Hydrolysis of dinitriles

Zhu, D., Mukherjee, C., Biehl, E.R. and Hua, L. (2007) Nitrilase-catalyzed selective hydrolysis of dinitriles and green access to the cyanocarboxylic acids of pharmaceutical importance. AdviOU cd Synthesis and Catalysis, 349, 1667-1670. 

Dinitriles and diamides also can sometimes be partially hydrolyzed by use of enzymes. As with other enzymatic reactions, small structural modifications can substantially modify the suitability of a given substrate. Scheme 10.3 gives illustrative examples of the highly substrate-dependent hydrolysis of dinitriles and diamides by use of a microorganism. 

Scheme 10.3. Microorganism-mediated hydrolysis of dinitriles and diamides [9],...

Another interesting example from DSM is the synthesis of monomers for novel polyamides. In contrast to chemical routes, an enzyme (nitrilase) performs single hydrolysis of dinitrile to a mono-acid that can then be hydrogenated to novel cyclic polyamide (co)monomers (Figure 2.18). This is also an example of integration between bio- and chemo-catalysis. 

In addition to the outstanding chemoselectivity, high regioselectivity can also be found in the hydrolysis of dinitriles and has been used for example in the chemo-enzymatic production of lactams from aliphatic a,co-dinitriles. Using a nitrilase from Acidovomxfacilis or a nitrile hydratase/amidase system from Comamonas testosteroni high yields of the lactams have been achieved (see Scheme 12.1-14)164. ... 

Scheme 2.105 Regioselective microbial hydrolysis of dinitriles Enantioselective Hydrolysis of Nitriles...

Diamide TM 13a is available by controlled hydrolysis of dinitrile 7.13b, and now this second-generation target molecule can be disconnected in re/ro-Michael mode to 2-phenylbutyronitrile and acrylonitrile. 

Methyliminodiacetic acid has been prepared by the action of methylamine on formaldehyde cyanohydrin, subsequent hydrolysis of the dinitrile with barium hydroxide, and regeneration from the barium salt with sulfuric acid.1 This method was found by the submitter to be much less satisfactory than the procedure given above. 

Naphthalic anhydride has been prepared by the hydrolysis of the dinitrile of ,2-naphthaIic acid,1 by the oxidation of suitably substituted hydrocarbons or ketones,2 or by the dehydrogenation of the 3,4-dihydro compound with bromine 3 or with sulfur.4... 

The nitrilase from cyanobacterium Synechocystis sp. PCC6803 was found to effect the stereoselective hydrolysis of phenyl-substituted /3-hydroxy nitriles to (S)-enriched /3-hydroxy carboxylic acids. The enzyme also effected the conversion of y-hydroxynitrile, albeit with lesser enantioselectivity (Table 8.10). Interestingly, this enzyme was also was found to hydrolyze aliphatic dinitriles, such that for 1,2-dicyanoethane and 1,3-dicyanopropane the... 

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. 

Suggest a mechanism. What would you anticipate would be the effect of SCN on the hydrolysis rate The hydrolysis of the corresponding dinitrile (substituted on adjacent N s) gives the monoamide after a few seconds. No bisamide is formed after a longer time. Why ... 

Nitrilases catalyze the synthetically important hydrolysis of nitriles with formation of the corresponding carboxylic acids 7-11). Enantioselectivity is relevant in the kinetic resolution of racemic nitriles or desymmetrization of prochiral dinitriles. Both versions have been applied successfully to a number of different substrates using one of the known currently available nitrilases. Recently, scientists at Diversa expanded the collection of nitrilases by metagenome panning 150). Nevertheless, in numerous cases the usual limitations of enzyme catalysis become visible, including poor or only moderate enantioselectivity and limited activity. 

The synthesis of l,2-bis(thiophen-3-yl)maleic anhydride involves the dimerisation of a 3-cyanomethyl derivative of thiophene (1.45) by reaction with aqueous NaOH in the presence of CCl. Alkaline hydrolysis of the dinitrile (1.46) and dehydration produces the anhydride (1.47) as shown in Figure 1.12. ... 

ZIEGLER METHOD. Cydization of dinitriles at high dilution in dialkyl ether in the presence of ether-soluble metal alkylamlide and hydrolysis of the resultant imino-nitril with formation of macrocyclic ketones in good yields. 

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). 

Hendecanedioic acid has been prepared by hydrolysis of the corresponding dinitrile, obtained from 1,9-dibromononane or 1,9-diiodononane 4-6 by oxidation of 11-hydroxyhendecanoic acid 7,8 by the Arndt-Eistert synthesis from 9-carbethoxynonanoyl9 and nonanedioyl chloride 10 and by the Willgerodt reaction on un-decylenic acid.11 The present method, previously described briefly,12 13 appears to represent the most convenient preparation of dibasic acids having an odd number of carbon atoms greater than ten. It has been applied to several other dibasic acids.14... 

The application of nitrilases is broad. A purified nitrilase from Bacillus pallidus was employed to hydrolyse a wide variety of aliphatic, aromatic and heteroaromatic nitriles and dinitriles (Scheme 6.33) [102]. Nitrilases have also been patented for the hydrolysis of a-substituted 4-methylthio-butyronitriles, however, no stereoselectivity was reported [103]. 

Meth-Cohm, O. and Wang, M.X. 1997a. Rationalisation of the regioselective hydrolysis of aliphatic dinitriles with Rhodococcus rhodochrous AJ270. Chemical Communications, 1041-2. 

Most dicarboxylic acids are prepared by adaptation of methods used to prepare monocarboxylic acids. Where hydrolysis of a nitrile yields a monocarboxylic acid, hydrolysis of a dinitrile or a cyanocarboxylic acid yields a dicarboxylic acid where oxidation of a methylbenzene yields a benzoic acid, oxidation of a di-methylbenzene yields a phthalic acid. For example ... 

The degradation of nitriles by nitrilases (EC 3.5.5.1) has been the subject of intense study, especially as it relates to the preparation of the commodity chemical acrylamide. Nitrilases catalyze the hydrolysis of nitriles to the corresponding acid plus ammonia (Figure 1 reaction 5), whereas nitrile hydratases (EC 4.2.1.84) add water to form the amide. Strains such as Rhodococcus rhodo-chrous Jl, Brevibacterium sp., and Pseudomonas chlororaphis have been used to prepare acrylamide from acrylonitrile, which contain the hydratase and not nitrilase activity [12]. A comparison of these strains has been discussed elsewhere [98]. Other uses of nitrilases, however, have primarily been directed at resolution processes to stereoselectively hydrolyze one enantiomer over another or regiose-lectively hydrolyze dinitriles [99-101]. 

Terephtalic acid can be obtained by hydrolysis of the Dinitrile (DN) followed by thermal cracking (Lummus process)[6]. 

We already have a good idea how to resolve a carboxylic acid by making a salt with an enantiomerically pure amine. In this case the first amine you think of, phenylethylamine 2, works very well. Here is the asymmetric synthesis, carried out on a 50-100 g scale at Celltech.7 The hydrolysis of the dinitrile 35 is chemoselective because the intermediate 39 is formed. The salt with 2 crystallises in good yield (39% out of a possible 50%) and in excellent ee. 

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. 

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