Benzoin Condensation
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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. RESONANCE April 2008 355 GENERAL ARTICLE 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 con- tent 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 = 2857gkg 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. 356 RESONANCE April 2008 GENERAL ARTICLE 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. RESONANCE April 2008 357 GENERAL ARTICLE 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 358 RESONANCE April 2008 GENERAL ARTICLE 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 O 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 RESONANCE April 2008 359 GENERAL ARTICLE H3C CH3 CH3 N CN OCH3 H3CO (S)-Verapamil OCH 2+ 3 H3CO (Ca channel blocker) 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 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 360 RESONANCE April 2008 GENERAL ARTICLE 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. RESONANCE April 2008 361 GENERAL ARTICLE - - - - - - - - - - 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).