Cyanhydrine Reaction

Lubavin, in 1882, stated that glycine was formed by the action of ammonium cyanide upon glyoxal, which probably first breaks down into formaldehyde and then by the cyanhydrin reaction yields glycine —... 

Since the cyanhydrine reaction takes place smoothly in most cases, it is frequently used for the preparation of a-oxyadds. 

Thus in the sugar group the cyanhydrine reaction is of extreme Importance, not only for its value in determining constitution, but also for the syntheses of sugars or sugar-like substances containing long chains of carbon atoms. 

After repeated cyanhydrin reactions, four tetroses will provide a total of eight pentoses (each tet-rose provides a pair of new diastereomers with one more chiral center), which can then yield sixteen stereoisomeric hexoses. The compounds derived from D-glyceraldehyde are designated as D-aldoses and those from L-glyceraldehyde as L-aldoses. 

CHjiCH-CN. Volatile liquid b.p. 78"C. Manufactured by the catalytic dehydration of ethylene cyanhydrin, by the addition of hydrogen cyanide to ethyne in the presence of CuCI or the reaction of propene, ammonia and air in the presence of a molybdenum-based catalyst. 

To 2 ml. of the ester, add 2--3 drops of a saturated freshly prepared solution of scdium bisulphite. On shaking, a gelatinous precipitate of the bisulphite addition product (D) of the keto form separates, and on standing for 5-10 minutes usually crystallises out. This is a normal reaction of a ketone (see p. 344) hydrogen cyanide adds on similarly to give a cyanhydrin. 

Induction of Asymmetry by Amino Acids. No fewer than sis types of reactions can be carried out with yields of 75—100% usiag amino acid catalysts, ie, catalytic hydrogenation, iatramolecular aldol cyclizations, cyanhydrin synthesis, alkylation of carbonyl compounds, hydrosdylation, and epoxidations (91). 

Mandelic Acid.—The reaction furnishes a simple and general method for obtaining hydroxy-acids from aldehydes or ketones by the aid of the cyanhydrin. The formation of the cyanhydrin may be effected in the manner described or by the action of hydrochloric acid on a mixture of the aldehyde or ketone with potassium cyanide, or, as in the case of the sugais, by the use of liquid hydrocyanic acid and a little amme-nia. 

Dodge has based a process for the determination of benzaldehyde. A strong (2 5 N) alcoholic potash solution is required for the estimation, which is performed. by allowing a mixture of 10 c.c. of this solution with 1 to 2 grams benzaldehyde to stand at the ordinary temperature for twenty-four hours, after which the unabsorbed pota is titrated back with N/2 hydrochloric acid. A blank test is also made, and from the amount of potash entering into reaction, the percentage of aldehyde can be calculated. The process breaks down in the assay of natural oil of bitter almonds, probably due to the presence of benzaldehyde cyanhydrin. 

Decomposition by cyanide gives the same products (except that the sugar forms the cyanhydrin) and probably involves coordination of cyanide in the trans position, followed by the elimination of Co(III) and oxygen (as RO ) to give the olefin. For further references and discussion about both these reactions see Chapter 13 of ref. (136). These two methods of decomposition... 

Both acrylic acid and methacrylic acid polymerise to give water soluble hard resins. The viscous solutions so formed have been used as emulsifying agents, adhesives and as thickening agents for inks and dyes. Polymers of esters of these acids are of greater commercial importance. Esters can be prepared from cyanhydrins by reaction with an alcohol ... 

Allyl derivatives of a range of cyanhydrins have been obtained from the liquiddiquid two-phase reaction catalysed by Aliquat at 0°C [17]. Yields range from ca. 25% to 45%. 

Method E (using acetone cyanhydrin) TBA-CN or TBA-OH (11 mmol) in MeCN (10 ml) is added dropwise over 20-30 min to the haloalkane (10 mmol) and Me2C(OH)CN (1.3 g, 15 mmol) in MeCN (20 ml) and the mixture is stirred until TLC analysis indicates the reaction to be complete. The mixture is evaporated and the residue taken up in H20 (10 ml) and Et20 (40 ml). The organic phase is separated, washed with H20 (3x5 ml), dried (MgS04), and evaporated to yield the nitrile. 

Aqueous NaOH (50%, 0.2 ml), TEBA-CI (15 mg, 0.06 mmol), and the cyanhydrin benzoate (1 mmol) in PhH (4 ml), are stirred at room temperature under argon for 10 min. The aryl aldehyde (1 mmol) in PhH (4 ml) is then added at 0°C and the mixture is stirred at room temperature for ca. 5 h (monitored by TLC). On completion of the reaction, the organic solution is separated and washed well with H20, dried (MgS04), and evaporated to yield the benzoin benzoate (Table 6.15). 

The mechanism for replacement of a methoxyl group by cyanide in these reactions follows Scheme 6.7. The radical-cation reacts with cyanide ion at the point of highest positive charge density. Oxidation of the radical so formed to the carbon-ium ion is followed by elimination of proton and formaldehyde [79]. The elimination step is analogous to the conversion of cyanhydrins to the carbonyl compound and cyanide ion in basic solution. 

Initial preparative work with oxynitrilases in neutral aqueous solution [517, 518] was hampered by the fact that under these reaction conditions the enzymatic addition has to compete with a spontaneous chemical reaction which limits enantioselectivity. Major improvements in optical purity of cyanohydrins were achieved by conducting the addition under acidic conditions to suppress the uncatalyzed side reaction [519], or by switching to a water immiscible organic solvent as the reaction medium [520], preferably diisopropyl ether. For the latter case, the enzymes are readily immobilized by physical adsorption onto cellulose. A continuous process has been developed for chiral cyanohydrin synthesis using an enzyme membrane reactor [61]. Acetone cyanhydrin can replace the highly toxic hydrocyanic acid as the cyanide source [521], Inexpensive defatted almond meal has been found to be a convenient substitute for the purified (R)-oxynitrilase without sacrificing enantioselectivity [522-524], Similarly, lyophilized and powered Sorghum bicolor shoots have been successfully tested as an alternative source for the purified (S)-oxynitrilase [525],... 

It is interesting to note that supplementary reactions leading to impurities may take place outside the reaction space, mostly in the aqueous phase during the first separation steps of quench and absorption in water. Typical examples are the formation of propion-cyanhydrine and dinitrile-succinate favored by a basic pH ... 

HFA and cyanotrimethylsilane react stoichiometrically with formation of the substituted cyanhydrin 9 (775). Increasing the molar ratio of the reactants to 4 1 yields, in addition to 9, compound 10, with nitrile-isonitrile equilibrium competing with direct attack of HFA (242). The five-membered ring is also formed in the reaction of organic iso-nitriles with HFA (188). The same structural feature in addition to insertion has been found when triethylamine is present as a catalyst, as well as minor amounts of 9 (83, 242). 

Pyridazine 3-carbaldehyde can be prepared from 3-hydroxymethylpy-ridazine by oxidation with selenium dioxide (82BSB153). Its 2-oxide was obtained similarly (78JMC1333). Contrary to aromatic aldehydes, py-ridazine-4-carbaldehydes behave differently under the reaction conditions typical for benzoin condensation or cyanhydrin formation. In the first case, a crossed Cannizzaro reaction takes place and, with an equivalent amount of hydrocyanic acid, compound 80 is obtained. This is transformed with acetic anhydride into a mixture of E- and Z-isomers of 81. On attempted chromatographic separation, the mixture is converted into methyl 4-pyridazinecarboxylate (78JHC637). 

It should be evident that the maximum yield of a particular enantiomer normally available from a racemic mixture is 50%. However, in some enzymic catalysed kinetic resolutions it is possible to obtain >50% yield of one enantiomer from a racemate. For this to occur, it is necessary to have the desired chemical reaction, e.g. enzyme-catalysed stereoselective esterification, occurring at the same time as the enantiomers of the racemic starting compound are interconverting under equilibrium conditions. A successful example of this technique is provided by ben-zaldehyde cyanhydrin (2-hydroxy-2-phenylacetonitrile), whose R and S enantiomers, 49 and 50, respectively, equilibrate in the presence of a basic anion-exchange resin (Scheme 3.5). In the presence of lipase, (S)-ben-zaldehyde cyanhydrin acetate 51 was formed in 95% yield and in 84% enantiomeric excess (see Inagaki et al.u and Ward15). 

Extension of the carbon chain of an aldose from the carbonyl by one unit at a time can be carried out fairly readily by the Kiliani reaction. A cyanhydrin is formed by addition of cyanide ion, followed by reduction and hydrolysis (in either order) historically, the sugar was unprotected, and the cyanohydrin was hydrolysed to the sugar lactone, and then reduced with sodium amalgam (Figure 1.4). Because a new asymmetric centre is formed, two epimeric sugars result (epimers are diastereomers that differ in the configuration of only one carbon). 

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