Acetone cyanohydrin formation

The formamide is dehydrated to HCN which is recycled back to make acetone cyanohydrin. The overall reaction is acetone + methyl formate — MMA + H2O. 

Cyanohydrin Synthesis. Another synthetically useful enzyme that catalyzes carbon—carbon bond formation is oxynitnlase (EC 4.1.2.10). This enzyme catalyzes the addition of cyanides to various aldehydes that may come either in the form of hydrogen cyanide or acetone cyanohydrin (152—158) (Fig. 7). The reaction constitutes a convenient route for the preparation of a-hydroxy acids and P-amino alcohols. Acetone cyanohydrin [75-86-5] can also be used as the cyanide carrier, and is considered to be superior since it does not involve hazardous gaseous HCN and also virtually eliminates the spontaneous nonenzymatic reaction. (R)-oxynitrilase accepts aromatic (97a,b), straight- (97c,e), and branched-chain aUphatic aldehydes, converting them to (R)-cyanohydrins in very good yields and high enantiomeric purity (Table 10). 

A" -3-Ketones do not undergo the exchange reaction with acetone cyanohydrin, although the formation of a 3-cyaiiohydrin has been reported by reaction with hydrocyanic acid. ... 

Semicarbazones can be prepared from 17-ketones by the conventional procedure. The formation of 17-cyanohydrins by exchange with acetone cyanohydrin and the use of this protective group has been already discussed (see section II-A-2). ... 

The formation of adducts of enamines with acidic carbon compounds has been achieved with acetylenes (518) and hydrogen cyanide (509,519,520) (used as the acetone cyanohydrin). In these reactions an initial imonium salt formation can be assumed. The addition of malonic ester to an enamine furnishes the condensation product, also obtained from the parent ketone (350,521). 

Cyanohydrins are readily prepared from 3-ketones by exchange with acetone cyanohydrin.54 Selective cyanohydrin formation at C-3 is achieved in the presence of a 20-ketone unsubstituted at the 17- and 21-positions in dilute solution. Thus 5or-pregnane-3,20-dione (60) gives the 3-monocyanohydrin (61) in ethanol, but in neat acetone cyanohydrin the dicyanohydrin (62) is obtained.73... 

The excess of ammonia is necessary to cause the formation of the aminonitrile from the acetone cyanohydrin formed in the first stage of the process. 

The effect of solvent change on an equilibrium involving non-ionic species is expected to be small. While specific effects do show up, this expectation is realized in the hydration of sym-dichloroacetone in dioxane-water mixtures (Bell and McDougall, 1960) and in the formation of acetone cyanohydrin in various solvents (Stewart and Fontana, 1940) (Table 7). 

The acetone cyanohydrin is employed as a solvent this means it is present in great excess. Under thermodynamic control this reaction preferentially leads to the formation of a cyanohydrin with an axial nitrile group and an equatorial OH group, since a nitrile group is smaller than an OH group. 

The reversibility of cyanohydrin formation is of more than theoretical interest. In parts of Africa the staple food is cassava. This food contains substantial quantities of the glucoside of acetone cyanohydrin (a glucoside is an acetal derived from glucose). We shall discuss the structure of glucose later in this chapter, but for now, just accept that it stabilizes the cyanohydrin. 

Methyl methacrylate (MMA) is one of the most important monomers [80-82]. It forms the basis of acrylic plastics and of polymer dispersion paints. The traditional production is by the formation of acetone cyanohydrin, elimination of water and hydrolysis of the nitrile group, followed by the ester formation. In the carbon-carbon bond forming reaction large amounts of excess HCN and ammonium bisulfate are left as waste. Although these problems have been addressed there is still much room for improvement. In particular the number of reaction steps should be reduced and, in order to achieve this, cyanide should be avoided. The building block to replace it is CO. 

Enzyme-catalyzed reactions in this area include reaction with glycine catalyzed by L-threonine aldolase to afford 164 <2000SL1046> and the use of almond oxynitrilase to catalyze the formation of cyanohydrin 165 by reaction of 161 with acetone cyanohydrin <2001T2213>. 

In the hydrocyanation of alkynes containing heteroatoms in the side chain, the branched isomer predominates unexpectedly. In a series of reactions with alkyne ethers 37, chelative reaction control is observed. Thus, a reaction pathway is entered, directing to the formation of the nitriles 38 with the cyano group attached to the carbon next to the oxygen-carrying carbon. Further treatment of the reaction products with aqueous acid yields the stereospecifically substituted methylene y-lactones 39a (eq. (10)). Alternatively acetone cyanohydrin can be used as a source of HCN [61]. 

When certain cyclodipeptides are used as catalysts for the enantioselective formation of cyanohydrins, an autocatalytic improvement of selectivity is observed in the presence of chiral hydrocyanation products [80]. A commercial process for the manufacture of a pyrethroid insecticide involving asymmetric addition of HCN to an aromatic aldehyde in the presence of a cyclic dipeptide has been described [80]. Besides HCN itself, acetone cyanohydrin is also used (usually in the literature referred to as the Nazarov method), which can be activated cata-lytically by certain lanthanide complexes [81]. Acetylcyanation of aldehydes is described with samarium-based catalysts in the presence of isopropenyl acetate cyclohexanone oxime acetate is hydrocyanated with acetone cyanohydrin as the HCN source in the presence of these catalytic systems [82]. 

The traditional acetone cyanohydrin (ACH) process is the most widely used in Europe and North America, while other processes are more often used in Asia. In the ACH process (Figure 2.63), acetone and hydrogen cyanide react to yield acetone cyanohydrin the latter is then reacted with an excess of concentrated sulfuric add to form methacrylamide sulfate. In a later stage, methacrylamide is treated with excess aqueous methanol the amide is hydrolyzed and esterified, with formation of a mixture of methyl methacrylate and methacrylic acid. The ACH process offers economical advantages, especially in Europe, where large plants are in use - most of them have been in operation for decades. The process also suffers from drawbacks that have been the driving forces for the development of alternative technologies. 

The ACH process has been improved by Mitsubishi Gas [332]. Acetone cyanohydrin is first hydrolyzed to 2-hydroxyisobutylamide with a Mn02 catalyst the amide is then reacted with methyl formate to produce the methyl ester of 2-hydroxyisobutyric acid, with co-production of formamide (this reaction is catalyzed by sodium meth-oxide). The ester is finally dehydrated with an Na-Y zeolite to methyl methacrylate. Formamide is converted into cyanhydric acid, which is used to produce acetone cyanohydrin by reaction with acetone. The process is elegant, since it avoids the co-production of ammonium bisulfate, and no net income of HCN is present. However, there are many synthesis steps, and a high energy consumption. 

So far HNLs from more than 11 cyanogenic plants have been characterized. Nature has evolved (R)- and (S)-selective HNLs, in contrast to other enzymes (for instance lipases) which act only on one stereoisomer. Interestingly, some enzymes, for example the one from Hevea brasiliensis, show pronounced stereoselectivity in the cyanohydrin formation, although their natural substrate is symmetric (acetone cyanohydrin) and their natural task is cyanohydrin cleavage. 

These two methods involve the potential release of toxic HCN during the reaction and a cleaner as well as a safer method is to use acetone cyanohydrin 128 as a cyanide transfer reagent. The enzyme from the Brazilian rubber tree Hevea brasiliensis, called a hydroxynitrile lyase, catalyses cyanohydrin formation from aliphatic as well as aromatic aldehydes.40... 

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