Water-assisted Tautomerization Research Articles

DFT investigation on the intramolecular and intermolecular proton transfer processes in 2-aminobenzothiazole (ABT) in the gas phase and in different solvents

DFT at the B3LYP/6-311++G(d,p) level of theory was performed to geometrically, thermodynamically, and kinetically investigate the tautomerism process of 2-aminobenzothiazole (ABT) with n water molecules (n = 1–3) and without water in the gas phase and in different solvents with a gradual increase in their dielectric constants. The geometries of the envisaged tautomers were optimized in the gas phase and in solution with the polarized continuum model (PCM). Equilibrium and rate constants for the forward and reverse intra-/intermolecular isolated and water-assisted tautomerism reactions were also calculated. The results suggest that the activation energy of the transition state of direct proton transfer in the isolated reaction is very high and that the rate constant is very slow (~ 10−24 s), reflecting that the reaction is thermodynamically unfavored, whereas the barrier differences between the transition states of the tautomers decrease gradually as the number of water molecules increases from one to three. Moreover, the rate constants of the proposed reactions are ~ 1023–1025 faster than those of the isolated reaction, and the water-assisted tautomerism paths can be performed quickly, especially with the assistance of two molecules of water.

Mechanism of Kynurenine 3-Monooxygenase-Catalyzed Hydroxylation Reaction: A Quantum Cluster Approach.

The mechanism of the hydroxylation reaction between l-Kyn and model flavin adenine dinucleotide (FAD)-hydroperoxide was investigated via density functional theory (DFT) calculations in the absence and in the presence of the kynurenine 3-monooxygenase (KMO) enzyme by considering possible pathways that can lead to the product 3-hydroxykynurenine (3-HK). Crystal structure (pdb code: 5NAK )-based calculations involved a quantum cluster model in which the active site of the enzyme with the substrate l-Kyn was represented with 348 atoms. According to the deduced mechanism, KMO-catalyzed hydroxylation reaction takes place with four transformations. In the initial transition state, FAD delivers its peroxy hydroxyl to the l-Kyn ring, creating an sp3-hybridized carbon center. Then, the hydrogen on the hydroxyl moiety is immediately transferred back to the proximal oxygen that remained on FAD. These consequent transformations are in line with the somersault rearrangement previously described for similar enzymatic systems. The second step corresponds to a hydride shift from the sp3-hybridized carbon of the substrate ring to its adjacent carbon, producing the keto form of 3-HK. Then, keto-3-HK is transformed into its enol form (3-HK) with a water-assisted tautomerization. Lastly, FAD is oxidized with a water-assisted dehydration, which also involves 3-HK as a catalyst. In the proposed pathway, Asn54, Pro318, and a crystal water molecule were seen to play significant roles in the proton relays. The energies obtained via the cluster approach were calculated at the B3LYP/6-311+G(2d,2p)//B3LYP/6-31G(d,p) level with solvation (polarizable continuum model) and dispersion (DFT-D3(BJ)) corrections.

Tandem synthesis of 4-aminoxanthones is controlled by a water-assisted tautomerization: a general straightforward reaction.

Aminoxanthones constitute a group of therapeutically promising compounds that so far have been synthetically challenging. Here, we report the synthesis of both aminodihydroxanthones and fully aromatized aminoxanthones by an easy to perform, one-step multicomponent reaction of isocyanides, 3-carbonylchromones and dienophiles. The mechanism of the reaction involves a sequence of a [4 + 1] cycloaddition, iminolactone-aminofuran tautomerization, [4 + 2] cycloaddition, oxygen ring opening and aromatization. Remarkably, DFT quantum chemical computations revealed that the iminolactone-aminofuran tautomerization requires the assistance of a water molecule and, contrary to intuition, it is the rate-determining step. Conversely, both the [4 + 1] and the [4 + 2] cycloadditions have relatively low calculated energy barriers, regardless the substituents on the starting materials. Thus, we have stablished a straightforward and a wide-ranging synthesis of diversely substituted xanthones. This highly convergent process has also been applied to the synthesis of biologically important chromenophenantridines and secalonic acid related xanthone dimers.

DFT Study To Explore the Importance of Ring Size and Effect of Solvents on the Keto-Enol Tautomerization Process of α- and β-Cyclodiones.

We have explored the effect of ring size on keto–enol tautomerization of α- and β-cyclodiones using the M062X-SMDaq/6-31+G(d,p)//M062X/6-31+G(d,p) level of theory. The calculated results show that the activation free energy barrier for the keto–enol tautomerization process of α-cyclopropanedione (1) is 54.9 kcal/mol, which is lower compared to that of the other cyclic diketo systems studied here. The four-membered α- and β-cyclobutanedione (2 and 6) do not favor keto–enol tautomerization unlike other studied cyclic systems because of the ring strain developed in the transition-state geometries and their corresponding products. Water-assisted keto–enol tautomerization with one molecule reveals that the free energy activation barriers reduce almost half compared to those for the uncatalyzed systems. The two-water-assisted process is favorable as the activation free energy barriers lowered by ∼10 kcal/mol compared to those of the one-water-assisted process. The ion-pair formation seems to govern the lowering of activation barriers of α- and β-cyclodiones with two water molecules during the keto–enol tautomerization process, which however also overcomes the favorable aromatization in the three-membered ring system. The free energy activation barriers calculated with the M062X-SMDaq/6-31+G(d,p) level predicted that the keto–enol tautomerization process for the α-cyclodiones follows the following trend: 2 > 3 > 4 > 5 > 1. Water-assisted tautomerization of α-cyclodiones also predicted 1-W and 1-2W as the most favored processes; however, 5-W and 5-2W were found to be disfavored in this case. The β-cyclodione systems also showed similar trends as obtained with α-diketone systems. The influence of bulk solvent on the keto–enol tautomerization process favors the formation of the enol form in a more polar solvent medium even under mixed solvent conditions in acetonitrile and hexane at M062X-SMDacetonitrile/6-31+G(d,p) and M062X-SMDhexane/6-31+G(d,p) levels of theory.

A Ligand-Dissociation-Involved Mechanism in Amide Formation of Monofluoroacylboronates with Hydroxylamines

Acylborons, as a growing class of boron reagents, were successfully applied to amide ligation and showed potential in chemoselective bioconjugation reactions in recent years. In this manuscript, a density functional theory (DFT) study was performed to investigate the mechanism of the amide formation between monofluoroacylboronates and hydroxylamines. An updated pathway was clarified herein, including water-assisted hemiaminal formation, pyridine ligand dissociation, elimination via a six-membered-ring transition state, and water-assisted tautomerization. The proposed mechanism was further examined by applying it to investigate the activation barriers of other monofluoroacylboronates, and the related calculations well reproduced the experimentally reported relative reactivities. On the basis of these results, we found that the ortho substitution of the pyridine ligand destabilizes the acylboron substrates and the hemiaminal intermediates by steric effects and thus lowers the energy demand of the ligand dissociation and elimination steps. By contrast, the para substitution of the pyridine ligand with an electron-donating group enhances the coordination of the ligand by electronic effects, which is a disadvantage to the ligand dissociation and elimination steps. The ligand bearing a rigid linkage blocks the rotation of the pyridine ligand and makes ligand dissociation difficult.

Intriguing Tautomerism of Lumichrome in Binary Aqueous Solvent Mixtures: Implications for Probing Microenvironments.

The water-assisted tautomerism of lumichrome (LC) in binary aqueous-organic solvent mixtures exhibits intriguing spectroscopic features. An especially striking and novel observation is the occurrence of an induction period or lag time for the evolution of the isoalloxazine form of LC from the excited alloxazine form. It is inferred that the observed lag time provides an overview of the changing H-bond network of the surrounding water molecules, at various compositions of the mixed solvent systems. The unique spectral changes for the water-assisted tautomerization of LC, along with the observed lag times, can offer exciting prospects for the use of LC as a promising site-specific probe, to examine complex aqueous microenvironments and active biological systems.

Theoretical Investigation of Proton Transfer in Thiazolidine-2-thione and Oxazolidine-2-thione via Direct Transition and Self-Assisted and Water-Assisted Tautomerization

Thione–thiol transformation of thiazolidine-2-thione and oxazolidine-2-thione via direct transition, as well as self-assisted and water-assisted tautomerization was investigated using the quantum-chemical calculations. The thione complexes are more stable than the corresponding thiols. The calculations revealed that the proton transfer energy barriers are significantly lower in the presence of water molecules. Direct transition is more difficult than the water-assisted and self-assisted processes. The cooperative effects in terms of additive interaction energies and cooperativity factors of the clusters are measured and discussed. The electronic properties of the complexes are analyzed using parameters derived from atoms-in-molecules and natural bond orbital methodologies. Also, the influence of the hydrogen bond on the molecular and topological properties, as well as nuclear magnetic resonance one- and two-bond spin–spin coupling constants are investigated.

Simple and water-assisted tautomerism in succinimide

Isomerizations and tautomerisms in succinimide were studied using B3LYP and MP2 methods. Activation energies (Ea) and Gibbs free energies of activation (∆G#) were calculated for O–H rotations, keto–enol, and amine–imine tautomerisms. The calculated activation energies for the O–H rotations were generally smaller than 30 kJ/mol and for keto → enol and amine → imine tautomerisms were about 300 and 210 kJ/mol, respectively. Water molecules were used to catalyze the proton transfer reactions in the keto–enol and amine–imine tautomerisms. It was found that water molecules decrease the activation energies of the tautomerisms. Also, catalytic effect of two water molecules was more than that of one water molecule.

Formation of a Thymine‐HgII‐Thymine Metal‐Mediated DNA Base Pair: Proposal and Theoretical Calculation of the Reaction Pathway

A reaction mechanism that describes the substitution of two imino protons in a thymine:thymine (T:T) mismatched DNA base pair with a Hg(II) ion, which results in the formation of a (T)N3-Hg(II)-N3(T) metal-mediated base pair was proposed and calculated. The mechanism assumes two key steps: The formation of the first Hg(II)-N3(T) bond is triggered by deprotonation of the imino N3 atom in thymine with a hydroxo ligand on the Hg(II) ion. The formation of the second Hg(II)-N3(T) bond proceeds through water-assisted tautomerization of the remaining, metal-nonbonded thymine base or through thymine deprotonation with a hydroxo ligand of the Hg(II) ion already coordinated to the thymine base. The thermodynamic parameters ΔGR =-9.5 kcal mol(-1), ΔHR =-4.7 kcal mol(-1), and ΔSR =16.0 cal mol(-1) K(-1) calculated with the ONIOM (B3LYP:BP86) method for the reaction agreed well with the isothermal titration calorimetric (ITC) measurements by Torigoe et al. [H. Torigoe, A. Ono, T. Kozasa, Chem. Eur. J. 2010, 16, 13218-13225]. The peculiar positive reaction entropy measured previously was due to both dehydration of the metal and the change in chemical bonding. The mercury reactant in the theoretical model contained one hydroxo ligand in accord with the experimental pKa value of 3.6 known for an aqua ligand of a Hg(II) center. The chemical modification of T:T mismatched to the T-Hg(II)-T metal-mediated base pair was modeled for the middle base pair within a trinucleotide B-DNA duplex, which ensured complete dehydration of the Hg(II) ion during the reaction.

Investigation of simple and water assisted tautomerism in a derivative of 1,3,4-oxadiazole: A DFT study

Investigation of tautomerism and transition states in a derivative of 1,3,4-oxadiazole (A, B, C and D) in the gas phase and in solution and in a micro hydrated environment with 1–3 water molecules was performed by calculations at the DFT-B3LYP/6-311++G(d,p) level of theory. The solvent effect is taken into account via the self-consistent reaction field (SCRF) method. The geometries of four possible tautomers of 5-amino-1,3,4-oxadiazole-2(3H)-one were optimized in the gas phase and solution with polarized continuum model (PCM). It was found that in the gas phase and different solvents, A and C tautomers are the most stable and unstable forms, respectively.The results show that the tautomeric interconversion C to D has the lowest Gibbs free energy changes and so the highest equilibrium constant in the gas phase and solution. The equilibrium and rate constants of intermolecular tautomerism in the absence and presence of 1–3 molecules of water were also calculated. The calculated results show that the presence of water molecules considerably reduces the barrier energy of the various reactions. Therefore, this water-assisted tautomerism can be performed fast, especially, with the assistance of two molecules of water.

New Insights into the Reaction Paths of Hydroxyl Radicals with 2′-Deoxyguanosine

The reaction of HO(•) radical with 2'-deoxyguanosine is intensively studied as a model for DNA damage. Several aspects related to the reaction paths responsible for the most relevant lesions are not well understood. We have reinvestigated the reaction of HO(•) with 2'-deoxyguanosine by pulse radiolysis and extended our studies to a variety of substituted derivatives. The main path of hydrogen abstraction was confirmed to be from the exocyclic NH(2) group, followed by a water-assisted tautomerization. The rate constant (k = 2.3 × 10(4) s(-1)) obtained from the spectral changes at 620 nm is influenced by the substituent at the C8 position. When N1-H is replaced by N1-CH(3), the tautomerization does not occur. The spectral changes at 370 nm that correspond to a rate constant of 6.9 × 10(5) s(-1) were assigned to the cyclization of 2'-deoxyguanosin-5'-yl radical with formation of 5',8-cyclo-2'-deoxyguanosine as the product. When NEt(2) replaces the exocyclic NH(2), the spectral changes at all wavelengths follow second-order kinetics, suggesting a "slow" ring-opening of the 8-hydroxyl adduct of 2'-deoxyguanosine.

DFT and MP2 study of simple and water-assisted tautomerism in amidrazones

DFT and MP2 methods were used to calculate structural parameters, vibrational modes, solvent effect, and energetic properties of amidrazones. Amidrazones can be presented by three tautomeric forms and six isomers. All tautomers and transition states were optimized at the B3LYP/6-311++g** and MP2/6-311++G** levels of theory. The relative stabilities of amidrazone isomers in the gas phase were found to be as 1Z > 1E > 2E > 2Z > 3E > 3Z > TS(1–2) > TS(1–3). The calculated energy differences between E and Z isomers are very low and between different tautomers are nearly low, but the energy barriers for tautomerism interconversions at the gas phase are high. The kinetic and thermodynamic data in solvents (chloroform, tetrahydrofuran, acetone, and water) are nearly similar to those in the gas phase but their rate constants are slightly less than those in the gas phase. Moreover, equilibrium and rate constants of intermolecular tautomerism in presence of 1–3 molecules of water were calculated. Computed energy barriers show that the barrier energy of water-assisted tautomerism is very lower than that in simple tautomerism and also calculated binding energies show that water can stabilize transition states more than tautomers. Therefore, this water-assisted tautomerism can be performed fast, especially with the assistance of two molecules of water.

Kinetic and thermodynamic study of inter- and intramolecular proton transfer in N ′-acetyl formohydrazide tautomers

Nine tautomers and eleven possible tautomeric interconversions of N′-acetyl formohydrazide have been studied at B3LYP/6-311++G** level of theory. From these calculations, optimized geometries, molecular parameters, IR frequencies, NMR chemical shifts, and energetic results are obtained. In all tautomers except tautomers 4, E isomer is more stable than Z isomer. Energetic data were used to calculate the energy barriers of tautomeric interconversions and very high energy barriers were obtained for all tautomeric interconversions. Moreover, study of solvent effects on relative stabilities of tautomers and transition states showed that they are similar to those in the gas phase. In addition, intermolecular proton transfer with the assistance of one to three water molecules has been studied and the results showed that activation barriers in water-assisted tautomerism are in general lower than those in the gas phase. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011

Computational study of simple and water-assisted tautomerism of 1,3-oxazine-4,6-diones and 1,3-thiazine-4,6-diones

Density functional theory (DFT) calculations are applied to optimise the structure of three possible tautomers of some 5H-1,3-oxazine-4,6-diones and 5H-1,3-thiazine-4,6-diones and their transition states using B3LYP/6-311++G** level of theory. Then, important molecular parameters, IR frequencies and energetic parameters are calculated. In all cases, tautomer 2 is about 0.7–8.7 kcal/mol more stable than tautomer 1 and about 10.4–14.4 kcal/mol more stable than tautomer 3. Our results confirm the available experimental data approving the higher stability of tautomer 2. Furthermore, barrier energies and reaction rate constants of the hydrogen exchange between each pair of tautomers in the presence of one, two and three water molecules are calculated. The computed activation barriers in the presence of water molecules are about 23.8–76.2 kcal/mol lower than those in the gas phase.

Hydrolytic Deamination of 5,6-Dihydrocytosine in a Protic Medium: A Theoretical Study

The mechanism for the deamination reaction of 5,6-dihydrocytosine with H(2)O in a protic medium was investigated by DFT calculations at the B3LYP/6-311G(d,p) level of theory as a model reaction for the deamination reaction of 5,6-saturated cytosine derivatives. Two pathways were found. Pathway dhA, which can explain the deamination in a protic medium at acidic pH, and pathway dhBt, more representative of the reaction in a protic medium at neutral pH. Pathway dhA is a two-step mechanism initiated by the nucleophilic addition of a water molecule to carbon C4 of N3-protonated 5,6-dihydrocytosine with the assistance of a second water molecule, followed by elimination of an ammonium cation to form 5,6-dihydrouracil. The nucleophilic addition is rate-determining with an activation free energy of 116.0 kJ/mol in aqueous solution. Pathway dhBt is a four-step mechanism which starts with the water-assisted tautomerization of 5,6-dihydrocytosine to form the imino tautomer. This intermediate undergoes nucleophilic addition of water to carbon C4, which after protonation eliminates an ammonium cation, as in pathway dhA. The nucleophilic addition is again rate-determining, with an activation free energy of 113.3 kJ/mol in aqueous solution. The latter value is about 25 kJ/mol lower than its counterpart for cytosine, in agreement with the experimental observation that 5,6-saturated cytosine derivatives exhibit a much shorter lifetime in aqueous solution than their unsaturated counterparts. The evaluation of reactivity indices derived from conceptual DFT leads to the conclusion that this lower activation free energy can be attributed to a larger local electrophilic power of carbon C4 in 5,6-saturated derivatives.

Computational study of simple and water-assisted tautomerism of hydroxamic acids

All important aspects of some simple hydroxamic acids (HAs), their tautomers and transition states in the gas phase and solvent are explored using DFT-B3LYP/6-311++G** calculations. Three tautomers as presented in Fig. 1 are identified for each HAs (molecules 1– 8), namely the keto form (N-hydroxy amide, tautomer a), iminol form (α-hydroxy oxime, tautomer b) and nitroso form (α-nitroso alcohol, tautomer c). In all cases, the order of stability of tautomers is found to be as tautomer a > tautomer b > tautomer c. Furthermore, two transition states are found between tautomers. TS1 (between tautomers a and b) is more stable than TS2 (between tautomers b and c). Our results confirm the available experimental data approving higher stability of the tautomer a. Because of high energy barriers between tautomers, their interconversions are very slow at room temperature. Moreover, geometry optimization of the tautomers and transition state species of molecule 1 and location of its reaction path have been carried out at the same level of theory in the presence of 1–3 water molecules. Activation barriers in the presence of water molecules are in general lower than those in the gas phase. This difference increases with the increase of water molecules.

Theoretical investigation of tautomerism in N-hydroxy amidines

A DFT study with QST3 approach method is used to calculate kinetic, thermodynamic, spectral and structural data of tautomers and transition state structures of some N-hydroxy amidines. All tautomers and transition states are optimized at the B3LYP/6-311++g** and B3LYP/aug-cc-pvtz level, with good agreement in energetic result with energies obtained from CBS-QB3, a complete basis set composite energy method. The result shows that the tautomer a (amide oxime) is more stable than the tautomer b (imino hydroxylamine) as is reported in the literature. In addition, our finding shows that, the energy difference between two tautomers is only in about 4-10 kcal/mol but the barrier energy found in traversing each tautomer to another one is in the range of 33-71 kcal/mol. Therefore, it is impossible to convert these two tautomers to each other at room temperature. Additionally, transition state theory is applied to estimate the barrier energy and reaction rate constants of the hydrogen exchange between tautomers in presence of 1-3 molecules of water. The computed activation barrier shows us that the barrier energy of solvent assisted tautomerism is about 9-20 kcal/mol and lower than simple tautomerism and this water-assisted tautomerism is much faster than simple tautomerism, especially with the assisting two molecules of water.

Ab initio study of gas phase and water-assisted tautomerization of maleimide and formamide

Maleimide serves as an important starting material in the synthesis of drugs and enzyme inhibitors. In the present paper, knowing the importance of tautomerization in maleimide for its drug action, potential energy surface of maleimide is studied and its tautomerization has been discussed and compared with tautomerization of formamide. Gas phase tautomerization of maleimide requires large amount of energy (23·21 kcal/mol) in comparison to formamide (15·05 kcal/mol) at HF/6-31+G* level. Thus making the proton transfer reaction a difficult process in gas phase. Water molecule lowers the energy barrier of tautomerization thus facilitating the tautomerization of maleimide to 5-hydroxy-pyrrol-2-one. Water assisted tautomerization of maleimide requires 19·60 kcal/mol energy at HF/6-31+G* and 17·63 kcal/mol energy at B3LYP/6-31+G* level, a decrease of 3·61 and 5·96 kcal/mol over gas phase tautomerization. Whereas, tautomerization of formamide requires 14·16 and 12·84 kcal/mol energy, a decrease of 0·89 and 2·01 kcal/mol energy over gas phase tautomerization at HF/6-31+G* and B3LYP/6-31+G* level, respectively. Water-assisted tautomerization in maleimide and formamide showed that difference in energy barrier reduces to 2·83 kcal/mol from 10·41 kcal/mol (in gas phase) at B3LYP level, which resulted that maleimide readily undergoes tautomerization in water molecule.

The role of water in solvating the hydrogen-bonding center of 2-(2′-hydroxyphenyl)benzoxazole

2-(2′-Hydroxyphenyl)benzoxazole (HBO) has been useful as a probe to study tautomerization in DNA. In order to clarify the role of water in solvating the hydrogen-bonding center of HBO, we examine here the effect of water on the ground- and excited-state properties of HBO by steady state absorption and fluorescence spectroscopy, and by ab initio calculations. The study was carried out in solvents of varying polarity and hydrogen-bonding capability and in binary mixtures of 1,4-dioxane/water and methanol/water. HBO exists in three equilibrium structures in its ground state which are solvent-dependent, solvated and closed syn-enols and anti-enol. Only closed syn-enol is able to undergo tautomerization in the excited state to form syn-keto tautomer. Fluorescence due to solvated HBO was observed at 370 nm. The intensity change in the fluorescence peak at 370 nm as a function of water content in the binary solvents was quantitatively analyzed. Two water molecules were found to solvate the hydrogen-bonding center of the syn-enol tautomer in the ground state. The ground-state structures of the syn-enol tautomer with one to four water molecules were calculated by performing ab initio calculations at the MP2/6–31G(d) level and it was found that only two water molecules interact with the hydrogen-bonding center of HBO, confirming the above results. As water content increased in the binary mixtures, the keto tautomer fluorescence shifted to the blue and increased in intensity. This change was attributed to the formation of an anion species in the excited state which is stabilized in high polar binary mixtures. This result was confirmed by measuring the fluorescence in aqueous solution of pH 13. At high water contents, the behavior of the binary mixtures approaches that of pure water in which HBO undergoes water-assisted tautomerization to give the syn-keto tautomer.

Theoretical Studies on the Intramolecular Hydrogen Bond and Tautomerism of 8-Mercaptoquinoline in the Gaseous Phase and in Solution Using Modern DFT Methods

A theoretical quantum chemical study of the intramolecular hydrogen bonding interactions in 8-mercaptoquinoline has been carried out. Special attention has been paid to the rotation of S-H bond and intramolecular proton-transfer reactions. Therewith, the B3LYP/6-311++G(d,p), B3LYP/6-31+G(2d,2p), MPW1K/6-311++G(d,p), MPW1K/6-31+G(2d,2p), BH&HLYP/6-311++G(d,p), and G96LYP/6-311++G(d,p) methods have been used. By means of the Onsager and PCM reaction field methods, the effects of solvent on hydrogen-bond energies, conformational equilibria, rotational barriers, and tautomerism in aqueous solution have been studied. These simulations were done at the MPW1K/6-311++G(d,p) and B3LYP/6-311++G(d,p) levels. Natural-bond orbital analysis has been performed to study the intramolecular hydrogen bond (IHB) in the gaseous phase and in aqueous medium. The stability of forms under consideration in solution does not coincide with that in the gaseous phase, underlining a great importance of the electrostatic influence of solvent. Double-proton transfer in the prototropic tautomerization of 8-mercaptoquinoline, one water molecule complex in the gaseous phase and in solution, has been systematically studied. The double-proton transfer occurs concertedly and synchronously. The water-assisted tautomerization is kinetically less, but thermodynamically more favorable, compared to that of the single-proton transfer. As in the case with single-proton transfer, for water-assisted reaction, the tautomerization energies and barrier heights decrease with the increase in dielectric constant, which implies faster and more complete tautomerization of 8-mercaptoquinoline in a polar solvent.