Stereoelectronic Effects in Phosphates

Molecules containing the phosphate (O—PO32-) moiety are ubiquitous in biochemistry. Phosphoryl transfer reactions that break and form the O—P phosphoryl bond are central to biological processes as diverse as energy metabolism and signal transduction. As described by Westheimer, the utility of phosphates stem from their ability to be kinetically stable while thermodynamically unstable. This dissertation uses electronic structure theory to investigate, at an elementary chemical level, the thermodynamic and kinetic properties of phosphate esters in an attempt to answer the question, "Why nature chose phosphates?". Chapter 1 formulates the question to be answered. Chapter 2 provides the underlying theoretical background to the computational methods employed. In Chapter 3, the anomeric effect, a stereoelectronic effect is first identified as a contributor to the high-energy status of N-phosphoryl-guanidines using electronic structure methods. In Chapter 4 it is further found that the anomeric effect can contribute to the thermodynamic poise of a range of phosphates. Chapter 5 investigates the connection between phosphoryl transfer mechanisms and the anomeric effect. It is found that the anomeric effect promotes O—P bond cleavage and plays a dominant role in the dissociative mechanism of phosphoryl transfer. The impact of other stereoelectronic effects such as hyperconjugation upon the hydrogen bonding properties of phosphates is also examined in Chapter 6. Compelling evidence is obtained suggesting the role of the O—P bond weakening anomeric effect in discriminating phosphoryl transfer potentials and controlling reaction rates in a range of biologically important phosphoryl compounds. Strong correlations between phosphoryl transfer potentials, rates of reaction in solution, O—P bond weakening, and the magnitude of the n(O)→σ*(O—P) anomeric effect is shown. This dissertation articulates a fundamental property of phosphates that may provide an answer to the age old question of "Why nature chose phosphates".