Metal-promoted hydrolysis

A growing number of protein crystal structures has provided solid evidence that in many phosphoesterase enzymes, two and sometimes even three, di- or trivalent metal ions are involved in substrate transformation. Consequently, the high catalytic efficiency is, in part, the result of a perfectly coordinated catalytic cooperation of the metal ions. Dinu-clear phosphoiyl transfer enzymes have been discussed thoroughly in recent reviews [1-3]. Therefore, this chapter (Section 2) only gives a brief description of enzymes for which two-metal promotion of phos-phoester hydrolysis was proposed on the basis of detailed mechanistic or crystallographic studies (Table 1). 

Once again, a better understanding of the basis of these effects has emerged from studies of the Co(III) complexes. Hydrolysis of chelates of the type O occurs by rate-determining attack of OH by a mechanism similar to that shown in (6.17) and (6.18) with OR replaced by NHR. The metal promotes hydrolysis by OH by a factor of about 10 (Table 6.4) and... 

Some interesting conclusions can be drawn from the thermodynamic parameters for base hydrolysis of the MA+ complexes (Table 19). The rate enhancements in the metal ion-promoted reactions arise from more positive values of AS41 and, in general, lower enthalpies of activation. In addition, there is a close correspondence between values of log XMA+ and AG (Figure 5). The general trends in AH and AS in the metal-promoted reactions can be rationalized in terms... 

The metal ions must exert their effect in the transition state by stabilization of the leaving group (53). Somewhat similar effects are seen in the metal-promoted hydrolysis of benzaldehyde methyl 8-quinolyl acetals.221... 

Although metal-promoted hydrolysis of phosphate esters is a topic of very current interest (Section 61.4.4), little work has been published dealing with the effects of metal ions on the hydrolysis of sulfate esters. The acid-catalyzed hydrolysis of aryl sulfates has been shown to occur by an A-l mechanism (Scheme 34).434 Nucleophilic catalysis by amines has been observed in the hydrolysis of p-nitrophenyl sulfate435 and intramolecular carboxyl group catalysis occurs with salicyl sulfate436 as with salicyl phosphate. 

A very specific example of the hydrolysis of an amide is seen in the metal-promoted hydrolysis of urea, CO(NH2)2 as depicted in Eq. (3.1). 

Another special example of the metal-promoted hydrolysis of an amide is seen with the lactam rings of cephalosporins or penicillins. The hydrolysis of penicillin, 3.5, is accelerated 100 million times in the presence of copper(n) salts. Unfortunately, the precise mechanism of the reaction, whether it involves intra- or intermolecular attack by hydroxide or water, or even the site of co-ordination, is not known with any certainty. 

Preparation of metal oxides by the sol—gel route proceeds through three basic steps (/) partial hydrolysis of metal alkoxides to form reactive monomers (2) the polycondensation of these monomers to form coUoid-like oligomers (sol formation) and (i) additional hydrolysis to promote polymerization and cross-linking leading to a three-dimensional matrix (gel formation). Although presented herein sequentially, these reactions occur simultaneously after the initial processing stage. 

In the following discussions, recent examples of metal-promoted phosphate hydrolysis will be described, whereby one or two metals have been shown to play a key role, and metal ion participation in the hydrolysis process will be assessed. Metal-promoted hydrolysis seems to be a more suitable term than metal-catalyzed hydrolysis, because up to now one cannot find any case of an efficient metal-catalyzed nucleic acid hydrolysis in the literature. In order to hydrolyze a phosphate ester with water, with a half-life of 1 hr, the... 

Table II. Metal-Promoted Hydrolysis of Phenanthroline 2-Carboxamide...

The pH-dependent NMR spectrum of [Ru(bipy)2(py)2] salts has been shown not to involve the formation of covalent hydrates. The reaction of 2,4,6-tris(2-pyridyl)-l,3,5-triazine (46) with aqueous copper(I) salts results in a metal-promoted hydrolysis to yield complexes of 2-pyridinecarboxamide and (47). A number of metal complexes have been characterized structurally from these reactions. 

Four representative roles are conceivable for metals in metal-promoted peptide bond hydrolysis (Fig. 3) [31, 32]. First, metals act as a Lewis acid, and activate... 

Very large rate enhancements have been observed in the zinc(ii)- and copper(ii)-promoted hydrolysis of (18) thus, [ME+] undergoes base hydrolysis ca. 2 X 10 times faster than E. The metal-promoted reactions involve intramolecular attack by co-ordinated OH and this effect, in conjunction with a perturbation of 6 pJlTa units in the acidity of the leaving group, leads to rates of hydrolysis comparable to the catalytic rate constants for the hydrolysis of a good ester substrate by CPA. Hay and Clark favour the mechanism shown in Scheme 10 and propose this reaction as a model for catalysis by CPA (but cf. Scheme 9). 

Also obtained by reaction of sec-butyllithium on 2-bromo-4,6-di-tert-butylphe-nyl acetate in ethyl ether at -95° and -78°, followed by hydrolysis of mixture with saturated ammonium chloride (metal-promoted Fries rearrangement) (43-52%) [3648]. 

Also obtained by reaction of 2-bromophenyl propionate in a ethyl ether/hexane/ THF mixture at low temperature (-78 to -95°) with sec-butyllithium to give, after hydrolysis, the titled ketone (metal-promoted Fries rearrangement) (17%) [6590]. 

Also obtained by reaction of sec-butyllithium (1.1 equiv) with 2-bromo-4,6-dimethylphenyl propionate in tetrahydrofuran/ethyl ether/hexane at -95° for 30 min and -78° for 30 min, then hydrolysis with saturated ammonium chloride (31%) (Metal-promoted Fries rearrangement) [6590]. 

METAL-PROMOTED HYDROLYSIS OF POLYMERIC CHELATING AGENTS CHELATORS ON DEMAND... 

PVA-QA was insoluble in water and ethanol but soluble in mixtures of the two solvents. Therefore, the solution kinetics were determined in 50% aq. ethanol buffered at pH 7.5 with HEPES. It has been demonstrated that this buffer does not bind to the metals studied, or modify the kinetics of metal-promoted hydrolysis. ... 

Comparison of kobs for PVA-QA with the rate constants reported for metal promoted hydrolysis of methyl quinaldate (Table 1) shows the latter is more rapid and the difference between metals is greater.The difference in the solvent (water vs. 50% aq. ethanol) and the ester alkyl groups does not allow any conclusions about the contribution of the polymeric environment to the kinetics. 

The complete kinetic expression for the metal-promoted hydrolysis of PVA-QA in the solid state requires the inclusion of terms for the rates of diffusion of the metal ion into the film and diffusion of the cleaved metal chelate out of the film into external buffer. The limited case of metal influx coupled to hydrolysis may be solved by assuming the diffusion is Fickian and the reaction rate is proportional to the average concentration of the metal in the film. Then, combining the kinetic expression for sorption from a fixed volume by a film with that of metal promoted hydrolysis, and integrating, leads to Equation 1, which is only valid if the rate of egress of the metal-chelate is rapid relative to its formation. ... 

Metal-Promoted Hydrolysis of Polymeric Chelating Agents Chelators on Demand... 

---