Benzaldehydes hydrocyanation

Amygdalin (the glucoside of bitter almonds) is a white crystalline compound, soluble in water, readily hydrolysed on heating with dilute sulphuric acid to benzaldehyde, hydrocyanic acid and glucose. 

Benzaldehyde, hydrocyanic acid (1-5-4%), phenoxy-acetonitrile Artificial benzaldehyde, nitrobenzene... 

There appeal s to be little doubt that the action above indicated for the decomposition of amygdalin does not take place as simply as indicated. Recent researches by Eosenthaler and othei-s indicate that the enzyme is not a single body but a mixture of fei-ments, and that the system amygdalin-emulsin gives rise to the following series of reactions, which end up with the oil containing benzaldehyde, hydrocyanic acid, and benzaldehyde-cyanhydrin —... 

Mandelic acid is best prepared by the hydrolysis of mandeloni-trile with hydrochloric acid. The mandelonitrile has been prepared from amygdalin, by the action of hydrocyanic acid on benzaldehyde, and by the action of sodium or potassium cyanide on the sodium bisulfite addition product of benzaldehyde. ... 

As early as 1908, Rosenthaler found in the ferment mixture of emulsin a u-oxynitrilase , which directed the addition of hydrocyanic acid (hydrogen cyanide) to benzaldehyde asymmetrically to give x-hydroxybenzeneacetonitrilc (mandelonitrile)9. This result was confirmed1 °, however, it was not until 1963 that Pfeil ct al. first isolated and characterized the enzyme (R)-oxyni-trilase [EC 4.1.2.101 from bitter almonds (Prunus amygdalus)1 12. The yellow-colored enzyme contains a flavin-adenine dinucleotide (FAD)11 and loses its activity by splitting off this prosthet-... 

Figure 1. Rate of the chemical (---) and enzymatic additions (—) of hydrocyanic acid to benzaldehyde (initial concentration 5 mM) in water/ethanol and in ethyl acetate/cellulose.

Starting from enantiomerically pure 4-methylsulfanyl-mandelonitrile, thiamphenicol and florfenicol have been enantioselectively synthesized (Figure 5.14). The enantiomerically pure 4-methylsulfanyl-mandelonitrile was obtained by hydrocyanation reaction of 4-methy lsulfany 1-benzaldehyde catalyzed by (M)-hydroxynitrile lyase of Badamu (almond from Xinjiang, China) (Prunus communis L. var. dulcis Borkh), which, after an extensive screening, was found to be a highly effective bio-catalyst for this reaction [85]. 

Further evidence for the formation of intermediate compounds in catalytic reactions is afforded by the observation (a) that optically active camphor is formed from optically inactive (racemic) camphor carboxylic acid in the presence of the d- or /-forms of quinine, quinidine or nicotine and (6) that optically active bases, e.g., quinidine, catalyze the synthesis of optically active mandelonitrile from benzaldehyde and hydrocyanic acid.10 These results hardly admit of any other interpretation than the intermittent production of a catalyst-reactant compound. 

Heat amygdalin with dilute sulphuric acid under reflux for a short time. Remove benzaldehyde and hydrocyanic acid by steam distillation. Test for benzaldehyde (phenylhydrazone test) and hydrocyanic acid (Prussian blue test) in distillate, and for glucose (osazone test) in residue. 

The methods of analysis are those used for other spirits in addition, for nut-fruit spirits, hydrocyanic acid and benzaldehyde and sometimes nitrobenzene are tested for and determined as follows ... 

B) Quantitative Determination. In spirits from nut-fruits, the hydrocyanic acid is partly free and partly combined with benzaldehyde (cyanohydrin). That in the latter form is determined indirectly as the difference between the total and free amounts. 

The total hydrocyanic acid is determined similarly, but after the cyanohydrin of benzaldehyde has been decomposed. For this purpose, 100 c.c. of the spirit in a 300 c.c. flask are rendered strongly alkaline with ammonia and then treated with a measured excess of the silver nitrate solution. The whole is shaken, immediately acidified with dilute nitric acid and diluted to the mark, an aliquot part of the filtered liquid being then treated as in the determination of the free hydrocyanic acid. 

The combined hydrocyanic acid — total less free acid, and 1 gram of combined hydrocyanic acid = 4-92 grams of benzaldehyde cyanohydrin. 

Artificial products, obtained by addition of aromatic substances to commercial alcohol, may however be recognised, as they contain little or no hydrocyanic acid and are rich in benzaldehyde. Kirschwasser and similar spirits are prepared, although rarely, from alcohol and bitter almond or cherry laurel water and in such cases hydrocyanic acid is present. Artificial products are generally prepared from rectified alcohol and thus have a low coefficient of impurity and contain only very small amounts of higher alcohols. 

Several studies have tackled the structure of the diketopiperazine 1 in the solid state by spectroscopic and computational methods [38, 41, 42]. De Vries et al. studied the conformation of the diketopiperazine 1 by NMR in a mixture of benzene and mandelonitrile, thus mimicking reaction conditions [43]. North et al. observed that the diketopiperazine 1 catalyzes the air oxidation of benzaldehyde to benzoic acid in the presence of light [44]. In the latter study oxidation catalysis was interpreted to arise via a His-aldehyde aminol intermediate, common to both hydrocyanation and oxidation catalysis. It seems that the preferred conformation of 1 in the solid state resembles that of 1 in homogeneous solution, i.e. the phenyl substituent of Phe is folded over the diketopiperazine ring (H, Scheme 6.4). Several transition state models have been proposed. To date, it seems that the proposal by Hua et al. [45], modified by North [2a] (J, Scheme 6.4) best combines all the experimentally determined features. In this model, catalysis is effected by a diketopiperazine dimer and depends on the proton-relay properties of histidine (imidazole). R -OH represents the alcohol functionality of either a product cyanohydrin molecule or other hydroxylic components/additives. The close proximity of both R1-OH and the substrate aldehyde R2-CHO accounts for the stereochemical induction exerted by RfOH, and thus effects the asymmetric autocatalysis mentioned earlier. 

Some examples are depicted in Scheme 6.5. Unfortunately, the 3,4-and 3,5-disubstituted benzaldehydes needed for the synthesis of the pharmaceuticals (—)-salbutamol or (—)-terbutaline performed only poorly (variable yields, ee < 50%) in the diketopiperazine-catalyzed hydrocyanation [48]. 

The Inoue laboratory reported the first asymmetric hydrocyanation of an aldehyde using a synthetic peptide, cydo[(S)-Phe-(S)-His] (38), to give the cyanohydrin of benzaldehyde in high optical purity (up to 90% ee at 40% conversion). The ee-value of the product was found to diminish with increased reaction time (Scheme 6.5) [57]. The catalytic activity of 38 is presumed to arise from the bifunctional character of the catalyst, wherein aldehyde activation occurs through hydrogen-... 

Scheme 6.5 Synthetic peptide-promoted hydrocyanation of benzaldehyde.

The Strecker reaction is defined as the addition of HCN to the condensation product of a carbonyl and amine component to give a-amino nitriles. Lipton and coworkers reported the first highly effective catalytic asymmetric Strecker reaction, using synthetic peptide 43, a modification of Inoue s catalyst (38), which was determined to be inactive for the Strecker reactions of aldimines (see Scheme 6.5) [62], Catalyst 43 provided chiral a-amino nitrile products for a number of N-benzhydryl imines (42) derived from substituted aromatic (71-97% yield 64->99% ee) and aliphatic (80-81% yield <10-17% ee) aldehydes, presumably through a similar mode of activation to that for hydrocyanations of aldehydes (Table 6.14). Electron-deficient aromatic imines were not suitable substrates for this catalyst, giving products in low optical purities (<10-32% ee). The a-amino nitrile product of benzaldehyde was converted to the corresponding a-amino acid in high yield (92%) and ee (>99%) via a one-step acid hydrolysis. 

Do not confuse sweet almond with bitter almond (Prunus amygdalus var umu. a). The essential oil is extracted by steam distillation after maceration of pressed nuts. A major component is benzaldehyde (95%), which is moderately toxic. Hydrocyanic acid is also formed, which is poisonous. It is not suitable for aromatherapy but is used in the food industry. 

As noted above, enzymatic hydrocyanations are preferably performed at pH < 5, to suppress the non-enzymatic bacl ound reaction whereas the pH optimum of the common nitrilases is 7. A compromise pH is obviously required and we accordingly assessed the effects of the pH on the MeHnL-mediated hydrocyanation of benzaldehyde (2a, see Figure 16.3) in a biphasic aqueous-diisopropyl ether (DIPE) medium. We found that enantioselectivity was maintained at pH 5.5, which we adopted as a compromise pH for the bienzymatic reactions, provided that the aqueous buffer phase accounted for <10% of the reaction volume. PfNLase was the obvious choice for the second step as it stayed active at pH 5.5 and converted (S)- and (R)-la at comparable rates. 

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