Proton transfer at Carbon

Abstract

This thesis describes the determination of the pKa values of a number of carbon acids in 020 at 25 oc and fixed ionic strength (KCl). Second-order rate constants for the deprotonation of these carbon acids by deuteroxide ion k00 (M-1s- 1), in 0 20 at 25 oc were determined by 1H NMR spectroscopy. These k00 values could be used to calculate values for kHo (M-1s- 1), the second-order rate constant for deprotonation of the carbon acid by hydroxide ion to give the corresponding conjugate base in water. This thesis deals with three different groups of carbon acids: the conjugate acids of N-heterocyclic carbenes, diketopiperazines, and thalidomide and thalidomide analogues. Oiaminocarbenes are of significant interest as ligands in organometallic catalysis and in medicinal chemistry. The syntheses and determination of the pKa values of a series of the azolium ions including 1,3-disubstituted imidazolium ions, 4,5~dihydroimidazolium ions, and 3,4,5-trihydropyrimidinium ions are described. Values for kHo (M-ls- 1), the second order-rate constant for deprotonation at C2 of each azolium ion, were determined as described above. Evidence is presented that the reverse rate constant for carbine protonation by solvent water is limited by solvent reorganization and occurs with a rateconstant of kHoH = kreorg =1011 s- 1. Values for kHo and kHoH permitted the calculation ofreliable carbon acid pKas for ionization of the azolium ions in water. The effects of the N-substituents and ring size of the heterocycle on kHo and pKa values are discussed. The relative hydrolytic stabilities of the azolium ions is also discussed. Oiketopiperazines (DKPs) are an important class of biological compound. The synthesis and determination of the pKa values of bis-0-proline and bis-L-proline diketopiperazine are described. Values for kHo (M- 1s- 1), the second order-rate constant for deprotonation at the a-carbon of the OKP were determined as described above. Evidence is presented that the reverse rate of protonation of the OKP enolates by solvent water is likely to be less than diffusion controlled. Hence, the pKa values were determined by extrapolation from a Bremsted plot of log kHo values against pKa values of other neutral simple carbon acids. The OKP kHo and pKa values are compared with analogous values for acyclic peptide analogues. Thalidomide and analogues such as the chemokine inhibitors, N-(2-0xo-piperidine-3yl)propionamide and N-(2-0xo-azapan-3-yl)propionamide, have been of considerable interest to the pharmaceutical industry for some time. Determination of the rates of hydrolysis and the pKa values for thalidomide and the analogues in 0 20 at 25oC and fixed ionic strength (KCl) are described. The pKa values were determined from a Bronsted plot of log kHo values against pKa of other neutral simple carbon acids in a similar manner to that performed for the diketopiperazines. The rates of hydrolysis and the relative stereo integrity of the species are discussed.