NPTEL Chemistry Reagents and Organic reactions

Module II Reduction Reactions

Lecture 14

2.1.1 Lithium Aluminum Hydride (LAH)

2.1.1.1 Introduction

Lithium aluminum hydride (LAH) is a strong reducing agent with chemical formula
LiAlH4. It can reduce a variety of functional groups such as aldehydes, esters,
acids, ketones, nitriles, epoxides and azides. It vigorously reacts with water and
all the reactions are performed in polar aprotic solvents.

2.1.1.2 Preparation

It was first prepared by treating lithium hydride (LiH) with aluminum chloride
(AlCl3) (Scheme 1).

4LiH + AlCl3 LiAlH4 + 3LiCl

Scheme 1

In industrial scale, it is prepared from sodium aluminum hydride which is

prepared by reaction of sodium, aluminum and hydrogen at high temperature and
pressure (Scheme 2).

Na + Al + 2H2 NaAlH4

NaAlH4 + LiCl LiAlH4 + NaCl

Scheme 2

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2.1.1.3 Reduction of Aldehydes and Ketones

The aldehydes and ketones are reduced to give the corresponding alcohols
when treated with LAH (Scheme 3). For the reduction of aldehydes and ketones,
the reaction is generally performed in ether solvents at low temperature.

O OH
R H LiAlH4 R H
or or
O OH
R R' R R'

O OH
LiAlH4
Br Br
Me Me
Et2O, -78 C

Scheme 3

Mechanism

The hydride from LAH is transferred to the carbonyl group to form alkoxy anion
which then forms complex with aluminum (Scheme 4). Similarly, four hydride
atoms are replaced by four alkoxy groups and the aluminum complex thus
formed is then hydrolyzed by dilute acid to give the desired alcohol.

R R
O H O H R
O H H O H O H
H R H
O Al H R H H
H Al H O Al H O Al O
R H R H R R
H H H
H H H H H H O

R H

R
H R
OH H O H
H3O H
4 R H O Al O
H R O H
H H H
R

Scheme 4

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2.1.1.4 Reduction of Acids

The acids are often reduced with LAH to prepare the corresponding alcohols
(Scheme 5). The other comparable method for reduction of acid is using BH 3 as
a reducing agent. The three hydride ions are consumed for reducing one acid
group.

O
LiAlH4
R OH R OH

Me Me
O LiAlH4

OH Et2O OH

Scheme 5

2.1.1.5 Reduction of Esters and Amides

The esters and amides are reduced to the corresponding alcohols and amines,
respectively, when treated with LAH (Scheme 6). Each molecule of ester or
amides consumes two molecules of hydride ions.

O
R'
R O R OH + R' OH
or LiAlH4 or
O
R'
R' R N
R N
R'
R'

Me Me
O O LiAlH4 HO OH
O O
Et2O O O
O O Me Me
Me Me

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LiAlH4
NH NH
O OH THF
OH

Me Me

Scheme 6

2.1.1.6 Reduction of Azides, Nitriles and Nitro Compounds

The azides, nitriles and nitro compounds are reduced to the corresponding
amines in presence of LAH (Scheme 7). The aromatic nitro compounds do not
give the desired amines.

R N3
or
LiAlH4
R C N R NH2
or
R NO2

Scheme 7

2.1.1.7 Reduction of Epoxides

The epoxides are reduced to the corresponding alcohols (Scheme 8). The
hydride ion is transferred to the less hindered side of the epoxides.

Me LiAlH Me
4
O OH

HO
O Me Me
LiAlH4
H O H O
Et2O/THF
O 0 C O
CO2Me
OH

Scheme 8

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2.1.2 Lithium Trialkoxyaluminum Hydride [LiAlH(OR)3]

2.1.2.1 Introduction

Though LAH is a powerful reducing agent but is less selective. The reactivity and
selectivity can be modified by replacing the three hydride ion with alkoxy groups
such as tert-butoxy or ethoxy group. The resulting reagents are less reactive but
more selective than LAH.

2.1.2.2 Preparation

The lithium trialkoxyaluminum hydride can be prepared by treating LAH with the
alcohol and better to prepare in situ prior to use (Scheme 9).

3 t-BuOH LiAlH(Ot-Bu)3
LiAlH4 + or or + 3H2
3 EtOH LiAlH(OEt)3

Scheme 9

2.1.2.2.1 Lithium tri-t-Butoxyaluminum Hydride [LiAlH(Ot-Bu)3]

This is less reactive compared to LAH and reduces aldehydes and ketones to
alcohols and acid chlorides to aldehydes (Scheme 10). The other functional
groups such as acids, amides and nitriles do not react or react very slowly.

O O
LiAlH(Ot-Bu)3
Cl H
diglyme, -78 C
NC NC

Scheme 10

2.1.2.2.2 Lithium tri-Ethoxyaluminum Hydride [LiAlH(OEt)3]

Lithium tri-ethoxyaluminum hydride is comparatively stronger reducing agent

than lithium tri-t-butoxyaluminum hydride (Scheme 11). It can reduce amides and
nitriles to the corresponding aldehydes in good yield.

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O
CN LiAlH(OEt)3 H
Et2O

Scheme 11

2.1.3 Sodium bis(2-Methoxyethoxy)aluminum Hydride (SMEH)

[NaAlH2(OCH2CH2OMe)2]

Sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH) is a commercially

available reducing agent with trade name Red-Al. It is more selective than LAH
and the reduction can be carried out in aromatic hydrocarbons as well as other
ethers solvent (Scheme 12).

M. Gugelchuk, Encyclopedia of Reagents for Organic Synthesis, John Wiley and

Sons., Inc., L. A. Paquette, Ed., New York, 1995, 7, 4518.

R NH2
R'
R NH2
R
R' N R
H R
R' O NO2
R' CN R
H2N
N R

O O O
or OH OH
R OR' R R' R H or
R'OH + R OH Red-Al R R' R H

O O
O R R
O NR'2
R O O

R Cl R OH
R OH R NR'2

R OH

Scheme 12

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Examples:

OH OH OH OH
Reduction
+ +
Ether
TMS TMS TMS
TMS
LAH 19 49 32

SMEAH 100 0 0

S. E. Denmark, T. K. Jones, J. Org. Chem. 1982, 47, 4595.

OH OH
HOH2C
OH SMEAH OH

N Toluene N
t-Bu
30%

M. Ishizaki, O. Hoshino, Y. Iitaka, J. Org. Chem. 1992, 57, 7285.

O Al O Al
O H Al
Me O SMEAH Me O
Me O C
Me THF Me Al
Me

O
OH
Al
O
Me
Me Me CH2OH
Me

R. B. Gammill, L. T. Bell, S. A. Mizsak, Tetrahedron Lett. 1990, 31, 5301.

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2.1.4 Diisobutylaluminum Hydride (DIBAL-H)

The diisobutylaluminum hydride (DIBAL-H) is a commercially available selective

reducing agent. It can selectively reduce esters and nitriles to the corresponding
aldehydes. The reaction is carried out in inert and moisture free atmosphere.

P. Galatsis, Encyclopedia of Reagents for Organic Synthesis, John Wiley and

Sons, Inc., L. A. Paquette, Ed., New York, 1995, 3, 1908.

2.1.4.1 Reduction of Esters to Aldehydes

The esters are selectively reduced to the corresponding aldehydes at low

temperature. The DIBAL-H transfer one hydride to the ester group and forms a
tetrahedral intermediate which is stable at low temperature. The hydrolytic work
up of the intermediate gives the desired aldehydes (Scheme 13). The presence
of alkoxy or amino group to the close proximity can stabilize the tetrahedral
intermediate and hence give better result.

CO2Me DIBAL-H CHO

O O
Me Toluene -78 C Me
MeO MeO

Me

Me
Me O
O Me Me Al
Al O H3O
R' Me R H
R O Me H Me R'
R O
H
tetrahedral
intermediate

Scheme 13

2.1.4.2 Reduction of Nitriles

The nitriles are selectively reduced to the corresponding aldehydes with one
equivalent of DIBAL-H at low temperature. The use of two equivalent of DIBAL-H
gives the corresponding primary amine.

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Me Me
H H
CN CHO
DIBAL-H
CH2Cl2, -78 C
Me Me

Scheme 14

Examples:

O O
O ClH2C O
ClH2C DIBAL

iPrOH, PPTS
79%

J. L. Vicario, A. Job, M. Wolberg, M. Muller, D. Enders, Org. Lett. 2002, 4, 1023.

O O
O DIBAL O

PhH
CN CHO

80%

R. V. Stevens, L. E. Dupree, P. L. Lowenstein, J. Org. Chem. 1972, 37, 977.

Problems
A. How will you carry out the following reduction reactions using aluminum hydride
based reagents?
CHO CH2OH
1. Ph Ph

CHO CH2OH
2. Ph Ph

O O

3. NMe2 H

4. CN CHO

5. CO2Me CHO

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B. Provide mechanism for the following reaction.

DIBAL-H OH
CO2Me
THF

Text Book

M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004.

Lecture 15

2.1.5 Borohydrides

Different borohydrides are available depending on the metal cations and ligands
such as sodium borohydride, lithium borohydride, zinc borohydride, lithium or
potassium trialkylborohydride and sodium cyanoborohydride. All the
borohydrides reduce aldehydes and ketones to the corresponding alcohols but
due to its counter cations and ligands it shows some special selectivity towards
some functional groups.

2.1.5.1 Sodium Borohydride (NaBH4)

The sodium borohydride is an ideal reducing agent for the reduction of aldehydes
and ketones to give the corresponding alcohols (Scheme 1). Unconjugated
ketones and aldehydes are rapidly reduced, usually in preference to a
conjugated carbonyl group that may be present elsewhere in the molecules. The
reactions are performed in polar solvents such as THF, DME, diglyme, hydroxyl
solvent and water but the ethanol is the solvent of choice.

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O O

O HO
NaBH4, EtOH/CH2Cl2

NH4Cl
S HS S
HS

Scheme 1

In contrast, in the presence of CeCl3, conjugated ketone is reduced much faster

compared to the normal ketone (Scheme 2). The combination of NaBH4 and
CeCl3 is called Luche reagent and the reaction is known as Luche reduction.

O OH
Me Me
NaBH4/CeCl3
CO2Me CO2Me
MeOH
OH OH
Me O Me Me O Me
91%

Scheme 2

Proposed Mechanism

The cerium reagent coordinates to the carbonyl, making only a 1,2-addition

possible (Scheme 3).

CeCl3 + NaBH4 HCeCl2

Cl
Cl Cl
O Ce Ce Cl
H O H3O+ OH
H H
R
R R

Scheme 3

The esters react slowly and the carboxylic acids in normal condition do not react
but are reduced to alcohol in presence of catalytic amount of iodine in reflux
condition in THF (Scheme 4). This method provides effective route for the

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conversions of amino acids to amino alcohols, which serve as ligands for

asymmetric catalysis.

CO2H NaBH4, I2 Ph OH
Ph
H NH2 THF, reflux H NH2

Scheme 4

Amides are not reduced directly by NaBH4, but if they are first converted to an
imimium salts that readily proceed the reduction to give an amine (Scheme 5).

O + Cl
Cl Cl Cl
N N NaBH4 N
POCl3

EtOH

Scheme 5

Examples:

O OH OH
MeOH
+

NaBH4 0 100
NaBH4/CeCl3 96 4

J. L. Luche, J. Am. Chem. Soc. 1978, 100, 2226.

O OH
CO2Me Luche reduction CO2Me

CHO CHO
76%

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

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O HO

Luche reduction
OTBS OTBS
O O
Me Me
77%

K. Takao, G. Watanabe, H. Yasuki, K. Tadno, Org. Lett. 2002, 4, 2941.

OHC TIPS HOH2C TIPS

Luche reduction

CO2Ph CO2Ph

D. L. Comins, A. L. William, Org. Lett. 2001, 3, 3217.

2.1.5.2 Lithium Borohydride (LiBH4)

Lithium borohydride is prepared by reaction of NaBH4 with lithium bromide. It is

more powerful reducing agent than NaBH4, reducing not only aldehydes,
ketones, but also epoxides, esters and lactones (Scheme 6). This is due to the
fact that the Li+ cation is stronger Lewis acid than Na+ cation. Therefore, Li+ ion
can co-ordinate with carbonyl compound which increases the electrophilicity of
carbonyl carbon and facilitates the hydride transfer.

Me Me
H H
CONMe2 LiBH4 CONMe2

CO2Me OH
Me Me

Scheme 6

2.1.5.3 Zinc Borohydride [Zn(BH4)2]

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The zinc borohydride is prepared from zinc chloride and NaBH 4 in ether. It is
most useful for the reduction of -unsaturated aldehydes and ketones to give
saturated alcohols (Scheme 7).

O OH OH
Zn(BH4)2
+
H3O+
96% 4%

Scheme 7

2.1.5.4 Lithium or Potassium Trialkylborohydride

The presence of three alkyl groups in boron atom makes the hydride strongly
nucleophile and hence it is a strong reducing agent compared to other
borohydrides, and it can reduce the aldehydes and ketones even at -78 C
temperature. The commonly used trilakylborohydrides are lithium
triethylborohydride, Li(Et3BH), and lithium and potassium tri-sec-butylborohydride
(L- and K-Selectrides). The bulky L- and K-selectrides can reduce carbonyl
compound from less hindered side resulting selective products (Scheme 8).

H H
L-Selectride
OH
O
H THF, -78 C H H
H H
Et Et
H H
Scheme 8

J. L. Hubbard, Encyclopedia of Reagents for Organic Synthesis, John Wiley and

Sons, Inc., L. A. Pauette, Ed., New York, 1995, 5, 3172.

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Examples:

Me Me
Me Me
L-Selectride

THF OH
SO2 O
SO2
N(iPr)2
N(iPr)2
92%

W. Oppolzer, C. Chapuis,G. Bernardinelli, Tetrahedron Lett. 1984, 25, 5885.

OTBDMS OTBDMS
Me Me
L-Selectride
O O
H H ClCH2OMe OMe H H
Et2NH
MeO2C OTBDMS MeO2C OTBDMS
90%

E. Piers, M. A. Romero, Tetrahedron 1993, 49, 5791.

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OMe
CN OTBDMS K-Selectride CN
O OTBDMS
O
Me ClCH2OMe Me
Et2NH 60%

J. Nokami, M. Ohkura, Y. Dan-Oh, Y. Sakamoto, Tetrahedron Lett. 1991, 32,

2400.

Other than the carbonyl groups, lithium triethylborohydride can reduce primary
bromides and tosylates to the corresponding hydrocarbons (Scheme 9). The
epoxides are also cleaved to give the alcohols and the hydride is transferred to
the less hindered side if epoxides. Lithium triethylborohydride is called super
hydride and an extremely powerful source of hydride.
OTs
Me

Li(Et3BH), THF
NaOH, H2O2

Scheme 9

M. Zaidlewicz, H. C. Brown, Encyclopedia of Reagents for Organic Synthesis,

John Wiley and Sons, Inc., L. A. Pauette, Ed., New York, 1995, 5, 3180.

Examples:

H
H
Super hydride N
N O
O HOH2C
MeO2C THF
O
O
97%

N. Toyooka, M. Okumura, H. Nemoto, J. Org. Chem. 2002, 67, 6078.

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Super hydride
Me Me

Me N CO2Me Me N CH2OH
CO2Me CO2Me
90%

N. Toyooka, A. Fukutome, H. Nemoto, J. W. Daly, T. F. Spande, H. M. Garraffo,

T. Kaneko, Org. Lett. 2002, 4, 1715.

O O
CO2H
H
O + O
Et
Et Et
O
Source Yield (%) Ratio

DIBAL 64 25 75
Super hydride 83 85 15
L-Selectride 65 75 25

N. Pourahmady, E. J. Eisenbraun, J. Org. Chem. 1983, 48, 3067.

2.1.5.5 Sodium Cyanoborohydride (NaBH3CN)

NaBH3CN is less reactive reducing agent than sodium borohydride due to the
presence of electron withdrawing cyano group. Reaction of NaBH4 with HCN
gives NaBH3CN, which is soluble in THF, MeOH, H2O, HMPA and DMF.
NaBH3CN cannot reduce the aldehydes or ketones in neutral condition but it
reduces the protonated aldehydes and ketones at around pH 3 (Scheme 10).
The iminium ion could be reduced to the corresponding amine with almost
quantitative yield (Scheme 11).

CO2Et H CO2Et
H
NaBH3CN H
O N
N pH ~4 OH

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O O NaBH3CN O O
OHC HOH2C
MeOH, pH 4
NHCO2CH2Ph NHCO2CH2Ph
89%

Scheme 10

Ph Ph
N N
H NaBH3CN H
N N
N MeOH N
Bn Me Bn Me

Scheme 11

The other important reaction is the deoxygenation of carbonyl compound via

tosyl hydrazone formation (Scheme 12). It can reduce tosyl hydrazone to the
corresponding hydrocarbon.

NHTs
N Me
CHO NaBH3CN
NH2NHTs
DMF, heat

Scheme 12

It is also useful for the reductive alkylation of amines. For example,

dimethylamino derivative can be prepared from the amine by treatment with
HCHO and NaBH3CN, even in the presence of functional groups such as the
conjugated ketones and the ester. Furthermore, the selectivity for the example
shown in Scheme 13 is the major advantage in using NaBH3CN rather than other
reducing agents.
O O
NaBH3CN, HCHO CO2Me
CO2Me
Me Me
MeCN, H2O
NH2 NMe2

Scheme 31

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Problems:
A. Complete the following reactions.
OH
N
1.

2. Br
O

B. What major products would you expect in the following reactions.

O
OEt NaBH4
1. Ar
EtOH, -30 oC
O

H H
Ph O
2. N NaBH4
N EtOH
O Br
Me

H NaBH4
3. O N S
O THF
O

C. Provide mechanistic rational for the following reaction.

OH 3.3 equiv NaOH
CCl3 1.5 equiv NaBH4 CO2H
t-BuOH, heat

Text Book

M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004.

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Lecture 16

2.2 Dissolving Metal Reductions (Na-Liq. NH3, Li-Liq.

NH3, etc.)

2.2.1 Introduction

The solution of alkali metal in ammonia (at -33 C) can generate solvated
electrons and metal cations.

M + (NH3)liquid M+ [ H3N e- NH3]

solvated electron

These solvated electrons can reduce conjugated double bonds, triple bonds and
aromatic compounds. Most of the organic compounds are not soluble in liquid
ammonia and, therefore, the compounds are dissolved in THF or Et2O and are
added to the dissolved metal solution.

2.2.2 Reduction of Conjugated Dienes

The conjugated dienes are readily reduced to the corresponding 1,4-dihydro

compounds with dissolved metal ammonia reagents (Scheme 1).

Me Me
Na, (NH3)liquid
Me
Me

Scheme 1

2.2.3 Reduction of ,-Unsaturated Ketones

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The ,-unsaturated ketones could be reduced to the corresponding saturated

carbonyl compounds or alcohols depending on the reaction conditions with
dissolved metal in ammonia (Scheme 2). For examples, the ,-unsaturated
ketone, cyperone, when treated with lithium in ammonia, it gives the
corresponding saturated ketone but when treated with lithium in ammonia and
ethanol, a good proton source, it gives the corresponding alcohol.

Me Me
Li, (NH3)liquid

O Et2O O
H
then aq. NH4Cl Me Me
Me Me
cyperone

Me Me
Li, (NH3)liquid

O EtOH HO
H
Me Me Me Me

cyperone

Scheme 2

Mechanism

The solvated electron is transferred to the conjugated system to give the radical
anion which is protonated by added alcohol or ammonia and then the second
electron transfer generates the enolate anion which on protonation during work
up gives the desired carbonyl compound (Scheme 3).

O Li O OH OH Li O

Li, (NH3)liquid protonation Li, (NH3)liquid

Me Me Me Me Me
Li
aq. NH4Cl

Me

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Scheme 3

2.2.4 Reduction of Aromatic Compounds (Birch Reduction)

The reduction of aromatic compounds to 1,4-cyclohexadiene compounds in

presence of alkali metal liquid ammonia and an alcohol is called Birch reduction.
A variety of aromatic compounds containing electron donating or electron
withdrawing groups could be readily converted to the corresponding 1,4-
cyclohexadiene derivatives (Scheme 4).

Li, (NH3)liquid
EtOH

Scheme 4

The regioselectivity towards the products in Birch reduction of substituted

aromatic compound depends on the nature of the substituent. For example, the
electron donating substituent such as alkyl or alkoxy group remains on the
unreduced carbon where as the electron withdrawing groups such as carboxylic
acid or primary amide remains on reduced carbon almost exclusively (Scheme
5).

X
X X
Birch reduction
or

X = -OH, -OR, -NR2, X = -CO2H, -CONH2

-SR, -PR2, -alkyl,
-CH2OR, -CH2OH,
- CHO, CO2R

Scheme 5

The aldehydes and esters groups are in the electron donation side because
these are reduced to the corresponding alcohols in Birch condition before the
reduction of aromatic ring (Scheme 6). The addition of one or two equivalent of
water or t-BuOH to the NH3 before the addition of metal can preserve the ester
group in Birch reduction.

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O O

OEt 1.5 equiv H2O OEt

Na, (NH3)liquid
THF

Scheme 6

Mechanism

The solvated electron accepts an electron and generates the radical anion which
then takes a proton from the alcohol and forms a radical intermediate (Scheme
7). The radical intermediate then takes another electron and converts to the
carbanion which on protonation gives the desired 1,4-cyclohexadiene derivatives.
The role of alcohol is to supply the proton because the NH3 is not sufficient acidic
to supply the proton to all the intermediate anion.

H H H H H H H H
- -
e ROH e ROH

H H H H H

Scheme 7

Examples:

O OMe O OMe
o
Et
K, NH3, t-BuOH, THP, -78 C
N N

TMS LiBr, Piperylene, EtI, -18 oC TMS

A. G. Schultz, L. Pettus, J. Org. Chem. 1997, 62, 6855.

CH2OH
CH2OH i. Li/NH
3

O
MeO ii. HO2C-CO2H,
H2O, t-BuOH

E. J. Corey, N. W. Boaz, Tetrahedron Lett. 1985, 26, 6015.

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HO2C OMe HO2C

Li/NH3 OMe
Me
MeI
OMe OMe
87%

A. Gopalan, P. Mangus, J. Am. Chem. Soc. 1980, 102, 1756.

2.2.5 Reduction of Alkynes

The reduction of alkynes to trans alkenes selectively is carried out by the

dissolved metal in ammonia. This reaction specifically gives the trans alkenes (E
alkenes) where as the reduction with Lindlar catalyst gives the cis alkenes (Z
alkenes) (Scheme 8).

Na, NH3 R'

R R' R
E alkene

Lindlar R R'
catalyst
R R'
H2 Z alkene

Scheme 8

Proposed Mechanism for Lindlar Reduction

R R
R R
H H H H

Examples:

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Br
Br N
Lindlar
N N3 Br O
Br O H H2, MeOH
O H2N N
O
H2N

T. Lindel, M. Hochgurtel, J. Org. Chem. 2000, 65, 2806.

Pr
CH2OH
H2
Pr
Lindlar catalyst
quinoline, MeOH
OH

A. Tai, F. Matsumura, H. C. Coppel, J. Org. Chem. 1969, 34, 2180.

O O
H2
O
O Lindlar catalyst
Me Me

O O

O
O
96% Me
Me

Furstner, T. Dierkes, Org. Lett. 2000, 2, 2463.

Me H2 Me
N N
CHO Lindlar catalyst
CHO
92%

T. Itoh, N. Yamazaki, C. Kibayashi, Org. Lett. 2002, 4, 2469.

2.2.6 Reductive Deprotection of Benzyl Group

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The benzyl group and cyano group (alkyl nitrile) could be deprotected by
dissolved metal in ammonia (Scheme 9).

Me H Me H
Li, EtOH (7equiv)

H NH3, THF H
O BnO O HO

Ph Na, NH3 Ph
Ph CN Ph H
Ph Ph

Scheme 9

2.2.7 Bouveault-Blanc reduction

The reduction of carboxylic acid esters to the corresponding alcohols in presence

of sodium in ethanol is known as Bouveault-Blanc reduction (Scheme 10). This
was one of the important methods for the reduction of carboxylic esters before
the discovery of lithium aluminum hydride.

O
Na, EtOH
R OR' R OH + R' OH

H H
CO2Me CH2OH
Na, EtOH
COOH COOH
NH3
H H

Scheme 10

Proposed Mechanism

The carbonyl group of ester takes an electron and converts to the radical anion
which takes a proton from the alcohol and forms the radical intermediate. The

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latter takes the second electron and a proton and undergoes elimination of an
alcohol to give aldehydes that further proceeds further reduction to give the
desired alcohol.

H
O O OH OH O
e EtOH e EtOH
R OR' R OR' R OR' R OR' R OR'

-HOR'
OH OH OH O O
EtOH e EtOH e
R H R H R H R H R H

Examples:

CO2Me Na, NH3 CH2OH

CO2H alcohol CO2H

72%

L. A. Paquette, N. A. Nelson, J. Org. Chem. 1962, 27, 2272.

Na
EtO2C HOH2C
CO2Et CH2OH
EtOH
75%

R. H. Manske, Org. Synth. CV2, 154.

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Problems

Complete the following rections.

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Na, EtOH
1.

OH

Li-NH3-EtOH
2.

OMe
Na, EtOH
3.
H3O

Na-NH3-EtOH
4.

CO2H

Na-NH3-EtOH
5.

OEt
Na-NH3-EtOH
6.

Na, EtOH
7.

8. Na, EtOH
NOH
reflux
O
(EtO2)2SiHMe
9. Ph
Br KF

Text Book

M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004.

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NPTEL Chemistry Reagents and Organic reactions

Lecture 17

2.3 Molecular Hydrogen

2.3.1 Introduction

Hydrogen is the most abundant chemical element in the universe with atomic
number 1 and symbol H. It has three isotopes hydrogen 1H, deuterium 2D and
tritium 3T and the 1H is the most abundant (99.98%). The hydrogen 1H and
deuterium 2D are stable isotopes whereas the tritium 3T is a radioactive. In
organic chemistry, hydrogen is used to reduce a variety of functional groups but
the hydrogen gas itself can not reduce any functional groups without a catalyst.

2.3.2 Reduction of Carbon-Carbon Double Bonds

The reduction of carbon-carbon double bond is academically as well as

industrially important transformation (Scheme 1). The order of hydrogenation of
substituted double bond is 1,1-di > 1,2-di > 1,2-tri > 1,2-tetra substituted.
Different metal catalysts have been used for the purpose. Among them, platinum
(Pt), iridium (Ir), ruthenium (Ru), rhodium (Rh), palladium (Pd) and nickel (Ni)
catalysts are commonly used.

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Ni Catalysts: C. R. Sarko, M. DiMare, Encyclopedia of Reagents for Organic

Synthesis, John Wiley and Sons, Inc., L. A. Paquette, Ed., New York, 1995, 6,
3701; Pd Catalysts: A. O. King, I. Shinka, Encyclopedia of Reagents for Organic
Synthesis, John Wiley and Sons, Inc., L. A. Paquette, Ed., New York, 1995, 6,
3867; E. M. Leahy, Encyclopedia of Reagents for Organic Synthesis, John Wiley
and Sons, Inc., L. A. Paquette, Ed., New York, 1995, 6, 3887; Pt Catalysts: A. O.
King, I. Shinka, Encyclopedia of Reagents for Organic Synthesis, John Wiley and
Sons, Inc., L. A. Paquette, Ed., New York, 1995, 6, 4159; 4160; Rh Catalysts: S.
Siegel, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons,
Inc., L. A. Paquette, Ed., New York, 1995, 6, 4405; Ru Catalysts: S. Siegel,
Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Inc., L.
A. Paquette, Ed., New York, 1995, 6, 4410.

Platinum oxide (PtO2) also known as Adams catalyst is generally used for the
platinum catalyzed hydrogenation reaction. Other catalysts such as Pd on
charcoal, Wilkinsons catalyst RhCl(PPh3)3, Crabtrees catalyst
[Ir(cod)(PChx3)(py)]PF6, Ru(OAc)2(BINAP), Raney nickel and Nickel boride (Ni2B)
are used. These reactions are performed in ethyl acetate, alcohols and acetic
acid as solvents.

Me Me
Me Me CO2H
CO2H
Pt, H2
AcOH

Me Me
O O
RhCl(PPh3)3
H2, toluene

Me Me Me

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OAc OAc
Me Me
Pd-C, H2
O H OAc O H OAc
EtOH H
Me Me Me H Me
MeO2C MeO2C

O O
Ni2B, H2

MeOH Me
Me

Scheme 1

For mechanism of hydrogenation, see: lecture 33, Principles of Organic

Synthesis

Vast number of chiral catalysts has been developed for asymmetric

hydrogenation reactions. Among them, Rh(I) and Ru(II) diphosphine complexes
revealed to be the most efficient for hydrogenation of functionalized alkenes
(Scheme S).

Et Et
P P

Et Et
(R,R)-DuPHOS

[(R,R)-Et-DuPHOS-Rh]+ CO2Me
CO2Me
NHAc
NHAc
99% ee

O OH
B-H
PPh2
O
PPh2
[Rh(COD)2]BF4 Me
Me 94% ee
(+)-BINAP
-78 oC (+)-BINAP

Scheme 2

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2.3.3 Reduction of Carbon-Carbon Triple Bonds

The carbon-carbon triple bonds are reduced to the corresponding carbon-carbon

single bonds when treated with Pt, Pd, Raney Ni catalysts and molecular
hydrogen (Scheme 3).

OH
OH OH
OH Pt, H2

Scheme 3

The carbon-carbon triple bonds are selectively reduced to carbon-carbon double

bonds in the presence of Lindlar catalyst (Pd/CaCO3/PbO) or Rosenmund
catalyst (Pd/BaSO4/quinoline) and molecular hydrogen (Scheme 4). The
hydrogenation of carbon-carbon triple bonds to carbon-carbon double bonds
always takes place from same side of the carbon-carbon triple bond providing
stereo specifically cis alkenes (Z alkenes).

Pd/BaSO4/quinoline

MeO2C CO2Me H2, MeOH

MeO2C CO2Me

Pd/CaCO3/PbO
H2, MeOH
Me CO2H Me
CO2H

Scheme 4

For Lindlar Catalyst, see: Lecture 16

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2.3.4 Reduction of Aromatic Compounds

Reduction of aromatic compounds could be performed with molecular hydrogen

in the presence of metal catalysts such as Pt, Pd, Rh, Ru and Raney nickel
(Scheme 5). The choice of metal catalyst depends on the nature of substrates.
For example, the aromatic ring could be selectively reduced in the presence of
an ester or acid group using molecular hydrogen with nickel or platinum catalyst.

CO2Et CO2Et
Ni, H2
100 atm., 50 C

PtO2, H2
CO2H CO2H
AcOH, 25 C

Scheme 5

2.3.5 Reduction of Aromatic Nitro Compounds

The aromatic nitro compounds can be reduced to give the corresponding amines
when treated with molecular hydrogen in the presence of Pt, Pd or Ni catalyst
(Scheme 6). The reaction is generally performed in methanol, ethanol or ethyl
acetate at ambient temperature.

NO2 NH2
Pd/C, H2
EtOAc, rt

Scheme 6

2.3.6 Reduction of Acid Chlorides

Acids chlorides undergo reduction to give the corresponding aldehydes in the

presence of molecular hydrogen and palladium catalyst (Scheme 7). When
Pd/BaSO4/quinoline is used as a catalyst along with molecular hydrogen the
reaction is called Rosenmund reaction.

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S. Siegel, Encyclopedia of Reagents for Organic Synthesis, John Wiley and

Sons, Inc., L. A. Paquette, Ed., New York, 1995, 6, 3861.

O O

Cl Pd/BaSO4/quinoline H
H2

Proposed Mechanism

O H2 O O

R Cl R Pd Cl R H
Pd-BaSO4

Scheme 7

Examples:

O H2, Pd/C/BaSO4 O

Cl CCl3 H CCl3
quinoline, petroleium ether
50%

J. W. Sellers, W. E. Bissinger, J. Am. Soc. 1954, 76, 4486.

O
O H2, Pd/C
H
Cl
Pd/PPTA 48%

Pd/PPTA = PdCl2 deposited on poly(p-phenylene terephthalamide)

V. G. Yadav, S. B. Chandalia, Organic Process Research and Development 1997, 1,

226.

O O
H2, Pd-BaSO4
Cl H
quinoline, NaOH, xylene

E. B. Hershberg, J. Cason, Org. Synth. CV3, 626.

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O
O
H2, Pd-C, quinoline MeO H
MeO Cl
MeO
MeO NaOAc, toluene
OMe
OMe

A. I. Rachlin, H. Gurien, D. P. Wagner, Org. Synth. 1971, 51, 8.

B.

2.3.7 Reduction of Aldehydes, Ketones and Esters

Hydrognation of carbonyls of aldehydes, ketones and esters have been well

developed with chiral metal complexes in the presence of molecular hydrogen.
For example, rhodium complexes with molecular hydrogen have shown good
catalytic activity towards to the reduction of ketonic substrates possessing no
functionality adjacent to the carbonyl group (Scheme 8).

O OH

Me [RhCl2(bipy)2]Cl 2H2O Me

0.3 M NaOH in MeOH

H2, 30 oC 98%

Scheme 8

Chiral rhodium phosphine complexes with molecular hydrogen are effective

catalysts for the hydrogenation of ketopantolactone with good enantioselectivity
(Scheme 9).

Ph2P
OH PPh2
O [(RhCl(COD)]2- N
(2S,4S)-BPPM O O CO2C(Me)3
O O
H2 87 ee (2S,4S)-BPPM

Scheme 9

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2.3.8 Deprotection of Functional Groups

The benzyl ethers, N-Cbz (Cbz = carboxy benzyl), and thioketal groups could be
removed by reaction with molecular hydrogen and Pd or nickel catalyst (Scheme
10). The benzyl ethers and N-Cbz are deprotected by Pd-catalyst and molecular
hydrogen whereas the thioketal groups are reduced to the corresponding alkanes
when treated with Raney nickel and molecular hydrogen.

NHCbz NH2
O O

O O O H2, Pd/C, HCl O O O

THF O
O H2N NH2
CbzHN NHCbz
O O

O
O
O
H2, Pd/C, 0.01N HCl O
OBn
EtOAc-EtOH OH

OPBz
OPBz

Raney Ni
S S
H2
S S

Scheme 10

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Problems

Provide suitable reagents/catalysts for the following transformations.

1.

2.
NC NC

3.

OH OH
4.

OH

CO2H CO2H
5.

OH OH
6.

7.

Text Book

M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004.

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Lecture 18

2.4 Miscellaneous Reducing Agents

2.4.1 Tributyltin Hydride (Bu3SnH)

Tributyltin hydride (TBTH) is an organotin compound can acts as a reducing

agent when treated with a radical initiator such as azobisisobutyronitrile (AIBN) or
by photo irradiation. It is a colourless liquid and is generally purified by distillation.

T. V. Rajanbabu, Encyclopedia of Reagents for Organic Synthesis, John Wiley

and Sons, Inc., L. A. Paquette, Ed., New York, 1995, 7, 5016.

2.4.1.1 Reductive Dehalogenation

The halogens are removed by TBTH in presence of AIBN in aromatic

hydrocarbon solvent such as benzene, toluene. The AIBN acts as a radical
initiator and needed in catalytic amount (2-5 mol %). The reactivity order of the
halogens is I > Br > Cl and F does not work under these conditions (Scheme 1-
2).

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Me
Me 60 C Me Me
N N Me 2 + N2
NC
Me CN
NC
AIBN

Bu H
Me Me Me Me
+ H Sn Bu Bu3Sn +
CN Bu CN

Bu3Sn X R Bu3SnX + R (X = Cl, Br, I)

Bu
R + H Sn Bu Bu3Sn + R H
Bu

Scheme 1

O O
H H
Bu3SnH (1.2 equiv)

AIBN (0.05 equiv)

H benzene H
Br

R' R'
Bu3SnH (1.2 equiv)
R R
N AIBN (0.05 equiv) N
H H
Br toluene, 110 C

Scheme 2

2.4.1.2 Radical Cyclization

The radical cyclization of the suitably substituted halides could be performed in

presence of TBTH to give the desired cyclized products (Scheme 3). The
reaction undergoes via radical pathway.

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R
EtO2C CO2Et EtO2C R
O Me CO2Et
Me Bu3SnH-AIBN O
O Me Me
N Ph benzene, heat N O Me
Br
Ph Me
Ph
Ph

O O
NH Bu3SnH-AIBN NH

I benzene, heat

Scheme 3

2.4.1.3 Reductive Dehydroxylation via Thiocarbonyl and

Selenides Derivatives

Reductive dehydroxylation via thiocarbonyl and selenide derivatives in presence

of TBTH is an important method in synthetic organic chemistry. The thioacylation
or selenation of alcohols gives thioesters or selenides which is then treated with
Bu3SnH-AIBN reagent to give the desired dehydroxylated product (Scheme 4).
The advantage of this method is that it works in such cases where other methods
fail.

BnO Bu3SnH-AIBN BnO

BnO PhSeCN
Ph toluene, 105 C Me
Bu3P, THF Se
HO OH OH
OH

S
NaH, CS2 Bu3SnH-AIBN
Me R Me
R OH R O S
MeI toluene, heat

Scheme 4

Mechanism

The tributyltin radical reacts with the sulfur atom to give a radical intermediate
which then cleaves to give the desired radical and reacts with TBTH to
regenerate the tributyltin radical and the product (Scheme 5).

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S SnBu3
NaH, CS2 Me S
R OH R O S Me
MeI R O S

AIBN
Bu3SnH Bu3Sn

SnBu3
S
R Me R Me
O S
Bu3SnH

Scheme 5

Examples:

Me Me
TBTH, AIBN . Me
CH2I Me
Me CH2
Me
Me Me
Me
80%

D. P. Curran, D. M. Rakiewicz, Tetrahedron 1985, 41, 3943.

.
IH2C .
O H3C
O OH O
TBTH, AIBN
CO2Et
CO2Et
PhH
CO2Et CO2Et
45%

P. Dowd, S. C. Choi, J. Am. Chem. Soc. 1987, 109, 6548.

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2.4.2 Diimide (HN=NH)

Diimide can be prepared in situ, by the copper-catalyzed oxidation of hydrazine

in the presence of hydrogen peroxide or oxygen as terminal oxidant or the
decomposition of azodicarboxylic acid or sulfonylhydrazines (Scheme 6).

Cu2+
NH2-NH2 HN=NH
H2O2

heat
HO2CN NCO2H HN NH + CO2
MeOH
O
heat SO3H
S NH-NH2
O HN NH +
Diglyme

Scheme 6

D. J. Pasto, Encyclopedia of Reagents for Organic Synthesis, John Wiley and

Sons, Inc., L. A. Paquette, Ed., New York, 1995, 3, 1892.

The reduction using diimide finds unique applications because:

The reagent is extremely tolerant of other functional groups

The reduction is highly stereoselective and takes place cis-addition, from

the less-hindered face.

H H H H H H
N N N N

Reactivity decreases with increasing substitution about the alkene bond.

Alkynes show greater reactivity compared to alkenes.

Alkenes with electron withdrawing groups show greater reactivity

compared to those with electron donating groups.

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Use of deuterium or tritium-labeled diimide gives a method of cis-reduction

without scrambling of label.

Examples:

CH2-OTBS CH2-OTBS
KO2CN=NCO2K
HO HO
O O O
O
91%
t-Bu t-Bu

M. H. Haukaas, G. A. ODoherty, Org. Lett. 2002, 4, 1771.

HO CH2Br CH2Br
HO
KO2CN=NCO2K
HO HO
AcOH, MeOH
80%

D. A. Frey, C. Daun, T. Hudlicky, Org. Lett. 1999, 1, 2085.

O O
O O
KO2CN=NCO2K

Me Me
AcOH, MeOH
77%

E. J. Corey, J. P. Dittame, J. Am. Chem. Soc. 1985, 107, 256.

OTHP OTHP
Cu(OAc)2/H2O2

EtOH/N2H4

E. J. Corey, H. Yamamoto, J. Am. Chem. Soc. 1970, 90, 6636.

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2.4.3 Silanes

Silane hydrides can be used for the reduction of carbonyls and alkenes. Addition
of transition metal salts such as ZnCl2 or copper salts to the silane facilitates the
reduction (Scheme 7).

Me Me
Et3SiH

TFA
72%

(EtO)2SiHMe CH2OH
CHO Ph
Ph
KF

O O
Ph2SiH2

ZnCl2-Pd(PPh3)3
CHCl3

Scheme 7

Asymmetric reduction involving silanes is possible when a chiral additive is used.

For an example, acetophenone can be reduced to (R)-phenyl ethanol with good
enantioselectivity in the presence of chiral ligand (Scheme 8).

O HO H
Ph2SiH2, L* Me
Me N N
H2O Ph H
Yield: 99% L* Me
Ee: 84%

Scheme 8

2.4.4. Meerwein-Ponndorf-Verley Reduction

The reduction of aldehydes and ketones to the corresponding alcohols with

aluminum isopropoxide [Al(OiPr)3] in the presence of 2-propanol (reverse of the

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Oppenauer Oxidation) is called Meerwein-Ponndorf-Verley reduction (Scheme

9).

CHO Al(OiPr)3 CH2OH

NO2 NO2
OH O

Al(OiPr)3
Cl COMe Cl CH(OH)Me

OH O

Mechanism

PrOi OiPr
Al Al(OiPr)2
O Al(OiPr)3 O O O O H+ OH
+
R i-PrO- H R
H H R
R

Scheme 9

Examples:

MeO O O
Al(OiPr)3 MeO
O O

O O toluene O
OH
OH 79% O

T. K. Shing, C. M. Lee, H. Y. Lo, Tetrahedron Lett. 2001, 42, 8361.

O OH
AlMe3

i-PrOH, toluene
82%

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O OH
Cl AlMe3 Cl

i-PrOH, toluene
91%

E. J. Campbell, H. Zhou, S. T. Nguyen, Org. Lett. 2001, 3, 2391.

Problems

A. Predict the major products for the following reactions.

diimide
OH
1.

OH diimide
2.

Bu3SnH
3.
N AIBN
H
Br

H
Bu3SnH
4. O
O AIBN, Toluene, Reflux
PhS H

1.2 equiv PhSiH3, 10 mol% Bu3SnH

5.
tBuOOtBu, Toluene, Reflux

B. Provide mechanistic rational for the following reaction.

Cl Bu3SnH O

O AIBN

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Text Book

M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004.

Lecture 19

2.5 Photoreductions and Bio-reductions

2.5.1 Photoreduction

The electron transfer to a certain functional groups can be induced by irradiation

with light source. Reductions are possible when a proton source along with a
sensitizer and a source of irradiation are employed. The reduction proceeds via
photo-induced electron transfer (PET).

2.5.1.1 Reduction of Carbonyl Compound

The aliphatic and aromatic carbonyl compounds are reduced to a variety of

products depending on the reduction conditions. For examples, the aromatic
ketones, benzophenone or acetophenone, in isopropanol or methanol undergo
photoreduction to give dimeric pinacol in good yield (Scheme 1). In contrast,
benzophenone in isopropanol under reflux condition undergoes photoreduction to
give the secondary alcohol Ph2CHOH.

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O OH OH OH O
+ hv
Ph Ph +
Ph Ph Me Me Me Me
Ph Ph

O OH OH O
+ hv +
Ph Ph Me Me reflux Ph Ph Me Me

Scheme 1

Aliphatic compounds undergo reduction of carbonyl compound to give the

corresponding alcohols (Scheme 2). The reaction proceeds via excitation of
benzophenone from ground state to excited [n, *] singlet state (Scheme 3). The
excited [n, *] singlet state then undergoes intersystem-crossing to give [n, *]
triplet state which abstracts proton from the alcohol to generate
diphenylhydroxymethyl radical which then dimerises to give the benzpinacol.

O OH
OH O
hv
Me Me + Me Me + Me Me
Me Me
Me Me Me Me

Scheme 2

n, * n, * OH
O 1 O Intersystem 3 O OH
hv crossing (ISC) Me Me
Ph Ph n Ph Ph Ph Ph Ph Ph
*

dimerization

OH OH
Ph Ph
Ph Ph

Scheme 3

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H R' R' OH R'

O hv OH cyclization R
R R No
rris
ht
yp
eI
I
O
+ R'
R Me

Scheme 4

The intramolecular cyclization of carbonyl compounds via -hydrogen abstraction

is also possible to give four membered cyclic alcohols (Scheme 4). This reaction
is facilitated by the presence of a heteroatom at the -position of the alkyl chain.
The side reaction which can give degradation products is known as Norrish type
II reaction (Scheme 5).

O O OH
hv
Me Ph Me + Me + Ph
Ph

Norrish type II

OH
O Me
hv Ph
N
Ph Ph N
Ph

OH Me
O Me
hv Me Me
Me Me
O O

Scheme 5

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hv R3N
+ R3N

H+

e-, H+

H H H H
dimerization

Scheme 6

2.5.1.2 Reduction of Aromatic Compounds

The aromatic hydrocarbons such as benzene, biphenyl, naphthalene and

anthracene in their excited states react with amine to give reduced or aminated
products. The reaction involves the transfer of lone pair electron of amine to the
excited state singly occupied molecular orbital of aromatic compound (Scheme
6).

The excited aromatic compounds could also be reduced by hydride source such
as sodium borohydride, lithium aluminum hydride of metal hydride (Scheme 7).
The reaction may undergo via the following sequences.

CN CN CN H H CN CN

hv NaBH4 H3O+

Scheme 7

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2.5.2 Bio-reduction

The bio-reduction is one of the important procedures in biological system. There

are mainly two different pathways through which most of the biological reductions
takes place, enzymatic and non-enzymatic reduction. The advantages of these
protocols are, it is very much substrate specific, that they work under ambient
condition in aqueous medium.

2.5.2.1 Reduction of Carbonyl Group

The reductions of carbonyl groups have been studied most by using different bio-
reductants such as Bakers yeast or with reductase enzyme. For example, the
reductions of -ketoesters have been studied extensively (Scheme 8). The ethyl
acetoacetate could be reduced to give the corresponding 3-hydroxybutyrate. On
the other hand, 4-chloroacetoacetate when reduced with Bakers yeast, gives the
corresponding (S)-alcohol with opposite selectivity. Therefore, the
stereochemistry of the reduced product depends on the shape and size of the
prochiral starting substrates. It also says that the Bakers yeast has at least two
different active reducing sites.
O O Baker's yeast OH O

Me OEt Me OEt
H2O, sucrose, 30 C

O O Baker's yeast OH O
Cl Cl
OEt OEt
H2O, sucrose, 30 C

Scheme 8

The reduction with Bakers yeast is very much substrate dependant and it works
well with -keto substrates but it is less selective with other keto-functional
substrates. Therefore, it promoted further study on this subject for better results.
For example, a better result has been achieved with lyophilized whole cells of
Rhodococcus ruber DSM 44541, for asymmetric reduction of aryl ketones and
other unfunctional ketones with good enantiomeric excess (Scheme 9).

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Me O Rhodococcus ruber Me OH

Me Me phosphate buffer, iPrOH Me Me

Scheme 9

Another important microorganism is Geotrichum candidum which can perform the

asymmetric reduction of aliphatic, aromatic and trifluoromethane substituted
ketones with very high enantioselectiovity (Scheme 10).

O OH
G. candidum, NAD+
Me Me Me Me
secondary alcohol

O OH
Br G. candidum, NAD+ Br
Me Me
secondary alcohol

O OH
G. candidum, NAD+
CF3 CF3
secondary alcohol

Scheme 10

The reduction with isolated enzymes have also been studied and the advantage
of this protocol is that it reduces the effect of other interfering enzymes which are
present in a cell but the weak point is that the stability of isolated enzymes and
use of expensive specific co-factor such as NADP (Nicotinamide adenine
dinucleotide phosphate) (Scheme 11).

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H2N H2N
O O OH O
+ enzyme
H R R' R R' +
O N O
N H
O O
O O
P O P O
OH OH O OH OH
O O P
O P O
O O O N
N
O NH2 O N NH2
N

N N N
HO O N HO O
PO3H PO3H
NADPH NADP+

formate dehydrogenase

CO2 HCOO-

Scheme 11

For an example, the following symmetrical diketone could be reduced by enzyme

horse liver alcohol dehydrogenase (HLADH) to give the corresponding chiral
alcohol with high enantioselectivity (Scheme 12).

H H
O OH
HLADH

O cat. NADH, EtOH O

H phosphate buffer, 30 C H

Scheme 12

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NPTEL Chemistry Reagents and Organic reactions

Problems:
A What products would you expect from the following reactions?

O O
Baker's yest
1.
OEt

O
light
Ph
2.

O
light
3.
OH

O O

OEt Baker's yest

4.
S

B. Rationalize the following photoreduction process.

O OH
light Ph
Ph +
+
NH
NH2

Text Book

M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004.

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