Addition of HCN

Addition of HCN to aldehydes produces cyanohydrins. Since HCN is a toxic gas, it is not used in the reaction directly. CN- salts of active metals such as Na and K react with mineral acids such as H3P04 and then the HCN formed reacts with the carbonyl group. 

While it is necessary to use an acid catalyst to react poor nucleophiles like H20 and ROH with aldehydes, there is no need to use a catalyst for a strong nucleophile such as CN-. 

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The Kiliani-Fischer synthesis pro ceeds by nucleophilic addition of HCN to an aldose followed by con version of the cyano group to an al dehyde A mixture of stereoisomers results the two aldoses are epi meric at C 2 Section 25 20 de scribes the modern version of the Kiliani-Fischer synthesis The example at the right illus trates the classical version... 

Cyanohydrins are formed by nucleophilic addition of HCN to the carbonyl group of an aldehyde or a ketone Cycloadd ition (Section 10 12) Addition such as the Diels-Alder reaction in which a ring is formed via a cyclic transition state... 

Addition of HCN to unsaturated compounds is often the easiest and most economical method of making organonitnles. An early synthesis of acrylonitrile involved the addition of HCN to acetylene. The addition of HCN to aldehydes and ketones is readily accompHshed with simple base catalysis, as is the addition of HCN to activated olefins (Michael addition). However, the addition of HCN to unactivated olefins and the regioselective addition to dienes is best accompHshed with a transition-metal catalyst, as illustrated by DuPont s adiponitrile process (6—9). 

DuPont currentiy practices a butadiene-to-adiponittile route based on direct addition of HCN to butadiene (6—9). It was first commercialized in 1971. AH reactions are catalyzed by soluble, air and moisture sensitive, ttiarylphosphite-nickel(0) complexes. 

Processes rendered obsolete by the propylene ammoxidation process (51) include the ethylene cyanohydrin process (52—54) practiced commercially by American Cyanamid and Union Carbide in the United States and by I. G. Farben in Germany. The process involved the production of ethylene cyanohydrin by the base-cataly2ed addition of HCN to ethylene oxide in the liquid phase at about 60°C. A typical base catalyst used in this step was diethylamine. This was followed by liquid-phase or vapor-phase dehydration of the cyanohydrin. The Hquid-phase dehydration was performed at about 200°C using alkah metal or alkaline earth metal salts of organic acids, primarily formates and magnesium carbonate. Vapor-phase dehydration was accomphshed over alumina at about 250°C. 

A second commeicial route to aciylonitiile used by Du Pont, Ameiican Cyanamid, and Monsanto was the catalytic addition of HCN to acetylene... 

Cycloahphatics capable of tertiary carbocation formation are candidates for nucleophilic addition of nitriles. HCN in strong sulfuric acid transforms 1-methyl-1-cyclohexanol to 1-methyl-1-cyclohexylamine through the formamide (47). The terpenes pinene (14) [2437-95-8] and limonene [5989-27-5] (15) each undergo a double addition of HCN to provide, after hydrolysis, the cycloahphatic diamine 1,8-menthanediamine (16) (48). 

Cyanohydrins are formed by nucleophilic addition of HCN to the carbonyl group of an aldehyde or a ketone. 

Cyanohydrin (Section 19.6) A compound with an -OH group and a -CN group bonded to the same carbon atom formed by addition of HCN to an aldehyde or ketone. 

Several reports on DKR of cyanohydrins have been developed using this methodology The unstable nature of cyanohydrins allows continuous racemization through reversible elimination/addition of HCN under basic conditions. The lipase-catalyzed KR in the presence of an acyl donor yields cyanohydrin acetates, which are not racemized under the reaction conditions. 

The addition of HCN to aldehydes or ketones produces cyanohydrins (a-hydroxy nitriles). Cyanohydrins racemize under basic conditions through reversible loss of FiCN as illustrated in Figure 6.30. Enantiopure a-hydroxy acids can be obtained via the DKR of racemic cyanohydrins in the presence of an enantioselective nitriletransforming enzyme [86-88]. Many nitrile hydratases are metalloenzymes sensitive to cyanide and a nitrilase is usually used in this biotransformation. The DKR of mandelonitrile has been extended to an industrial process for the manufacture of (R)-mandelic acid [89]. 

The addition of HCN to aldehydes or ketones produces cyanohydrins. This is an equilibrium reaction. For aldehydes and aliphatic ketones the equilibrium lies to the right therefore the reaction is quite feasible, except with sterically hindered ketones such as diisopropyl ketone. However, ketones ArCOR give poor yields, and the reaction cannot be carried out with ArCOAr since the equilibrium lies too far to the left. With aromatic aldehydes the benzoin condensation (16-54) competes. With oc,p-unsaturated aldehydes and ketones, 1,4 addition competes (15-33). Ketones of low reactivity, such as ArCOR, can be converted to cyanohydrins by treatment with diethylaluminum cyanide (Et2AlCN see OS VI, 307) or, indirectly, with cyanotrimethylsilane (MesSiCN) in the presence of a Lewis acid or base, followed by hydrolysis of the resulting O-trimethylsilyl cyanohydrin (52). The use of chiral additives in this latter reaction leads to cyanohydrins with good asymmetric... 

The hydroxynitrile lyase (HNL)-catalyzed addition of HCN to aldehydes is the most important synthesis of non-racemic cyanohydrins. Since now not only (f )-PaHNL from almonds is available in unlimited amounts, but the recombinant (S)-HNLs from cassava (MeHNL) and rubber tree (HbHNL) are also available in giga units, the large-scale productions of non-racemic cyanohydrins have become possible. The synthetic potential of chiral cyanohydrins for the stereoselective preparation of biologically active compounds has been developed during the last 15 years. 

For practical applications of HNLs as catalysts for the preparation of chiral cyanohydrins, three objectives have been achieved first, to get high enantioselec-tivity it is decisive to suppress the non-enzymatic addition of HCN to the substrate ... 

In the first step, (R)-2-chlorobenzaldehyde cyanohydrin is prepared by the almond meal-catalyzed addition of HCN to 2-chlorobenzaldehyde. The cyanohydrin is then transformed into the corresponding 2-hydroxy ester by Pinner reaction. Subsequently, the hydroxy group is activated by sulfonylafion and reacted with tetrahydrothieno[3.2-c]pyridine to give, under complete inversion of configuration, the (5 ) — a-amino acid derivative CLOPIDOGREL. ... 

Since the chemical addition of HCN always results in mixtures of cis/trans-isomers, the stereoselective HNL-catalyzed addition is of great advantage in the synthesis of natural products. The syntheses of the natural monoterpenes cis-p-menth-8-ene-l,7-diol and cA-/ -menthane-l,7,8-triol are interesting examples for the application of this methodology (Scheme 9). ... 

While the chemical addition of HCN to 4-(2-propenyl)cyclohexanone affords a cis/trans ratio of 13 82, the MeHNL-catalyzed addition gives almost exclusively the c 5-isomer (>96%). The chemoenzymatic syntheses of rengyol and isorengyol are other examples for applications of HNL-catalyzed additions of HCN to cyclohexanones. ... 

Although considerable progress has been made in metal-catalyzed preparations of non-racemic cyanohydrins, the HNL-catalyzed reaction is still the most important method for the synthesis of chiral cyanohydrins, especially for large-scale reactions. The usefulness of HNLs as catalysts for the stereoselective addition of HCN to carbonyl compounds has increased substantially because (7 )-PaHNL... 

For a given carbonyl compound, K will be influenced by the size of the nucleophile thus the value of K for addition of the very bulky bisulphite anion (S2O320, p. 213) to (MeCH2)2C=0 is only 4 x 10-4, compared with K = 38 for addition of HCN (above) to the very similar ketone, MeCH2COMe. The value of K is also influenced by the nature of the atom in the nucleophile that attacks the carbonyl carbon atom, and of the bond that is thereby formed as is observed in the following sequence for reaction with the same carbonyl compound ... 

Although addition of HCN could be looked upon as a carbanion reaction, it is commonly regarded as involving a simple anion. It is of unusual interest in that it was almost certainly the first organic reaction to have its mechanistic pathway established (Lapworth 1903). HCN is not itself a powerful enough nucleophile to attack C=0, and the reaction requires base-catalysis in order to convert HCN into the more nucleophilic CN the reaction then obeys the rate law ... 

Figure 8.12 Conversion of benzaldehyde into enantiomerically pure (S)-mandelic acid by the sequential addition of HCN catalyzed by the (.S )-selective oxynitrilase from Manihot esculenta (MeHnL), and subsequent hydrolysis of the resultant (5)-mandelonitrile by the nitrilase from Pseudomonas fluorescens ECB 191 (PfNLase)...

Considerable effort has been directed towards the catalytic addition of HCN to vinylarenes since this represents a route to 2-arylpropionic acids, well-known anti-inflammatory agents.75 High levels of asymmetric induction are required (R)-naproxen has undesirable properties associated with it and only the ([Pg.277]

This same trend is produced upon addition of HCN to 4-isobutylstyrene, but in the case of 6-methoxy-2-vinylnaphthalene, all three ligands afford ca. 30% enantiomeric excess. 

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