Amide hydrolysis zinc-mediated

A limited number of mechanistic studies of stoichiometric amide hydrolysis reactions promoted by Zn(II) complexes have been reported. Groves and Chambers reported studies of the zinc-mediated hydrolysis of an internal amide substrate wherein amide carbonyl coordination to the zinc center is not possible (Scheme 15).93 Examination of the rate of this reaction as a function of pH (6.5-10.5) yielded a kinetic pKa = 9.16. First-order rate constants at 70 °C (/i = 0.5 (NaC104)) for the Zn-OH2 and Zn-OH-mediated amide hydrolysis reactions differed by a factor of 100 when the data was fit to Equation (1) for the proposed mechanism shown in Scheme 16. The activation parameters determined for this reaction (Ai7 = 22(1) kcal mol-1 and AS = — 18(3) eu) are consistent with an intramolecular hydrolysis process wherein a zinc-bound hydroxide acts as an intramolecular nucleophile to attack the amide carbonyl in the ratedetermining step. 

Scheme 16 Proposed mechanism and rate law for the zinc-mediated amide hydrolysis reaction.

As with amide hydrolysis reactions, extensive mechanistic studies of metal-mediated phosphate monoester hydrolysis reactions have been performed using exchange inert mononuclear Co(III) complexes.9,188-202 To date, only a few zinc complexes that promote phosphate monoester hydrolysis have been reported. A binuclear zinc complex supported by a macrocyclic cryptate ligand (Fig. 36)... 

Groves, J. T., and Baron, L. A. "Models of Zinc-Containing Proteases. Catalysis of Cobalt(lII)-Mediated Amide Hydrolysis of Pendant Carboxyl-... 

Thus, many metal ions catalyze the hydrolysis of esters [7,8], amides [9], and nitriles [10] via electrophilic activation of the C=0 or C=N group. This type of catalysis is characteristic of coordination complexes and is very common in metalloenzyme-mediated processes. Zinc(II), for example, is a key structural component of more than 300 enzymes, in which its primary function is to act as a Lewis acid (see Chapter 4). The mechanism of action of zinc proteases, e.g., thermolysin, involves electrophilic activation of an amide carbonyl group by coordination to zinc(II) in the active site (Figure 4). 

A mononuclear zinc hydroxide complex supported by a hydrophobic hydro-tris(pyrazolyl)borate ligand mediates the stoichiometric hydrolysis of an activated amide.94 As shown in Scheme 17, treatment of [(TpCum,Me)Zn-OH] with... 

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