Salicyl phosphate, hydrolysis

Metal ion catalysis of salicyl phosphate hydrolysis is much more complicated than that of Sarin, since the former substrate can combine with metal ions to give stable complexes, and some of the complexes formed do not constitute pathways for the reaction. In addition the substrate undergoes intramolecular acid-base-catalyzed hydrolysis which is dependent on pH because of its conversion to a succession of ionic species having different reaction rates. Therefore a careful and detailed equilibrium study of proton and metal ion interactions of salicyl phosphate would be required before any mechanistic considerations of the kinetic behavior in the absence and presence of metal ions can be undertaken. 

Figure 3. Mechanism of salicyl phosphate hydrolysis in presence and absence of...

To determine the nature of the catalysis of salicyl phosphate hydrolysis by metal chelates, two diamine-Cu(II) chelates were selected for detailed study, N-/ -hydroxyethylethylenediamine-Cu(II) ion (XXV) and a,a -bipyridine-Cu(II) ion (XXVI) (II). 

Of special interest is the comparison of the inactivity of bipyridine-Cu(II) as a catalyst in salicyl phosphate hydrolysis, with its strong catalytic effect on the hydrolysis of dicarboxyphenyl-2-phosphate. A comparison of formulas XXVII with XXXIV and XXXVI shows that mixed complex formation of Cu+2 with salicyl phosphate and bipyridine would prevent attack of the phosphate group via the proposed mechanism. The formation of the analogous mixed chelate with DCPP (XXXIV and XXXVI) would produce a reaction intermediate for the reaction, since the metal ion would tie up one of the carboxylate ions but leave... 

METAL ION AND METAL CHELATE CATALYSIS OF SALICYL PHOSPHATE HYDROLYSIS. 

It is clear that the high efficiency is a property of the salicylate system and is not limited to acetal hydrolysis. Similar highly efficient catalysis is observed also in the hydrolysis of salicyl phosphate [12], and a similar mechanism appears to be involved (Bromilow and Kirby, 1972). The essential structural... 

Catalysis by Cu(II) Ion and Cu(II) Complexes. The rate profiles for the hydrolysis of salicyl phosphate in the absence of metal ions, and in the presence of an equimolar concentration of Cu(II) ion, are given in Figure 2. As the pH increases, the rate of hydrolysis of salicyl phosphate increases because of conversion of the carboxyl group to the carboxylate anion. The latter is required for the reaction, which is considered to take place via intramolecular nucleophilic attack of the carboxylate group in the phosphorus atom, as first suggested by Chanley and coworkers (1, 2,3). As the pH is further increased, the rate of reaction begins to drop off as the result of the dissociation of the proton attached to the phosphate... 

Figure 2. Rate profiles for hydrolysis of 1.00 x 10 SM salicyl phosphate at 30°...

Correlation of the observed rates with the concentrations of the substrate species (10) indicates that the metal ion does not catalyze the hydrolysis of the monoanionic form of salicyl phosphate. Combination of the monoanionic form of the substrate with the vanadyl ion would result in an unreactive complex having a neutral carboxyl group. Shift of the proton to the phosphate group could not take place in accordance with the requirements of the general reaction mechanism illustrated in Figure 3. Thus the vanadyl ion would be expected to catalyze the hydrolysis of only the di- and trinegative forms of the substrate. 

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. 

On the other hand, phosphorane intermediates are not expected to be involved in the hydrolysis of phosphate monoesters, so the effective observed catalysis by the carboxyl group of salicyl phosphate 3.21 [51] (Scheme 2.26) is presumed to be concerted vith nucleophilic attack. (The hydrolysis reaction involves the less abundant tautomer 3.22 of the dianion 3.21, and the acceleration is >10 -fold relative to the expected rate for the pH-independent hydrolysis of the phosphate monoester dianion of a phenol of pK 8.52.) However, this system differs from the methoxy-methyl acetals discussed above, in that there is a clear distinction between neutral nucleophiles, which react through an extended transition structure similar to 3.16 in Scheme 2.23, and anions, which do not react at a significant rate, presumably because of electrostatic repulsion. This distinction is well-established for the dianions of phosphate monoesters with good leaving groups (p-nitrophenyl [52] and... 

The effect of metal ions or metal chelates on the rate of hydrolysis of salicyl phosphate is difficult to evaluate quantitatively, for several reasons. Salicyl phosphate itself undergoes intramolecular acid-base-catalyzed hydrolysis in a series of reactions, each of which is pH dependent and has its own rate constant. Moreover, salicyl phosphate reacts with metal ions or chelated metal ions to give a variety of metal chelates, some of which are mixed ligand chelates. The hydrolysis reaction, however, does not take place via all of these chelates. From a careful study of the solution equilibria involved and the effect of various solution parameters on the rate of hydrolysis of salicyl phosphate, the following conclusions have been reported (105). 

Chelated metal ions having uncoordinated positions increase the rate of hydrolysis of salicyl phosphate, although in general a free metal ion has a greater effect than a chelated metal ion. The following metal ions are arranged in the order of increasing effect on the hydrolysis Cu(II), U02(VI), VO(IV), ZrO(IY), and Fe(III), whereas Ni(II), Co(II), Zn(II), and Cd(II) have no effect. 

A general mechanism that has been proposed for the effect of a metal ion or metal chelate on the hydrolysis reaction involves the combination of salicyl phosphate with the metal ion or metal chelate in such a manner that an intramolecular nucleophilic attack of the phosphate group by the carboxylic acid group can take place (14%)-... 

Several studies on intramolecular catalysis of the solvolysis of phosphate esters have been reported. The larger hydrolysis rate of the zwitterion of 8-hydroxyquinoline phosphate (20) compared with that of pyridyl 3-phosphate (21) was attributed, on the basis of the kinetic isotope effect, to intramolecular general acid catalysis. A similar general acid catalysis by the hydroxy-group seems to operate in the (3-hydroxy-2-pyridyl)methyl phosphate dianion (22), which hydrolyses faster than either the monoanion or the neutral molecule. From a study of 4- and 5-substituted derivatives of salicyl phosphate (23) it is suggested that the negligible solvent isotope effect is inconsistent with preliminary proton transfer, and that here also intramolecular general acid catalysis by the... 

Spontaneous hydrolysis of salicyl phosphate in aqueous buffers was very slow, but under micellar conditions in either SDS or Triton-X-100, the reaction was dramatically accelerated. ... 

New kinetic and equilibrium data (1-4) on the hydrolysis of salicyl phosphate and its analogs in the presence of metal ions and metal chelate compounds reveals many patterns of behavior which determine (a) whether catalysis does or does not take place, and (b) the degree of catalytic activity achieved. 

The data in Table I indicate that the rates of hydrolysis of the ionized species of l,3-dicarboxy-2-phenylphosphate [IV-VII] are higher than the analogous forms of salicyl phosphate [I-IV], as would be expected from the presence of the second negative carboxylate group adjacent to the phosphate... 

The 1 1 dipyridyl-Cu(II) chelate was found to have no catalytic activity toward the hydrolysis of [II] and [III], This result is interpreted as being due to the formation of a mixed ligand chelate compound in which the carboxylate group is bound to the metal ion and is thus prevented from attacking the phosphate group, A similar interpretation is offered for the failure of the 1 1 Cu( II)-N-hydroxyethylethylenediamine chelate to show catalytic activity. However, the 1 1 vanadyl complexes of 3,5-disulfopyrocatechol, 5-sulfo--8-hydroxyquinoline, and 5-sulfosalicylic acid which do not form stable mixed ligand chelates with salicyl phosphate, were found to have considerable catalytic activity. 

The most thoroughly investigated examples of this behaviour are found in the hydrolysis of salicyl phosphate and salicyl sulphate. The pH-rate profile for the hydrolysis of salicyl phosphate is bell-shaped... 

The requirement for the carboxyl group to lie in the plane of the aromatic ring in order to provide intramolecular catalysis appears to be more stringent here than in the hydrolysis of the acetals. Thus the dianion of salicyl phosphate is hydrolysed about thirty three times... 

Intramolecular catalysis may occur in the hydrolysis of the dianion of 8-carboxy-l-naphthyl phosphate, but the rate enhancement is not as large as that found in the hydrolysis of salicyl phosphate. The rate constant is only about 7.5 times greater than that for hydrolysis of the dianion of m-carboxyphenyl phosphate [118]. This result is similar to that found with the analogous acetals (see p. 345) and presumably the smaller rate enhancement arises from the greater difficulty of proton transfer via a seven-membered ring in this stereochemical situation. 

Salicylic acid was used for phosphite protection in the synthesis of glycosyl phosphites and phosphates. This derivative is very reactive and readily forms a phosphite upon treatment with an alcohol or a phosphonic acid upon aqueous hydrolysis. ... 

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