Benzoin Condensation

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 intermediateandistheprecursortotheacylanionequivalent. G Nagendrappa, retired Cyanohydrins are found in plants as glycosides. A reaction from Bangalore Univer- completely analogous to benzoin condensation occurs in our sity, Bangalore, is body, which however neither involves cyanohydrin interme- presently Professor and diate nor is catalysed by cyanide ion. It is catalysed by the Head of the Department of Medicinal Chemistry, Sri thiazolium moiety of the co-enzyme thiamine pyrophosphate Ramachandra University, (TPP). This article shows the common links and inclusive Porur, Chennai. His main chemistry aspects among cyanohydrin formation, naturally work is in the areas of occurring cyanohydrins, conversion of cyanohydrins to ben- organosilicon chemistry, organic synthesis, reaction zoins/acyloins, the role of vitamin B1 (thiamine) andthe use of mechanism and synthetic thiazolium compounds in benzoin/acyloin condensation. 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 addi- Keywords tion being reversible. Cyanoglycosides hydrolyse enzymatically Benzoin condensation, acyloin as well as nonenzymatically in the body to sugar and cyanohy- condensation, cyanoglycosides, cyanohydrins, vitamin B cataly- drins, which release hydrogen cyanide, Scheme 1. Ingestion of 1 sis, cyanide catalysis, thiazolium cyanoglycosides through consumption of such plant materials salt catalysis, nitrile-containing may cause cyanide poisoning if the cyanide concentration in the natural products.

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1 1 R R R1 hydrolysis Sugar O + sugar + HCN 2 O 2 OH R R 2 CN CN R

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: Thecyanideinhaled asHCN orconsumedas itssalts such asNaCN, KCNetc,

orreleased in the bodyon hydrolysisof cyanogenicglycosides eaten as food,causes poisoning. Orl-hmn LDL0 –1 –1 –1 = 2857gkg for NaCN or KCN. Orl-rat LD50 = 5 mgkg for KCN, and 6.44 mg kg for NaCN.

This is How it Poisons: Cyanide ion binds very strongly to Fe3+ ofmethemoglobin in mytochondria and forms cyanomethemoglobin, which cannot carry oxygen to tissues. The cellular respiration is arrested and the death is imminent. _ _ 3+ HbFe + CN HbFe3+CN Methemoglobin 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.MinorquantitiesofCN– areremovedbyoxidationtocyanate(CNO–)orcombiningwithcobalamin

to form cyanocobalamin (vitamin B12).

_ _ HbFe3+CN HbFe3+ + CN

_ _ Rhodana+ se CN SCN 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.

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Roots of cassava (tapioca), an important food crop in many Even in the case of countries of the world, including India, contain acetone cyanohy- apple seeds, seeds of drin glucoside called linamarin. Tapioca that contains linamarin other fruits, and bitter in excess of 100 mgkg–1 of fresh roots is not recommended for tapioca which have a food use. Even then, to make it suitable for edible purpose it has relatively high to be processed properly to bring down the toxin content to less cyanoglycoside than 50 mgkg–1, a limit that is considered as acceptable. content, one has to A long recognised source of a cyanogenic glucoside is bitter consume huge almond, whosebitterness is due to amygdalin, or D-mandelonitrile- quantities of them -D-gentiobioside, (Scheme 1). Historically, benzaldehyde was before they could first obtained from bitter almonds. 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. 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- Detoxification of minor sides which serve as defense against their predators. amounts of cyanide in the body is brought 2. Non-glycosidic Cyano Compounds about by the enzyme Cyano group occurs in natural products not only in cyanohydrin rhodanase present in glycosides, but also in non-cyanohydrin form. Some examples liver, erythrocytes, and are given in Figure 1. other tissues.

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H Me Me CH2CONH2 H2NOC CH2 H

Me CH2CH2CONH2 N CN N Me Co+ H NH N H Me H NOCH C 2 2 Me

Me H H2C Me CH2CH2CONH2 CH2 N Me CO HN

H2C N Me

O O Me OH O P H H -O H Vitamin B12 O CH2OH H

H3C NC NC NC O

CN Glc-O Glc-O Glc-O OR1

O OR2 N N O

3 CH3 OH OH OR Ricinin (Alkaloid) (name depends on Merisclausin Ehreticide B (from Castor oil seeds) R1, R2, R3 ) 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

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Figure 1. Continued... O OH O O

NH O NC NC MeO H N O N H H O H H O

Saframycin A OMe Cyanopuupehenone (antibiotic and antitumor activities) (antiviral activitiy against HIV II)

OH O

MeO O N H NMe2 OH N

H2 O3PO OH H O H O

CN OH OMe Calyculin J (antitumour activitiy) Br R2

R1O CN 1 2 3 R = H, R = R = CH2CH = C(CH3)2 1 2 3 R = R = H, R = CH2CH = C(CH3)2 R1 = R2 = R3 = H CN OR1

3 R Epurpurins

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H3C CH3 CH3

CN OCH3

H3CO (S)-Verapamil OCH 2+ 3 H3CO (Ca channel blocker)

CN N N

CH3

O N N

Ph + + N (H / K ATPase inhibitor) CN Zaleplan (ultrashort acting sleep inducer) Ph Ph

NC N H C H H Ph 3 N N S CH3

CO2C2H5 HN Diphenoxylate N N (antidiarrheal agent) CN Cimetidine (Tagamet) (antiulcer drug)

Figure 2. 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

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2 OH OR2 OR LDA _ RCHO + HCN R C H R C H R C

CN CN CN

2 R = O , R1X R1 X = Variety of electrophiles OR2 1 R R 1 Hydrolysis R C R C

O CN

intermediates because of their versatility for further useful trans- Scheme 2. 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 The cyano group efficient classic nucleophiles, the most common methods of facilitates the cyanation exploit this property, such as in (1) the direct displace- formation of - ment of halides, tosylates or similar leaving groups by cyanide, carbanion and then and (2) the addition of cyanide to aldehydes, ketones and their ensures its stability. ,-unsaturated analogues. This has been Cyanide’s high nucleophilic efficiency is due to its easy exploited in pole polarisability and low steric hindrance to its attack. (It is the reversal (umpolung) smallest carbon nucleophile). It is ranked high in the nuclephilicity of aldehydic carbon.

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

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

_ O O O _ O x OH _ 2 R CX _ C 3 + x3C R CH CX (1) 3 OH R 3 R OH OH x = halogen

O O _ Base _ CO2 + Cl3C (2) Cl3C O Cl3C OH O _ Base H Ph CH CH COOH Ph CH CH O Ph CH C_ Br

Br Br Br Br Br (3)

Ph CH CH Br O Br Br Br _ COOH _ O Base N N N

O O O (4)

Br Br

H+ _ N N

O O

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_ OH O O Base _ R C R1 1 + R C R + CN (5) H R R1 CN CN

t-BuOK - HCN H3C (6) H2C NC a reaction in vitamin B12 synthesis

The cyano group attached to an alkoxy carbon departs very easily, Scheme 4. 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 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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_ O O HO _ a b _ R C H + CN R C H R C NC (N) CN

R1 c O (7) H _ _ O HO O HO OH O d R C C R1 e R C C R1 R C C R1

H CN H CN H

Scheme 5. R R1 Yield (%)

Table 1. Some examples of benzoin condensation in Scheme 5.

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NH NH 2 2 + + N N N N S S O O _ H3C N H3C O P O P O H C H C OH 3 N 3 O_ O_

Vitamine B1 (Thiamine) Thiamine pyrophosphate (TPP)

The uniquely successful role of cyanide ion in catalyzing benzoin Figure 4. reaction is due to its four qualities, namely, (1) high nucleophilic 1 The preparation of benzoin activity, (stage a), (ii) facilitating the á proton transfer, (stage b), using thiamine (vitamin B1) as (iii) ability to stabilize negative charge in active aldehyde inter- catalyst is one of the experi- mediate N, (stage c), and (iv) ability to depart finally, (stage e). ments being carried out by our I semester MSc. Medicinal Vitamin B and Thiazolium Salts as Catalysts Chemistry students. It is a neat 1 reaction, which gives pure, crys- In principle, any chemical entity that incorporates all these four talline bezoin in high yield. The preparatory procedure being fol- features should be capable of bringing about benzoin condensa- lowed is the one that is given in tion. In fact, Nature has been performing this task efficiently in a [7] listed in Suggested Reading. 1 It is highly instructive experiment completely analogous manner using (vitamin B1) thiamine pyrophosphate, TPP, (Figure 4), a coenzyme present in our body, and from the point of chemistry, bio- chemistry, environmental chem- other living organisms. TPP catalyses several reactions that in- istry, and bio- and organo- clude decarboxylation of pyruvic acid to acetaldehyde, conver- catalysis. sion of pyruvic acid to acetoin, (Scheme 6), transfer of 2-carbon Scheme 6.

OH OH O C CH3 _ H3C C _ O O R + O H N S _ R + C N S R N S + O H3C C

H3C 1 O R H C 1 A 1 Pyruvate 3 R H3C 1 R

_ _ O OH HO O H3C C C CH3 H C _ 3 C C CH3 H H O R + R + OH N S N S R + N S H3C C C CH3 + 1 H 1 H3C R H3C R 1 H3C R acetoin

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O HO OH HO H

H2C C CH2OH O H H H OH CH2OH P R B N S o C

HO H R1 H3C

H OH OH OH H OH CH2 O P HO H C CH OH G 2 2 OH O H H H OH P _ N S C CH2OH

CHO 1 R H3C R H OH N S C CH2 O P OHC F H C 1 3 E R H OH

H OH A = Thiamine pyrophosphate B = sedoheptalose-7-phosphate (ketose donor) H OH C = TPP-ketosedonor adduct

D = Ribose-5-phosphate CH2 -O -P E = Resonance stabilized carbanion D F = Glyceraldehyde-3-phosphate (aldose acceptor) G = Xylose-5-phosphate

Scheme 7. group from sedoheptalose-phosphate to glyceraldehyde-3-phosphate to produce xylose-5-phospate (an acyloin reaction), The key feature of (Scheme 7), which involve acyl ion or its equivalent intermediate thiazolium moiety in as in cyanide catalysed benzoin reaction. facilitating this reaction so efficiently The key feature of thiazolium moiety in facilitating this reaction lies in the fact that the so efficiently lies in the fact that the hydrogen on the carbon hydrogen on the between sulphur and nitrogen (i.e. the position 2) is acidic enough

carbon between to be exchanged with deuterium in D2O. Removal of this proton sulphur and nitrogen by base carries forward the reaction, as depicted in Schemes 6–8, (i.e., the position 2) is in a manner that is completely analogous to the cyanide ion- acidic. catalysed one, (Scheme 5).

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The recognition that thiazolium ion in TPP catalyses these reac- _ tions has led to development of improvised thiazolium ion-based R X N S catalysts (Figure 5), which are simpler than TPP, yet bring about + benzoin condensation effectively(Scheme 8). In factthe thiazolium catalysts show more scope in applicability in that they are able to H3C OH catalyse the condensation of a wider variety of aldehydes and not only aromatic aldehydes. An added advantage is that they bring R = Ph-CH2, X = Cl (T-1) R = C2H5, X = Br (T-2) about condensation at room temperature and that too without the R = CH3, X = I (T-3) hazardous risks of environmental pollution posed by cyanide. The replacement of cyanide by the harmless thiazolium salts as Figure 5. catalysts for benzoin condensation is one of the finest examples of Green Chemistry in action. Scheme 8.

_ O R1 _ R1 R + R + O R + N S N S N S

Et3N H

H C H3C H C 3 OH 3 OH OH

HO R1 C _ H R + O N S HO O O OH R2 2 1 2 R1 CH C R + R C CH R H C 3 OH

CHO Et3N, EtOH T_1 OH O Et3N, EtOH C9H19CHO C9H19 C CHOH C9H19 T_2 O OH OH O Et3N, EtOH ArCHO RCHO + Ar C CH R + Ar CH C R T_3

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