Dinitriles, hydrolysis

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... 

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. 

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 ... 

Feuer and co-workers extended their studies to the alkaline nitration of a,Nitration with potassium ferf-butoxide and amyl nitrate in THF at —30 °C yields the corresponding dipotassium salt of the a,nitronate salts from these reactions are isolated via methanol-induced precipitation from the aqueous reaction liquors, a process which also separates the product from impurities. These salts undergo hydrolysis on treatment with aqueous potassium hydroxide, and subsequent acidification yields the corresponding Q, y-dinitroalkane. This route has been used to synthesize 1,4-dinitrobutane (27) from apidonitrile (95) in 30 % overall yield. 

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. ... 

A very popular route to piperid-4-ones is by a Dieckmann or Thorpe cyclization of appropriate diesters or dinitriles. In most cases the nitrogen atom is tertiary, to avoid the formation of amides as by-products. A simple example is provided by the synthesis of the piperidone ester (129) which, after hydrolysis and decarboxylation, gives the piperid-4-one (130) (45JOC277). The diesters are available by addition of amines to acrylates and so the two ester fragments can be different. For the production of AT-benzoylpiperid-4-one (132) the whole operation from benzamide and ethyl acrylate to the ester (131) can be achieved... 

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). 

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],...

Since an important feature of Biicherer-Bergs hydantoin formation is that the process can only work for a-aminonitriles without substituent on the amino group, it follows that one compound of the equilibrium mixture formed from an aldehyde, ammonia, and cyanide is selectively reacted through an irreversible process leaving N-alkylated aminonitriles or imino-dinitriles unreacted. However, the difficulty with this process is that CAAs and hydantoins are poorly reactive towards hydrolysis and need long periods of time to be converted into free AAs. But, CAAs may also have per se a prebi-otic importance in activation pathways towards polypeptides (see Sect. 3.3.7). CAAs can also be synthesized by reaction of free amino acids with cyanic acid/cyanate (a likely prebiotic compound [50]). In the presence of a steady-state concentration of either cyanate or urea in aqueous medium, CAAs are at equilibrium with A A [51]. 

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. 

An alternative mechanism may include first an O-inserhon step, followed by the transformation of the oxidized compound into the cyano-containing compound. An example might be the oxidation of butadiene to maleic anhydride followed by hydrolysis to the acid, the formation of the diamide and the oxydehydrogenation to the dinitrile. 

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 ... 

Ammonia and amines react with partially or fully activated carboxylic acid derivatives (acylating reagents) like acid anhydrides, acid halides, ammonium salts of monoesters, monoamides with heating, diesters under basic conditions and dinitriles after partial hydrolysis. ... 

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