Cobalt hydroxide amino acid ester hydrolysis

It has been known for many years that the rate of hydrolysis of a-amino acid esters is enhanced by a variety of metal ions such as copper(II), nickel(II), magnesium(H), manganese(II), cobalt(II) and zinc(II).338 Early studies showed that glycine ester hydrolysis can be promoted by a tridentate copper(II) complex coupled by coordination of the amino group and hydrolysis by external hydroxide ion (Scheme 88).339 Also, bis(salicylaldehyde)copper(II) promotes terminal hydrolysis of the tripeptide glycylglycylglycine (equation 73).340 In this case the iV-terminal dipeptide fragment... 

We saw in Chapter 3 that the hydrolysis of chelated amino acid esters and amides was dramatically accelerated by the nucleophilic attack of external hydroxide ion or water and that cobalt(m) complexes provided an ideal framework for the mechanistic study of these reactions. Some of the earlier studies were concerned with the reactions of the cations [Co(en)2Cl(H2NCH2C02R)]2+, which contained a monodentate amino acid ester. In many respects these proved to be an unfortunate choice in that a number of mechanisms for their hydrolysis may be envisaged. The first involved attack by external hydroxide upon the monodentate A-bonded ester (Fig. 5-62). This process is little accelerated by co-ordination in a monodentate manner. 

Figure 5-68. The labelling experiment that distinguished between the various pathways for hydrolysis of amino acid esters. The site of the label may be determined by IR spectroscopy or other methods. Pathway A involves co-ordinated hydroxide nucleophile and pathway B, external hydroxide. Both pathways are found to be important for cobalt(m).

Two mechanisms of cobalt(III)-mediated peptide-bond cleavage have been investigated. The first one involves hydrolysis of a directly activated amino acid ester, or peptide (equation 4). The other mechanism involves the intramolecular attack of an amino acid ester or peptide by a cis coordinated hydroxide or water molecule (equation 5). In both cases, the cobalt(III) complex must have two open coordination sites cis to each other. For the directly activated mechanism, these sites are needed to bind the amino acid ester or peptide. The intramolecular reaction requires one site for coordination of the ester or peptide, and one site for the coordination of the hydroxy or water molecnle. One of the initial cobalt(III) complexes to be investigated was... 

One of the main questions in the cobalt(III)-promoted hydrolysis of activated amino acid esters is whether the ratedetermining step is addition of hydroxide to the carbonyl carbon, or loss of the alkoxide from the intermediate. Work with /3-alanine ester showed that below pH 8.5 the ratedetermining step was the elimination of alkoxide. At pH 10 and above, the rate-determining step changes and the addition of hydroxide to the activated ester becomes the rate-controlling step. This is due to the fact that above pH 10 the hydroxyl group of the intermediate becomes deprotonated (equation 7). The deprotonation of the hydroxyl group accelerates the loss of alkoxide by 10 times. ... 

The hydrolysis of chelated amino acid esters, H2NCHRCO2R, is known to be accelerated by metal ions, most notably cobalt(III). Dramatic enhancements are also observed with copper(II). Mechanistic studies of the hydrolysis of amino acid esters with copper(II) complexes of glycyl-DL-valine and dien (H2HCH2CH2NHCH2CH2NH2) have been reported/ The hydrolysis of benzyl-penicillin (30) by copper(II) salts to give (31) has been further investigated, and it is proposed that the key step involves intramolecular attack by metal-coordinated hydroxide in an intermediate of type (32). 

Co(in) complexes promote similar reactions. When four of the six octahedral positions are occupied by amine ligands and two cis positions are available for further reactions, it is possible to study not only the hydrolysis itself, but the steric preferences of the complexes. In general, these compounds catalyze the hydrolysis of N-terminal amino acids from peptides, and the amino acid that is removed remains as part of the complex. The reactions apparently proceed by coordination of the free amine to cobalt, followed either by coordination of the carbonyl to cobalt and subsequent reaction with OH or H2O from the solution (path A in Figure 12-15) or reaction of the carbonyl carbon with coordinated hydroxide (path B). As a result, the N-terminal amino acid is removed from the peptide and left as part of the cobalt complex in which the a-amino nitrogen and the carbonyl oxygen are bonded to the cobalt. Esters and amides are also hydrolyzed by the same mechanism, with the relative importance of the two pathways dependent on the specific compoimds used. 

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