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355RESONANCE April 2008

GENERAL ARTICLE

Benzoin condensation is an important carbon–carbon bond

forming reaction. It is achieved by generating an acyl anion

equivalent from one aldehyde molecule which adds to a

second aldehyde molecule. The reaction is traditionally

catalysed by a cyanide ion. Cyanohydrin anion is the first

intermediate and is the precursor to the acyl anion equivalent.

Cyanohydrins are found in plants as glycosides. A reaction

completely analogous to benzoin condensation occurs in our

body, which however neither involves cyanohydrin interme-

diate nor is catalysed by cyanide ion. It is catalysed by the

thiazolium moiety of the co-enzyme thiamine pyrophosphate

(TPP). This article shows the common links and inclusive

chemistry aspects among cyanohydrin formation, naturally

occurring cyanohydrins, conversion of cyanohydrins to ben-

zoins/acyloins, the role of vitamin B1 (thiamine) and the use of

thiazolium compounds in benzoin/acyloin condensation.

Introduction

Cyano Group in Natural Products

1. Cyanoglycosides

Hydrogen cyanide is a deadly poisonous substance. A variety of

plants produce it, though in the hidden form of cyanoglycosides,

the sugar derivatives of cyanohydrins. Cyanohydrins are formally

the products of HCN addition to ketones or aldehydes, the addi-

tion being reversible. Cyanoglycosides hydrolyse enzymatically

as well as nonenzymatically in the body to sugar and cyanohy-

drins, which release hydrogen cyanide, Scheme 1. Ingestion of

cyanoglycosides through consumption of such plant materials

may cause cyanide poisoning if the cyanide concentration in the

Keywords

Benzoin condensation, acyloin

condensation, cyanoglycosides,

cyanohydrins, vitamin B1cataly-

sis, cyanide catalysis, thiazolium

salt catalysis, nitrile-containing

natural products.

Benzoin Condensation

The Cyanide Connection with Tapioca and Vitamin B1

Gopalpur Nagendrappa

G Nagendrappa, retired

from Bangalore Univer-

sity, Bangalore, is

presently Professor and

Head of the Department of

Medicinal Chemistry, Sri

Ramachandra University,

Porur, Chennai. His main

work is in the areas of

organosilicon chemistry,

organic synthesis, reaction

mechanism and synthetic

methodologies.

356 RESONANCE April 2008

GENERAL ARTICLE

body goes beyond the tolerance limit, (see Box 1). This works as

a defense mechanism in plants, since high cyanoglycoside con-

tent makes such plant parts (seeds, roots, leaves, etc.) bitter.

However, we consume many food materials that contain

cyanoglycosides.

R1

R2

CNO Sugar

R1

R2

CN

OH

R1

R2

O sugar HCN+ +hydrolysis

Linamarin: R1

= R2

= CH3; Sugar = -D-glucose

Amygdalin: R1

= Ph, R2

= H; Sugar = -D-gentiobiose

Prunarin: R1

= Ph, R2= H; Sugar = -D-glucose

Scheme 1.

Box 1. Toxicity and Detoxification of Cyanide

Cyanide’s Murderous Course: The cyanide inhaled as HCN or consumed as its salts such as NaCN, KCN etc,

or released in the body on hydrolysis of cyanogenic glycosides eaten as food, causes poisoning. Orl-hmn LDL0

= 2857gkg–1 for NaCN or KCN. Orl-rat LD50

= 5 mgkg–1 for KCN, and 6.44 mg kg–1 for NaCN.

This is How it Poisons: Cyanide ion binds very strongly to Fe3+ of methemoglobin in mytochondria and forms

cyanomethemoglobin, which cannot carry oxygen to tissues. The cellular respiration is arrested and the death

is imminent.

+HbFe3+HbFe3+CN

Methemoglobin CyanohemoglobinCN

_ _

Detoxification: Small amounts of cyanide present as glycosides in foods we consume is detoxified by the

enzyme rhodanase present in liver, erythrocytes, and other tissues by facilitating the conversion of cyanide to

thiocyanate. Minor quantities of CN– are removed by oxidation to cyanate (CNO–) or combining with cobalamin

to form cyanocobalamin (vitamin B12

).

+

+HbFe3+HbFe3+CN

_

_

CN_

CN_

SCNRhodanase

a sulphurtransferase

Antidote: Nitrite (NO2

–) functions as antidote for cyanide poisoning. Nitrite is administered either by

inhalation or injection, oxygen being given as adjunct along with or after NO2

– . Giving oxygen alone is not

effective.


GENERAL ARTICLE

Roots of cassava (tapioca), an important food crop in many

countries of the world, including India, contain acetone cyanohy-

drin glucoside called linamarin. Tapioca that contains linamarin

in excess of 100 mgkg–1 of fresh roots is not recommended for

food use. Even then, to make it suitable for edible purpose it has

to be processed properly to bring down the toxin content to less

than 50 mgkg–1, a limit that is considered as acceptable.

A long recognised source of a cyanogenic glucoside is bitter

almond, whosebitterness is due to amygdalin, or D-mandelonitrile-

-D-gentiobioside, (Scheme 1). Historically, benzaldehyde was

first obtained from bitter almonds.

Seeds of apple, peaches, plums, apricots, cherries, etc., contain

considerable amounts of amygdalin. Cyanoglycosides are present

even in common edible plants such as sorghum, soybeans, lima

beans, maize, millet, sweet potatoes, spinach, sugar cane, and

bamboo shoots. However, the toxin content in these is low, and is

handled by liver and eliminated, (see Box 1). Even in the case of

apple seeds, seeds of other fruits, and bitter tapioca which have a

relatively high cyanoglycoside content, one has to consume huge

quantities of them before they could pose toxicity problem.

The name cyanide evokes, in laypersons, a spectre of poisoning

and instant death, made famous by authors of detective stories.

Indeed, cyanide is one of the most toxic substances. Detoxifica-

tion of minor amounts of cyanide in the body is brought about by

the enzyme rhodanase present in liver, erythrocytes, and other

tissues, through its rapid conversion to thiocyanate, (see Box 1).

Some insects and mollusks eat plants containing cyanogenic

glycosides and accumulate sufficient quantities of these glyco-

sides which serve as defense against their predators.

2. Non-glycosidic Cyano Compounds

Cyano group occurs in natural products not only in cyanohydrin

glycosides, but also in non-cyanohydrin form. Some examples

are given in Figure 1.

Even in the case of

apple seeds, seeds of

other fruits, and bitter

tapioca which have a

relatively high

cyanoglycoside

content, one has to

consume huge

quantities of them

before they could

pose toxicity problem.

Detoxification of minor

amounts of cyanide in

the body is brought

about by the enzyme

rhodanase present in

liver, erythrocytes, and

other tissues.


GENERAL ARTICLE

Vitamin B12

N N

NH N

Co+

CN

H

H2NOCH2CMe

CH2CONH2

CH2CH2CONH2

Me

Me

Me

Me

Me

Me

CH2

H2NOC

H

N

MeN

P

O

Me

H

CH2OH

OH

H H

O-O

H2C

HN

CO

Me

H2C

CH2

H

O

CH2CH2CONH2

H

Me

O

H

H

N

CN

O

CH3

O

H3C

Ricinin (Alkaloid)

(from Castor oil seeds) Merisclausin Ehreticide B(name depends on

R1, R2, R3 )

Non cyanogenic cyanoglycosides

N O

OH

NC

Glc-O

OH

NC

Glc-O

OR3

NC

Glc-O OR1

OR2

Figure 1. Nitrile-(Cyano Group) Containing Drugs

Though cyanohydrins pose as much toxicity problem as the

inorganic cyano compounds, (NaCN, KCN, HCN, Cu(CN)2,

K3Fe-

(CN)6, etc.,), the other types of organic nitriles may not be as toxic


GENERAL ARTICLE

N

N

O

O

MeO

NH

O

O

O

OMe

NC

H

H

H

O

NC

OH

O

H

H

NH

N

O

O

OO

NMe2 OH

OH O

OMe

Br

CN

H

H2 O3POOH

OH

H

MeO

CN

CN

R2

R1O

OR1

R3

Cyanopuupehenone

(antiviral activitiy against HIV II)

Saframycin A

(antibiotic and antitumor activities)

R1 = H, R2 = R3 = CH2CH = C(CH3)2R1 = R2 = H, R3 = CH2CH = C(CH3)2R1 = R2 = R3 = H

Epurpurins

Calyculin J(antitumour activitiy)

Figure 1. Continued...


GENERAL ARTICLE

because they do not release the cyanide easily. In fact, a good

number of common drug molecules contain cyano group as an

important functional group. A few examples are given in

Figure 2.

Nitrile (Cyano Group): A Versatile Intermediary Func-

tional Group

Synthetic routes of even larger number of drugs employ nitriles as

N

Ph

CO2C2H5

NC

PhPh

Figure 2.

N

CH3H3CCH3

CN

H3CO

OCH3

OCH3

H3CO (S)-Verapamil

(Ca2+ channel blocker)

O

N

N

Ph

CH3

CN

(H+ / K+ ATPase inhibitor)N

NN

CN

N

O

Zaleplan(ultrashort acting sleep inducer)

Diphenoxylate(antidiarrheal agent)

NHN

H3C

S

HN

HN

CH3

N

CN

Cimetidine (Tagamet)(antiulcer drug)


GENERAL ARTICLE

intermediates because of their versatility for further useful trans-

formation. The nitrile can be transformed into a variety of other

functions such as amine, carboxylic acid, ester, amide, ketone,

aldelhyde, heterocycle and others. Consequently nitriles have

acquired great importance as intermediates in the manufacture of

chemicals, including drugs.

Being a strong electron withdrawing group the cyano group

facili tates the formation of -carbanion and then ensures its

stability. This has been exploited in pole reversal (umpolung) of

aldehydic carbon from being electrophilic to nucleophilic, as

represented in Scheme 2.

Cyanide: A Good Nucleophile

Cyano group can be introduced into organic molecules by a

variety of methods. Since cyanide is one of the very effective and

efficient classic nucleophiles, the most common methods of

cyanation exploit this property, such as in (1) the direct displace-

ment of halides, tosylates or similar leaving groups by cyanide,

and (2) the addition of cyanide to aldehydes, ketones and their

,-unsaturated analogues.

Cyanide’s high nucleophilic efficiency is due to its easy

polarisability and low steric hindrance to its attack. (It is the

smallest carbon nucleophile). It is ranked high in the nuclephilicity

RCHO HCNLDA

R1X

+ R C

OH

CN

H R C

OR2

CN

R C

OR2

CN

R1R1

C

O

R Hydrolysis

R C

OR2

CN

H_

R1 X = Variety of electrophiles

R2 = O ,

Scheme 2.

The cyano group

facilitates the

formation of -

carbanion and then

ensures its stability.

This has been

exploited in pole

reversal (umpolung)

of aldehydic carbon.


GENERAL ARTICLE

order for SN2 reactions (in protic solvents), much above OH-,

(Figure 3).

Cyanide as Leaving Group

It is a well-known fact that many good nuclephiles, such as

halides, are also good leaving groups. (Of course, all nuclephiles

are also leaving groups, in principle, though the two characters do

not match in all cases). Carbanions, on the other hand, are good

nucleophiles, but are generally not good leaving groups. The

exceptions are the groups with carbon bonded to strong electrone-

gative atoms or groups. Some examples are given in Scheme 3.

RS- > ArS- > I- > CN- > OH- > N3- > Br- > ArO- > Cl- > Pyr > AcO- > H2O

Figure 3.

R CH3

O

R CX3

O

CR CX3

O

OHR OH

O

+

Cl3C OH

O

Cl3C O

O

+

_

_

_ Cl3C

_

CO2

OH_

OH_

x2x3C

x = halogen

Base

Ph CH CH Br

Ph CH CH COOH

Br Br

Ph CH CH

Br Br

O Ph CHHC

Br

Br_

_Base

O

O

N

Br

COOH

Base

O

N

Br

O

O

O

N

Br

O

N

Br

O

N

Br

H+

_

_

_

Scheme 3.

(1)

(2)

(3)

(4)


GENERAL ARTICLE

The cyano group attached to an alkoxy carbon departs very easily,

which is the reversal of cyanide addition to carbonyl of ketones

and aldehydes forming cyanohydrins, (Scheme 4). However, only

strong bases can eliminate HCN from alkyl nitriles, and this is

used in one of the steps of vitamin B12

synthesis.

Because of this dual character (i.e., easy additions to aldehyde

and easy departure from cyanohydrin), cyanide possesses the

unique ability to catalyse a useful reaction, the benzoin condensa-

tion, in which two aldehyde molecules condense to give a -

hydroxy ketone.

The Benzoin Reaction

Cyanohydrins are the normal end products of nucleophilic addi-

tion of NaCN, KCN or HCN to aldehydes or ketones in aqueous

alcoholic solution. However, in the case of aldehydes the reac-

tion may proceed further to add a second aldehyde molecule, to

produce -hydroxy ketones, (Scheme 5, Table 1).

The highlight of the reaction is the fascinating way in which the

cyanide ion facilitates and directs it, particularly by transforming

the intermediate cyanohydrin adduct to the crucial nucleophilic

carbanion species N, which then adds to another aldehyde mol-

ecule to finally deliver benzoin. The mechanism of this reaction

was proposed as early as 1903. Though the correctness of this

mechanism was doubted at some stage, but it was finally accepted

in 1971. The important steps involved are given in Scheme 5.

CR R1

CN

OH

CR R1

CN

O

R R1

O

+ CN

_

_Base

H+

H3C

NC

H2C

t-BuOK

a reaction in vitamin B12 synthesis

- HCN

Scheme 4.

(5)

(6)


GENERAL ARTICLE

R C H

O

+ CN R C

NC

H

O

R C

CN

HO

R1

H

O

R C

CN

OH

C

O

H

R1R1C

HO

H

C

O

R

a b

c

de

_ _

_

_

_

R C

CN

O

C

HO

H

R1

(N)

(7)

Scheme 5.

Table 1. Some examples of

benzoin condensation in

Scheme 5.

R R1 Yield (%)


GENERAL ARTICLE

The uniquely successful role of cyanide ion in catalyzing benzoin

reaction is due to its four qualities, namely, (1) high nucleophilic

activity, (stage a), (ii) facilitating the á proton transfer, (stage b),

(iii) ability to stabilize negative charge in active aldehyde inter-

mediate N, (stage c), and (iv) ability to depart finally, (stage e).

Vitamin B1

and Thiazolium Salts as Catalysts

In principle, any chemical entity that incorporates all these four

features should be capable of bringing about benzoin condensa-

tion. In fact, Nature has been performing this task efficiently in a

completely analogous manner using (vitamin B1)1 thiamine pyro-

phosphate, TPP, (Figure 4), a coenzyme present in our body, and

other living organisms. TPP catalyses several reactions that in-

clude decarboxylation of pyruvic acid to acetaldehyde, conver-

sion of pyruvic acid to acetoin, (Scheme 6), transfer of 2-carbon

N SR

H3CR1

_

+

+N S

R

H3C R1

+

C

H3CC

CO

O

O

_

OH

H3C

O

O_

N SR

H3C R1

C C

HO

H3C

O

N SR

H3C R1

C C

O

H3C

OH

N SR

H3C R1

_

+H

CH3

_

CH3

H

_

N SR

H3C R1

C

HO

CH3

OH

acetoin

+H3C C

O

C

OH

H

CH3

A1Pyruvate

++

N

N

NH2

H3C

NS

OH

+

H3C

N

N

NH2

H3C

NS

O PO

O

O P

O

O

OH3C

+

_

__

Vitamine B1

(Thiamine) Thiamine pyrophosphate (TPP)

Figure 4.

Scheme 6.

1 The preparation of benzoin

using thiamine (vitamin B1) as

catalyst is one of the experi-

ments being carried out by our

I semester MSc. Medicinal

Chemistry students. It is a neat

reaction, which gives pure, crys-

talline bezoin in high yield. The

preparatory procedure being fol-

lowed is the one that is given in

[7] listed in Suggested Reading.

It is highly instructive experiment

from the point of chemistry, bio-

chemistry, environmental chem-

istry, and bio- and organo-

catalysis.


GENERAL ARTICLE

group from sedoheptalose-phosphate to glyceraldehyde-3-phos-

phate to produce xylose-5-phospate (an acyloin reaction),

(Scheme 7), which involve acyl ion or its equivalent intermediate

as in cyanide catalysed benzoin reaction.

The key feature of thiazolium moiety in facilitating this reaction

so efficiently lies in the fact that the hydrogen on the carbon

between sulphur and nitrogen (i.e. the position 2) is acidic enough

to be exchanged with deuterium in D2O. Removal of this proton

by base carries forward the reaction, as depicted in Schemes 6–8,

in a manner that is completely analogous to the cyanide ion-

catalysed one, (Scheme 5).

CH2OH

C

HHO

OHH

CH2 O P

N S

H3C R1

N SR

H3C R1

C

OH

CH2OH

CHO

OH

CH2

H

O P

N S

H3C R1

CH2OH

OHH

OH

OH

H

OH

H

HO

H

H2C

H2C

HO

H

OH

H

HO

H

H

OH

C

O

CH2OH

O

O

P

OHC

OHH

OHH

OHH

CH2 -O -P

oR

G

E

_

F

C

B

D

P

A = Thiamine pyrophosphateB = sedoheptalose-7-phosphate (ketose donor)C = TPP-ketosedonor adductD = Ribose-5-phosphateE = Resonance stabilized carbanionF = Glyceraldehyde-3-phosphate (aldose acceptor)G = Xylose-5-phosphate

Scheme 7.

The key feature of

thiazolium moiety in

facilitating this

reaction so efficiently

lies in the fact that the

hydrogen on the

carbon between

sulphur and nitrogen

(i.e., the position 2) is

acidic.


GENERAL ARTICLE

The recognition that thiazolium ion in TPP catalyses these reac-

tions has led to development of improvised thiazolium ion-based

catalysts (Figure 5), which are simpler than TPP, yet bring about

benzoin condensation effectively (Scheme 8). In fact the thiazolium

catalysts show more scope in applicability in that they are able to

catalyse the condensation of a wider variety of aldehydes and not

only aromatic aldehydes. An added advantage is that they bring

about condensation at room temperature and that too without the

hazardous risks of environmental pollution posed by cyanide.

The replacement of cyanide by the harmless thiazolium salts as

catalysts for benzoin condensation is one of the finest examples

of Green Chemistry in action.

SNR

H3C OH

X

_

+

R = Ph-CH2, X = Cl (T-1)R = C2H5, X = Br (T-2)R = CH3, X = I (T-3)

Figure 5.

N SR

H3COH

+N S

R

H3C

+N S

R

H3COH

+

_

Et3N

R1

H

O

O R1_

N SR

H3COH

+

CHO R1

_

R2

H

O

R1 C

O

CH

OH

R2R1 CH

HO

C R2

O

+

CHO

O

OH

C9H19 C

O

CHOH C9H19

+ Ar C

O

CH

OH

R + Ar CH

OH

C

O

RRCHO

C9H19CHO

ArCHO

Et3N, EtOH

Et3N, EtOH

Et3N, EtOH

T_1

T_3

T_2

Scheme 8.

OH


GENERAL ARTICLE

Suggested Reading

[1] T Laird, in Comprehensive Organic Chemistry, (Series Editors: D H R

Barton and W D Ollis), Vol.1 (Editor: J F Stoddart), pp.1142–1147,

Pergamon Press, Indian Print, 2007.

[2] G Tennant, in Comprehensive Organic Chemistry, (Series Editors: D H

R Barton and W D Ollis), Vol.2 (Editor: I O Sutherland), pp.528–550,

Pergamon Press, Indian Print, 2007.

[3] L A Paquette, Encyclopedia of Reagents for Organic Synthesis, Vol.6,

pp. 4208–4212; Vol.7, pp.4537–4538, John Wiley & Sons, 2005.

[4] F F Fleming, Nitrile-Containing Natural Products, Natural Products

Report, Vol.16, pp.597–606, 1999.

[5] D A Williams and T L Lemke, Foye’s Principles of Medicinal Chemistry,

V Edn., Lippincott Williams & Williams, pp.211, 2002.

[6] H Stetter and H Kuhlman, Organic Synthesis, Coll., Vol.7, pp.95–99,

John Wiley, 2005.

[7] J Werner, Greener Approaches to Undergraduate Chemistry Experi-

ments, pp. 14–17, 2002.

[8] D L Nelson amd M M Cox, Lehninger: Principles of Biochemistry, IV

Edn., W H Freedman & Company, pp.761, 2007.

Address for Correspondence

G Nagendrappa

# 13, Basappa Layout

Gavipuram Extension

Bangalore 560 019, India.

Email:

[email protected]

Gujjar

A K Raychaudhuri

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