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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.
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355
RESONANCE 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, Bang alore, is
presently Professor and
Head of the Department o f
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
CN
OSugar
R1
R2
CN
OH
R1
R2
Osugar 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 Cyanohemoglobin
CN
_
_
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 qu antities of CNare removed b yox idation to cyanate (CNO) or c ombining with cob alamin
to form cyanocobalamin (vitamin B12 ).
+
+
HbFe3+
HbFe3+CN
_
_
CN
_
CN
_
SCN
Rhodanase
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.
357
RESONANCE April 2008
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, whose bitterness 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.
358 RESONANCE April 2008
GENERAL ARTICLE
Vitamin B12
N N
NH N
Co+
CN
H
H2NOCH2CMe
CH2CONH2
CH2CH2CONH2
Me
Me
Me
Me
Me
Me
CH2
H2NOC
H
N
Me
N
P
O
Me
H
CH2OH
OH
HH
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
NO
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
359
RESONANCE April 2008
GENERAL ARTICLE
N
N
O
O
MeO
NH
O
O
O
OMe
NC
H
H
H
O
NC
OH
O
H
H
N
H
N
O
O
O
O
NMe2OH
OH O
OMe
B
r
CN
H
H2O3PO
OH
OH
H
MeO
CN
CN
R2
R1O
OR1
R
3
Cyanopuupehenone
(antiviral activitiy against HIV II)
Saframycin A
(antibiotic and antitumor activities
)
R1= H, R2= R3= CH2CH = C(CH3)2
R1= R2= H, R3= CH2CH = C(CH3)2
R
1
=
R
2
=
R
3
=
H
Epurpurins
Calyculin J
(antitumour activitiy)
Figure 1. Continued...
360 RESONANCE April 2008
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
Ph
Ph
Figure 2.
N
CH3
H3C
CH3
CN
H3CO
OCH3
OCH3
H3CO (S)-Verapam il
(Ca2+ channel blocker)
O
N
N
P
CH3
CN
(H
+
/ K
+
ATPase inhibitor) N
NN
CN
N
O
Zaleplan
(ultrashort acting sleep inducer)
Diphenoxylate
(antidiarrheal agent)
N
HN
H3C
S
H
NH
N
CH3
N
CN
Cimetidine (Tagamet)
(antiulcer drug)
361
RESONANCE April 2008
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
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 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 HCN LDA
R1X
+R C
OH
CN
HR C
OR2
CN
R C
OR2
CN
R1
R1
C
O
RHydrolysis
R C
OR2
CN
H
_
R1X = 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.
362 RESONANCE April 2008
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
RCX3
O
C
R CX3
O
OH ROH
O
+
Cl3COH
O
Cl3CO
O
+
_
_
_Cl3C
_
CO2
OH
_OH
_
x2x3C
x = halogen
Base
Ph CH CH Br
Ph CH CH COOH
Br Br
Ph CH CH
Br Br
OPh CH H
C
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)
363
RESONANCE April 2008
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
RR1
O
+CN
_
_
Base
H+
H3C
NC
H2C
t-BuOK
a reaction in vitamin B
1
2
synthesis
-HCN
Scheme 4.
(5)
(6)
364 RESONANCE April 2008
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
R1
R1
C
HO
H
C
O
R
ab
c
d
e
__
_
_
_
R C
CN
O
C
HO
H
R1
(N)
(7)
Scheme 5.
Table 1. Some examples of
benzoin condensation in
Scheme 5.
R R1Yield (%)
365
RESONANCE April 2008
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 B1and 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)1thiamine 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
NS
R
H3C
R1
_
+
+NS
R
H3CR1
+
C
H3C
C
CO
O
O
_
OH
H3C
O
O_
NS
R
H3C R1
C C
HO
H3C
O
NS
R
H3CR1
C C
O
H3C
OH
NS
R
H3CR1
_
+H
CH3
_
CH3
H
_
NS
R
H3CR1
C
H
O
CH3
OH
a
c
e
t
o
i
n
+
H3C C
O
C
OH
H
CH3
A1
Pyruvate
+
+
N
N
N
H
2
H3C
NS
OH
+
H3C
N
N
N
H
2
H3C
NS
OP
O
O
OP
O
O
O
H3C
+
_
_
_
Vitamine B1(Thiamine) Thiamine pyrophosphate (TPP)
Figure 4.
Scheme 6.
1The preparation of benzoin
using thiamine (vitamin B1) as
catalyst is one of the experi-
ments being carried out by our
I se m es t er M Sc. Medi cin al
Chemistry students. It is a neat
reaction, whic h gives pure, crys-
talline bezoin in high yield. The
preparatory pro cedure being fol-
lowed is the one that is given in
[7] listed in Suggested Reading.
It is highly ins tructive experiment
from the point of chemistry, bio-
chemistry, environm ental chem-
istr y, and bio- and org an o-
catalysis.
366 RESONANCE April 2008
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
OH
H
CH2O P
NS
H3CR1
NS
R
H3CR1
C
OH
CH2OH
CHO
OH
CH2
H
OP
NS
H3CR1
CH2OH
OH
H
OH
OH
H
OH
H
HO
H
H2C
H2C
HO
H
OH
H
HO
H
H
OH
C
O
CH2OH
O
O
P
OHC
OH
H
OH
H
OH
H
CH2-O -P
o
R
G
E
_
F
C
B
D
P
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
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.
367
RESONANCE April 2008
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
benzoincondensation 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.
S
N
R
H3COH
X
_
+
R = Ph-CH2, X = Cl (T-1)
R = C2H5, X = Br (T-2)
R = CH3, X = I (T-3)
Figure 5.
N S
R
H3COH
+N S
R
H3C
+
N S
R
H3COH
+
_
Et3N
R1
H
O
OR1
_
N S
R
H3COH
+
C
HO R1
_
R2
H
O
R1C
O
CH
OH
R2
R1CH
HO
CR2
O
+
CHO
O
OH
C9H19 C
O
CHOH C9H19
+Ar C
O
CH
OH
R+Ar CH
OH
C
O
R
RCHO
C9H19CHO
ArCHO
Et3N, EtOH
Et3N, EtOH
Et3N, EtOH
T_1
T
_
3
T_2
Scheme 8.
OH
368 RESONANCE April 2008
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 Le mke, Foye’s Pr inciples of Medic inal Chemistry ,
V Edn., Lippincott Williams & Williams, pp.211 , 2002.
[6] H Stetter and H Kuhlman, Orga nic Synthesis, Coll., Vol.7, pp.95–99,
John Wiley, 2005.
[7] J Werner, Greener Approaches to Und ergraduate Chem istry 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:
gnagendrappa@gmail.com
Gujjar
A K Raychaudhuri
... This reaction is catalysed by CN À , thiamine or thiazolium salts and benzimidazolium salts in organic solvents (Scheme 11). [56][57][58][59][60][61][62][63][64][65][66] It has been demonstrated that the reaction can take place in aqueous media under mild conditions when the catalyst is immobilized on solid supports. In spite of the feasibility of this route to diesel-range fuel intermediates from HMF or furfural, it has not been considered for the same purpose. ...
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Electronic effects are important directing forces in the course of chemical reactions. Small differences in these effects can bring about considerable changes in the results of very similar reactions. Thus, although the ambident nucleophiles urea, ophenylenediamine and dibenzyl ketone are expected to take comparable double condensation pathway in their respective reaction with benzil, urea reacts differently by causing benzil-to-benzilic acid type rearrangement. This is attributed to the reduced availability of the lone pair of electrons on nitrogen in urea that is needed for assisting the dehydration of the intermediate.
Chapter
[7726-95-6] C26H24Br4P2 (MW 718.04) InChI = 1S/C26H24P2.2Br2/c1-5-13-23(14-6-1)27(24-15-7-2-8-16-24)21-22-28(25-17-9-3-10-18-25)26-19-11-4-12-20-26;2*1-2/h1-20H,21-22H2;; InChIKey = NMRKFQBGSCFFJM-UHFFFAOYSA-N (reagent capable of effecting the conversion of alcohols and tetrahydropyranyl ethers into bromides rapidly and efficiently in the presence of other sensitive functional groups1)Solubility: sol CH2Cl2.Preparative Method: generated in situ by treatment of 1,2-bis(triphenylphosphino)ethane with 2 equiv of bromine in dry dichloromethane at 0 °C under an inert atmosphere.1Handling, Storage, and Precautions: the usual care should be taken to avoid contact of the skin with liquid bromine.
Greener Approaches to Undergraduate Chemistry Experiments
  • J Werner
J Werner, Greener Approaches to Undergraduate Chemistry Experiments, pp. 14-17, 2002.
  • H Stetter
  • H Kuhlman
H Stetter and H Kuhlman, Organic Synthesis, Coll., Vol.7, pp.95-99, John Wiley, 2005.