Correlating structure and reactivity. Electronic and strain effects in a range of systems

The work described herein investigates the effects of altering structure upon the reactivity of several chemical systems, utilising pKa values to quantify and analyse the effects of structural changes upon reactivity in order to facilitate the rationalisation and, in future, prediction of the reactivity of such species. In each case, a series of structurally related species were chosen and prepared. The acidity of these species were determined through titration with standards with known pKa values prior to the evaluation of the reactivity of each series. For a series of aniline substituted furazano[3,4-b]pyrazines, which are useful as mitochondrial uncouplers, it was found that increasing the electron withdrawing nature of substituents on the aniline ring led to an increase in acidity, allowing accurate prediction of acidity of these species. The mitochondrial uncoupling activity of these furazano[3,4-b]pyrazines was shown to increase with both the lipophilicity and acidity of the species, demonstrating that both properties are key to the future design of these systems. A series of thiazolium salts were evaluated, revealing that the acidity decreased through the addition of electron donating substituents at the 4ꞌ-position and through methylation at the 4,5- or 2ꞌ,6ꞌ-positions; such effects were shown to be additive. Examining the catalytic efficacy of the corresponding carbenes in a Stetter reaction showed that the less acidic salts formed the more effective catalysts which allows for rational prediction of catalytic efficacy. In order to examine the effects of strain upon series of acenaphthenones and similar diphenylethanones, the effects of substitution at the 5,6- and 4',4ꞌꞌ-positions, respectively, were examined, demonstrating that the acidity increased with the electron withdrawing nature of the substituent and though the introduction of strain. Examining the rate constants of α-deuteration of the acenaphthenones and diphenylethanones showed that the process was favoured by electron donating substituents. O-Silylation of the corresponding anions was favoured by more acidic ketones, suggesting that the substituents alter the electron density upon the oxygen atom, which may be key to understanding reactivity. Comparison of the acenaphthenone and diphenylethanone data indicate that strain present in the acenaphthenone core significantly reduces transmission of electronic effects across the molecule