Reduction: Definition

Reduction is a process of
 Addition of hydrogen, electropositive group or atoms to multiple
bonds
 Removal of oxygen, electronegative atoms or groups
 Increase of negative charge or decrease of positive charge
 Gain of electrons or decrease of oxidation number.

There are three methods that can be used for the reduction of many
functional groups:

(a) Catalytic hydrogenations

(b) Metal hydride reductions
(c) Dissolving metal reductions.
 Catalytic Hydrogenation

Catalytic hydrogenation is the reaction of a compound with hydrogen in the

presence of catalyst.
Catalytic hydrogenation usually effected in the laboratory by stirring or shaking of
solution of compound to be reduced with a catalyst under an atmosphere of
hydrogen gas.
Our discussion will mainly focus on the addition of hydrogen to an unsaturated
group such as alkene, alkyne, carbonyl, nitro group and aromatic nucleus.

Examples: H2 H2 H2
(i) C C C C
Catalyst

H2
(ii) C O C OH

CO 2 C 2 H 5 CO 2 C 2 H 5

H2
(iii)
Catalyst

NO 2 NH 2
 Catalytic Hydrogenation

The selection of reaction conditions such as solvent, reaction temperature and

hydrogen pressure for a given hydrogenation depends on the catalyst chosen.
Based on the activity, the hydrogenation catalyst are divided into two groups:
1. Noble metal catalyst like Pt, Pd, Ru, Rh and active grade of Ra-Ni: These
catalyst are used with;
• Relatively low reaction temperature (0-100 oC)
• Relatively low hydrogen pressure (1-4 atm)
• Solvents: Ethyl acetate, acetic acid, ethanol, water and mixture of acetic
acid and perchloric acid.

Examples: H2 (3 atms)
Pt
C6H5-CH=CH-COC6H5 C6H5-CH2-CH2-COC6H5
CH3CO2C2H5

CH2COOH
H2 (3 atms) CH2COOH
Pt
CH3CO2H, 25 oC
 Catalytic Hydrogenation

2. Less active catalyst: Raney-nickle, copper chromate, Ruthenium

supported on carbon and alumina. These catalyst are used with;
 Relatively High reaction temperature(25-300 oC)
 Relatively high hydrogen pressure(100-300 atm)
 Solvents: Ethanol, water, cyclohexane and methylcyclohexane,
sometime no solvents.

Examples:
OH OH
H2(275 atm) OH
+
Ra-Ni
C2H5OH, 90 oC 86 % 7%
CO2C2H5 CO2C2H5

H2( 100 atms)

Pd on C
C2H5OH, 90 oC
N N

CH2CO2C2H5 CH2CO2C2H5
 Reduction: Definition

Strongly acetic solvents or reactant cannot be used for Ra-Ni or copper

chromate because these catalyst will dissolve.
The rate of high pressure hydrogenation may be increased by
 Increasing the hydrogen pressure
 Increasing the amount of catalyst
 Increasing the reaction temperature

Many compounds can be reduced by both low and high pressure hydrogenation.
Then the methods are selected on the basis of the quantity of the compounds.
For 10-100 g (small), low pressure hydrogenation
10-1000 g (large), High pressure hydrogenation
 Reduction: Definition
Variety of functional groups can be reduced by catalytic hydrogenation. Some
common functional groups are listed in order of decreasing ease of catalytic
hydrogenation.
Functional groups Reduction Products Comments
R-CO-Cl R-CHO Most easily reduced
R-NO2 R-NH2
R C C R R-CH=CH-R(cis)

R-CHO RCH2OH With Pt catalyst, reduction is accelerated by ferrous ion

Ease of reduction is decreased by the presence of

R-CH=CH-R R-CH2-CH2-R
additional substituents

R-CO-R R-CH(OH)-R
C6H5-CH2OR C6H6-CH3 + ROH
R C N R-CH2-NH2

Also partial reduction to other PAH

RCOOR RCH2OH + ROH Pt and Pd catalyst fail to effect these reduction

RCONHR RCH2NHR

Least easily reduced

RCO2-Na+ Inert
 Hydrogenolysis

Catalytic hydrogenation may saturated or causes the cleavage of bonds. The

cleavage of a single bond by catalytic hydrogenation termed as hydrogenolysis.
It is normally found in allylic or benzylic amines or alcohol having the structural
units.
C C C O or C C C N

and with compounds containing C-X and C-S single bonds.

Hydrogenolysis also observed with N-N, N-O and O-O single bond as well as C-
C bon in small ring and C-O, C-N bond in three membered ring heterocycles.
(H3C)2C CH2
H2 (4-5 atm)
(CH3)3C-NH2
Ra-Ni
N dioxane
H

H2(200 atms)
CuCr2O4 [C6H5CH2OH] Hydrogenolysis
C6H5-CO2C2H5 + C6H5-CH3 + H2O
C2H5OH C2H5OH
200-250 oC
 Reduction: Definition

The hydrogenolysis of small aryl ester is difficult to realize because of further

reaction to toluene and it requires the use of excess catalyst and lower
temperature.

The relative ease of cleavage of benzyl groups

C6H5CH-N > C6H5CH-O > C6H5CH-N

For example

H OCH2C6H5H OCH2C6H5H
H

H2( 1 atm)
10% Pd on C
+ C6H5CH3
o
CH3COOH, 25 C

N(CH3)CH2C6H5 NHCH3
 Catalytic Hydrogenation

Catalyst poison: The chemicals that are used to reduce the activity of catalyst
called catalyst poison. In Rosenmund reduction of acid chloride to aldehyde ease
the C-X bond cleavage.

Here the sulfur-quinolone mixture works as catalyst poison.

A variety of substances are poisonous for hydrogenation. Most commonly used
poisons are mercury, divalent sulfur compound and lesser degree of amine.
The poisons are believed to function by preferentially bonded to catalyst surface
preventing the interaction between catalyst and the molecule to be reduced.

Lindlar Catalyst: The reduced activity catalyst, i.e. Pd on BaSO4 particularly

poisoned with quinoline or lead acetate. It is used to stop the hydrogenation at
certain stage.
 Catalytic Hydrogenation: Mechanism

There are two types of catalytic hydrogenation

(i) Heterogeneous catalytic hydrogenation
(ii) Homogeneous catalytic hydrogenation

Mechanism and stereochemistry of Heterogeneous catalytic Hydrogenation:

The early studies of hydrogenation by Linstead and coworker leads to the

concept that the less hindered side of an unsaturated molecules adsorbed on the
catalyst surface followed by the simultaneous transfer of two or more hydrogen
atoms from the catalyst to adsorbed molecule.
The result is the cis-addition of the two hydrogen atom from the less hindered
side of the multiple bond.
H 2 (1 a tm ) H H
5% Pd on BaSO 4
(H 3 C )H C O 2 H 3 C C C C (C H 3 )C O 2 C H 3 C C
Q u in o lin e , C H 3 O H
25 oC H 3 C O 2 C (H 2 C ) 3 C (C H 2 ) 3 C O 2 C H 3

97%
 Heterogeneous Catalytic Hydrogenation

Reduction of ketone also takes place from the less hindered side

CH3 CH3 OH CH3

O H
H H2( 1 atm) H H
H3C Pt(from PtO2) H3C H H3C OH
+
CH3CO2H
20 oC
CH3 CH3 83% CH3 17%

The rate of the reduction of carbon-carbon triple bond is nearly equal to the
carbon-carbon double bond when the triple bond is a part of conjugated system.
The studies of the isomerization of olefin over hydrogenation catalyst of
hydrogen-deuterium exchange and the stereochemistry of catalytic
hydrogenation showed that the hydrogen transfer to adsorbed molecule must
occur in the stepwise manner.
The common mechanism of this process is postulated by “Horiuti and Polanyi”
involves a series of equilibrium which implicate both π-bonded intermediate and
half hydrogenated intermediate.
Heterogeneous Catalytic Hydrogenation
H H

H2 +

Catalyst surface
C C C
1 2 3 H

H H H C C C
CH C C
H H

[3] [1]

C C C
H H H
+
H CH C C H

[2] Product

1 3
CH C C
2
+
H H
 Homogeneous Catalytic Hydrogenation
The soluble tris(triphenylphosphine)rhodium chloride is of the special interest,
since it reacts with hydrogen to form metal hydride which rapidly transfer two
hydrogen atom to cabon-carbon double bond.
The preparation and the function of this catalyst is given below
C2H5OH
RhCl3.H2O + (C6H5)3P [(C6H5)3P]3RhCl
Reflux
88%, Red crystal

(C6H5)3P + [(C6H5)3P]2(solvent)RhCl dimer

[(C6H5)3P]3RhCl

H2

C4H9-n
H H H
(C6H5)3P CH2=CH-C4H9-n (C6H5)3P Solvent
Rh H Rh
H H H
(C6H5)3P (C6H5)3P
Cl Cl

Usually fast
H [(C6H5)3P]3RhCl + CH3CH2C4H9-n
(C6H5)3P
Rh C4H9-n
(C6H5)3P C C
Cl H2 H2
 Homogeneous Catalytic Hydrogenation

The indicated rapid transfer of two hydrogen atoms to olefins is consistent with
the ability of the catalyst to convert unhindered olifins to didurataed alkanes.

The stereochemical result of hydrogenation from both homogeneous and

heterogeneous catalyst are similar.

D2( 1 atm)
n-C8H17 C CH2 n-C8H17 CH CH2
H [(C6H5)3P]3RhCl
C6H6, RT D D
 Homogeneous Catalytic Hydrogenation

Advantages: The principle advantages offered by homogeneous rhodium

catalyst is its degree of selectivity for reducing only unhindered carbon-carbon
double bond even in the presence of keto, nitrile, nitro and sulfide groups.

H2
(C 6 H 5 ) 3 P ) 3 R hC l
C 6H 5S C H 2C H = C H 2 C 6H 5S C H 2C H 2C H 3
C 6H 6

H 2 (4-6 atm )
(C 6 H 5 ) 3 P ) 3 R hC l
O 2N C H =C H -N O 2 O 2N C H 2 C H 2 -N O 2
o
C 6 H 6 , C 2 H 5 O H 40-60 C

O H 2 ( 1 atm ) O
(C 6 H 5 ) 3 P ) 3 R hC l
C 6 H 6 , 25 o C
 Metal Hydrides Reductions

The main drawback of catalytic hydrogenation is the inability of selective

reduction of carbonyl function of ketones, acids, esters and amides in the
presence of cabon-cabon double bonds which leads to the widespread uses of
certain complex of metal hydrides for the reduction of carbonyl groups.
The most common and commercially available metal hydrides are :
Lithium aluminum hydride (LiAlH4),
Lithium borohydride (LiBH4), and
Sodium borohydride (NaH4).

Preparation of metal hydrides:

LiAlH4: 4 LiH +AlCl3 LiAlH4 + 3LiCl

2 LiH + 2Al + 3H2 2 LiAlH4

Na + Al + 2H2 NaAlH4

NaAlH4 + LiCl LiAlH4

 Metal Hydrides: Preparations

NaBH4:

Solvents: LiAlH4: Et2O, THF, diglyme etc. (Aprotic solvents)

NaBH4: H2O, CH3OH, C2H5OH etc. (Protic Solvents)
Advantages:
 These can be used for selective reduction of polar multiple bond such as
C=O, C=N, N=O in the presence of C=C, and carbon-carbon triple bond etc.
 These contain a large amount of hydrogen in a small quantity of reagent.
 Sterically hindered ketone can be reduced by LiAlH4.
Comparisons:
 LiAlH4 is more reductive than NaBH4, it can be used to reduce aldehyde,
ketone, amide, ester etc. but NaBH4 can be used to reduced only aldehyde
and ketone.
 NaBH4 can be used with water, alcohol to reduce the compound such as
sugar that are not soluble in ether.
 LiAlH4 is more reactive and less selective than NaBH4.
 Reduction of Aldehyde and Ketone with LiAlH4

Reduction of aldehyde and ketone with LiAlH4 involves the transfer of hydride
anion form the metal atom to carbonyl carbon atom. This transfer is presumably
assisted by the prior or concurrent association of carbonyl oxygen atom with
lithium cation.

L i+ H 3A l
O O Li
A lH 3 H
C Li H 3A l O C H (C H 3 )2
C A -1
H
H 3C CH3
H 3C CH3

(C H 3)2C O (C H 3 )2 C O
Li H 2A l O C H (C H 3 )2 2
L i A lH O C H (C H 3)2 3
A -2 A -3

(C H 3 )2 C O H 2O
Li Al O C H (C H 3 )2 4
4 HO C H (C H 3 )2
A -4

Finally the alcohol is obtained by hydrolysis of tetralkoxyaluminium anion.

 Reduction of Aldehyde and Ketone with NaBH4

Reduction of aldehyde and ketone with NaBH4 differ from LiAlH4 requiring the
presence of electrophilic catalyst such as a protic solvent or Lithium or
magnesium cation in order to occur the reaction.

H3C
CH O H
H3C O
(CH3)2CHOH + H3B O CH(CH3)2
C B-1
H3B H
H3C CH3

(CH3)2CO (CH3)2CO
H3B O CH(CH3)2 H2B O CH(CH3)2 2 HB O CH(CH3)2 3
B-2 B-3

(CH3)2CO
B-4 B O CH(CH3)2 4

However, the reduction with NaBH4 is not analogous with LiAlH4, because for
NaBH4 B-1 is the rate limiting whereas for LiAlH4, A-4 is rate limiting. This is due to
the rapid disproportion of the initially formed alkoxyborohydride anion so that the reducing
agent is always borohydride.
 Stereochemistry of Ketone Reduction

The stereochemistry of the ketone reduction by metal hydride is influence by the

presence of asymmetry in the molecule. The best example are those having the
asymmetric center adjacent to carbonyl group.
C2H5 C2H5 C2H5
C C C6H5 LiAlH4 C C C6H5
C C C6H5 + H
H3C H3C H3C
H O OAlH3 H OAlH3

Optically Active

H2O

C2H5 C2H5
C C C6H5 + C C
H C6H5
H3C H3C
H O OH
H
Racemic Optically Active

Since metal hydride particularly LiAlH4, may function as strong base, one might
expect an optically active ketone having an α-hydrogen to be converted to its
enolate and consequently a small amount racemized prior to the reduction. The
reduced product also formed without racemization.
 Stereochemistry of Ketone Reduction

This is because, enolate anion reacts very slowly with LiAlH4 and racemic ketone
produce by the hydrolysis during the isolation process when no excess reagent
remain.

Since no protic solvent are present during the reduction with LiAlH4, racemic
ketone obtained by transfer of a proton form starting ketone. When this proton
transfer become slower than reduction, then reduction product is obtained.

For NaBH4, reduction carried out in hydroxylic solvent, so proton transfer to

enolate with racemization and subsequent reduction become very probable, But
the lower the base strength of BH4- greatly diminishes the formation of anion and
permit the reduction of carbonyl functional group without racemization.
 Stereochemistry of Ketone Reduction

Product development control: The transition state geometry for the reduction of
unhindered ketone resembles the geometry of alcohol product. The favored
transition state give the major product. This circumstances is descried as product
development control.

Steric Approach Control: For the reduction of hindered ketone, the transition
state geometry resembles to the starting ketone in geometry. In reduction of this
type attributed to attract of the metal hydride from the less hindered side of the
carbonyl group. This is termed as Steric approach control.
 Stereochemistry of Ketone Reduction

H.W: Discuss the result of carbonyl reduction when α-carbon contain a polar
group.
• Reduction of 4- tBu-cyclohexanone with LiAlH4 give equatorial alcohol as
major product. Explain why?

H OH

O OH H
LiAlH4 + (H3C)3C
(H3C)3C
(H3C)3C (C2H5)2O H
H 10-12%
H 80-90%

When the steric environment is comparable on each side of the ketone, the
major reduction product is the more stable product, i.e. equitorial alcohol.

This results can be explained with the help of transition state geometry. The
stereochemistry of the product is determined by the combination of steric
interference, torsional strain and electrostatic effects in the transition state.
 Stereochemistry of Ketone Reduction

The transition state (A) which leads to equatorial alcohol avoids the torsional
stain, steric interference.

On the other hand, the transitional state (B) which leads to axial alcohol also
avoids the torsional stain but it has significant steric repulsion with axial
hydrogen (Ha)
 Question

Write the product of the following reaction with composition and explain the reason.

H3C CH3 CH3 H3C CH3

H3C
CH3 CH3 CH3

O LiAlH4 OH H
+
(C2H5)O H OH

90% of product 10% of product

Ans: In metal hydride reduction, metal hydride usually prefer to approach from
the less hindered side. Here, the major product is formed by the addition of
hydride ion from the less hindered side. On the other hand, in minor product
the hydride ion faces some steric repulsion from the methyl groups.
Some Examples of Metal hydride Reduction

O
OH
H
(C2H5)2O H2O
+ LiAlH4
o
N 25 C N

O
OH H H HO

NaBH4
+
CH3OH, 0oC
H2O

H CHO2CH3 CHO2CH3
CO2CH3 H
68% 32%

NaBH4
CH3CO(CH2)2CH2-NO2 CH3CH(CH2)2CH-NO2
CH3OH-H2O
25 oC OH

NaBH4
CH3COCH2Br CH3CHCH2Br
CH3OH, H2O
25 oC OH
 Reduction with Dissolving Metals

A variety of organic compounds are reduced by reaction with metal either in the
presence of proton donor or followed by the treatment with proton donor.

The commonly used alkali metal are Li, Na, K as well as Ca, Zn, Mg, Sn and Fe.
Proton donor are water, alcohol (ethanol, t-BuOH) and acid etc.

The alkali metal and calcium have been used as solution in Liq NH3 (bp -33oC),
in low molecular weight aliphatic amine, in hexamethylphosphamide as very
dilute solution or as very dilute solution in ether or THF of certain alkali metals(K,
Ce) complexes with macrocyclic polymers.

Reaction of Liq NH3, often used as co-solvent such as ether, THF, 1,2-
dimethoxyethane to increase the solubility of organic compounds.
 Reduction with Dissolving Metals

The dissolving metal reductions are considered as internal electrolytic

reduction in which one electron transferred from metal surface to organic
compounds to be reduced giving an anion, radical which in many cases is
immediately protonated. The resulting radical subsequently takes another
electron from metal and form anion which may protonated immediately or remain
as anion until work up.
Example-1:

C6H5 C C6H5 Na C6H5 C C6H5 C6H5 C C6H5

O O O

C2H5OH

H H H
C6H5 C C6H5 C2H5OH C6H5 C C6H5 C6H5 C C6H5
Na
OH O O
 Reduction with Dissolving Metals

Example-2:
In some cases second electron may be added to anion radical to form a
dianion or two anion in case of fusion reaction.

H
Na
Na

CH3OCH2CH2OCH3
H

Li (Dark blue)
Napthalide ion
O

H Li H Li
Li

H H Li
O
(Purple)
 Reduction Carbonyl Group

Although the salt of carboxylic acids are not reduce by alkali metal in liq NH3,
solution of metal in higher boiling solvent such as methylamine , ethylamine will
reduce to aldehyde derivatives
O
Li CH3NH2 HCl, H2O
n-C4H9 CO2H n-C4H9 CH 2Li n-C4H9 C N n-C4H9 CHO
CH3NH2 H2O, NH4Cl H
O CH3

The carbonyl group of aldehyde and ketone is reduced to alcohol by reaction

with variety of metals in protic solvents.
Z n, N aO H
(C 6H 5)2C O (C 6H 5)2C H 2-O H
C 2H 5O H , 7 0 oC

F e, C H 3C O 2H
n -C 6H 13C H O n -C 6H 13C H 2-O H
o
H 2O , 1 0 0 C

O N a -H g O
C 2H 5O H
6 0 -7 0 oC HO H
O
 Clemensen Reduction

The reduction of ketone with Zn-Hg in strong aq. acid to convert methylene group
known as Clemensen reduction. As illustrated in the following equation, the
reaction have been commonly been run as three phase mixture of toluene, aq.
HCl and Zn-Hg.

Zn-Hg
C6H5-CO-CH2CH2CO2H C6H5-CH2-CH2CH2CO2H
HCl, H2O
Toluene, Reflux

Zn-Hg
n-C6H13COCH3 n-C6H13CH2CH3
AcOH, H2O, HCl
Reflux

OCH3 OCH3
HO Zn-Hg HO

HCl, H2O
CHO AcOH, Reflux CH3
 Birch Reduction

Selective reduction of organic compounds with alkali metals in presence of liq

NH3 is known as Birch reduction.

Birch reductions are usually effected with solution of Li, Na, K in liq NH3. In some
reaction alcohols are added as proton donor. Under these conditions, conjugated
dienes, α,β-unsaturated ketone, styrene derivatives and benzene ring can be
reduced to dihydro derivatives.

Solution of alkali metals in liq NH3 contain solvated electron as

M + NH3 M+(NH3) + e-( NH3)

Solubility of many organic compounds in liq NH3 is low at room temperature. So

the co-solvent as ether, THF are often used to increase the solubility.
 Birch Reduction

Mechanism:

Example:
 Questions

Q: Reduction of alkyne with Na in liq NH3 gives trans product. Explain

Normally isolated carbon-carbon double bonds are not effected by metals in liq
NH3. But carbon-carbon triple bons are very much selectively effected by this
reagenst and gives trans product.

The reaction takes place by stepwise addition of electrons to carbon-carbon

triple bond to form dianion as:
Na Na Na
Na in liq NH3
C C C C C C C C
H H Na

C C C C

Due to the interaction of two negatively charged spe orbitals, they occupy
more stable trans configuration. This dianion then protonated to gives trans
olefins. + H
Na C2H5OH
C C C C
Na+ H
 Questions

Q: Conjugated double bonds are reduced by metal Na-liq NH3 but not isolated
double bonds. Why?
Isolated double bonds are not usually reduced by dissolving metals because the
intermediate formed is not so stable for the electrostatic repulsion. The
intermediate, electron addition product requires more energy than ordinary
reagents can provide.

Na C C C C Electrons are not localized

On the other hand, reduction is possible in conjugated system because the

intermediate is stabilized by delocalization of electrons.

Na C C C C C C C C C C C CH P ro d u c t
 Birch Reduction

Example: 2- Hexane is not effected by Na in liq NH3

Na in liq NH3
H3CHC CH(CH2)2CH3 Uneffected
Alcohol
On the other hand conjugated dienes are readily reduced to dihyroderivateds in
the absence of added proton donor. The reduction of isoprene gives 2-methyl-2-
butene. CH3 CH 3
Na in liq NH3
H2C C C CH2 H3C C C CH
H Alcohol H 3

Mechanism:
CH3 CH3 CH3
N a in liq N H 3
H 2C C C CH2 H 2C C C CH2 H 2C C C CH3
Na H H H

N a in liq N H 3

CH3 CH3

H 3C C C CH3 H 2C C C CH3
H H