Methyl ethylene phosphate, hydrolysis

Ah initio calculations to map out the gas-phase activation free energy profiles of the reactions of trimethyl phosphate (TMP) (246) with three nucleophiles, HO, MeO and F have been carried out. The calculations revealed, inter alia, a novel activation free-energy pathway for HO attack on TMP in the gas phase in which initial addition at phosphorus is followed by pseudorotation and subsequent elimination with simultaneous intramolecular proton transfer. Ah initio calculations and continuum dielectric methods have been employed to map out the lowest activation free-energy profiles for the alkaline hydrolysis of a five-membered cyclic phosphate, methyl ethylene phosphate (247), its acyclic analogue, trimethyl phosphate (246), and its six-membered ring counterpart, methyl propylene phosphate (248). The rate-limiting step for the three reactions was found to be hydroxyl ion attack at the phosphorus atom of the triester. ... 

Fig, 5. pH-product profile for the hydrolysis of methyl ethylene phosphate in water at 25°C. 

Species (23) and (24) function as the intermediates for the water-catalyzed hydrolysis of methyl ethylene phosphate which gives 25% exocyclic cleavage. Ionization to generate (26) followed by pseudorotation to (27), viz. 

Lim, C. and Tole, P. (1992) Concerted Hydroxl Ion Attack and Pseudorotation in the Base-Catalyzed Hydrolysis of Methyl Ethylene Phosphate, J. Phys. Chem. 96, 5217-5219. 

Pseudorotations involving oxyligands are generally fast equilibria. Rapid rate-accelerated processes, such as the exocyclic cleavage observed in the hydrolysis of methyl ethylene phosphate, necessarily involve pseudorotation of TBP intermediates (Kluger et al., 1969 Boyd, 1969 Kluger and Thatcher, 1985, 1986). In spite of this, no pseudorotation has ever been demonstrated in an enzyme system in which nucleophilic substitution occurs at phosphorus. The evidence for this assertion is based on stereochemical analysis, employing chiral ( 0, 0-labelled) phosphates and chiral thiophos-phates as substrates. 

On this basis, Gorenstein and coworkers predicted a stereoelectronic acceleration in the hydrolysis of methyl ethylene phosphate via endocyclic cleavage (Gorenstein et al., 1977a,b, 1979). As we have seen, studies on methyl ethylene phosphate and related systems formed a foundation for the development of Westheimer s guidelines (Westheimer, 1968). 

To account for the observation of exocyclic cleavage in strong base, Gorenstein and coworkers reexamined the product distribution of MEP hydrolysis at pH 4.7, 6.0, 7.0, 8.0, 9.0 and in 5 m NaOH, using a quench procedure and P nmr analysis (Taira et al., 1984a,b). These workers observe. . no exocyclic cleavage (0 + 3%) for methyl ethylene phosphate... 

A final analogy with the hydrolysis of methyl ethylene phosphate should be noted. Gorenstein accounts for exocyclic cleavage (<50%) of MEP in dilute acid by the proposition of a reverse anomeric effect , which he argues overcomes the normally dominant app lone-pair stereoelectronic effect (p. 185). This anomeric effect is a dipole-repulsion effect, favouring... 

The hydrolysis of poly(oxyalkylene phosphate)s have been studied by Penczek et al. [297]. The rate of hydrolysis was determined by direct titrimetric and NMR methods. H NMR gave quantitative information on the rate constants of hydrolysis of the main chain (k ) and the side group (k ). The rate constants for poly(methyl ethylene phosphate) 1 have been found to be close to those measured for the corresponding low molecular-weight models. 

In the case of acid hydrolysis of methyl ethylene phosphate, ring opening occurs with only 30% of the material and 0-C fission occurs in the remainder (5.357). Exclusive 0-C fission with complete retention of the ring occurs in hydrolysis (5.358). 

Kluger, R., Covitz, F., Dennis, E., Williams, D., and Westheimer, F. H. "pH-Product and pH-Rale Profile for the Hydrolysis of Methyl Ethylene-phosphate. Rate limiting Pseudorotation." /. Am. Chem. Soc., 91,6066-6072 (1%9). 

A consideration of the hydrolysis of methyl ethylene phosphate indicates that the hydrolysis of organophosphates does not necessarily proceed by a simple displacement mechanism. If this were the case, then exclusive opening of the strained ring would be expected to occur ... 

In fact, acid-catalyzed hydrolysis of methyl ethylene phosphate leads to significant displacement of the methoxy function ... 

Fig. 10 Relationship of percentage of dimer [62] to MEP in hydrolysis of M EP in 0.33 M NaOD. The equation for the curve is not given. The stated error in each point is 1.5% (e.g. (11.2 1.5) % dimer). [Reprinted with permission from Tetrahedron 43, Gorenstein et a/., Alkaline hydrolysis of methyl and ethyl ethylene phosphates . Copyright 1987, Pergamon Journals Ltd.]...

The high rate of acid hydrolysis of ethylene phosphate and its methyl ester is probably due mainly to release of ring strain on formation of a 5-coordinated intermediate with O/P/O = 90° (13.138). The fact that pseudorotation can occur is itself proof that trigonal bipyramidal structures are involved. 

The factors involved and mechanistic pathways in the hydrolysis of phosphate esters, particularly those of a cyclic nature, continue to be the source of much speculation. A further study of the simplest cyclic triester, ethylene methyl phosphate, seems only to have served to consolidate already polarized views. The original, experiments of Westheimer s group employed gc and H nmr spectroscopy and demonstrated that ethylene methyl phosphate (26) hydrolyses under alkaline conditions by... 

There has been controversy over the mechanism of hydrolysis of ethylene methyl phosphate and investigations into the nature of metaphosphate and its role in the hydrolysis of phosphorus esters have continued. Elegant experiments relating to each of these problems have been reported. 

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