Proton Tautomerism Research Articles

Stationary External Electric Field-Mimicking the Solvent Effect on the Ground-State Tautomerism and Excited-State Proton Transfer in 8-(Benzo[d]thiazol-2-yl)quinolin-7-ol.

The effect of the external electric field on the ground-state tautomerism in 8-(benzo[d]thiazol-2-yl)quinolin-7-ol has been studied by using density functional theory. The compound exists as an enol tautomer (off state) and under the influence of the external electric field a long-range intramolecular proton transfer can occur, placing the tautomeric proton at the quinolyl nitrogen atom (on state). This is a result of the much higher dipole moment of the end keto tautomer and indicates that the external electric field can be used to mimic the implicit solvent effect in tautomeric systems. In the excited state, the further stabilization of the most polar on state leads to a situation when the excited-state intramolecular proton transfer becomes impossible, limiting the intramolecular rotation to the conical intersection region.

Fabricating of turquoise/white luminescent azo-Schiff bases bearing benzimidazole and imidazole rings

New azo dyes (1a-b) were prepared by the azo coupling reaction of 2-nitro-1,4-phenylenediamine with 5-chlorosalicylaldehyde and 5-chloro-2-hydroxyaniline. Corresponding Schiff base derivatives (2a-b) bearing conjugated benzimidazole and imidazole moieties were obtained via the condensation reaction of these dyes with 2-aminobenzimidazole and 4-imidazolecarboxaldehyde. Their structures were characterized by elemental analysis, FT–IR, 1H/13C NMR, LC-MS and UV–Vis spectroscopic techniques. Chromic (solvato-, acido-, thermo-) and photoluminescence behaviour of compounds 2a and 2b were evaluated depending on their donor–π–acceptor molecular system and intramolecular proton tautomerism. The absorption and emission spectra of 2a and 2b were recorded in DMSO, DMF and CHCl3. 2a emitted turquoise luminescence in DMSO and DMF, and white luminescence in CHCl3, while 2b emitted strong turquoise luminescence in only CHCl3.

Proton tautomerism and stereoisomerism in 5-[(dimethylamino)methylidene]-4-[3/4-(trifluoromethylphenyl)amino]-1,3-thiazol-2(5H)-ones: synthesis, crystal structure and spectroscopic studies.

5-[(Dimethylamino)methylidene]-4-{[3-(trifluoromethyl)phenyl]amino}-1,3-thiazol-2(5H)-one and the [4-(trifluoromethyl)phenyl]amino derivative, both C13H12F3N3OS, with the trifluoromethyl group substituted at the arene ring at the meta and para positions, were synthesized to study the structural changes associated with proton tautomerism of the amidine system. The studied compounds were found to be in the amine tautomeric form in both the solid and the liquid (dimethyl sulfoxide solutions) phase. In both isomers, the [(trifluoromethyl)phenyl]amino residue assumes a synperiplanar conformation with respect to the thiazolone system, while the 5-[(dimethylamino)methylidene] residue adopts the Z configuration. Density functional theory (DFT) calculations correctly predicted that the synperiplanar arrangement is favoured in both isomers. In the crystal, the whole independent molecule of the para compound is disordered over two alternative positions, with occupancy factors of 0.926 (3) and 0.074 (3).

Proton tautomerism and stereoisomerism in isomeric 4-(metoxyphenyl)amino-1,3-thiazol-2(5H)-one derivatives: Synthesis, crystal structure and spectroscopic studies

In this article, we have reported the most recent results of our systematic studies of phenyl-ring substituent effect on proton tautomerism and stereoisomerism in 4-phenylamino-1,3-thiazol-2(5H)-one derivatives. The work concerns the synthesis, analysis of 1H and 13C NMR and FT-IR spectra, and X-ray crystal studies of three isomeric compounds, i.e. 5-dimethylaminomethylidene-4-(o-,m-,p-methoxyphenyl)amino-1,3-thiazol-2(5H)-ones. All three isomers were found to solely exist in the amino tautomeric form, both in the DMSO solution and the solid phase. In the molecules of all the title compounds, the o-,m-,p-methoxyphenylamine residue has synperiplanar disposition with respect to the thiazolone system, while the 5-dimethylaminomethylidene residue adopts the Z-configuration. DFT calculations correctly predict that the synperiplanar arrangement is favored in all investigated materials

Free Energy Landscapes of the Tautomeric Interconversion of Pyridoxal 5'-Phosphate Aldimines at the Active Site of Ornithine Decarboxylase in Aqueous Media.

The pyridoxal 5'-phosphate (PLP) acts as a coenzyme for a large number of biochemical reactions. It exists in mainly two bound forms at the active site of the concerned enzyme: the internal aldimine, in which the PLP is bound with the ϵ-amino group of lysine at the active site, and the external aldimine, where the PLP is bound to the substrate amino acid. Both the internal and external aldimines have Schiff base linkage (N-H-O) and can exist in two tautomeric structures of ketoenamine and enolimine forms. In this work, we have investigated the free energy landscape for the tautomeric proton transfer in the internal and external aldimines at the active site of the ornithine decarboxylase enzyme in an aqueous medium. We performed hybrid quantum-classical metadynamics and force field-based molecular dynamics simulations, which revealed that the ketoenamine tautomer is more stable than the enolimine form. The QM/MM metadynamics calculations show that the free energy difference between the ketoenamine and enolimine forms for the internal aldimine is 3.9 kcal/mol, and it is found to be 5.8 kcal/mol for the external aldimine, with the ketoenamine form being more stable in both cases. The results are further supported by calculations of the binding free energies from classical simulations and static quantum chemical calculations in different environments. We have also analyzed the configurational structure of the microenvironment at the active site in order to have better insights into the interactions of the active site residues with the PLP in its two tautomeric forms.

Perturbational Effects of Lithium Cation on Phenytoin Tautomers

Phenytoin is a long-standing, anti-seizure drug used in the treatment of epilepsy, however it has been classified as possibly carcinogenic to humans. It may exhibit 1,3- and 1,5-type proton tautomerism. In the present study, within the constraints of density functional theory at the level of B3LYP/6-31++G(d,p), tautomerism of phenytoin has been investigated. The obtained data collected for vacuum as well as aqueous conditions indicated that the equilibrium concentration of the enol type tautomer should be low. On the other hand, lithium is often referred as an antimaniac drug and used clinically to prevent mood swings in patients with bipolar effective disorder. The present study also considers the mutual interaction of lithium cation and phenytoin at the molecular level. Both the unperturbed and perturbed (by lithium cation) phenytoin tautomers have exothermic heat of formation values and favorable Gibbs free energy of formation values. They are electronically stable. Various quantum chemical data for the unperturbed and perturbed tautomers of phenytoin have been collected and discussed.

DFT Treatment of Betazole Tautomerism

Betazole belongs to pyrazole type medicines and selectively targets and binds to the H2-type receptors. Tautomerism can only be demonstrated in pyrazole derivatives and not in the pyrazole itself. In the present density functional treatment of tautomers of betazole (within the constraints of density functional theory) calculations have been performed at the level of B3LYP/6-311++G(d,p). Betazole may exhibit 1,3- and 1,5-type proton tautomerism involving pyrazole ring system so that in some tautomers aromaticity of the ring is destroyed. The results have revealed that all the tautomers possess thermo chemically favorable formation values at the standard conditions and are electronically stable. Some quantum chemical and spectral properties of those tautomeric systems as well as nucleus independent chemical shift (NICS) values for the aromatic ones have been obtained and discussed.

Moroxydine Tautomers - A DFT Treatment

Moroxydine is an orally active non-nucleoside type antiviral agent of biguanide structure. Biguanides constitute an important class of therapeutic agents suitable for the treatment of a wide spectrum of diseases. In the present density functional study (B3LYP/6-311++(d,p)) tautomers of moroxydine have been investigated within the constraints of the theory and the basis set employed. Moroxydine may exhibit 1,3- and 1,5-type proton tautomerism. Presently, all those possible tautomeric forms are considered. All the tautomers are electronically stable and have thermo chemically favorable formation values at the standard conditions. Some quantum chemical and spectral properties of those tautomeric systems have been obtained and discussed. The effect of tautomeric variations on the chemical function descriptors have been determined. Also, the variation of polar surface areas of the tautomers have been considered in relation to their ability to penetrate the blood-brain barrier.

TFE assisted mechanochemical synthesis of new pyrazolones from Meldrum acid carbothioamides-Experimental and theoretical studies

Facile synthesis of Meldrum acid carbothioamides 3 from condensation of Meldrum acid and aryl isothiocyanates under ultrasonication is reported. The structure of carbothioamides was investigated in solid and solution state from X-ray diffraction and spectroscopic studies, respectively. Studies on photo-tautomerism emanating from proton switching between O and S under UV irradiation have been reported. S-methyl derivatives 4 of carbothioamides 3 were also prepared and solid state structure of the representative compound was described. Novel synthetic mechanochemical route to synthesis of functionalized pyrazolones 5 from reaction of carbothioamides 3 or their S-methyl derivatives and hydrazine hydrate in presence of 2,2,2-trifluoroethanol has been developed. The structure and proton tautomerism of pyrazolones has been assigned on spectroscopic grounds and authenticated by single crystal X-ray diffraction (SCXRD) studies. The tautomeric equilibrium between different forms of pyrazolone 5a has been studied by ab initio calculations. Experimental studies are in congruous with theoretical results. Further, synthesis of new thiazole derivatives 6 and thiazolidin-5-one derivatives 7 linked with Meldrum's acid (MA) moiety was achieved from reaction of 3 with 3-chloro-2,4-pentanedione and chloroacetyl chloride, respectively. Spectroscopic studies confirmed the structure of new developed products.

Diazoxide and its Tautomers - A DFT Treatment

Diazoxide have several potential effectors that may potentially contribute to cardio protection. It is used to manage symptoms of hypoglycemia that is caused by pancreas cancer, surgery, or other conditions. It also acts as a non-diuretic antihypertensive agent. Diazoxide possessing various tautomeric forms should display variable biological properties depending on its tautomer content. It may exhibit 1,3- and 1,5-type proton tautomerism. Presently, all those possible tautomeric forms are considered. All the calculations have been performed within the realm of density functional theory with the constraints of B3LYP/6-311++G(d,p) level. All the tautomers are electronically stable and thermo chemically favorable formation values at the standard conditions. Some quantum chemical and spectral properties of those tautomeric systems as well as nucleus-independent chemical shift (NICS) values have been obtained and discussed.

Observation of proton-transfer-coupled spin transition by single-crystal neutron-diffraction measurement.

The application of single-crystal neutron diffraction (SCND) to observe proton-transfer phenomena in crystalline compounds exhibiting unusual protonation states or proton dynamics has garnered significant research interest in recent years. However, proton tautomerism, which results in different protonation states before and after proton transfer, has never been observed using the SCND technique. Thus, to observe the proton tautomerism phenomenon by SCND measurements, we developed an iron(II) complex that forms a large crystal and exhibits a proton-transfer-coupled spin transition (PCST). The presence of the two types of proton tautomers was determined by conventional analysis of the proton position by X-ray crystallography, infrared spectroscopy, and density functional theory calculations. Finally, our results confirmed that proton tautomerism was successfully observed for the first time using variable-temperature SCND measurements.

Proton tautomerism and stereoisomerism of 4-amino-1,3-thiazol-2(5H)-one derivatives bearing substituents with opposite electronic effects: Synthesis, structure and spectroscopic studies

New compounds of high pharmacological interest: 5-dimethylaminomethylidene-4-phenylamino-1,3-thiazol-2(5H)-one and 5-methoxycarbonylmethylidene-4-phenylamino-1,3-thiazol-2(5H)-one, were synthesized and investigated. Their crystal structure, chemical environment, and intermolecular interactions were studied by X-ray diffraction method and by NMR and FT-IR spectroscopy. The molecular interactions in the crystals were analyzed using Density Functional Theory (DFT), Quantum Theory of Atoms in Molecules (QTAIM), Hirshfeld surfaces, and fingerprint plots, with special emphasis on stereoisomerism and proton tautomerism. Both investigated compounds occur in the solution (DMSO) and in the solid state in the amine tautomeric form. The ylidene substituent with electron-donating effect only could significantly decrease the resonance effect of the carbonylimino group with the phenylamino moiety. In the molecules of both compounds, the phenylamino group has a synperiplanar conformation, and the ylidene substituent has the Z configuration. The theoretical conformational analysis shows that the coplanar arrangement of the thiazolin-2-one and phenyl systems is preferred.

Tautomerization of diazenehydrazine via single proton tautomerization, spectral, XRD/HSA-interactions, optical and DFT/TD-DFT of new hydrazine ligand

A novel methyl (Z)-2-(2-(2-oxonaphthalen-1(2H)-ylidene)hydrazineyl)benzoate isomer ligand has been prepared instead of (E)-methyl 2-((2-hydroxynaphthalen-1-yl)diazenyl)benzoate isomer in very good yield. The tautomerization of diazene to hydrazine was computed via DFT; the single proton tautomerization S(6) process was confirmed by XRD. Moreover, the XRD-crystal measurements supported the hydrazine form as the preferred kinetic isomer; the structure of the desired ligand was also examined by IR, UV–vis., Carbon, Hydrogen and Nitrogen elemental analysis (CHN-EA), and NMR. Hirshfeld surface analysis (HSA) computation was performed to support the lattice interactions resulting by X-ray diffraction (XRD) measurement. Furthermore, the time-dependent density functional theory (TD-DFT) and B3LYP/IR computation were used to support the UV–visible as well as FT-IR experimental results.

Vibrational probes of anharmonic interactions in the molecular ferroelectric 2-methylbenzimidazole

We report experimental and computational characterization of the anharmonic interactions between the constituents of the molecular ferroelectric material 2-methylbenzimi-dazole (MBI). Using experimental Raman spectroscopy measurements across a wide range of temperatures we assess the anharmonic properties of this material’s vibrations we expect to play a major role in proton tautomerism (PT) mechanism that explain ferroelectric switching in MBI. Through an application of the standard theory of anharmonic contributions to the interatomic potential energy of MBI we develop and apply a method to decipher how cubic and quartic anharmonic coupling to low frequency lattice vibrations affect the frequency of an intramolecular ring vibration of the molecular constituents of this material capable of modulating carbon-nitrogen double bonds that alternate in the PT mechanism. In addition, we use the theory of vibrational solitons to show the appearance of satellites peaks red-shifted from the N-H stretching vibration of MBI stem from self-trapped vibron states. We assess the number of these trapped states and the modes along which trapping occurs to show MBI possesses distinct phases in which excitations of the N-H stretching vibration couple to different low frequency lattice vibrational modes. We propose increased N-H stretching vibrational trapping at low temperature helps explain reductions in the temperature-dependent dielectric constant of MBI measured previously. These results highlight the important role vibrational spectroscopy can play in understanding how intermolecular interactions impact the structural dynamics of materials central to sustainable information storage and nonlinear optical technologies

The underappreciated influence of ancillary halide on metal-ligand proton tautomerism.

Syntheses of Vaska-type complexes [IrP2X(CO)] (P = phosphine, X = halide) with all four common halides (fluoride, chloride, bromide, and iodide) was attempted using a protic and hemilabile imidazolyl di-tert-butyl phosphine ligand. In the solid-state, all four complexes were found to be ionic with the halides in the outer-sphere, and the fourth coordination site of the square plane occupied by the imidazole arm of the ligand. In solution, however, the chloride complex was found to be in equilibrium with an octahedral IrIII–H species at room temperature. For the bromide and iodide analogs, the corresponding IrIII–H species were also observed but only after heating the solutions. The neutral IrI Vaska's analogs for X = Cl, Br, and I were obtained upon addition of excess halide salt, albeit heating was required for X = Br and I. The IrIII–H species are proposed to originate from tautomerization of minor amounts of the electron rich neutral Vaska analog (halide inner-sphere and phosphines monodentate) that are in equilibrium with the ionic species. Heating is required for the larger anions of bromide and iodide to overcome a kinetic barrier associated with their movement to an inner-sphere position prior to tautormerization. For the fluoride analog, the IrIII–H was not observed, attributable to strong hydrogen bonding interactions of the imidazolyl proton with the fluoride anion.

Understanding the proton tautomerism mechanism in organic molecular ferroelectrics: insights from quantum crystallography

Understanding the proton tautomerism mechanism in organic molecular ferroelectrics: insights from quantum crystallography

Quantum-chemical study on the relative stability of sildenafil tautomers

The tautomeric equilibrium of sildenafil molecule was theoretically studied using B3LYP and M06-2X density functional theory (DFT) methods in connection with aug-cc-pVDZ correlation consistent basis set. Calculations were performed for gas phase and water solution conditions modelled by polarizable continuum model (PCM). Three tautomeric forms are possible. Two keto forms: A — where the tautomeric proton in more distant from carbonyl group and B — where it is closer, and one enol form denoted, C. Both DFT methods qualitatively give similar tautomer stability order: B > A > C. The B tautomer is dominant in gas phase and water environment, whereas the C tautomer is too high in energy to be present in the tautomeric mixture. Regarding the A tautomer, it is not present in the gas phase but is present in small amounts in water solution. According to B3LYP/aug-cc-pVDZ, the relative Gibbs-free energies for A and C relative to B are 10.05 kcal/mol and 11.91 kcal/mol for gas phase and 5.49 kcal/mol and 12.49 kcal/mol for water solution. According to M06-2X/aug-cc-pVDZ, the relative Gibbs-free energies for A and C are 9.12 kcal/mol and 10.60 kcal/mol for gas phase and 4.27 kcal/mol and 10.23 kcal/mol for water solution. Therefore, for in vivo conditions, we expect that the B tautomer is dominant, and there may exist small amounts of the A tautomer. The C enol tautomer is not present at all. This picture is very different from the parent tautomeric system: 4-hydroxypyrimidine/4-pyrimidinone where the C enol tautomer is less stable than keto B only by about 1 kcal/mol in the gas phase and the A keto tautomer is the least stable and not present in the tautomeric mixture. In order to understand these differences, we performed additional calculations for a series of parent molecules starting from 4-hydroxypyrimidine/4-pyrimidinone, going through two in-between model molecules and ending at Sildenafil molecule. We found that the most important reasons of C form destabilization are dearomatization of the 6-membered ring caused by the fusion with pyrazole ring, lack of strong intramolecular hydrogen bond in C form of sildenafil and presence of destabilizing steric interaction of oxygen and nitrogen atoms of two 6-memberd rings in this tautomer.

Double Proton Tautomerism via Intra- or Intermolecular Pathways? The Case of Tetramethyl Reductic Acid Studied by Dynamic NMR: Hydrogen Bond Association, Solvent and Kinetic H/D Isotope Effects.

Using dynamic liquid-state NMR spectroscopy a degenerate double proton tautomerism was detected in tetramethyl reductic acid (TMRA) dissolved in toluene-d8 and in CD2Cl2. Similar to vitamin C, TMRA belongs to the class of reductones of biologically important compounds. The tautomerism involves an intramolecular HH transfer that interconverts the peripheric and the central positions of the two OH groups. It is slow in the NMR time scale around 200 K and fast at room temperature. Pseudo-first-order rate constants of the HH transfer and of the HD transfer after suitable deuteration were obtained by line shape analyses. Interestingly, the chemical shifts were found to be temperature dependent carrying information about an equilibrium between a hydrogen bonded dimer and a monomer forming two weak intramolecular hydrogen bonds. The structures of the monomer and the dimer are discussed. The latter may consist of several rapidly interconverting hydrogen-bonded associates. A way was found to obtain the enthalpies and entropies of dissociation, which allowed us to convert the pseudo-first-order rate constants of the reaction mixture into first-order rate constants of the tautomerization of the monomer. Surprisingly, these intrinsic rate constants were the same for toluene-d8 and CD2Cl2, but in the latter solvent more monomer is formed. This finding is attributed to the dipole moment of the TMRA monomer, compensated in the dimer, and to the larger dielectric constant of CD2Cl2. Within the margin of error, the kinetic HH/HD isotope effects were found to be of the order of 3 but independent of temperature. That finding indicates a stepwise HH transfer involving a tunnel mechanism along a double barrier pathway. The Arrhenius curves were described in terms of the Bell–Limbach tunneling model.

Acylhydrazone Subunits as a Proton Cargo Delivery System in 7-Hydroxyquinoline.

The reimagined concept of long-range tautomeric proton transfer using crane subunits is shown by designing and synthesising two new acylhydrazones containing a 7-hydroxyquinoline (7-OHQ) platform. The acylhydrazone subunits attached to the 7-OHQ at the 8th position act as crane arms for delivering proton cargo to the quinoline nitrogen. Light-induced tautomerization to their keto forms leads to Z/E isomerization of the C=C axle bond, followed by proton delivery to the quinoline nitrogen by the formation of covalent or hydrogen bonds. The axle's being either an imine or ketimine bond is the structural difference between the studied compounds. The -CH3 group in the latter provides steric strain, resulting in different proton transport pathways. Both compounds show long thermal stability in the switched state, which creates a tuneable action of bidirectional proton cargo transport by using different wavelengths of irradiation. Upon the addition of acid, the quinoline nitrogen is protonated; this results in E/Z configuration switching of the acylhydrazone subunits. This was proven by single-crystal X-ray structure analysis and NMR spectroscopy.

The role of structural symmetry on proton tautomerization: A DFTB/Meta-Dynamics computational study

Porphyrins, phthalocayanines and their derivatives have found interesting applications in various fields such as molecular electronics, optoelectronics, and sensorics. Common to this class of molecules with a metal-free core is the existence of hydrogen tautomerization reactions. Since the reaction only involves the motion of a pair of hydrogen atoms, it provides a rather simple, yet non-trivial test bed for advanced simulation tools. In this investigation, we exploit state-of-the-art quantum Metadynamics simulations complemented with Nudged Elastic Band (NEB) calculations, to study the effect of structural symmetry on the proton transfer tautomerism of functionalized porphyrins and porphyrazines. Calculated activation barriers using Metadynamics and NEB show a rather good quantitative agreement. We also demonstrate that the set of chosen collective variables in the Metadynamics simulations plays an important role for the appropriate description of the reaction path and dynamics of the system.