Bell-Shaped pH-Rate Profile in a Reaction Involving a Pentacoordinated Phosphorus Intermediate Andre ´s Nu ´n ˜ ez and Oswaldo Nu ´n ˜ ez* Laboratorio de Fisico-Quı ´mica Orga ´ nica, Departamento de Procesos y Sistemas, Universidad Simo ´ n Bolı ´var, Apartado postal 89000, Caracas, Venezuela Received April 18, 1996 X Kinetics of the nucleophilic monosubstitution of imidazole by p-nitrophenolate (PNP - ) in hexaimi- dazolylcyclotriphosphazene (2) in water: THF 4:1 (5.5 < pH < 7.5) at 24 °C have been studied. The reaction was followed by the disappearance of the PNP - under pseudo-first-order conditions using the initial-rate procedure. A constant excess of KCl is needed in order to avoid medium effects. A bell-shaped curve is obtained when the k obs values (obtained from the leveling or the extrapolation to zero of k obs vs [H 2 PO 4 - ] T plots) are plotted against the pH. From this plot, a kinetically determined pK a of 5.4 was obtained for 2. From the same plot, a 5.7 L mol -1 s -1 value for the second-order rate constant for the nucleophilic PNP - attack to the protonated species of 2 was found. A two-step mechanism is proposed. The formed pentacoordinated intermediate cleaves to the (p-nitrophenoxy)pentaimidazolyl)cyclotriphosphazene (3) in a general-acid-catalyzed reaction. As expected of the proposed mechanism, a change in the rate-limiting step is observed at pH > 7.0 when the [buffer] T increases and k obs becomes independent of [buffer]. The implications of the present results on the controversial mechanism of hydrolysis of RNA and derivatives are discussed. Introduction In the search for polyphosphazenes with possible anticancer 1 properties, we have prepared 2 the polymer precursor mono[Pt(bipyridyl)(tyrosil)Cl]pentaimidazolyl- cyclotriphosphazene (1). Since the capacity of the ty- rosine phenol group to displace the imidazol is relevant to the synthesis of 1, we were interested in studying the removal of the first imidazole group in the hexaimida- zolylcyclotriphosphazene (2) by phenol derivatives. In this paper we present the kinetic results of the displace- ment of imidazole by p-nitrophenolate (PNP - ) in 25% aqueous THF. The kinetics reported were obtained under conditions in which [PNP - ] is important, thus precluding the mechanistic contribution of the base- catalyzed deprotonation of PNP. The advantage of the experimental conditions is that an unambiguous distinc- tion can be made between the anionic attack on the neutral and the protonated state of 2 by kinetics means. In general, this is an important undertaking in reactions involving pentacovalent phosphorus intermediates. In addition to contributing to a better understanding of the phosphazene substitution and the direct kinetic mea- surement of the pK a of 2, this study may contribute to settling the existing controversy 3-6 on the catalyzed hydrolysis of RNA and derivatives. In fact, some of the manifestations (leveling in plots of k obs vs [buffer], bell- shaped pH-rate profiles and strong medium effect dependency) used to argue in favor of or against the unsymmetrical 7 mechanism or the sequential bifunctional- catalyzed mechanism 8 were also present in this study; nevertheless, they are explained without bias by a symmetrical catalyzed mechanism. Results and Discussion Results. It has been shown 9 that the hydrolysis of 2, at pH range 6.5-7.8 in 20% aqueous THF, produces hydroxypentaimidazolylcyclotriphosphazene. Likewise, the reaction of PNP with 2, under the conditions of this study (pH range 5.4-7.5, water:THF 4:1), produces (p- nitrophenoxy)pentaimidazolylcyclotriphosphazene (3). This X Abstract published in Advance ACS Abstracts, November 1, 1996. (1) Allcock, H. R.; Allen, R. W.; O’Brien, J. P. J. Am. Chem. Soc. 1977, 99, 3984. (2) Angulo, L. M.Sc. Thesis, Universidad Simo ´n Bolı ´var, 1992. (3) Breslow, R.; Huang, D.-L. J. Am. Chem. Soc. 1990, 112, 9621. (4) Menger, F. M. J. Org. Chem. 1991, 56, 6251. (5) Haim, A. J. Am. Chem. Soc. 1992, 114, 8384. (6) Breslow, R.; Xu, R. J. Am. Chem. Soc. 1993, 115, 10705. (7) Oakenfull, D. G.; Richardson, D. I., Jr.; Usher, D. A. J. Am. Chem. Soc. 1967, 89, 5491. (8) Anslyn, E.; Breslow, R. J. Am. Chem. Soc. 1989, 111, 4473. (9) Allcock, H. R.; Fuller, T. J. J. Am. Chem. Soc. 1981, 103, 2251. N P N P N P O N N N N N N N N N N N P N P N P N N N N N N N N N N N CH 2 CH N N NH 2 O N N P N P N P N N N N N N N N N O N NO 2 2: hexaimidazolylcyclotriphosphazene Cl – 1: mono[Pt(bipyridyl)(tyrosil)Cl]penta(imidazolyl)cyclotriphosphazene O Pt + 3: (p-nitrophenoxy)pentaimidazolylcyclotriphosphosphazene 8386 J. Org. Chem. 1996, 61, 8386-8390 S0022-3263(96)00712-8 CCC: $12.00 © 1996 American Chemical Society