2-cyanopyridine, hydrolysis

Cyanopyridines are usually manufactured from the corresponding picoline by catalytic, vapor-phase ammoxidation (eq. 7) in a fixed- or fluid-bed reactor (28). 3-Cyanopyridine (25) is the most important nitrile, as it undergoes partial or complete hydrolysis under basic conditions to give niacinamide... 

A number of routes are available for the synthesis of 2,2 -bipyridines where one of the pyridine rings is built up from simpler entities. For example, condensation of 2-(aminomethyl)pyridine (31) with acetaldehyde or acetylene over a silicon-alumina catalyst at 450°C gives 2,2 -bipyridine, ° whereas 2-cyanopyridine reacts with acetylene at 120°C in the presence of a cobalt catalyst to afford 2,2 -bipyridine in 95% yield.2-Acetylpyridine with acrolein and ammonia gives 2,2 -bipyridine in the presence of dehydrating and dehydrogenating catalysts, and related condensations afford substituted 2,2 -bipyridines. ° In a similar vein, condensation of benzaldehyde with 2 mol of 2-acetylpyridine in the presence of ammonia at 250°C affords 2,6-di(2-pyridyl)-4-phenylpyridine, ° and related syntheses of substituted 2,2 6, 2"-terpyridines have been described. Likewise, formaldehyde with two moles of ethyl picolinoylacetate and ammonia, followed by oxidation of the product and hydrolysis and decarboxylation, affords a good... 

Nicotinic acid and nicotinamide, members of the vitamin B group and used as additives for flour and bread enrichment, and as animal feed additive among other applications, are made to the extent of 24 million pounds (nearly 11 million kilograms) per year throughout the world. Nicotinic acid (pyridine-3-caiboxylic acid), also called niacin, has many uses. See also Niacin. Nicotinic acid is made by the oxidation of 3-picolme or 2-mcthyl-5-cthylpyridine (the isocinchomcnc acid produced is partially deearboxylated). Alternatively, quinoline (the intermediate quinolinic acid) is partially deearboxylated with sulfuric add in the presence of selenium dioxide at about 300° C or with nitric acid, or by electrochemical oxidation. Nicotinic acid also can be made from 3-picoline by catalytic ammoxidation to 3-cyanopyridine, followed by hydrolysis. 

In recent years there has been considerable interest in the reactions of nitriles in the coordination sphere of metal ions. Breslow et al.312 first reported that the hydrolysis of 2-cyano-l,10-phenanthro-line to the corresponding carboxamide is strongly promoted by metal ions such as copper(II), nickel(II) and zinc(II). Base hydrolysis of the 1 1 nickel complex is 107 times faster than that of the uncomplexed substrate. The entire rate acceleration arises from a more positive value of AS. Somewhat similar effects have been observed for base hydrolysis of 2-cyanopyridine to the corresponding carboxamide. In this case rate accelerations of 109 occurred with the nickel(II) complex.313... 

The process is configured as a series of three stirred-tank reactors with the substrate 3-cyanopyridine continuously fed at 10-20 wt.% concentration and the biocatalyst flowing countercurrently. Enzymatic hydrolysis yields the desired nicotinamide at > 99.3% selectivity, in contrast to the chemical alkaline hydrolysis process which results in about 3-5% nicotinic acid, an undesirable by-product because it causes diarrhea in farm animals (instead of supporting growth for animal feed supplements, see Chapter 6, Section 6.4). Thus, the enzymatic process competes well with the chemical hydrolysis. 

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. 

A new route to prepare nicotinic acid starts from 2-methylglutaronitrile, a major side-product in the adiponitrile process and, as such, a readily available starting-material. It is easily hydrogenated to 2-methylpentanediamine, which is then condensed to methyl piperidine and dehydrogenated to 3-picoline. The gas-phase ammoxidation of the latter to cyanopyridine is followed by hydrolysis to either nicotinamide or nicotinic acid (Scheme 20.4). The cyanopyridine route for the production of nicotinic acid has the advantage of a significantly better selectivity with respect to the direct oxidation route from 3-picoline owing to the easy decar-... 

Scheme 20.4 Ammoxidation of 3-picoline and hydrolysis of cyanopyridine to niacinamide (nicotinamide) and niacin (nicotinic acid). Adapted from [106].

Cyanopyridine generated by the ammoxidation is hydrolyzed using an enzymatic catalyst with practically quantitative yields. This efficient procedure avoids the consecutive hydrolysis reaction to nicotinic acid (here a by-product ). 

In contrast to the chemical alkaline hydrolysis of 3-cyanopyridine with 4% byproduct of nicotinic acid (96% yield) the biotransformation works with absolute selectivity and no acid or base is required. The biotransformation (a continuous process) is operated at low temperature and atmospheric pressure. In contrast to the old synthesis route of nicotinamide at Lonza, the new one is environmentally friendly and safe. There is only one organic solvent used throughout the whole process in four highly selective continuous and catalytic reactions. The process water, NH3 and H2 are recycled. 

The cyanopyridine cation is obtained by the addition of chlorocyane to pyridine. During its hydrolysis, the pyridine ring is opened, forming gluta-cone aldehyde 0CH-CH=CH-CH2-CH0. This reacts with barbituric acid to form a colour whose intensity is proportional to the hydrogen cyanide concentration [18]. 

An interesting synthesis of ( )-[2 - C]nicotine using the cyclopropyl-imine synthon (for other applications, see Vol. 2, p. 133 and Vol. 3, p. 211) has been reported. Thus treatment of 3-[ C]-cyanopyridine with cyclopropyl-lithium gave, after hydrolysis, the ketone (29) which, when refluxed in N-methylform-amide, produced (+)-[2 - C]nicotine. 

Benzonitrile acts in a similar way to form benzoic acid but requires sulfuric acid in the reacting mixture. Nicotinic acid amide (nicotinamide) has been prepared by the mild hydrolysis of 3-cyanopyridine, and acrylamide by the partial hydrolysis of acrylonitrile. Acrylonitrile may also be hydrolyzed to acrylic acid with mineral acids or with alkalies. Polyacrylonitrile is partially converted to the amide by nitric acid, and the nitrile oups of a number of polymers and copolymers have been hydrolyzed to amide and carboxylic acid groups to produce water-soluble polyelectrolytes. Isooyanides are stable toward alkalies but hydrolyze in the presence of acids to form an acid and an amine ... 

Pyridine-3-carboxamide (nicotinamide, niacin), mp 130°C, is commercially produced by ammoxi-dation of 3-picoline, followed by partial hydrolysis of the intermediate 3-cyanopyridine ... 

The hydrolysis of coordinated nitriles has recently attracted some attention. A very facile hydrolysis of nitriles to the corresponding amides at platinum(IV) centers has been described.The complex [Cu(H2NCOCH2CONHNH2)Cl] is formed from the reaction NCCH2CONHNH2 the copper(II) both promotes the hydrolysis and is reduced to copper(I). The hydrolysis of 2-cyanopyridine to 2-pyridinecarboxamide is accelerated several hundred times by the copper(II) complexes of the ligands (21) and (22). In the case of the (22) some picolinic acid was formed, resulting from the intramolecular attack of alkoxide to yield an intermediate iminoester. ... 

M. L. Kaliya, A. E. Nechitailo, and E. M. Guseinov [Kinet. Katali., 30, 699-702 (1990)] studied the kinetics of the hydrolysis of both cyanopyridines (C) and pyridine carboxamides (A). In basic solution these consecutive reactions can both be regarded as pseudo first-order ... 

Under hydro(solvo)thermal conditions, Cd and Zn coordination networks ean be obtained by reactions of metal salts with cyanopyridine or pyiidinecarboxaldehyde. Cyano-, carboxal-dehyde-, and ester-substituents slowly hydrolyze to form corresponding earboxylie acid facilitating network formation. For instance, bis[4- 2-(4-pyridyl)ethenyl benzoato]-Zn° and Cd with eightfold diamondoid network structures were obtained by slow hydrolysis of (E)-4-(4-cyanos-tyryl)pyridine under hydro(solvo)thermal conditions (3-D diamondoid net Scheme 6a). ... 

---