Acid/base properties of α-methyl and gem-dimethyl derivatives of cysteine and serine from the extended kinetic method

Abstract

The gas-phase proton affinities (PA) for the non-protein α-methyl cysteine (1), gem-dimethyl cysteine (penicillamine) (2), α-methyl serine (3) and 3-methylthreonine (4) have been determined using the extended kinetic method in an ESI-tandem mass spectrometer. Experimental proton affinities of 923.5 ± 9.8, 925 ± 8.5, 932.1 ± 10.1, and 924.5 ± 7.7 kJ/mol were determined for 1–4, respectively. Gas-phase enthalpies of deprotonation (ΔHacid) for 2, 3 and 4 were also determined experimentally to be 1380 ± 9 and 1379 ± 12 and 1378 ± 12 kJ/mol. Hybrid density functional theory calculations at the B3LYP/6–311++G(d,p)//B3LYP/6-31+G(d) level of theory give predictions for the proton affinities of 1–4 and ΔHacid for 2–4 that are in excellent agreement with the measured values. A computed ΔHacid for 1 of 1389 kJ/mol was also determined. Computed acidities for 2–4 were also determined and the agreement with the experimental acidity for 2 is excellent. The computed acidities for 3 and 4 are somewhat larger than the experimental acidities, but are within the experimental error limits, For 1 and 2, the preferred deprotonation site is the SH group on the side chain rather than the COOH group similar to other cysteine analogs that have previously been studied in our lab.