Nitriles acid-catalysed

There is obviously a relation with the classic activation of molecules by Lewis acids, but here we have confined ourselves to the activation of "soft" substrates by "soft" acids. Examples of "hard" acid activated reactions include Diels-Alder additions, nitrile solvolysis, ester solvolysis, ester formation, Oppenauer reactions etc (see Lewis acid catalysed reactions, 2.11). 

You will recall that nitriles are easily converted into carboxylic acids by hydrolysis. This involves heating the nitrile with an aqueous acid. The hydrogen ions of the acid catalyse the reaction. 

The sequence can be rationalized mechanistically as involving nucleophilic attack of ammonia onto the aldehyde to produce an imine, which then acts as the electrophile for further nucleophilic attack, this time by the cyanide ion (see Section 7.7.1). The racemic amino acid is then formed by acid-catalysed hydrolysis of the nitrile function, as above (Box 7.9). 

Acid-catalysed hydrolysis. The acid-catalysed hydrolysis of nitriles resembles the acid-catalysed hydrolysis of an amide, with protonation of the nitrogen of the cyano group activating the nucleophilic attack by... 

DSM jointly with Du Pont de Nemours308 have patented platinum catalysts generated from the water soluble sulfonated ligand 30 (Table 2 m=0, n=0, m=l, n=2 m=l, n=l, Ar=nBu-S03Li) and used in the aqueous phase hydroformylation of internally unsaturated carboxylic acids, esters or nitriles to their corresponding formyl derivatives which are useful intermediates for the preparation of di-carboxylic acids (e.g. adipic acid). For example, TOFs up to 105 h-1 were achieved in the hydroformylation of 3-pentenoic acid catalysed by Pt/30 (m=0, n=0) at 100°C and 80 bar CO/H2 to give aldehydes with a selectivity of 83% (n/i=3.4), valeric acid (4.6%) and adipic acid (8.1%).308 The products were separated from the aqueous catalyst solution by extraction with ether. Five recycles of the aqueous catalyst solution showed that the Pt/30 (m=0, n=0) catalyst retains its activity. 

Kinetic investigations of amide hydrolysis showed that the rate of hydrolysis in basic media is proportional to the concentration of amide and hydroxide ion. Similarly, early work180-183 on the acid-catalysed hydrolysis of amides showed that the rate of acidic hydrolysis is, in general, proportional to the concentration of amide and hydroxonium ion. In several acidic hydrolyses, however, a maximum is observed in the pH-rate profile at 3-6 pH units, a phenomenon first reported by Benrath184 and since supported by other workers185"190. This behaviour of amides is in contrast to the hydrolysis of nitriles whose rate constant increases continuously with the hydrogen ion concentration191. 

The acid-catalysed reaction of hydrogen azide with electrophiles, such as carbonyl compounds, tertiary alcohols or alkenes. After a rearrangement and extrusion of N2, amines, nitriles, amides or imines are produced. 

Amidoximes can be prepared by acid-catalysed additon of hydroxylamine to nitriles. 

Nitriles (RCN) get hydrolysed to carboxylic acids (RC02H) in acidic or basic aqueous solutions. The mechanism of the acid-catalysed hydrolysis (Following fig.) involves initial protonation of the nitrile s nitrogen atom. This activates the nitrile group towards nucleophilic attack by water at the electrophilic carbon. One of the nitrile n bonds breaks simultaneously and both the n electrons move onto the nitrogen yielding a hydroxyl imine. This rapidly isomerises to a primary amide which is hydrolysed under the reaction conditions to form the carboxylic acid and ammonia. 

Fig. Acid-catalysed hydrolysis of nitrile to carboxylic acid.

They have been suggested as intermediates in acid-catalysed additions to nitriles. The hydration of nitriles probably involves initial protonation of the N end of the —C=N bond, as indicated by the nature of the product of the acid-catalysed reaction between acetonitrile and ethanol (Hill and Rabinowitz, 1926) (equation 36). 

Esters can be made directly from nitriles by acid-catalysed reaction with the appropriate alcohol. Suggest a mechanism. 

What about the regioselectivity The obvious explanation is that a cation is formed from die epoxide in a specific acid-catalysed ring opening. But why should the nitrile attack the bottom face of the cation We should expect it to attack the top face preferentially as die hydroxyl group partly blocks the bottom face. 

Undoubtedly, acid-induced decomposition of vinyl azides involves the loss of molecular nitrogen concerted with nev/ bond formation in a protonated azide species. For example, the acid catalysed decomposition of )3-azidovinyl phenyl ketones 73 (R = H) proceeds via two competitive pathways giving either nitriles (equadon 22) or isoxa-zoles (equation 23). 

The first step is a simple addition we used NaCN and HOAc in Chapter 6. The second is a nitrile reaction with ethanol - an acid-catalysed addition introduced on p. 294 of the text. FtnaUy, there is a double addition of a methyl-metal compound such as MeLi or MeMgBr. The first molecule substitutes at the ester and the second adds to the resulting ketone. This reaction appears on p. 297 of the chapter. 

Electrochemical reduction of [Ru(NH3)e] and related halide complexes, e.g. [Ru(NH3)5C1], produces Ru products hydrolysis of the chloride ligands then occurs. Reduction potentials of [Ru(NH3)sL] and [Ru(NH3)4L2] (L = py-X or RCN) have been measured by cyclic voltammetry. Nitriles have more positive E[ values than py and unsaturated R groups give the largest values electron-withdrawing X substituents increase Ef. Co-ordination of the N-bound 4-pyridine car-boxaldehyde slows the acid-catalysed hydration. 

F. C. Schaefer in S. Patai, Acid-Catalysed Reactions of Nitriles with Aldehyds, Vol. 9, S. 294 ff., Interscience Publ., New York London 1970. 

When, for instance, acetonitrile56 is heated with an equimolar amount of dry potassium methoxide at 140° for 5 h, it affords 70% of 4-amino-2,6-dimethylpyrimidine ( cyano-methine ), but 85% of 2,4,6-tris(dichloromethyl)-s-triazine is obtained from dichloroaceto-nitrile in the presence of aluminum chloride and hydrogen chloride at room temperature.57 Benzonitrile trimerizes in an acid catalysed reaction, most simply when its solution in chloro-sulfonic acid is kept at 0° for 1-2 days, giving 2,4,6-triphenyl-s-triazine (cyaphenin),58 but 85% of l,2-dihydro-2,2,4,6-tetraphenyl-s-triazine is formed under the influence of a sodium suspension.59... 

The oxime 7, prepared from salicyl aldehyde, is converted with iV-chlorosuccinimide into the hydrox-amic acid chloride 8. From this, the nitrile oxide is obtained with KHCO3, which reacts regioselec-tively with styrene to give the 3,5-diaryl-4,5-dihydroisoxazole 9. Catalytic hydrogenation leads to the y -hydroxy ketone 10, which on acid-catalysed cyclodehydration gives the flavanone 11. 

Triazines of type 3 are also accessible by an acid-catalysed cyclocondensation of imidic esters with elimination of alcohol [see (1)]. The joining of the three imidic ester molecules that function as activated nitriles probably takes place by an electrophilic addition-elimination mechanism involving immonium ions as intermediates. Cyclization of nitriles in the presence of NH3, catalysed by lanthanum(ni) ions, with initial formation of amides, is also effective [171]. 

Similarly, the acid-catalysed hydrolysis ofoximes " or of nitriles or amides doubtless involve electrophilic addition to carbon-nitrogen multiple bonds. 

There are comparatively very few kinetic studies of beta-eliminations giving imines or nitriles. Nitriles can be prepared by the acid-catalysed dehydration of amides or aldoximes or by the base-catalysed elimination from aldochlor-imines or esters of aldoximes. Imines often result in the attempted preparation of A-chloramines, dehalogenation occurring in the weakly alkaline hypochlorite solution which is used as the chlorinating reagent. 

Lewis acid catalysed [3 + 2] cycloaddition of A-alkoxycarbonylaziridines and cyanoalkane such as MeCN furnishes 2-imidazolidines [39] (Scheme 3.23). Although ring-fused aziridines are useable as substrates, cii-stereochemistry in the ring juncture is isomerized to frawi-stereochemistry in the bicyclic amidine products. Benzonitrile also serves as a nitrile source. 

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