GENERAL  ARTICLE
Benzoin Condensation
The Cyanide Connection with Tapioca and Vitamin B1
Gopalpur Nagendrappa
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 intermediate 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 benzoins/acyloins, the role of vitamin B1 (thiamine) and the use of
thiazolium compounds in benzoin/acyloin condensation.
G Nagendrappa, retired
from Bangalore University, 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.
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 addition being reversible. Cyanoglycosides hydrolyse enzymatically
as well as nonenzymatically in the body to sugar and cyanohydrins, 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
RESONANCE  April 2008
Keywords
Benzoin condensation, acyloin
condensation, cyanoglycosides,
cyanohydrins, vitamin B 1 catalysis, cyanide catalysis, thiazolium
salt catalysis, nitrile-containing
natural products.
355
GENERAL  ARTICLE
R1
R1
R2
O
CN
Sugar
R1
hydrolysis
O + sugar + HCN
OH
CN
R2
R2
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.
body goes beyond the tolerance limit, (see Box 1). This works as
a defense mechanism in plants, since high cyanoglycoside content makes such plant parts (seeds, roots, leaves, etc.) bitter.
However, we consume many food materials that contain
cyanoglycosides.
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
= 2857gkg–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+ + CN
Methemoglobin
HbFe3+CN
Cyanohemoglobin
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+CN
_
CN
HbFe3+
Rhodanase
a sulphurtransferase
+
+ CN
_
SCN
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.
356
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GENERAL  ARTICLE
Roots of cassava (tapioca), an important food crop in many
countries of the world, including India, contain acetone cyanohydrin 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, whose bitterness is due to amygdalin, or D-mandelonitrile-D-gentiobioside, (Scheme 1). Historically, benzaldehyde was
first obtained from bitter almonds.
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.
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. Detoxification 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 glycosides 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.
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Detoxification of minor
amounts of cyanide in
the body is brought
about by the enzyme
rhodanase present in
liver, erythrocytes, and
other tissues.
357
GENERAL  ARTICLE
H
H2NOC
Me
CH2CONH2
Me
CH2
H
Me
CH2CH2CONH2
CN N
N
Me
Co+
H
NH
N
Me
H
H2NOCH2C
Me
CO
N
H
CH2CH2CONH2
Me
N
Me
Me
H2C
CH2
Me
HN
H2C
O
Me
O
-O
O
OH
P H
H
H
Vitamin B12
O
CH2OH
H3C
NC
O
CN
N
H
O
CH 3
NC
Glc-O
NC
Glc-O
N
OH
OR2
O
OR 3
OH
Ricinin (Alkaloid)
(from Castor oil seeds)
Merisclausin
OR1
Glc-O
(name depends on
R1, R2 , R3 )
Ehreticide B
Non cyanogenic cyanoglycosides
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
358
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GENERAL  ARTICLE
Figure 1. Continued...
O
OH
O
O
NH
O
NC
NC
H
MeO
N
O
N
H
H
O
H
H
O
Cyanopuupehenone
OMe
Saframycin A
(antiviral activitiy against HIV II)
(antibiotic and antitumor activities)
OH
O
O
MeO
N
H
NMe2
OH
N
O
H2 O3PO
OH
H
H
O
CN
OH
OMe
O
Calyculin J
(antitumour activitiy)
Br
R
2
R1 O
CN
R1 = H, R2 = R3 = CH2CH = C(CH3)2
R1 = R2 = H, R3 = CH2CH = C(CH3)2
R1 = R2 = R3 = H
CN
OR1
R3
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Epurpurins
359
GENERAL  ARTICLE
CH3
H3C
CH3
N
CN
OCH3
(S)-Verapamil
H3CO
OCH3
(Ca2+ channel blocker)
H3CO
O
CN
N
N
CH3
N
O
N
N
Ph
N
+
(H / K+ ATPase inhibitor)
CN
Zaleplan
(ultrashort acting sleep inducer)
Ph
Ph
NC
N
Ph
H
N
H3C
H
N
CH3
S
CO2C2H5
Diphenoxylate
(antidiarrheal agent)
Figure 2.
HN
N
N
CN
Cimetidine (Tagamet)
(antiulcer drug)
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 Functional Group
Synthetic routes of even larger number of drugs employ nitriles as
360
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GENERAL  ARTICLE
RCHO
+ HCN
R
C
OR2
OR2
OH
LDA
H
R
C
CN
H
R
_
CN
CN
R2 = O
C
,
R1X
1
R X = Variety of electrophiles
OR2
R1
R
C
Hydrolysis
O
intermediates because of their versatility for further useful transformation. 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.
R
C
R1
CN
Scheme 2.
Being a strong electron withdrawing group the cyano group
facilitates 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 displacement 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
RESONANCE  April 2008
The cyano group
facilitates the
formation of carbanion and then
ensures its stability.
This has been
exploited in pole
reversal (umpolung)
of aldehydic carbon.
361
GENERAL  ARTICLE
RS - > ArS- > I- > CN - > OH - > N3 - > Br- > ArO - > Cl- > Pyr > AcO - > H 2O
Figure 3.
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 electronegative atoms or groups. Some examples are given in Scheme 3.
Scheme 3.
_
O
_
O
x2
R
CH3
O
O
OH
_
OH
R
CX3
R
O
O
Cl3C
OH
OH
R
(1)
_
Base
Cl3C
+ x3C
OH
x = halogen
_
CX3
C
O
(2)
+ Cl3C
CO2
_
O
Ph
CH
CH
Br
Br
COOH
Base
Ph
CH
CH
Br
Br
O
_
Ph
COOH
H
C
_
Br
(3)
Br
Ph
O
Br
Br
CH
Br
CH
CH
Br
_
_
O
N
O
Base
N
N
O
O
(4)
Br
Br
N
O
362
H+
_
N
O
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GENERAL  ARTICLE
_
OH
R
C
O
Base
R
1
+
H
R
C
O
R
R
CN
CN
_
+ CN
1
t-BuOK
- HCN
H3C
(6)
H2C
NC
(5)
R1
a reaction in vitamin B12 synthesis
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.
Scheme 4.
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 condensation, in which two aldehyde molecules condense to give a hydroxy ketone.
The Benzoin Reaction
Cyanohydrins are the normal end products of nucleophilic addition of NaCN, KCN or HCN to aldehydes or ketones in aqueous
alcoholic solution. However, in the case of aldehydes the reaction 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 molecule 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.
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363
GENERAL  ARTICLE
O
O
R
C
H
+
_
CN
a
R
C
_
HO
H
b
R
C
_
(N) CN
NC
R1
c
O
(7)
H
_
_
R
O
HO
C
C
R1
H
e
R
O
HO
C
C
CN
H
R1
d
R
OH
O
C
C
CN
H
R1
Scheme 5.
R
R1
Yield (%)
Table 1. Some examples of
benzoin condensation in
Scheme 5.
364
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GENERAL  ARTICLE
NH2
NH2
H3C
N
S
H3C
OH
H3C
N
+
N
N
+
N
H3C
N
Vitamine B1 (Thiamine)
S
O
O _
O PO P O
O_
O_
Thiamine pyrophosphate (TPP)
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 intermediate 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 condensation. In fact, Nature has been performing this task efficiently in a
completely analogous manner using (vitamin B1)1 thiamine pyrophosphate, TPP, (Figure 4), a coenzyme present in our body, and
other living organisms. TPP catalyses several reactions that include decarboxylation of pyruvic acid to acetaldehyde, conversion of pyruvic acid to acetoin, (Scheme 6), transfer of 2-carbon
Figure 4.
1
The preparation of benzoin
using thiamine (vitamin B1) as
catalyst is one of the experiments being carried out by our
I semester MSc. Medicinal
Chemistry students. It is a neat
reaction, which gives pure, crystalline bezoin in high yield. The
preparatory procedure being followed is the one that is given in
[7] listed in Suggested Reading.
It is highly instructive experiment
from the point of chemistry, biochemistry, environmental chemistry, and bio- and organocatalysis.
Scheme 6.
OH
OH O
R
_
H3C C
_
O
O
+
N
S
+ HC
3
H3C
R
_
C
C
O
O
R1
Pyruvate
C
+
O
CH3
H
N
S
R N
H3C
R1
H3C
S
A1
R1
HO
O
C
C
_
H3C
_
O
H3C
C
R
OH
C
CH3
+
N
R
S
+
N
O
OH
C
C
H
S
_
CH3
H3C
R
+
N
CH3
H
S
+
H
acetoin
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H3C
R1
H3C
R1
H3C
R1
365
GENERAL  ARTICLE
OH HO
HO
H
H2C
C
O
P
CH2OH
R
o
C
HO
H
H
H
H
H
CH2OH
OH
B
S
N
O
R1
H3C
OH
CH2 O
HO
P
OH
OH
H
H
H
OH
G
CH2OH
O
OH
_
H
P
C
N
CH2OH
CHO
R
OH
H
OH
H2C
CH2 O
S
R1
H3C
N
S
C
P
F
H3C
E
A = Thiamine pyrophosphate
B = sedoheptalose-7-phosphate (ketose donor)
C = TPP-ketosedonor adduct
D = Ribose-5-phosphate
E = Resonance stabilized carbanion
F = Glyceraldehyde-3-phosphate (aldose acceptor)
G = Xylose-5-phosphate
Scheme 7.
The key feature of
thiazolium moiety in
OHC
R1
H
OH
H
OH
H
OH
CH2 -O -P
D
group from sedoheptalose-phosphate to glyceraldehyde-3-phosphate to produce xylose-5-phospate (an acyloin reaction),
(Scheme 7), which involve acyl ion or its equivalent intermediate
as in cyanide catalysed benzoin reaction.
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.
366
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 ioncatalysed one, (Scheme 5).
RESONANCE  April 2008
GENERAL  ARTICLE
The recognition that thiazolium ion in TPP catalyses these reactions 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.
_
X
N
R
S
+
H3C
OH
R = Ph-CH2, X = Cl (T-1)
R = C2H5, X = Br (T-2)
R = CH3, X = I (T-3)
Figure 5.
Scheme 8.
_
R1
O
_
R
+
N
R
S
R1
+
N
N
S
H
Et3N
H3C
+
R
O
S
H3C
OH
H3C
OH
OH
HO
H
O
HO O
1
2
R1 CH C R
+ R
O
OH
C CH R
R
C_
R1
+
R2
N
S
2
H3C
OH
O
CHO Et3N, EtOH
T_ 1
OH
O
Et3N, EtOH
C9H19CHO
ArCHO + RCHO
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C9H19
T_ 2
C
O
Et3N, EtOH
T_ 3
CHOH
Ar
C
C9H19
OH
CH
OH
R + Ar
CH
O
C
R
367
GENERAL  ARTICLE
Suggested Reading
Address for Correspondence
[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.
D A Williams and T L Lemke, Foye’s Principles of Medicinal Chemistry,
V Edn., Lippincott Williams & Williams, pp.211, 2002.
[5]
G Nagendrappa
# 13, Basappa Layout
Gavipuram Extension
[6]
H Stetter and H Kuhlman, Organic Synthesis, Coll., Vol.7, pp.95–99,
John Wiley, 2005.
Bangalore 560 019, India.
[7]
J Werner, Greener Approaches to Undergraduate Chemistry Experiments, 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.
Email:
[email protected]
A K Raychaudhuri
Gujjar
368
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