Nitriles chemical hydrolysis

Hydrolysis of Nitriles. The chemical hydrolysis of nitriles to acids takes place only under strong acidic or basic conditions and may be accompanied by formation of unwanted and sometimes toxic by-products. Enzymatic hydrolysis of nitriles by nitrile hydratases, nittilases, and amidases is often advantageous since amides or acids can be produced under very mild conditions and in a stereo- or regioselective manner (114,115). 

Another example of a biocatalytic transformation ousting a chemical one, in a rather simple reaction, is provided by the Lonza nitotinamide process (Fig. 2.34) (Heveling, 1996). In the final step a nitrile hydratase, produced by whole cells of Rh. rhodoccrous, catalyses the hydrolysis of 3-cyano-pyridine to give nitotinamide in very high purity. In contrast, the conventional chemical hydrolysis afforded a product contaminated with nicotinic acid. 

A crude mixture of enzymes isolated from Rhodococcus sp. is used for selective hydrolysis of aromatic and aliphatic nitriles and dinitriles (117). Nitrilase accepts a wide range of substrates (Table 8). Even though many of them have low solubility in water, such as (88), the yields are in the range of 90%. Carboxylic esters are not susceptible to the hydrolysis by the enzyme so that only the cyano group of (89) is hydrolyzed. This mode of selectivity is opposite to that observed upon the chemical hydrolysis at alkaline pH, esters are more labile than nitriles. Dinitriles (90,91) can be hydrolyzed regioselectively resulting in cyanoacids in 71—91% yield. Hydrolysis of (92) proceeds via the formation of racemic amide which is then hydrolyzed to the acid in 95% ee (118). Prochiral 3-substituted glutaronitriles (93) are hydrolyzed by Phodococcus butanica in up to 71% yield with excellent selectivity (119). 

Similarly, DuPont employs a nitrile hydratase (as whole cells of P. chlororaphis B23) to convert adiponitrile to 5-cyanovaleramide, a herbicide intermediate [122]. In the Lonza nitrotinamide (vitamin B6) process [123] the final step (Fig. 1.42) involves the nitrile hydratase (whole cells of Rh. rhodocrous) catalysed hydration of 3-cyanopyridine. Here again the very high product purity is a major advantage as conventional chemical hydrolysis affords a product contaminated with nicotinic acid, which requires expensive purification to meet the specifications of this vitamin. 

Several investigators using enzymes of different microbial origin have reported on the monohydrolysis of dinitriles to the corresponding cyano-carboxylic acids in high yields. Selective hydrolysis of one cyano group of a dinitrile is very difficult to carry out by chemical hydrolysis and is, therefore, an intriguing aspect of nitrile bioconversion. 

An industrial process must be economic and safe for the environment. The chemical hydrolysis of nitrile in acid is well known (ref. 1). Nearly all nitriles react with either basic or acid catalysts, but considerable quantities of inorganic salts are always produced as by-products. The only way to suppress these by-products is to produce the ammonium carboxylate under neutral pH and then to recover the ammonia by dissociation of the salt between the weak base and acid. Therefore, we suggest the route shown in Figure 1. 

Since 1970, a new class of cyano compounds has been isolated from certain seed oils that are of interest as some members, like cyanogenic glycosides, liberate HCN on enzymic or mild chemical hydrolysis All the authenticated compounds occur in several genera of the Sapindaceae (soapberry) family " and they can comprise up to 50% v/v of the extract, e.g. in kusum seed oil. These cyanolipids are mono- or di-esters of mono- or dihydroxy-nitriles and 4 types are known (Figure 22). The chain length of the fatty acid moiety, which may be saturated or not (e.g. commonly from oleic acid), can be C14 to C22 with C18 and C20 predominant and the double bond in type 3 can be Z or E, but structural variations are few. After hydrolysis the a-hydroxynitriles derived from types 1 and 4 are cyanogenic. In many plant species one type occurs to the virtual exclusion of the others thus type 1 accumulates in Allophyllus and Paullina spp, whereas type 2 is characteristic of... 

Hydrolysis of nitriles Hydrolysis of [ CJnitrile functions represents a well-established route for the synthesis of [ C]carboxylic acids. For cases in which the harsh reaction conditions of chemical hydrolysis (e.g., 2 N NaOH, reflux) are incompatible with sensitive functionalities, application of enzymes might provide an alternative (Figure 12.17). Enzymatic hydrolysis of nitriles results in amides if catalyzed by nitrile hydratases or in the corresponding carboxylic acids if catalyzed by nitrilases". ... 

Even ia 1960 a catalytic route was considered the answer to the pollution problem and the by-product sulfate, but nearly ten years elapsed before a process was developed that could be used commercially. Some of the eadier attempts iacluded hydrolysis of acrylonitrile on a sulfonic acid ion-exchange resia (69). Manganese dioxide showed some catalytic activity (70), and copper ions present ia two different valence states were described as catalyticaHy active (71), but copper metal by itself was not active. A variety of catalysts, such as Umshibara or I Jllmann copper and nickel, were used for the hydrolysis of aromatic nitriles, but aUphatic nitriles did not react usiag these catalysts (72). Beginning ia 1971 a series of patents were issued to The Dow Chemical Company (73) describiag the use of copper metal catalysis. Full-scale production was achieved the same year. A solution of acrylonitrile ia water was passed over a fixed bed of copper catalyst at 85°C, which produced a solution of acrylamide ia water with very high conversions and selectivities to acrylamide. 

Conversion of the nitrile to the amide has been achieved by both chemical and biological means. Several patents have described the use of modified Raney nickel catalysts ia this appHcation (25,26). Also, alkaH metal perborates have demonstrated their utiHty (27). Typically, the hydrolysis is conducted ia the presence of sodium hydroxide (28—31). Owiag to the fact that the rate of hydrolysis of the nitrile to the amide is fast as compared to the hydrolysis of the amide to the acid, good yields of the amide are obtained. Other catalysts such as magnesium oxide (32), ammonia (28,29,33), and manganese dioxide (34) have also been employed. 

The hydrolysis of nitriles can be carried out with either isolated enzymes or immobilized cells. Eor example, resting cells of P. chlororaphis can accumulate up to 400 g/L of acrylamide in 8 h, provided acrylonitrile is added gradually to avoid nitrile hydratase inhibition (116). The degree of acrylonitrile conversion to acrylamide is 99% without any formation of acryUc acid. Because of its high efficiency the process has been commercialized and currentiy is used by Nitto Chemical Industry Co. on a multithousand ton scale. 

It has been pointed out that some important biomolecules have short half-lives at higher temperatures, as is clearly shown by laboratory experiments. The synthesis of adenine in the HCN oligomerisation demonstrated that chemical processes can also take place at lower temperatures. After hydrolysis of the oligomerisation products, adenine was isolated after 60-100 days from 0.01 M solutions at a pH of 9.2. Addition of glycol nitrile caused the yield to increase by a factor of four, i.e., to 48 pg/L (Schwartz et al., 1982). 

The enzymatic hydrolysis of nitriles provides a viable alternative for the generally harsh chemical conditions that are most often used. As a result of the ability of many nitrilehydrolyzing enzymes to give selective monohydrolysis, in the case of dinitriles, additional opportunities such as desymmetrization can be explored. With the previous examples, we have shown that, for several substrate classes, enzymatic desymmetrization of dinitriles is indeed a synthetically viable option. 

Chemical/Physical. Emits toxic fumes of nitrogen oxides, cyanides, and chlorine when heated to decomposition (Sax and Lewis, 1987). Chlorothalonil is resistant to hydrolysis under acidic conditions. At pH 9, chlorothalonil (0.5 ppm) hydrolyzed to 4-hydroxy-2,5,6-trichloroisophthalo-nitrile and 3-cyano-2,4,5,6-tetrachlorobenzamide. Degradation followed first-order kinetics at a rate of 1.8% per day (Szalkowski and Stallard, 1977). 

Chemical/Physical. In laboratory tests, the nitrile group was hydrolyzed to the corresponding carboxylic acid. The rate of hydrolysis is faster at higher temperatures and low pHs (Grayson, 1980). The chlorine atom may be replaced by a hydroxyl group forming 2((4-hydroxy-6-(ethyl-amino)-5-triazin-2-yl)amino)-2-methylpropanenitrile (Hartley and Kidd, 1987). 

The calculated hydrolysis half-life at 25 °C and pH 7 is 262 d (Ellington et al., 1988). The hydrolysis half-lives of methomyl in a sterile 1% ethanoEwater solution at 25 °C and pH values of 4.5, 6.0, 7.0, and 8.0 were 56, 54, 38, and 20 wk, respectively (Chapman and Cole, 1982). In both soils and water, chemical- and biological-mediated reactions transformed methomyl into two compounds — a nitrile and a mercaptan (Alexander, 1981). 

Copper-catalysts promoted with i) other group VIA or VIIIA metals and ii) alcaline or alcaline earth elements (IA or IIA) are used for selective hydrogenation of various organic compounds (1). Moreover Cu(Co) Zn-Al catalysts were extensively studied for the synthesis of methanol and of light alcohols (2,3). More recently, due to the development of fine chemical processes, detailed studies of copper catalysts were carried out in order to show, like for noble metals, the effect of supports (SMSI), of promoters and of activation-on metal dispersion or reduction, on alloy formation... For example modified copper catalysts are known for their utilization in the dehydrogenation of esters (4-6), in the hydrolysis of nitriles (7), in the selective hydrogenation of nitriles (8), in the amination of alcohols (9)... 

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