Hydrolysis of Schiff bases

Compounds containing carbon-nitrogen double bonds can be hydrolyzed to the corresponding aldehydes or ketones. For imines (W = R or H) the hydrolysis is easy and can be carried out with water. When W = H, the imine is seldom stable enough for isolation, and hydrolysis usually occurs in situ, without isolation. The hydrolysis of Schiff bases (W = Ar) is more difficult and requires acid or basic catalysis. Oximes (W = OH), arylhydrazones (W = NHAr), and, most easily, semicarbazones (W = NHCONH2) can also be hydrolyzed. Often a reactive aldehyde (e.g., formaldehyde) is added to combine with the liberated amine. 

Eichhom and his co-workers have thoroughly studied the kinetics of the formation and hydrolysis of polydentate Schiff bases in the presence of various cations (9, 10, 25). The reactions are complicated by a factor not found in the absence of metal ions, i.e, the formation of metal chelate complexes stabilizes the Schiff bases thermodynamically but this factor is determined by, and varies with, the central metal ion involved. In the case of bis(2-thiophenyl)-ethylenediamine, both copper (II) and nickel(II) catalyze the hydrolytic decomposition via complex formation. The nickel (I I) is the more effective catalyst from the viewpoint of the actual rate constants. However, it requires an activation energy cf 12.5 kcal., while the corresponding reaction in the copper(II) case requires only 11.3 kcal. The values for the entropies of activation were found to be —30.0 e.u. for the nickel(II) system and — 34.7 e.u. for the copper(II) system. Studies of the rate of formation of the Schiff bases and their metal complexes (25) showed that prior coordination of one of the reactants slowed down the rate of formation of the Schiff base when the other reactant was added. Although copper (more than nickel) favored the production of the Schiff bases from the viewpoint of the thermodynamics of the overall reaction, the formation reactions were slower with copper than with nickel. The rate of hydrolysis of Schiff bases with or/Zw-aminophenols is so fast that the corresponding metal complexes cannot be isolated from solutions containing water (4). 

In addition to the above-mentioned reactions, metal complexes catalyze decarboxylation of keto acids, hydrolysis of esters of amino acids, hydrolysis of peptides, hydrolysis of Schiff bases, formation of porphyrins, oxidation of thiols, and so on. However, polymer-metal complexes have not yet been applied to these reactions. 

It is postulated that the facile cleavage of the complex is due to the polarization of the carbon-nitrogen double bond. At pH 7, where these investigations were carried out, the spontaneous decomposition of the Schiff base is very slow, while the metal ion-catalyzed reaction has a half life of a few minutes. Since the hydrolysis of Schiff bases is catalyzed by hydrogen ion, the metal ion catalyst can be postulated to be a superacid catalyst present in neutral solution (17, 18). 

Hydrolysis of Schiff bases derived from benzidine (4,4 -diaminobiphenyl) and from substituted benzaldehydes has been studied in aqueous ethanol 34 attack of water molecules on the protonated substrates is suggested as the rate-determining step. 

A wide range of kinetic and thermodynamic parameters have been measured for the formation and hydrolysis of Schiff bases derived from pyridoxal S -phosphalc and L-tryptophan over a range of pH and temperature.22... 

In many cases, addition or removal of water proceeds sufficiently slowly that some of the physical properties of unstable species (such as hydrated neutral quinazoline or anhydrous 2-hydroxypteridine) can be observed. In these cases, reaction kinetics can also be examined. Addition of water to pteridine is of special interest in relation to studies of the formation and hydrolysis of Schiff bases. The reaction proceeds in two reversible stages, 3 4 5 ... 

Cordes, E. H. and W. P. Jencks. 1963. The mechanism of hydrolysis of Schiff bases derived from aliphatic amines. J. Am. Chem. Soc., 85 2843-2848. 

The results indicate significant advantages of covalent attachment of antibodies compared to nonspecific adsorption increase of the thermodynamic stability of immobilized layer, due to covalent bond formation, and kinetic stability as a result of complications due to the slow desorption hydrolysis of Schiff bases. 

Figure 5. The rate of hydrolysis of Schiff bases derived from substituted benzaldehydes and t-butylamine as a function of pH...

Rate constants for the formation and hydrolysis of Schiff bases derived from pyri-doxal 5 -phosphate and co-polypeptides have been determined in the pH range 4-11 at 25 °C. The co-polypeptides contain L-lysine, and aromatic L-amino acids, and... 

Aldehydes and ketones can react with primary and secondary amines to form Schiff bases, a dehydration reaction yielding an imine (Reaction 45). However, Schiff base formation is a relatively labile, reversible interaction that is readily cleaved in aqueous solution by hydrolysis. The formation of Schiff bases is enhanced at alkaline pH values, but they are still not stable enough to use for crosslinking applications unless they are reduced by reductive amination (see below). 

Structures have been determined for [Fe(gmi)3](BF4)2 (gmi = MeN=CHCF[=NMe), the iron(II) tris-diazabutadiene-cage complex of (79) generated from cyclohexanedione rather than from biacetyl, and [Fe(apmi)3][Fe(CN)5(N0)] 4F[20, where apmi is the Schiff base from 2-acetylpyridine and methylamine. Rate constants for mer fac isomerization of [Fe(apmi)3] " were estimated indirectly from base hydrolysis kinetics, studied for this and other Schiff base complexes in methanol-water mixtures. The attenuation by the —CH2— spacer of substituent effects on rate constants for base hydrolysis of complexes [Fe(sb)3] has been assessed for pairs of Schiff base complexes derived from substituted benzylamines and their aniline analogues. It is generally believed that iron(II) Schiff base complexes are formed by a template mechanism on the Fe " ", but isolation of a precursor in which two molecules of Schiff base and one molecule of 2-acetylpyridine are coordinated to Fe + suggests that Schiff base formation in the presence of this ion probably occurs by attack of the amine at coordinated, and thereby activated, ketone rather than by a true template reaction. ... 

The kinetic parameters above are very similar to those for the hydrolysis of a simple Schiff base, benzalaniline, having an activation energy of 13.2 kcal. and an entropy of activation of about —37 e.u. (40). It appears that the rate determining step for hydrolyses of the complexes is the second step, the splitting off of the aldehyde. Under suitable conditions, the intermediates in such hydrolyses for bis complexes (of Schiff bases derived from ethylenediamine) have been isolated. Only one of the ligands is hydrolyzed, and the nitrogen which had been present in the Schiff base is still coordinated to the central metal (17). 

The reductive silylation of Schiff bases is reported to yield (trimethylsilyl)benzylani-line (ASMA), after hydrolysis of the reaction medium. The reaction is highly sensitive to temperature.174 An anion-radical mechanism was postulated. Similar results are obtained from diversely N-substituted benzaldimines.175... 

The interest in the mechanisms of SchifF base hydrolysis stems largely from the fact that the formation and decomposition of SchifF base linkages play an important role in a variety of enzymatic reactions, for example, carbonyl transfers involving pyridoxal phosphate, aldol condensations, /3-decarboxylations and transaminations. The mechanisms for the formation and hydrolysis of biologically important SchifF bases, and imine intermediates, have been discussed by Bruice and Benkovic (1966) and by Jencks (1969). As the consequence of a number of studies (Jencks, 1959 Cordes and Jencks, 1962, 1963 Reeves, 1962 Koehler et al., 1964), the mechanisms for the hydrolysis of comparatively simple SchifF bases are reasonably well understood. From the results of a comprehensive kinetic investigation, the mechanisms for the hydrolysis of m- and p-substituted benzylidine-l,l-dimethylethylamines in the entire pH range (see, for example, the open circles in Fig. 13) have been discussed in terms of equations (23-26) (Cordes and Jencks, 1963) ... 

The alkylation of Schiff bases and hydrolysis of the resulting quaternary salts is an excellent method for obtaining certain secondary amines, RR NH, particularly where R = CHj. The procedure is less satisfactory for the introduction of large alkyl groups. The Schiff base is usually a derivative of benzaldehyde. It is readily prepared, and, without isolation, is alkylated furthermore, the salt is seldom isolated. An example is the treatment of the Schiff base from allylamine and benzaldehyde. Methyla-tion is accomplished by the action of methyl iodide at 80° for 16 hours subsequent hydrolysis furnishes methylallylamine in 71% yield. ... 

Reactions of Schiff bases coordinated with metal ions have been examined from the standpoint of stability and reactivity. Eichhorn (23, 25) examined the complex formed between bis-(thiaphenal)ethylene-diimine and copper(II). It was found that, when complexed to copper(II), the ligand becomes unstable and hydrolysis occurs this leads to the aldehyde and the copper-ethylenediamine complex. 

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