Metaphosphates, monomeric

Niecke et al. have prepare polyimido analogues of the metaphosphate ion, PO3, bylithiation ofthe corresponding amido compounds [16]. Thus the monomeric solvent-separated ion pair [(THF)4Li][P(NMes )3] (10) is obtained by treatment of (Mes N)2P(NHMes ) with "BuLi [16]. A monomeric contact ion pair (11) containing the unsymmetrical anion [P(N Bu)2(NMes )]" has also been reported [16]. By contrast the dilithium derivative of the trisimidometaphosphate [P(N Bu)3]" forms a dimer (12) [17], with a cubic structure reminiscent of that of (7). 

J. P. Guthrie, Hydration and Dehydration of Phosphoric Acid Derivatives Free Energies of Formation of the Pentacoordinate Intermediates for Phosphate Ester Hydrolysis and of Monomeric Metaphosphate, J. Am. Chem. Soc. 1977, 99, 3391. 

The involvement of monomeric metaphosphate in the phosphoryl transfer from phosphate monoesters, and of pentaco-ordinate intermediates from phosphotriesters represent two extremes in the mechanistics of the phosphoryl transfer process. Between the extremes are the (S 2)p processes involving transition states having various bond orders, but no true... 

The present survey is concerned exclusively with short-lived compounds of quinquevalent phosphorus with coordination number 3, which are not yet isolable in a classical sense with few exceptions they all possess at least one P/O double bond. Specifically, these are the metaphosphinates /, the metaphosphonates 2, and the metaphosphates 3. Studies of the methyleneoxophosphoranes 1 (X = O) and the monomeric metaphosphate ion 3 (Z = Oe, X = Y = O) have been especially thorough. 

The monomeric metaphosphate ion itself commands a fair amount of attention in discussions of metaphosphates. It is postulated as an intermediate of numerous hydrolysis reactions of phosphoric esters 52 S4,S5) and also of phosphorylation reactions S6> kinetic and mechanistic studies demonstrate the plausibility of such an assumption. In addition, the transient formation of ester derivatives of meta-phosphoric acid — in which the double-bonded oxygen can also be replaced by thio and imino — has also been observed they were detected mainly on the basis of the electrophilic nature of the phosphorus. 

The possible mechanisms for solvolysis of phosphoric monoesters show that the pathway followed depends upon a variety of factors, such as substituents, solvent, pH value, presence of nucleophiles, etc. The possible occurrence of monomeric metaphosphate ion cannot therefore be generalized and frequently cannot be predicted. It must be established in each individual case by a sum of kinetic and thermodynamic arguments since the product pattern frequently fails to provide unequivocal evidence for its intermediacy. The question of how free the PO ion actually exists in solution generally remains unanswered. There are no hard boundaries between solvation by solvent, complex formation with very weak nucleophiles such as dioxane or possibly acetonitrile, existence in a transition state of a reaction, such as in 129, or SN2(P) or oxyphosphorane mechanisms with suitable nucleophiles. 

Finally, the product resulting on reaction of benzoic anhydride with diphosphorus pentoxide was also regarded as monomeric benzoyl metaphosphate. The des-... 

More recent studies have shown that monomeric metaphosphates such as 147 are just as unisolable as the metaphosphate ion 102, and are even more electrophilic. Generation of metaphosphates is accomplished mainly in two ways, i.e. by thermal or photochemical fragmentation reactions, on the one hand, and by decomposition of suitably activated phosphates on the other. 

On the other hand, numerous examples are already known in which monomeric metaphosphoric esters are generated by thermolysis reactions. Most worthy of mention in this context is the gas phase pyrolysis of the cyclic phosphonate 150 which leads via a retro-Diels-Alder reaction to butadiene and monomeric methyl metaphosphate (151) 108,109, no). While most of the phosphorus appears as pyrophosphate and trimeric and polymeric metaphosphate, a low percentage (<5%) of products 152 and 153 is also found on condensation of the pyrolyzate in a cold trap containing diethylaniline or N,N,N, N,-tetraethyl-m-phenylene-diamine. The... 

The reaction of 151 with methanol to give dimethyl phosphate (154) or with N-methylaniline to form the phosphoramidate 155 and (presumably) the pyrophosphate 156 complies with expectations. The formation of dimethyl phosphate does not constitute, however, reliable evidence for the formation of intermediate 151 since methanol can also react with polymeric metaphosphates to give dimethyl phosphate. On the other hand, reaction of polyphosphates with N-methylaniline to give 156 can be ruled out (control experiments). The formation of 156 might encourage speculations whether the reaction with N,N-diethylaniline might involve initial preferential reaction of monomeric methyl metaphosphate via interaction with the nitrogen lone pair to form a phosphoric ester amide which is cleaved to phosphates or pyrophosphates on subsequent work-up (water, methanol). Such a reaction route would at least explain the low extent of electrophilic aromatic substitution by methyl metaphosphate. 

The formation of 151 from the phosphonate 171 could be proved only by indirect means. Electron-rich aromatic compounds such as N,N-diethylaniline and N,N,N, N -tetraethyl-m-phenylenediamine U0 1I9> and N-methylaniline 120> are phosphorylated in the para- and in the ortho- plus para-positions by 151. Furthermore, 151 also adds to the nitrogen lone pair of aniline to form the corresponding phosphor-amidate. Considerable competition between nucleophiles of various strengths for the monomeric methyl metaphosphate 151 — e.g. aromatic substitution of N,N-diethylaniline and reaction with methanol or aromatic substitution and reaction with the nitrogen lone pair in N-methylaniline — again underline its extraordinary non-selectivity. 

The extent to which 151 phosphorylates the aromatic amine in the phenyl ring is highly dependent upon the solvent. For instance, aromatic substitution of N-methylaniline is largely suppressed in the presence of dioxane or acetonitrile while pho.sphoramidate formation shows a pronounced concomitant increase. The presence of a fourfold excess (v/v) or pyridine, acetonitrile, dioxane, or 1,2-di-methoxyethane likewise suppresses aromatic substitution of N,N-diethylaniline below the detection limit. It appears reasonable to assume that 151 forms complexes of type 173 and 174 with these solvents — resembling the stable dioxane-S03 adduct 175 — which in turn represent phosphorylating reagents. They are, however, weaker than monomeric metaphosphate 151 and can only react with strong nucleophiles. 

The fact that the 3,P-NMR signal of 183a can only be observed in pyridine-containing solution provides food for thought124). Viewed in conjugation with the idea that alkyl metaphosphates could form adducts such as 173 and 174 U9,120) as discussed above, formulation as a zwitterionic pyridine/metaphosphate adduct (188) seems reasonable. Similar adducts have also been found in the reaction of TPS with dinucleotides and trinucleoside diphosphate 126). In any case, the reactions of 183 or 188 are in full accord with the expected properties of a monomeric metaphosphate and its reactivity towards alcohols is far greater than that of all other reactive phosphorylation intermediates which can arise on reaction of TPS with oligonucleotides 126). 

When monomeric metaphosphate anion POf (102) is generated form the phos-phonate dianion 170 in the presence of the hindered base 2,2,6,6-tetramethylpiper-idine, it undergoes reaction with added carbonyl compounds147), Thus, it phosphoryl-ates acetophenone to yield the enol phosphate, whereas in the presence of acetophenone and aniline the Schiff base is formed from both compounds, probably by way of the intermediate C6H5—C(CH3) (OPO e) ( NH2C6HS). This reactivity pattern closely resembles that of monomeric methyl metaphosphate 151 (see Sect. 4.4.2). 

Reactions of Phosphoric Acid and its Derivatives.—Theoretical studies on the conformational properties of cyclic and acyclic phosphate esters, including calculations of angle and torsional strain,66 and on the reactivity of monomeric metaphosphates,67 have appeared. 

Converging lines of evidence have led to a general acceptance of the monomeric metaphosphate mechanism for the hydrolysis of phosphate monoester monoanions. The pH rate profile for aryl and alkyl phosphate monoester hydrolyses commonly exhibits a rate maximum near pH 4. where the concentration of the monoanion is at a maximum. The proposed mechanism is based on these principal points of evidence (a) a general observation of P-O bond cleavage (b) the entropies of activation for a series of monoester monoanions are all close to zero, which is consistent with a unimolecular rather than a bi-molecular solvolysis where entropies of activation are usually more negative by 20 eu7 (c) the molar product composition (methyl phosphate inorganic phosphate) arising from the solvolysis of the monoester monoanion in a mixed methanol-water solvent usually approximates the molar ratio of methanol ... 

The validity of the assumption that random phosphorylation of the components in mixed solvents constitutes experimental evidence for monomeric metaphosphate can often be questioned. A relatively direct demonstration for the existence of an analogue of metaphosphate results from a study of the alkaline solvolysis of optically active methyl N-cyclohexylphosphoramidothioic chloride25, viz. 

The generation of alkyl-substituted monomeric metaphosphoric acid esters (254) has been described using two different methods and the metaphosphate produced spontaneously self-condensed to give polymeric P—O—P bonds, hi the presence of styrene polymerization is avoided and happing occurs instead to give a diastereomeric mixture of 2-alkoxy-l,3,2-dioxophospholane-2-oxides with (254 R = Me).232 Pyridine A -oxidc-tricthylaminc mixtures individually or together catalyse the phosphorylation of... 

Monomeric Metaphosphates in Enzymic and in Enzyme-Model Systems... 

Much of the chemistry of phosphate esters can best be interpreted in terms of monomeric metaphosphate (1). These unstable intermediates can be generated, among other ways, by the Conant-Swan fragmentation (2. 3,4 ) of P-halophosphonates, e.g. ... 

In the presence of water or other nucleophiles, monomeric metaphosphates yield orthophosphates... 

When the fragmentations yielding monomeric methyl metaphosphate (8,9.) or metaphosphate ion (10) are carried out in the presence of 2,2,6,6-tetramethylpiperidine in acetophenone as solvent, the major products are the enol phosphates. Presumably the processes take place by initial attack of the monomeric metaphosphates on the carbonyl group of the ketone. 

Monomeric metaphosphate ion will also activate the carbonyl group of esters (10). In particular, it promotes the reaction of ethyl acetate with aniline to yield O-ethyl-N-phenylacetimidate. The reaction is complete within seconds, whereas, in the absence of monomeric metaphosphate, the reaction between ethyl acetate and aniline is slow, and yields acetanilide. 

Despite these resemblances, questions must necessarily arise as to the detailed mechanisms of the enzymic processes. Does ATP dissociate to yield monomeric metaphosphate Does ATP (by way of monomeric phosphate or by direct reaction) attack carbonyl groups... 

Available evidence (14,15) favors the pathway for pyruvate kinase by way of phosphorylation of pyruvate enol. Furthermore, J. Knowles and his coworkers (16,17), using chiral thiophosphates and chiral (160,170,180) phosphate have shown that pyruvate kinase transfers phosphate from phosphoenolpyruvate to ADP with stereochemical inversion at phosphorus. Since monomeric metaphosphate is presumably planar, a chemical reaction by way of that ion should proceed with racemization. In the active site of an enzyme, however, all components might be held so rigidly that racemization need not occur. Furthermore, no information is yet available on the detailed mechanism of reactions catalyzed by cytidine synthetase our own experiments, designed to distinguish among the mechanisms here discussed, are as yet incomplete. 

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