Dianions of phosphates

The hydrolysis rates of the dianions of phosphate and phosphorothioate monoesters are substantially accelerated by the addition of polar aprotic solvents such as DMSO and MeCN because the activation barrier A becomes smaller due to a lowering of the enthalpy of activation. The enthalpy transfer of the transition states in the... 

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... 

As is apparent from Fig. 1, the dianions of monoalkyl phosphates normally resist hydrolysis. However, for leaving groups whose conjugate acids exhibit a pKa < 5 in water, hydrolysis of the dianion becomes faster than that of the monoanion. Fig. 2 shows a pH profile characteristic of this situation. Whereas the hydrolysis rate of 2,4,6-trichlorophenyl phosphate (pKa of the phenol 6.1) still shows the typical monoanion preference as seen for methyl phosphates (Fig. 1), the dianion of 2,4-dinitrophenyl phosphate (pKa of the phenol 4.09) is hydrolyzed far faster than the monoanion 2-chloro-4-nitrophenyl phosphate represents an intermediate case (pKa of the phenol 5.45)6S). 

Chemical shift and line width are related and can be used to describe conformational changes. The 831P value of 5 ppm and the line width of 20 Hz indicate that dianionic 5 phosphate is very tightly bound to the active site and tumbles with the protein. Lower values of chemical shift indicate more loosely bound phosphate. Higher values of the line width indicate the presence of two conformers in equilibrium. If the open and close form undergo slow interconvertion, two signals are observed in the 31P NMR spectra. 

Hydrolysis of phosphate monoester dianions RO-OPOJ [83] Hydrolysis of axial tetrahydropyranyl acetals [79]... 

Solvolysis studies of meta- and para-substituted phenyl phosphates (240) in anhydrous Bu OH and in Am OH have revealed that generally reactions of dianions are much faster in alcohols than in water. For example, the dianion of p-nitrophenyl phosphate (240 X = 4-NO2) reacts 7500- and 8750-fold faster in Bu OH and Am OH, respectively, than in water." The results of a theoretical study of the reactivity of phosphate monoester anions in aqueous solution do not support the generally accepted view that Brpnsted coefficients fhg = —1.23 and jSnuc = 0.13 determined more than 30 years ago for the uncatalysed reaction of water and a monophosphate dianion (241) represent conclusive evidence for the dissociative mechanism. It is suggested that, instead, the observed LFERs could correspond to a late transition state in the associative mechanism." ... 

With few exceptions the dianions of monoalkyl and monoaryl phosphates are unreactive but with a good leaving group, e.g. carboxylate, dianions undergo hydrolysis. The same reasoning applies to a dinitrophenoxide anion and the pH-rate profile for the hydrolyses of 2,4- and 2,6-dinitrophenyl phosphates differs from those of other aryl phosphates in that the dianion is more reactive than the monoanion species (Fig. 2)22-23. This reactivity is at-... 

Fig. 3. Bronsted plot for the reactions of substituted pyridines with the dianion of 2.4-dinitrophenyl phosphate. The line, which is taken from the corresponding plot for the monoanions, is included...

Catalysis may also be observed via transition states or intermediates which are more than six-membered. An example is the hydrolysis of glucose-6-phosphate dianion which surprisingly is more rapid (5 times) than the monoanion. Presumably the relatively acidic 1-hydroxyl group of glucose (p/Ca = 10.8, 100°C) can act as a general-acid catalyst of phosphate group expulsion (58),3 > even though the required chair conformation has all substituents axial, viz. 

Figure 19 Reconstruction of 3,P CSA powder spectra of monoanionic (left) and dianionic (right) phosphate groups in lyophilisates of L-phosphoserine prepared with LiOH, NaOH and KOH. Taken from Ref. [75].

The electrostatic model for the micellar effect on the hydrolysis of phosphate monoesters is also consistent with the results of inhibition studies (Bunton et al., 1968, 1970). The CTAB catalyzed hydrolysis of the dinitrophenyl phosphate dianions was found to be inhibited by low concentrations of a number of salts (Fig. 9). Simple electrolytes such as sodium chloride, sodium phosphate, and disodium tetraborate had little effect on the micellar catalysis, but salts with bulky organic anions such as sodium p-toluenesulfonate and sodium salts of aryl carboxylic and phosphoric acids dramatically inhibited the micelle catalysis by CTAB. From equation 14 and Fig. 10, the inhibitor constants, K, were calculated (Bunton et al., 1968) and are given in Table 9. The linearity of the plots in Fig. 10 justifies the assumption that the inhibition is competitive and that incorporation of an inhibitor molecule in a micelle prevents incorporation of the substrate (see Section III). Comparison of the value of for phenyl phosphate and the values of K for 2,4-and 2,6-dinitrophenyl phosphates suggests that nitro groups assist the... 

Figure 1 Designing mimics of phosphates and diphosphates is difficult because of their anionic character and tetrahedral geometry (as indicated by p/(a values, bond lengths, and bond angles), (a) p/(a values for inorganic phosphate (12). (b) p/Ca values for pyrophosphate (12). (c) P-O bond lengths of the hydrogen phosphate dianion (13). (d) P-O bond angles in the hydrogen phosphate dianion (13).

A word about the synthesis of the a-series, a-geraniol (73) and a-nerol (74), is warranted because they are often intermediates in the synthesis of 1-hydroxylated compounds (e.g., some diols described below). Weiler has continued his exploitation of the dianion of methyl acetoacetate to this end. Instead of prenylation (Vol. 4, p. 461, Ref. 73) he carried out a similar series of operations by alkylating the dianion with 4-bromo-2-methyl-l-butene, thus arriving at compounds of the a-series via the keto ester 75, methylating the enol phosphate to 76. He also prepared the double methylene isomer 77 (R = COEt) of geranyl propionate from the intermediate 75. The purpose of synthesizing this propionate was to prepare the pheromone of the San Jose scale, Quadraspidiotus pernicious, which is a mixture of the propionates of 73, 74,... 

Na+ compared to K+, since Na+ binds to a phosphate monoanion and K+ binds to a dianion. Recent T1+-NMR data indicates this monovalent cation binds 4.0 A from the enzyme bound Mn2+ and that this distance increases to 5,4 A on binding of phosphate consistent with the mechanism of Fig. 8 (81). However, the possibility of T1+ binding at an inhibitory site rather than its activating site has not been excluded. 

D-isomer to be monitored by enzyme-linked oxidation of NADH. The same technique was used to monitor the formation of dihydroxyacetone phosphate. The major reaction on formation of the enediolate, however, is loss of phosphate to give the enol of methylglyoxal. The formation of the enediolate is independent of pH between pH 6 and 10 because of intramolecular proton abstraction by the phosphate dianion. Above pH 10 and below pH 6, the pH-rate profile has a gradient of +1.0, in the former case a reflection of direct attack by OH on the phosphate dianion, in the latter a reflection of the proportion of reactive dianionic form of the substrate present. 

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