Solvent-assisted Proton Transfer Research Articles

Catalyst-Free Thia-Michael Addition to α-Trifluoromethylacrylates for 3D Network Synthesis.

Thia-Michael additions (1,4-additions of a thiol to a Michael acceptor) are generally catalyzed by an external Brønsted or Lewis base. A spontaneous (uncatalyzed) Michael addition of thiols to α-trifluoromethyl acrylates is described, as well as its application to the very efficient preparation of a thermoset. A thorough mechanistic investigation, based on an experimental kinetic study and on DFT calculations, is presented for the addition of arene- and alkanethiols to tert-butyl trifluoromethyl acrylate in polar aprotic solvents, unveiling a probable solvent-assisted proton transfer in the rate-determining step and a considerable lowering of the energy barrier induced by the CF3 group.

Solvent-assisted intramolecular proton transfer in thiopurinol: application of M06-2X functional

All available conformers of tisopurine as an important pharmaceutical molecule are optimized and frequency calculations calculated at M06-2X/6-311++G(2d,2p) level of theory. These conformers are classified in 22 different tautomers, tautomer Z showing the most stable tautomer in the gas phase. Effects of four different solvents on the most stable conformer of each tautomer is calculated. Solvents cause stabilization of all conformers and relative solvent stabilization is as follows: water > DMSO > acetone > toluene. Energy profile for such stabilization is illustrated and mechanism of proton transfer studied at the same level of theory. Solvent-assisted proton transfer performed when water and methanol used as solvents. Results indicate that explicit solvent effect has much more stabilization on tautomerization processes compared to implicit solvent effect.

A DFT-based mechanistic study on the formation of oximes

Oxime chemistry has been proven to be a reliable bioconjugation method for biomedical applications. Because of its stable and bio-orthogonal nature, a number of materials have been devised for in vitro and in vivo applications such as drug delivery, imaging, and biochemical assays. Polymers, synthetic molecules, nanoparticles, and biomolecules carrying alkoxyamine and aldehyde/ketone functional groups could be linked to each other through oxime bond, and a variety of modular platforms could be produced. Formation of oximes is catalyzed in acidic medium, and the proposed reaction mechanism follows classical imine formation pathways. Aniline has been found to accelerate the rate of oxime formation several orders of magnitude. In this computational study, we analyzed the proposed mechanism on model systems using DFT calculations including a solvation model. The energetics of the reaction steps in neutral and acidic conditions as well as in the presence of aniline was performed. Explicit water molecules were included in the calculations to study the energetics of solvent assisted proton transfer steps.

Hybrid MC/QC simulations of water-assisted proton transfer in nucleosides. Guanosine and its analog acyclovir

To provide an in-depth insight into the molecular basis of spontaneous tautomerism in DNA and RNA base pairs, a hybrid Monte Carlo (MC)–quantum chemical (QC) methodology is implemented to map two-dimensional potential energy surfaces along the reaction coordinates of solvent-assisted proton transfer processes in guanosine and its analog acyclovir in aqueous solution. The solvent effects were simulated by explicit inclusion of water molecules that model the relevant part of the first hydration shell around the solute. The position of these water molecules was estimated by carrying out a classical Metropolis Monte Carlo simulation of dilute water solutions of the guanosine (Gs) and acyclovir (ACV) and subsequently analyzing solute–solvent intermolecular interactions in the statistically-independent MC-generated configurations. The solvent-assisted proton transfer processes were further investigated using two different ab initio MP2 quantum chemical approaches. In the first one, potential energy surfaces of the ‘bare’ finite solute–solvent clusters containing Gs/ACV and four water molecules (MP2/6-31+G(d,p) level) were explored, while within the second approach, these clusters were embedded in ‘bulk’ solvent treated as polarizable continuum (C-PCM/MP2/6-31+G(d,p) level of theory). It was found that in the gas phase and in water solution, the most stable tautomer for guanosine and acyclovir is the 1H-2-amino-6-oxo form followed by the 2-amino-6-(sZ)-hydroxy form. The energy barriers of the water-assisted proton transfer reaction in guanosine and in acyclovir are found to be very similar – 11.74 kcal mol−1 for guanosine and 11.16 kcal mol−1 for acyclovir, and the respective rate constants (k = 1.5 × 101 s−1, guanosine and k = 4.09 × 101 s−1, acyclovir), are sufficiently large to generate the 2-amino-6-(sZ)-hydroxy tautomer. The analysis of the reaction profiles in both compounds shows that the proton transfer processes occur through the asynchronous concerted mechanism.

A DFT study of inter- and intramolecular proton transfer in 2-selenobarbituric acid tautomers

DFT studies were employed to study proton transfer in selenobarbituric acid tautomers in different environments including gas-phase, polarized continuum model (PCM) of solvent and solvent-assisted models. The calculations were performed using WB97XD, CAM-B3LYP and B3LYP methods with the AUG-CC-PVTZ and 6-311++G** basis sets. Among various tautomeric conversions (between ten tautomers), three systems have been selected to study their thermodynamic and kinetic behaviors via proton transfer. The gas-phase calculations showed that only 2-selenoxodihydropyrimidine-4,6(1H,5H)-dione is the major tautomer and the rates of converting this tautomer to the other tautomers are small (<2.73 × 10−14). Using PCM solvation model, the amount of other tautomers versus the major tautomer is increased but the rate constants for proton transfer are slightly decreased. In the solvent-assisted proton transfer, the concentration of the second tautomer (6-hydroxy-2-selenoxo-2,3 dihydropyrimidin-4(1H)-one) was increased to 5 % (in methanol) in comparison with the major tautomer. More importantly, the rate constants for the most of intermolecular proton transfer in solvent-assisted models were intensively increased. Calculated values showed that these processes could be done in solvent-assisted models and other minor tautomers (with different chemical and biological behaviors) could be observed in these systems.

Crystal Structures and Functional Characterization of Wild-Type CYP101D1 and Its Active Site Mutants

Although CYP101D1 and P450cam catalyze the same reaction at similar rates and share strikingly similar active site architectures, there are significant functional differences. CYP101D1 thus provides an opportunity to probe what structural and functional features must be shared and what features can differ but maintain the high catalytic efficiency. Crystal structures of the cyanide complex of wild-type CYP101D1 and it active site mutants, D259N and T260A, have been determined. The conformational changes in CYP101D1 upon cyanide binding are very similar to those of P450cam, indicating a similar mechanism for proton delivery during oxygen activation using solvent-assisted proton transfer. The D259N-CN- complex shows a perturbed solvent structure compared to that of the wild type, which is similar to what was observed in the oxy complex of the corresonding D251N mutant in P450cam. As in P450cam, the T260A mutant is highly uncoupled while the D259N mutant gives barely detectable activity. Despite these similarities, CYP101D1 is able to use the P450cam redox partners while P450cam cannot use the CYP101D1 redox partners. Thus, the strict requirement of P450cam for its own redox partner is relaxed in CYP101D1. Differences in the local environment of the essential Asp (Asp259 in CYP101D1) provide a strucutral basis for understanding these functional differences.

ONO Dianionic Pincer-Type Ligand Precursors for the Synthesis of σ,π-Cyclooctenyl Iridium(III) Complexes: Formation Mechanism and Coordination Chemistry

The σ,π-cyclooctenyl iridium(III) pincer compounds [Ir(κ3-pydc-X)(1-κ-4,5-η-C8H13)] (X = H (1), Cl, Br) have been prepared from [Ir(μ-OMe)(cod)]2 and the corresponding 4-substituted pyridine-2,6-dicarboxylic acids (H2pydc-X) or, alternatively, from their lithium salts (X = H) and [Ir(cod)(CH3CN)2]PF6. Deuterium labeling studies in combination with theoretical calculations have shown that formation of 1 involves a metal-mediated proton transfer in the reactive intermediate [Ir(κ2-Hpydc)(cod)], through the solvent-stabilized hydrido complex [IrH(κ3-pydc)(cod)(CH3OH)], followed by olefin insertion. The formation of this hydrido intermediate results from solvent-assisted proton transfer through a hydrogen-bonding network, forming an eight-membered metallacycle. In contrast, reaction of [Ir(μ-OMe)(cod)]2 with iminodiacetic acid derivatives, RN(CH2COOH)2, gave the stable iridium(I) mononuclear [Ir{κ2-MeN(CH2COOH)(CH2COO)}(cod)] (R = Me) complex having a free carboxymethyl group and the tetranuclear complex [Ir4...

Fate of anticancer drug ellipticine in reverse micelles in aqueous and methanolic environment: A photophysical approach

The present investigation explored a detailed photophysics of an anticancer agent ellipticine, in AOT reverse micelle using steady state and time resolved spectroscopy. We observed that ellipticines are entrapped as a cationic species in AOT/hexane system. Increase in water content in reverse micelles, entraps more number of cationic species while increase in methanol content causes switch over of cationic ellipticine to a neutral species. Unlike in pure methanol, we did not observe any solvent assisted proton transfer in AOT/hexane/methanol system. This unique observation was explained by the inhomogeneity of methanol entrapped in AOT/hexane system.

Oxygen Exchange in Uranyl Hydroxide via Two “Nonclassical” Ions

A recently proposed pathway for the scrambling of axial (uranyl) and equatorial O atoms in [UO(2)(OH)(4)](2-) (1) is refined using Car-Parrinello molecular dynamics (CPMD) simulations in an explicit solvent (water) and with model counterions (NH(4)(+)). According to constrained CPMD/BLYP simulations and thermodynamic integration, 1 can be deprotonated to [UO(3)(OH)(3)](3-) with a T-shaped UO(3) group (DeltaA = 7.1 kcal/mol), which in turn can undergo a solvent-assisted proton transfer via a cis-[UO(2)(OH)(4)](2-).OH(-) complex and a total overall barrier of DeltaA(double dagger) = 12.5 kcal/mol. According to computed relative energies of trans- and cis-[UO(2)(OH)(4)](2-) in the gas phase and in a polarizable continuum, "pure" functionals such as BLYP underestimate this overall barrier somewhat, and estimates of DeltaA(double dagger) approximately 16 and 17 kcal/mol are obtained at the B3LYP and CCSD(T) levels, respectively, in excellent agreement with the experiment.

Influence of the Position of tert-Butyl Substituents on Reactivity of Quinone Dimers Yielding Dibenzofuran-1,4-diones

Reactivity of two isomeric quinone dimers, 5,5'-di-tert-butyl-2,2'-bisbenzoquinone (2) and 6,6'-di-tert-butyl-2,2'-bisbenzoquinone (3) have been compared. Both quinone dimers underwent thermal cyclization in ethanol to give dibenzofuran-1,4-diones exclusively, the reaction proceeding faster for 3 than for 2. Molecular modeling analysis indicates that the different reactivity should be explained in terms of the steric hindrance of tert-butyl group in 2, which prevents approaching of solvent molecules to C=O moiety so that the solvent-assisted proton transfer occurs more slowly.

A theoretical study on the solvent-assisted proton transfer in 5-hydroxyisoxazole

The process of the ground-state solvent-assisted (water, ammonia and methanol) proton transfer between 5-hydroxyisoxazole (HIO) and 5-ketoisoxazole (KIO) is studied using density functional theory of quantum chemistry method at B3LYP/6-31G* and B3LYP/6-31G** level. The calculated results show that the enol tautomers of all the clusters is more stable with 1.75 to 2.84 kcal mol −1 than the keto tautomers, and the barriers of intermolecular proton transfer in the clusters are low, ranging from 6.26 to 9.60 kcal mol −1 at B3LYP/6-31G** level. The calculations at B3LYP/6-31G* level underestimate the stability of enol tautomers and the barrier of proton transfer.

Solvent assisted proton transfer processes in phenol–amine complexes revealed in effective dipole moments

The dipole moment of the 4-nitrophenol–tri-n-butylamine (PNP·TBA) adduct of the 1∶1 stoichiometry was studied in tetrachloroethylene, chloroform and 1,2-dibromoethane as a function of temperature. Based on the results obtained, the thermodynamic parameters for the O–H⋯N ⇆ O−⋯H–N+ proton transfer (PT) reaction were evaluated. The solvent effect on ΔGPT○, ΔHPT○ and ΔSPT○ is discussed in terms of two contributions. The short range solvation results from a specific direct interaction between the adduct and solvent molecules. The second solvation contribution can be ascribed to a non-specific long range bulk dielectric permittivity effect (reaction field effect). By using heterogeneous models of dielectric medium as well as empirical solvent parameters an attempt was undertaken to analyse quantitatively the solvent effect on thermodynamics of proton transfer.

Catalytic and bulk solvent effects on proton transfer: Formamide as a case study

Structural, thermodynamic, and kinetic aspects of the tautomerization of formamide through direct and solvent-assisted proton transfer have been investigated. Both specific and bulk effects of the solvent play a role in determining the overall result so that only a mixed discrete-continuum model is sufficiently reliable. Structural modifications induced by the solvent are significant, but have only a slight effect on thermodynamic and kinetic quantities. The same remarks apply to the vibrational shifts induced by the solvent. © 1997 John Wiley & Sons, Inc. J Comput Chem18: 1993–2000, 1997

Solvent-assisted proton transfer in catalysis by zeolite solid acids

Intermolecular proton transfer in the gas phase is usually strongly disfavoured because the charged products are highly unstable. It is promoted in aqueous solution, however, because the high dielectric constant (e = 78.3) of water allows efficient stabilization of the corresponding cations and anions. Zeolites—microporous catalysts used in petroleum refining and the synthesis of chemical feedstocks—provide another medium for proton-transfer reactions1,2,3, because their anionic aluminosilicate frameworks are highly acidic. The low dielectric constant of zeolites (e ≈ 1.6; ref. 3) suggests, however, that such processes in the zeolite channels should involve concerted action rather than strong charge separation, and thus resemble gas-phase reactions. Here we demonstrate that solution-like proton-transfer behaviour can be induced in zeolites. We find that the co-injection of nitromethane into a catalytic flow reactor clearly enhances the conversion of methanol, isopropanol and acetone over the zeolite catalyst HZSM-5. Conservation of nitromethane during the course of reaction and its effects on the reactant–zeolite interaction complex seen by solid-state NMR indicate that nitromethane behaves in a manner similar to polar solvents: it promotes proton transfer by stabilizing ion-pair structures. These findings suggest that rationally selected solvents might provide a simple means to increase the efficiency of these industrially important catalysts.

Picosecond raman studies of solvent-assisted proton transfer to the charge transfer excited state of pentaammine (4,4′-bipyridine) ruthenium(II)

Previous nanosecond experiments on the title compound have obtained evidence for intermolecular proton transfer occurring at rates significantly faster than are estimated for this reaction from equilibrium kinetics. The possibility that this fast reaction is driven by solvent relaxation around the highly charged MLCT states is investigated using picosecond Raman spectroscopy. No evidence is found for prealigned solvent states which facilitate proton transfer. It is more likely that the high concentrations of proton transfer species previously observed on the nanosecond time scale resulted from repeated cycling between the ground and excited states throughout the duration of the nanosecond pulse.