Reaction Mechanism and Tautomeric Equilibrium of 2-Mercaptopyrimidine in the Gas Phase and in Aqueous Solution:  A Combined Monte Carlo and Quantum Mechanics Study

Abstract

A combined Monte Carlo and quantum mechanical study was carried out to analyze the tautomeric equilibrium of 2-mercaptopyrimidine in the gas phase and in aqueous solution. Second- and fourth-order Møller-Plesset perturbation theory calculations indicate that in the gas phase thiol (Pym-SH) is more stable than the thione (Pym-NH) by ca. 8 kcal/mol. In aqueous solution, thermodynamic perturbation theory implemented on a Monte Carlo NpT simulation indicates that both the differential enthalpy and Gibbs free energy favor the thione form. The calculated differential enthalpy is DeltaH(SH)(-->)(NH)(solv) = -1.7 kcal/mol and the differential Gibbs free energy is DeltaG(SH)(-->)(NH)(solv) = -1.9 kcal/mol. Analysis is made of the contribution of the solute-solvent hydrogen bonds and it is noted that the SH group in the thiol and NH group in the thione tautomers act exclusively as a hydrogen bond donor in aqueous solution. The proton transfer reaction between the tautomeric forms was also investigated in the gas phase and in aqueous solution. Two distinct mechanisms were considered: a direct intramolecular transfer and a water-assisted mechanism. In the gas phase, the intramolecular transfer leads to a large energy barrier of 34.4 kcal/mol, passing through a three-center transition state. The proton transfer with the assistance of one water molecule decreases the energy barrier to 17.2 kcal/mol. In solution, these calculated activation barriers are, respectively, 32.0 and 14.8 kcal/mol. The solvent effect is found to be sizable but it is considerably more important as a participant in the water-assisted mechanism than the solvent field of the solute-solvent interaction. Finally, the calculated total Gibbs free energy is used to estimate the equilibrium constant.

Olefin Epoxidation by H2O2/MeCN Catalysed by Cyclopentadienyloxidotungsten(VI) and Molybdenum(VI) Complexes: Experiments and Computations

“…Water molecules, which are present in solution together with H 2 O 2 , can facilitate proton-transfer pathways by shuttling the proton, as they can establish H bonds with both the proton donor and the acceptor. Several theoretical studies have already reported the active participation of water clusters in tautomerisation [30] and proton-exchange processes, [5,31] acting as bifunctional catalysts. The energy profile computed with one additional water molecule is shown in Figure 7.…”

Hydrogen's isotopic exchange reaction in the C‐methyl sides in the medicinal agent xymedon: NMR spectroscopy and ab initio calculations

“…Such a shift could be due to the formation of the protonated form at N 3 and its exchange with the neutral structure in the water. Water can act as a weak acidic catalyst and transfer a proton to the acceptor site on the solute molecule. In this case, it can be hypothesized that a charged structure may further initiate the formation of tautomers with the deprotonation the 6‐Me or the 4‐Me groups.…”

“…But, as it is likely that the exchange process is intermolecular also for an effective proton‐deuterium exchange, it is also important that proton acceptors are presented in solution. In this case, water can act as a bifunctional catalyst, that is, it can accept a proton from the donor site of the solute molecule, eg, protons from the 6/4‐Me groups and transfer of the proton to the acceptor site in the solute. From this point of view, it is interesting to see how the system will behave if adding a stronger proton acceptor than water.…”

Alcohol associates as catalysts of tautomeric transformations

“…Catalysis of such reactions via the Brønsted-Lowry acids and bases gives rise to ionic transition states [4]. Water-catalyzed tautomeric transformations have been discussed in a number of reports [3,[5][6][7][8]. Enhancement of the catalytic action of water dimers as compared to that of water monomer has been revealed.…”

“…The water-catalyzed reactions occur via the synchronous mechanism as well. However, the mechanism of the catalytic action has not been elucidated in [3,[5][6][7][8].…”