of alkenes and alkynes.

CH3
O
CH3
O
Ph

II.C.2

Zinc in Acidic Media

Reduction of -haloketones

very mild

highly chemoselective

Example:

MeO 2C Br

MeO 2C H
O

AcO

AcOH

O
AcO

96%

AcO
AcO
AcO

Zn(0)

AcO
AcO
AcO

OAc

OAc

Note the lactone, acetate, glycosidic linkage and acetal all remain intact.

Q? What is the mechanism of reduction? Hint: the reaction involves single electron transfer.

1,4-Reduction of Enones

Example:

HO

HO
OH

Zn(0)

OH

AcOH
>82%
H

H
H

Note that there is a zinc enolate intermediate; this reaction can therefore be used for
regioselective formation of enolates.

Clemmensen Reduction

a classical method for complete reduction of a carbonyl group (in ketones and aldehydes).

reaction conditions are fairly vigorous.

Example:

H H

O
Zn/Hg
H
O

HCl
75%

H
H

II.D

Hydrogenation with Hydrogen and a Transition Metal Catalyst

Typical catalysts are Pt, Pd, Rh, Ru and Ni (late transition metals) - usually used as finely
dispersed solids or adsorbed on to an inert support such as charcoal or alumina.

reaction takes place on the surface of the metal - heterogeneous catalysis

hydrogen is invariably transferred on to the less hindered face in a syn addition

process.

Example:

H2 / Pt

H
H

A variety of homogeneous catalysts are also effective e.g. Wilkinson's catalyst [(PPh3)3RhCl]

transition metal catalysts in the presence of H2 will reduce carbonyl groups although the rate
is usually lower than the reduction of olefins (allows chemoselectivity).

Example:

OTHP

OTHP
[(PPh3) 3RhCl]

OAc

H2
90%

OAc

Q? How does the shape of the bicycle control the stereoselectivity of the hydrogenation?

Enantioselective reduction will NOT be discussed here.

II.D.1

Partial reduction of alkynes

a useful route to (Z)-alkenes

need to modify the catalyst to minimise over-reduction

Lindlar's catalyst (Pd-CaCO3-PbO) is the most widely used. The PbO tempers the reactivity
of the catalyst by acting as a catalyst poison.

Other systems include Pd-BaSO4 poisoned with quinoline.

Example:
O

O
O

OTBS

II.D.2

Lindlar Pd
CaCO3

O
O

25 C, EtOAc, pyridine

OTBS

Hydrogenolysis

Benzyl ethers are readily cleaved by Pd/C/H2 to provide the free alcohol and toluene.

Cleavage occurs under mild and neutral conditions

as a result, benzyl ethers are frequently used as alcohol protecting groups.

Pd / C
H2

ROH

II.E

Dissolving Metal Reductions (Sodium/Ammonia or Lithium/Ammonia)

a wide variety of uses, only three will be discussed here

reactions proceed via single electron transfer processes

II.E.i

Regiospecific Enolate Formation

OLi

O
Br

Li, NH3

45%

1 eq. H2O

major diastereoisomer
proton source

TMSCl

OTMS

silyl enol ether (latent enolate)

Enolates are ambident nucleophiles -

you should be able to account for the differing

regioselectivity of the reactions of the intermediate lithium enolate with the two different
electrophiles.

II.E.2

Birch Reduction

Partial reduction of aromatic rings

Mechanism:
H H
1e

H
H H

1e
H H

H H

under the (relatively controlled and mild) reaction conditions, reduction stops at the dihydro
stage.

the rate of reduction is influenced by the substituents on the ring - as the intermediates are
negatively charged, the rate is, not surprisingly, increased by electron-withdrawing
substituents.

substituents also dictate the regiochemistry of protonation:

OMe

OMe

OMe

1e

CO2

CO2

CO2
1e

Make sure you can rationalise the regiochemistry of these reactions.

Reduction of Alkynes

a useful route to (E)-alkenes

equilibration of the radical or radical anionic intermediates ensures the thermodynamically

more stable alkene is produced (usually the (E)-alkene).

mechanism:

1e
R

R
H

Na, NH3. tBuOH

1e

R
H

R
H

II.F

Free Radical Reductions

used to reduce alkyl halides

usual hydrogen atom donor is tributyltin hydride (Bu3SnH) (there are now less toxic
alternatives to tributyltin hydride e.g. (Me3Si)3SiH)

mechanism:
Bu3SnH (hydrogen donor)
R

AIBN (initiator)

PhH, reflux

heat

N N
NC

N2

CN

NC

H SnBu3
H SnBu3
SnBu3

Bu3SnX

R
R

Some examples:

O
O

O
Me3SnCl

NaBH4
AIBN

H
O

in situ formation
of Me3SnH

Br

D
Bu3SnD

Br

Br
Br

AIBN

D
D

SnBu3

Deoxygenation of xanthate esters:

OBn

S
PhS

OBn

OBn

Bu3SnH

Cl

AIBN
HO
OH

S
PhS

PhS

OH
O
AcO

i) NaH, CS2
ii) MeI
iii) Bu3SnH, AIBN

O
AcO

Q? What is the mechanism of this reaction? Hint: the driving force is formation of a C=O bond.

SUMMARY

In this section we have discussed a variety of methods for reducing carbonyl groups
chemo-, regio- and stereoselectively and seen that this has necessitated the development
of a wide variety of reducing agents. Furthermore, by understanding the mechanisms of
various reducing agents we can rationalise their reactivity towards potentially reactive
functional groups. We have also discussed various methods for reducing unsaturated
compounds (olefins, alkynes and aromatic compounds) and seen the importance of late
transition metals as catalysts for mediating such transformations. Reduction requires the
gain of electrons; metals are a potential source of electrons. We have seen that Zn in
acidic media and Li or Na in NH3 are good reducing systems. Free radical reduction
occupies a special niche; it is particularly useful for reducing halides and similar systems
under mild, and neutral conditions.