| In nature, many enzymes that promote the hydrolysis of phosphate esters have active sites containing two or more metal ions (Mx+ ). The active sites in these enzymes are largely non-aqueous and have effective dielectric constants more closely related to those of organic solvents than water. This thesis focuses on the spectacular catalysis of the methanolysis of phosphate esters afforded by metal ions in methanol.; The importance of storing genetic information in DNA and RNA led to the study of methanolysis of an anionic phosphate diester, in the presence of La(OTf)3 and a zinc-bound 1,5,9-triazacyclododecane (L41 ) complex. The intramolecular transesterification of 2-hydroxypropyl-4-nitrophenyl phosphate (HPNPP, 1), an RNA model, promoted by the above catalysts was studied under buffered conditions in methanol. A solution of 1 x 10 -3 M of either metal catalyst promoted the methanolysis of HPNPP with an unprecedented 108-fold rate enhancement relative to the background methoxide-promoted reaction at pssH pHCH3OH 9.; Activated organ ophosphates, phosphonates and phosphinates are commonly used as pesticides and in some cases as chemical warfare (CW) agents. These materials are effective neurotoxins due to their ability to inhibit the enzyme acetylcholinesterase. In the hope of finding an alternative method to decompose these toxins, the methanolysis of neutral phosphate triesters and some related derivatives promoted by La(OTf)3 and Zn(L41) was investigated. In particular, O,O-diethyl O-aryl phosphates and O,O-diethyl S-aryl phosphorothiolates, both containing the P=O unit, were used as models for CW G-agents (phosphonofluoridates) and V-agents (phosphonothiolates), respectively. It was found that as little as a 2 x 10-3 M of La(OTf)3 in methanol was capable of accelerating the rate of decomposition of the pesticide O,O-diethyl O-(4-nitrophenyl) phosphate (paraoxon, 8) and its S-aryl phosphorothiolate derivative (32) by 10 9-fold and 107-fold relative to the corresponding methoxide reactions at near neutral pssH 8.3 and ambient temperature. It is a particular advantage of this methodology that the methanolysis of all these classes of organophosphorus (OP) agents led to non-toxic and neutral products, and solubility of the substrates is greatly enhanced in the alcohol medium compared to an aqueous medium. A structure/reactivity study indicated that there was a large leaving group (LG) effect on the rate of Mx+-catalyzed methanolysis of the phosphate and phosphorothiolate substrates. The kinetic data suggested that these reactions proceed most likely via a concerted displacement of the leaving group (LG) in the transition state although a stepwise reaction process with rate-limiting departure of the LG cannot be ruled out. |
