UC San Diego

Secondary deuterium isotope effects on the acidities of carboxylic acids and phenols were measured at various temperatures using a highly accurate NMR titration method. Our measurements confirmed that deuteration decreases acidity. The contributions of enthalpy and entropy to the isotope effects were also determined to explore the origin of these secondary isotope effects on the acidities of carboxylic acids and phenols. While it has previously been shown that these isotope effects are predominantly due to changes in bond vibrational frequencies and zero-point energies upon deprotonation (which would be manifested in enthalpy) it was not known if there is also a smaller contribution from an inductive effect. An inductive contribution to the isotope effect could arise from an electrostatic interaction between the negatively charged carboxylate and the dipole moment of the C-D or C-H bond, and would be manifested in entropy. Our results settle a question that has been unanswered for over 50 years and finally confirm that IEs originate only from changes in vibrational frequencies and zero-point energies upon deprotonation, and that there is no contribution from an inductive effect. The rate constants and activation parameters for the thermal decomposition of malonic, methylmalonic, and dimethylmalonic anhydrides were reliably obtained using NMR spectroscopy. The highest rate of decomposition was found for methylmalonic anhydride and the lowest rate of decomposition was found for dimethylmalonic anhydride. The enthalpy of activation values provided additional evidence supporting the previously proposed [2+2] cycloreversion mechanism for the decomposition of the malonic anhydrides. Additionally, the enthalpy of activation values were used to determine the extent to which electronic and steric factors influence the rate of decomposition. Our results show that the dominant influence, on the rates of decomposition of malonic anhydrides, is the steric hindrance to the formation of the twisted Möbius transition state by the bulky methyl groups. We also found a smaller contribution from electronic effects due to the stabilization of the sp² carbons forming in the transition state by the electron donating methyl groups. The entropy of activation values for the decomposition of the three anhydrides are also discussed. Finally, the reactions of methylmalonic anhydride with various hindered bases were monitored by NMR spectroscopy and the relative acidity of methylmalonic anhydride was estimated. Preliminary work has been done towards developing a new isothermal titration calorimetry method to measure the enthalpies of proton transfer between isopropylamine and various large ring cycloalkylamines, which would ultimately allow us to dissect the relative basicities of these amines into enthalpic and entropic components. The enthalpic and entropic components to the relative basicities of cycloalkylamines and isopropylamine would clarify whether conformational effects or hindrance to the solvation of the cycloalkylammonium ions by additional carbons are responsible for the previously observed, unexpectedly low, basicities of large ring cycloalkylamines