Pinjari Rahul V, Kaptan Shreyas S, Gejji Shridhar P
Department of Chemistry, University of Pune, Ganeshkhind, Pune 411007, India.
Phys Chem Chem Phys. 2009 Jul 14;11(26):5253-62. doi: 10.1039/b812000e. Epub 2009 Apr 16.
The phosphodiester linkage central to biological systems has been modeled by methyl phosphodiester (MPDE) in various theoretical and experimental studies. Under physiological conditions, hydrolysis of the phosphodiester is negligible, however this process can be catalyzed in the presence of metal ions. To understand the role of alkali metals in MPDE hydrolysis and, in particular, how it influences the reaction pathway and the associated energetics, density functional calculations employing the 6-31+G(d,p) basis set have been carried out. Different pathways that include the reactant, intermediates and the products have been investigated for MPDE hydrolysis catalyzed by one or two lithium ions, characterized as stationary point geometries on the potential energy surface. The pathways A and B incorporate a single lithium ion bonded to different oxygens of the diester functionality. In pathway C, a six-membered ring was noticed wherein the nucleophile bridges two lithium ions interacting with different oxygens of the phosphoryl group. Furthermore, in the pathway (D) incorporating two lithium ions, one of the lithium ions interacts with the hydroxyl group and another with the methoxy oxygen; both metal ions are coordinated by the same phosphoryl oxygen. In addition to this, yet another pathway (E), where the metal ions are bound to different oxygens of the phosphoryl group, has also been dealt with. The calculations have shown that the A and B pathways lead to a single step reaction. A three-step mechanism including the nucleophilic (hydroxyl) attack, rotation of a methyl group and, finally, departure of the methoxy group has been predicted for the D and E profiles. Both D and E pathways are favored equally (with a marginal difference of 0.3 kJ mol(-1) in their activation energies) in the gas phase and a transition state corresponding to nucleophilic attack with an energy barrier of 32.5 kJ mol(-1) was located when lithium was used. A penta-coordinated phosphorous intermediate on the potential energy surface was characterized along these pathways. MPDE hydrolysis yielded a lower energy barrier for lithium than those for the remaining alkali metal ions. This agrees well with the experimentally observed trend for the hydrolysis rates: Li > Na > K. Self consistent reaction field (SCRF) calculations reveal the lower energy barrier between the reactant and the transition state for the nucleophilic attack in nonpolar solvents. The extent of bond formation (or cleavage) in different stationary point structures along the reaction path as estimated from the electron density at the bond critical point in the molecular electron density topography, has proven useful in distinguishing the associative or dissociative reaction pathways.
在各种理论和实验研究中，生物系统核心的磷酸二酯键已由甲基磷酸二酯（MPDE）进行模拟。在生理条件下，磷酸二酯的水解可忽略不计，然而在金属离子存在的情况下该过程可被催化。为了解碱金属在MPDE水解中的作用，特别是其如何影响反应途径和相关能量学，已采用6 - 31 + G(d,p)基组进行密度泛函计算。针对由一个或两个锂离子催化的MPDE水解，研究了包括反应物、中间体和产物的不同途径，这些途径在势能面上被表征为驻点几何结构。途径A和B包含一个与二酯官能团不同氧原子键合的单个锂离子。在途径C中，注意到一个六元环，其中亲核试剂桥连两个与磷酰基不同氧原子相互作用的锂离子。此外，在包含两个锂离子的途径（D）中，其中一个锂离子与羟基相互作用，另一个与甲氧基氧相互作用；两个金属离子均由同一个磷酰基氧配位。除此之外，还研究了另一种途径（E），其中金属离子与磷酰基的不同氧原子结合。计算表明，途径A和B导致单步反应。对于途径D和E的概况，预测了一种三步机制，包括亲核（羟基）进攻、甲基旋转以及最后甲氧基离去。在气相中，途径D和E同样有利（其活化能相差0.3 kJ mol⁻¹），当使用锂时，找到了一个对应亲核进攻的过渡态，其能垒为32.5 kJ mol⁻¹。沿着这些途径在势能面上表征了一个五配位磷中间体。MPDE水解对锂产生的能垒低于其余碱金属离子的能垒。这与实验观察到的水解速率趋势Li > Na > K非常吻合。自洽反应场（SCRF）计算揭示了在非极性溶剂中亲核进攻时反应物与过渡态之间较低的能垒。根据分子电子密度拓扑学中键临界点处的电子密度估计的沿反应路径不同驻点结构中的键形成（或断裂）程度，已被证明有助于区分缔合或解离反应途径。
