Rate (k) and equilibrium
(K)
constants for the reaction of tetrahydrofuranol with a series of Mg2+ complexes of methyl triphosphate analogues, CH3O-P(O2)-O-P(O2)-X-PO34–, X = O, CH2, CHCH3, C(CH3)2, CFCH3, CHF, CHCl, CHBr, CFCl, CF2,
CCl2, and CBr2, forming phosphate diester and
pyrophosphate or bisphosphonate in aqueous solution were evaluated
by B3LYP/TZVP//HF/6-31G* quantum chemical calculations and Langevin
dipoles and polarized continuum solvation models. The calculated log k and log K values were found to depend
linearly on the experimental pKa4 of the
conjugate acid of the corresponding pyrophosphate or bisphosphonate
leaving group. The calculated slopes of these Brønsted linear
free energy relationships were βlg = −0.89
and βeq = −0.93, respectively. The studied
compounds also followed the linear relationship Δlog k = 0.8Δlog K, which became less
steep, Δlog k = 0.6Δlog K, after the range of studied compounds was extended to include analogues
that were doubly protonated on γ-phosphate, CH3O-P(O2)-O-P(O2)-X-PO3H22–. The scissile Pα–Olg bond length
in studied methyl triphosphate analogues slightly increases with decreasing
pKa of the leaving group; concomitantly,
the CH3OPα(O2) moiety becomes
more positive. These structural effects indicate that substituents
with low pKa can facilitate both Pα–Olg bond breaking and the Pα–Onuc bond forming process, thus explaining the
large negative βlg calculated for the transition
state geometry that has significantly longer Pα–Onuc distance than the Pα–Olg distance.
The author has confirmed that details of the case have been disguised to protect patient privacy. The author thanks Michael Smith, M.D., for discussions of the case and guidance in preparing this report.
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