Theoretical investigation of solvent effects on tautomeric equilibrium of 2‐diazo‐4,6‐dinitrophenol

The density functional theory has been used to study the tautomeric equilibrium of 2‐diazo‐4,6‐dinitrophenol(DDNP) in the gas phase and in 14 solvents at the B3LYP/6‐31G* level. The solvent effects on the tautomeric equilibria were investigated by the self‐consistent reaction field theory (SCRF) based on conductor polarized continuum model (CPCM) in apolar and polar solvents and by the hybrid continuum‐discrete model in protic solvent, respectively. Solvent effects on the computed molecular properties, such as molecular geometries, dipole moments, E_LUMO, E_HOMO, total energies for DDNP tautomers and transition state, tautomerization energies and solvation energies have been found to be evident. The tautomeric equilibrium of DDNP is solvent‐dependent to a certain extent. The tautomer I (cyclic azoxy form) is preferred in the gas phase, while in nonpolar solvents tautomer I and II (quinold form) exist in comparable amounts, and in highly polar solvents, the tautomeric equilibrium is shifted in favor of the more polar tautomer II . © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Two tautomeric forms of 2‐amino‐5,6‐dimethylpyrimidin‐4‐one

Derivatives of 4‐hydroxypyrimidine are an important class of biomolecules. These compounds can undergo keto–enol tautomerization in solution, though a search of the Cambridge Structural Database shows a strong bias toward the 3H‐keto tautomer in the solid state. Recrystallization of 2‐amino‐5,6‐dimethyl‐4‐hydroxypyrimidine, C₆H₉N₃O, from aqueous solution yielded triclinic crystals of the 1H‐keto tautomer, denoted form (I). Though not apparent in the X‐ray data, the IR spectrum suggests that small amounts of the 4‐hydroxy tautomer are also present in the crystal. Monoclinic crystals of form (II), comprised of a 1:1 ratio of both the 1H‐keto and the 3H‐keto tautomers, were obtained from aqueous solutions containing uric acid. Forms (I) and (II) exhibit one‐dimensional and three‐dimensional hydrogen‐bonding motifs, respectively.     

Polymorphs of the antiviral drug ganciclovir

Ganciclovir (GCV; systematic name: 2‐amino‐9‐{[(1,3‐dihydroxypropan‐2‐yl)oxy]methyl}‐6,9‐dihydro‐1H‐purin‐6‐one), C₉H₁₃N₅O₄, an antiviral drug for treating cytomegalovirus infections, has two known polymorphs (Forms I and II), but only the structure of the metastable Form II has been reported [Kawamura & Hirayama (2009). X‐ray Struct. Anal. Online , 25 , 51–52]. We describe a successful preparation of GCV Form I and its crystal structure. GCV is an achiral molecule in the sense that its individual conformers, which are generally chiral objects, undergo fast interconversion in the liquid state and cannot be isolated. In the crystalline state, GCV exists as two inversion‐related conformers in Form I and as a single chiral conformer in Form II. This situation is similar to that observed for glycine, also an achiral molecule, whose α‐polymorph contains two inversion‐related conformers, while the γ‐polymorph contains a single conformer that is chiral. The hydrogen bonds are exclusively intermolecular in Form I, but both inter‐ and intramolecular in Form II, which accounts for the different molecular conformations in the two polymorphs.     

Substituent effects on the tautomer ratios between the hydra-zone imine and diazenyl enamine forms in 3-(arylhydra-zono)methyl-2-oxo-1,2-dihydroquinoxalines. Correlation of the hammett constants σp with the tautomeric equilibrium constants KT

The 3-(arylhydrazono)methyl-2-oxo-1,2-dihydroquinoxalines 1a-e and 2a-i showed tautomeric equilibria between the hydrazone imine A and diazenyl enamine B forms in dimethyl sulfoxide media. The sub-stituent effects on the tautomer ratios of A to B in compounds 1a-e and 2a-i were studied by the nmr spec-troscopy. The electron-donating or electron-withdrawing p-substituents R¹ in compounds 2a-i represented a tendency to increase the ratios of the tautomer A or the tautomer B , respectively, exhibiting the linear correlation of the Hammett constants σ_p (-0.17 to +0.78) with the tautomer ratios of A to B or the tautomeric equilibrium constants K_T. However, the presence of the ester group R² in compounds 1a-e induced the exclusive existence of the tautomer A regardless of the nature of the p-substituents R¹. In the tautomeric thermodynamic study, the elevating temperature increased the ratios of the hydrazone imine tautomer A in compounds 2a-i . The tautomeric thermodynamic parameters ΔG°, ΔH° and ΔS° were derived from the van't Hoff plots for compounds 2a , b , h , i , wherein the entropy term dominated the free-energy difference between the A and B tautomers.     

Supramolecular Stabilization of Metastable Tautomers in Solution and the Solid State

This work presents a successful application of a recently reported supramolecular strategy for stabilization of metastable tautomers in cocrystals to monocomponent, non‐heterocyclic, tautomeric solids. Quantum‐chemical computations and solution studies show that the investigated Schiff base molecule, derived from 3‐methoxysalicylaldehyde and 2‐amino‐3‐hydroxypyridine ( ap ), is far more stable as the enol tautomer. In the solid state, however, in all three obtained polymorphic forms it exists solely as the keto tautomer, in each case stabilized by an unexpected hydrogen‐bonding pattern. Computations have shown that hydrogen bonding of the investigated Schiff base with suitable molecules shifts the tautomeric equilibrium to the less stable keto form. The extremes to which supramolecular stabilization can lead are demonstrated by the two polymorphs of molecular complexes of the Schiff base with ap . The molecules of both constituents of molecular complexes are present as metastable tautomers (keto anion and protonated pyridine, respectively), which stabilize each other through a very strong hydrogen bond. All the obtained solid forms proved stable in various solid‐state and solvent‐mediated methods used to establish their relative thermodynamic stabilities and possible interconversion conditions.     

An X‐ray crystallographic and density functional theory study of (3Z)‐4‐(5‐ethylsulfonyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one and (3Z)‐4‐(5‐tert‐butyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one

The Schiff base enaminones (3Z)‐4‐(5‐ethylsulfonyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one, C₁₃H₁₇NO₄S, (I), and (3Z)‐4‐(5‐tert‐butyl‐2‐hydroxyanilino)pent‐3‐en‐2‐one, C₁₅H₂₁NO₂, (II), were studied by X‐ray crystallography and density functional theory (DFT). Although the keto tautomer of these compounds is dominant, the O=C—C=C—N bond lengths are consistent with some electron delocalization and partial enol character. Both (I) and (II) are nonplanar, with the amino–phenol group canted relative to the rest of the molecule; the twist about the N(enamine)—C(aryl) bond leads to dihedral angles of 40.5 (2) and −116.7 (1)° for (I) and (II), respectively. Compound (I) has a bifurcated intramolecular hydrogen bond between the N—H group and the flanking carbonyl and hydroxy O atoms, as well as an intermolecular hydrogen bond, leading to an infinite one‐dimensional hydrogen‐bonded chain. Compound (II) has one intramolecular hydrogen bond and one intermolecular C=O...H—O hydrogen bond, and consequently also forms a one‐dimensional hydrogen‐bonded chain. The DFT‐calculated structures [in vacuo, B3LYP/6‐311G(d,p) level] for the keto tautomers compare favourably with the X‐ray crystal structures of (I) and (II), confirming the dominance of the keto tautomer. The simulations indicate that the keto tautomers are 20.55 and 18.86 kJ mol⁻¹ lower in energy than the enol tautomers for (I) and (II), respectively.     

Reassessment of paracetamol orthorhombic Form III and determination of a novel low‐temperature monoclinic Form III‐m from powder diffraction data

Paracetamol [N‐(4‐hydroxyphenyl)acetamide, C₈H₉NO₂] has several polymorphs, just like many other drugs. The most stable polymorphs, denoted Forms I and II, can be obtained easily and their crystal structures are known. Crystals of the orthorhombic, less stable, room‐temperature Form III are difficult to grow; they need a special recipe to crystallize and suffer from severe preferred orientation. A crystal structure model of Form III has been proposed and solved from a combination of structure prediction and powder X‐ray diffraction (PXRD) [Perrin et al. (2009). Chem. Commun. 22 , 3181–3183]. The final R_wp value of 0.138 and the corresponding considerable residual trace were reasons to check its validity. A new structure determination of Form III using new high‐resolution PXRD data led to a final R_wp value of 0.042 and an improvement of the earlier proposed model. In addition, a reversible phase transition was found at 170–220 K between the orthorhombic Form III and a novel monoclinic Form III‐m. The crystal structure of Form III‐m has been determined and refined from PXRD data to a final R_wp value of 0.059.     

Hydration effect on the stability of the keto-enol tautomers of 5-hydroxy-6-methyluracil

The structure and energies of six tautomeric forms of 5-hydroxy-6-methyluracil (OMU) and their 1:n (n = 1−4) complexes with water were determined by the density functional theory (PBE/3z) method. The stability series of the tautomers and changes in it depending on the number of water molecules in the nearest environment of the tautomer were found. The effect of the water solvent was also included using the continuum (B3LYP/6-311+G(2d,p), COSMO) model. Both complex formation and medium effects significantly influenced the stability series of the tautomers. Although the decrease in the energy of the diketo form on hydration was smaller than for the enol states, diketo tautomer a remained the most stable form of OMU in solution. Inclusion of hydration in calculations suggests that the energies of three enol tautomers b–d were equalized (ΔH ≈ 5.5 kJ/mol). This should be taken into account for the conditions that facilitate the keto-enol tautomerism of OMU.     

The Structures of Indazolin‐3‐one (=1,2‐Dihydro‐3H‐indazol‐3‐one) and 7‐Nitroindazolin‐3‐one

The existence of polymorphism in parent indazolin‐3‐one (=1,2‐dihydro‐3H‐indazol‐3‐one; 1 ) is reported as well as an X‐ray and NMR CPMAS study establishing that its 7‐nitro derivative 2 exists as the 3‐hydroxy tautomer. Absolute shieldings calculated at the GIAO/B3LYP/6‐311++G(d,p) level were used to determine the tautomeric oxo/hydroxy equilibrium in solution, i.e., always the 1H‐indazol‐3‐ol tautomer predominates.     

Formation of N‐Heterocyclic Carbenes by Tautomerization of Mesomeric Betaines: Cyclic Boron Adducts and Palladium Complexes From 2‐(Imidazolium‐1‐yl)phenolates

2‐(Imidazolium‐1‐yl)phenolates are conjugated heterocyclic mesomeric betaines in tautomeric equilibrium with the corresponding N‐heterocyclic carbenes (NHCs), 3‐(2‐hydroxyphenyl)‐imidazol‐2‐ylidenes. The carbene tautomers can be trapped as thiones (X‐ray analysis). Moreover, bis(triphenylphosphine)palladium(II) dichloride in THF trapped the carbene tautomer as a palladium complex without participation of the phenolate group (X‐ray analysis). The corresponding anionic NHCs, 2‐phenolate‐substituted imidazol‐2‐ylidenes, can be trapped by triethylborane or triphenylborane to form 4,4‐diethyl‐ or 4,4‐diphenyl‐4H‐benzo[e]imidazo[2,1‐c][1,4,2]oxaza‐borininium‐4‐ides, respectively (two X‐ray analyses). These tricyclic systems are the first representatives of a new heterocyclic ring system. The results of DFT calculations concerning the HOMO/LUMO profiles and partial charges are also presented.     

Tautomerism of pyrimidyl-2-methane derivatives: medium effects,thermodynamics, kinetics and mechanism

The Investigation of tautomeric equilibria among pyrimidyl-2-methanes has been undertaken. Pyrimidyl-pyrimidyledene equilibrium has been found in the case of 5-substituted 2-pyrimidyl-cyanoacetic esters. Unsymmetrically substituted pyrimidyl-2-methanes form two types (1-NH and 3-NH) of ylidene tautomers, which differ in ring proton spin coupling constants. The effect of substituents in the pyrimidine ring and of the solvent on tautomeric equilibrium are discussed. A drastic effect is produced by acids (CF₃ COOH) which shift the equilibrium toward the ylidene tautomer of higher basicity. The thermodynamic and kinetic characteristics and the mechanism of the tautomeric equilibrium were examined.     

Rare Tautomers of 1‐Methyluracil and 1‐Methylthymine: Tuning Relative Stabilities through Coordination to PtII Complexes

We have computationally explored how the relative stabilities of 1‐methyluracil (1‐MeUH) tautomers can be tuned through coordination of these tautomers to Pt^II complexes with a particular set of ligands. This has been done using density functional theory at the BP86/TZ2P level. Thus, we have examined the water/1‐MeUH exchange reactions of [Pt^II(A)(B)(C)(OH₂)]^q + 1‐MeUH to uncover: i) which tautomers are best stabilized by the Pt^II complex, and ii) how the net charge q in the complex affects the reaction energy. The net charge q depends on the ligands A, B, and C, which can be the neutral NH₃ or anionic Cl^?. To reveal the effect of solvation, all reaction systems are studied both in the gas phase and in water. Also the stabilization of tautomers of 1‐methylthymine (1‐MeTH) by cisplatin is investigated. The calculations reveal that relative energies of the metal (here: Pt^II)‐complexed forms of the various tautomers (here: of 1‐MeUH and 1‐MeTH) do not parallel those of the free tautomers. Rather, a rare nucleobase tautomer, despite its low natural abundance, may become favored over the predominant one when complexed to a metal ion.     

Differential Behavior of Amino–Imino Constitutional Isomers in Nonlinear Optical Processes

A detailed study of the “blocked” amino–imino tautomers derived from N‐acridine‐substituted 2‐aminobenzothiazole—and their effect on the nonlinear optical response—is presented. The synthesis, characterization, and nonlinear optical properties of these frozen tautomers, namely, N‐methyl‐N‐(2‐nitroacridin‐6‐yl)‐2‐aminobenzothia‐zole and 3‐methyl‐N‐(7‐nitroacridin‐3‐yl)‐2‐iminobenzothiazole, are reported. A theoretical model based on valence–bond theory is also proposed and used to analyze the effects of the nuclear configuration corresponding to each frozen tautomer structure. In the present case, the aromatic form and the allylic‐anion‐like system of the ? N? C? N? group inherent to each isomer are crucial for understanding and analyzing the different responses of each “blocked” tautomer.     

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     

Prototropic tautomers of 5‐methylcytosine and enthalpy changes of their protonation,deprotonation, and deamination: Hybrid density functional B3LYP study

Molecular and thermodynamic properties such as geometric parameters, dipole moments, vibrational frequencies, the first ionization potentials, relative tautomerization energies, and tautomeric equilibrium constants of all prototropic tautomers of 5‐methylcytosine have been studied at the hybrid density functional level B3LYP/6‐31+G(d,p). The methylation on the C5 atom does not lead to significant geometric deformation of the pyrimidine structures of the corresponding tautomers of cytosine, which maintains the similar stability order. The tautomeric species 2‐oxo‐4‐amino [T(0)], 2‐hydroxy‐4‐amino [T(1‐2s) and T(1‐2t)], and trans‐2‐oxo‐4‐imino [T(3‐4t)] are predominated in the gas phase. The zwitterionic conformers of tautomerism [T(1‐4)] and protonation [P(4), P(1‐2s‐4), P(1‐2t‐4), and P(1‐3‐4)] are investigated for the first time due to their close relationship with deamination during genetic repair. Enthalpy changes (Δ_rH) of protonation, deprotonation, and deamination are calculated for these tautomeric species at room temperature; it is noted that the relative enthalpies [δ(ΔH)] of the tautomers are rationalized well in terms of a second‐order polynomial of the sum of the mean Δ_rH values of protonation and deprotonation processes. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2002     

Solid‐State and Solution Structural Studies of 4‐{[C(E)]‐1H‐Azol‐1‐ylimino)methyl}pyridin‐3‐ols

The new N‐salicylideneheteroarenamines 1 – 4 were prepared by reacting the biologically relevant 3‐hydroxy‐4‐pyridinecarboxaldehyde ( 5 ) with 1H‐imidazol‐1‐amine ( 6 ), 1H‐pyrazol‐1‐amine ( 7 ), 1H‐1,2,4‐triazol‐1‐amine ( 8 ), and 1H‐1,3,4‐triazol‐1‐amine ( 9 ). Solution ¹H‐, ¹³C‐, and ¹⁵N‐NMR were used to establish that the hydroxyimino form A is the predominant tautomer. A combination of ¹³C‐ and ¹⁵N‐CPMAS‐NMR with X‐ray crystallographic studies confirms that the same form is present in the solid state. The stabilities and H‐bond geometries of the different forms, tautomers and rotamers, are discussed by using B3LYP/6‐31G** calculations.     

Tautomerism of xanthine: The second-order MØller-Plesset study

Four 9H and four 7H tautomers of DNA base xanthine were studied by the ab initio LCAO-MO method at the MP2/6-311G^**//HF/6-31G^** and MP2/6-31G^**//HF/6-31G^** approximations. All calculated structures are minima at the HF/6-31G^** potential energy surface with the dioxo 7H tautomer (A1) being the global minimum. The second most stable tautomer, dioxo-9H (B1) is by 9 kcal/mol less stable. For the A1 B1 transition the calculated MP2 energy gap corresponds to the equilibrium constant of 2 × 10^–7. Therefore, only the major tautomeric form A1 is predicted to be detectable in the gas phase. The 7H and 9H groups of tautomers are discussed separately. Within both groups, the dioxo form (A1-7H, B1-9H) is the most stable one and is succeeded by the 2-dihydroxy (A2, B2) form. However, while the energy difference between A1 and A2 is 10 kcal/mol, the energy difference between B1 a B2 is only 2 kcal/mol. The effect of polar environment was estimated by the SCRF method, using a spherical cavity, at the HF/6-31G^** level. These calculations did not change the gas phase stability order of the tautomers. However, the energy difference between A1 and B1 decreased from 9 kcal/mol at the HF/6-31G^** level to 4 kcal/mol at the SCRF HF/6-31G^** level.     

Synthesis and structural analysis of 5‐cyanodihydropyrazolo[3,4‐b]pyridines

Several new 3‐aryl‐5‐cyanopyrazolo[3,4‐b]pyridines were easily prepared from 3‐amino‐5‐arylpyrazoles and α‐cyanochalcones. Structural analysis using NMR solution studies revealed the 2H‐tautomers as the preferred tautomer in solution (DMSO‐d₆). X‐ray diffraction confirmed the 2H‐tautomers as the unique tau‐tomer species in the crystalline state as well. Geometry optimization of 1H and 2H‐tautomers at semi‐empirical levels (AM1, MINDO/3) were performed, indicating that in all cases the 2H‐tautomers are more stable than the corresponding 1H‐tautomers.     

Polymorphic forms of bisoprolol fumarate

Bisoprolol fumarate is a beta blocker-type drug substance which has been well known for several decades. However, no relevant data can be found in the literature about its crystal polymorphism. The purpose of this paper was to present two anhydrous forms (Form I and Form II) and a hydrate of bisoprolol fumarate substance. Crystalline forms were studied by various solid-state analytical methods: Fourier transform infrared (FT-IR) spectroscopy, X-ray powder diffraction (XRPD), dynamic vapor sorption (DVS) and thermoanalytical methods (thermogravimetry and differential scanning calorimetry). Thermodynamic stability and solubility of the presented polymorphs were also investigated. Both FT-IR and XRPD methods were found to be suitable for the characterization of the different crystal structures. Thermoanalytical measurements showed that (1) Form I and Form II own clearly different melting points and (2) both Form II and hydrate forms can transform into Form I at higher temperature values. Results of the DVS measurements prove that both Form I and Form II became metastable under extremely humid conditions (>?80% RH) and converted into the hydrate. Thermodynamic stability studies showed that Form I and Form II polymorphs are in enantiotropic relationship with an enantiotropic point at about 40–45 °C. Solubility studies indicated that all of the prepared forms are highly soluble, and no difference was found between them. Considering the recommendations of the corresponding International Conference of Harmonization guideline, it can be stated that no specification is required for crystal polymorphism in case of this substance.

     

Measuring the Elasticity of Poly‐l‐Proline Helices with Terahertz Spectroscopy

The rigidity of poly‐l ‐proline is an important contributor to the stability of many protein secondary structures, where it has been shown to strongly influence bulk flexibility. The experimental Young's moduli of two known poly‐l ‐proline helical forms, right‐handed all‐cis (Form I) and left‐handed all‐trans (Form II), were determined in the crystalline state by using an approach that combines terahertz time‐domain spectroscopy, X‐ray diffraction, and solid‐state density functional theory. Contrary to expectations, the helices were found to be considerably less rigid than many other natural and synthetic polymers, as well as differing greatly from each other, with Young's moduli of 4.9 and 9.6 GPa for Forms I and II, respectively.