La3+-Catalyzed Methanolysis of Hydroxypropyl-p-nitrophenyl Phosphate as a Model for the RNA Transesterification Reaction

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Abstract
The methanolysis of hydroxypropyl-p-nitrophenyl phosphate (HPNPP, 1) promoted by La(OTf)3 under buffered conditions was studied in methanol as a function of pH at 25 °C. 31P NMR studies at −90 °C indicate that there are at least three La/1 complexes formed at pH ≈ 5.3 of 1:1, 2:2, and 1:2 stoichiometry. Kinetic studies of the observed pseudo-first-order rate constants for the methanolysis of 1 as a function of [La3+] at 4.5 < pH < 10.5 indicate there are two general pH regimes. In the low pH regime between 4.5 and 7.6, the plots of kobs versus [La3+] exhibit saturation behavior with very strong 1:1 binding, with a plateau rate constant that depends on [OCH3-]. The catalytically productive species is shown to be a 2:2 complex of La3+ and 1, where the phosphate is proposed to be doubly activated, thereby promoting the methoxide reaction by some 4.6 × 1010-fold. In the high pH regime from 7.9 to 10.5, 1:1, 2:2, and 2:1 La3+/1 complexes are formed with the La3+ coordinated in the form of [La3+(OCH3-)]1,2. Throughout this pH regime at high [La3+], a saturation complex, (La3+OCH3-)2/1, is formed that spontaneously decomposes with a rate constant of (5−10) × 10-3 s-1, leading to an acceleration of 109-fold at pH 8.0.