Amine-imine tautomerism in adenines

CNDO/2 calculations predict that while the amine form of adenine should be the most stable one for the N(9)H, N(7)H and N(3)H tautomers of this substance, the inline form should on the contrary be the most stable for the N(1)H tautomer. The prediction is verified by experiment.This work was supported by the RCP No. 173 of the Centre National de la Recherche Scientifique et Technique and grant No. 67-00-532 of the Délégation Générale à la Recherche Scientifique et Technique.     

The Structure of 1H-Perimidin-2(3H)-one and Its Derivatives in the solid state (x-ray crystallography and CP/MAS 13C-NMR), in solution (13C-NMR), and in the gas phase (mass spectrometry)

The X-ray crystal and molecular structures of 1-methyl- 1H-perimidin-2(3H)-one ( 5b ) and 1,3-dimethyl-1H-perimidin-2(3H)-one ( 6 ) were determined. The crystals are built of piles of dimers faced head-to-head in 5b and of alternating independent head-to-tail molecules in 6 , both along the b axis. Semiempirical calculations at the AM 1 level revealed that the eclipsed conformation of the Me groups with respect to the C?O group, found in the crystals, is the most stable. The lack of planarity of the whole molecules is a consequence of the packing forces since it is not found in the calculations. A comparative NMR study was carried out in solution (¹H and ¹³C) and in the solid state (CP/MAS ¹³C) for 1H-perimidin-2(3H)-one ( 2 ) and 1H-benzimidazol-2(3H)-one ( 3 ) with the conclusion that in both heterocycles the oxo tautomer is the most abundant. The structure in the gas phase was approached by mass spectrometry. In the case of 3 , the oxo tautomer loses CO after ionization, while the oxo form of 2 tautomerizes to the hydroxy form which loses, H₂O after a [1,3]-H shift. AM 1 calculations were carried out on the ground and ionized states of 2 .     

Solid-state structures of 2-(4-hydroxyphenyl)-substituted phenalene-1,3-dione and indan-1,3-dione

The structure of 2-(4-hydroxyphenyl)-substituted indan-1,3-dione and phenalene-1,3-dione is investigated using a combination of solid-state NMR, single crystal X-ray analyses and quantum chemical calculations. It is shown that 2-(4-hydroxyphenyl)-1,3-indandione exists as a diketo tautomer while 2-(4-hydroxyphenyl)-1,3-phenalenedione exists in the enol form.     

Preparation and Characterization of Pure Thiosulfuric Acid

Pure thiosulfuric acid has not been prepared yet, although it is described in most textbooks of inorganic chemistry. Furthermore, no experimental evidence for the structure of thiosulfuric acid is known. Theoretical calculations predict the (SH)(OH) tautomer to be more stable than the (OH)(OH) tautomer. In this work we present the synthesis and spectroscopical characterization of pure thiosulfuric acid. X₂S₂O₃ (X = H, D) was obtained from the reaction of dry Na₂S₂O₃ with anhydrous HF at –60 °C. The experimental vibrational and NMR spectra together with quantum chemical calculations provide evidence for the predicted (SH)(OH) tautomeric structure.     

Tautomers and conformers of malonamide, NH2-C(O)-CH2-C(O)-NH2: vibrational analysis, NMR spectra and ab initio calculations

The conformational and tautomeric compositions of malonamide, NH2-C(O)-CH2-C(O)-NH2 were determined by vibrational spectroscopy and theoretical calculations (HF/6-31G*, B3PW91/6-31G*). Solid state Fourier transform infrared and Raman spectra were analysed. They reveal the existence of a diketo tautomer. Theoretical calculations predict a diketo structure belonging to the C1 symmetry group. No enol form is present in the molecule in the solid. 13C-NMR studies show only signals of a diketo tautomer.     

The ring-opening of an unsymmetrical tetrahedral intermediate - 2-hydroxy-1,3-oxathiolane

Ab initio calculations were performed on 2-hydroxy-1,3-oxathiolane: and the two products of its breakdown: Complete geometry optimizations were performed at minimal (STO-3G) and split-valence (3-21G) basis set levels. In addition, a single point calculation was performed at 6-31G* level withd orbitals added on sulfur only. The conformation of the oxathiolane intermediate and its stability relative to the breakdown products was investigated. The STO-3G basis set gave an envelope form while 3-21G gave the twist form of the five-membered ring as the most stable. For all three basis sets the ester product was more stable than thioester.     

DFT studies on tautomerism of C5-substituted 1,2,4-triazoles

DFT (B3LYP/6-311++G**, B3PW91/6-311++G**) Gibbs free energy and single point CCSD(T)/6-311++G**//DFT total energy calculations were performed to investigate stability and tautomerism of C5-substituted 1,2,4-triazoles. Three different tautomers are possible for the substituted 1,2,4-triazoles: N1–H, N2–H, and N4–H. Unlike for the 1,2,3-triazoles, where the most stable is the N2–H tautomer regardless of substituent applied, for the 1,2,4-triazoles, the electron donating substituents (–OH, –F, –CN, –NH₂, and –Cl) and the C5-cation stablize the N2–H tautomer, whereas the electron withdrawing substituents (–CONH₂, –COOH, –CHO, –BH₂, and –CFO) and the C5-anion stablize the N1–H tautomer. Except for the C5-anion and C5-cation, the N4–H form is the least stable tautomer. The relative stability of the C5-substituted 1,2,4-triazole tautomers is strongly influenced by attractive and/or repulsive intramolecular interactions between substituent and electron donor or electron acceptor centres of the triazole ring.     

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.     

Thermodynamic stability of 2,4,6-tris(nitromethyl)-1,3,5-triazine: an experimental and theoretical study

The molecular geometries and electronic structures of 2,4,6-tris(nitromethyl)-1,3,5-triazine isomers were investigated by the density functional method DFT/B3LYP/6-311++G** to elucidate the structural factors responsible for the stability of these systems. It was shown that a characteristic feature of the nitromethyl tautomer (1) of 2,4,6-tris (nitromethyl)-1,3,5-triazine consists in nonvalence interactions between an oxygen atom of nitro group and a carbon atom of triazine ring, which are probably due to Coulomb attraction between them. The tautomer with the 2,4,6-tris (nitromethylene)-hexahyrdo-1,3,5-triazine structure (2) is stabilized trough direct polar conjugation between the amino and nitro groups at the double bond. Structural strain of the molecule with the 2,4,6-tris(aci-nitromethyl)-1,3,5-triazine structure (3) is the reason for its thermodynamic instability. X-ray data indicate that the compound under study exists in the triazine tautomeric form 1 and the distances between oxygen atoms of nitro group and carbon atom of the triazine ring are shortened. NMR data suggest the existence of triazine in the nitromethyl form 1 in acetonitrile and acetone and a tautomeric equilibrium between the nitromethyl and nitromethylene forms in a more polar solvent (DMSO). The results obtained suggest a Coulomb-type stabilization of the 2,4,6-tris(nitromethyl)-1,3,5-triazine molecule in the gas phase, in the crystal, and in nonpolar solvents.     

Tautomerism and Regioselectivity of the Protonation of 2-Pyrrolidone. Stereoselectivity of Complexation between Palladium(II), Chloride Ion,and 2-Pyrrolidone

According to the AM1, PM3, HF/6-31G(d,p), and MP2/6-31G(d,p)//HF/6-31G(d,p) calculations, it is the lactam tautomer of 2-pyrrolidone that is thermodynamically most stable in both the gas phase and an aqueous solution. Analysis of the PM3 data with consideration of the medium showed that the tautomeric equilibrium of 2-pyrrolidone (pyrroline-2-ol) in aqueous solution is shifted to the lactim form, which thus can be involved in complexation with palladium(II). 2-Pyrrolidone was found to be protonated at the O atom in both the gas phase and aqueous solution, in agreement with the concept of the mesomeric displacement of the electron density in the amide fragment. The aqueous medium stabilizes the lactim tautomer of 2-pyrrolidone more strongly than the lactam tautomer and the O-protonated cyclic amide than the N-protonated one. The stereoselectivity of complexation between palladium(II), chloride ion, and pyrroline-2-ol was explained. The initially formed tetragonal-pyramidal adduct with an axial organic ligand undergoes rearrangement into an intermediate with an extra axial Cl atom, which is a precursor of the cis-product. The thermodynamically less stable cis-isomer of the complex [PdCl₂(pyrrolin-2-ol)₂] is formed from the thermodynamically most favorable intermediate in associative nucleophilic substitution. At the supramolecular level, the cis-product can be stabilized by intermolecular dipole-dipole association in the crystal.__________Translated from Koordinatsionnaya Khimiya, Vol. 31, No. 7, 2005, pp. 523–529.Original Russian Text Copyright © 2005 by Pankratov, Borodulin, Chaplygina.     

Triclabendazole: An Intriguing Case of Co‐existence of Conformational and Tautomeric Polymorphism

The crystal polymorphism of the anthelmintic drug, triclabendazole ( TCB ), is described. Two anhydrates (Forms I and II), three solvates, and an amorphous form have been previously mentioned. This study reports the crystal structures of Forms I ( 1 ) and II ( 2 ). These structures illustrate the uncommon phenomenon of tautomeric polymorphism. TCB exists as two tautomers A and B. Form I (Z′=2) is composed of two molecules of tautomer A while Form II (Z′=1) contains a 1:1 mixture of A and B. The polymorphs are also characterized by using other solid‐state techniques (differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), PXRD, FT‐IR, and NMR spectroscopy). Form I is the higher melting form (m.p.: 177 °C, ΔH_f=≈105±4 J g^?1) and is the more stable form at room temperature. Form II is the lower melting polymorph (m.p.: 166 °C, ΔH_f=≈86±3 J g^?1) and shows high kinetic stability on storage in comparison to the amorphous form but it transforms readily into Form I in a solution‐mediated process. Crystal structure analysis of co‐crystals 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 further confirms the existence of tautomeric polymorphism in TCB . In 3 and 11 , tautomer A is present whereas in 4 , 5 , 6 , 7 , 8 , 9 , 10 the TCB molecule exists wholly as tautomer B. The DFT calculations suggest that the optimized tautomers A and B have nearly the same energies. Single point energy calculations reveal that tautomer A (in Form I) exists in two low‐energy conformations, whereas in Form II both tautomers A and B exist in an unfavorable high‐energy conformation, stabilized by a five‐point dimer synthon. The structural and thermodynamic features of 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 are discussed in detail. Triclabendazole is an intriguing case in which tautomeric and conformational variations co‐exist in the polymorphs.     

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.     

Molecular Structure of an Isocytosine Analog: Combined X-ray Structural and Computational Study of 2-Diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone

The structure of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone has been studied by X-ray crystallography and quantum-chemical calculations. X-ray analysis established that 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone exists exclusively as the lactam tautomer protonated at the N3 ring nitrogen in the solid state. Crystals of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone are monoclinic (space group P2₁/n); the unit-cell dimensions are: a = 11.0460(8) Å, b = 5.0064(4) Å, c = 22.8358(17) Å, = = 90°, = 90.521(1)°. In the crystal, molecules of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone are assembled in planar centrosymmetric dimers by strong resonance-assisted N—H···O intermolecular hydrogen bonds from the NH group of one molecule to the C=O of the adjacent molecule (N—H···O distance 2.804 Å). Bond distances and angles are generally similar to those reported for the corresponding tautomer of isocytosine and derivatives. Quantum-chemical calculations on 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone are also reported in order to estimate the relative energies of the possible tautomeric forms; ab initio and DFT results predict the coexistence of the N3 and AH tautomers in the gas phase. There is excellent correspondence between the crystal and the HF/6-311G** or B3LYP/6-31G* calculated structures of the N3 lactam form; the largest deviations between the experimental and computed structures are mostly the effects of strong intermolecular H bonds in the crystal.     

Acidity of adenine and adenine derivatives and biological implications. A computational and experimental gas-phase study

The gas-phase acidities of adenine, 9-ethyladenine, and 3-methyladenine have been investigated for the first time, using computational and experimental methods to provide an understanding of the intrinsic reactivity of adenine. Adenine is found to have two acidic sites, with the N9 site being 19 kcal mol(-1) more acidic than the N10 site; the bracketed acidities are 333 +/- 2 and 352 +/- 4 kcal mol(-1), respectively. Because measurement of the less acidic site can be problematic, we benchmarked the adenine N10 measurement by bracketing the acidity of 9-ethyladenine, which has the N9 site blocked and allows for exclusive measurement of the N10 site. The acidity of 9-ethyladenine brackets to 352 +/- 4 kcal mol(-1), comparable to that of the N10 site of the parent adenine. Calculations and experiments with 3-methyladenine, a harmful mutagenic nucleobase, uncovered the surprising result that the most commonly written tautomer of 3-methyladenine is not the most stable in the gas phase. We have found that the most stable tautomer is the "N10 tautomer" 10, as opposed to the imine tautomer 3. The bracketed acidity of 10 is 347 +/- 4 kcal mol(-1). Since 10 is not a viable species in DNA, 3 is a likely tautomer; calculations indicate that this form has an extremely high acidity (320-323 kcal mol(-1)). The biological implications of these results, particularly with respect to enzymes that cleave alkylated bases from DNA, are discussed.     

Singlet Nitric Oxide Dimer Revisited: An Unexpected High Stability Isomer

A new form of the asymmetric cis isomer of the nitric oxide dimer, a cyclic parallelogram, has been found and characterized as the second most stable conformation by ab initio computational methods. Optimum equilibrium geometries, energetics, and harmonic frequencies are computed for the cyclic structure and the more common symmetric cis and trans isomers at the levels of second-order perturbation theory (MP2) and coupled-cluster theory limited to double excitations (CCD) using the 6-311G(2d) and 6-311+G(2d) basis sets. Single-point, more highly correlated calculations are then performed at these CCD optimum geometries. In addition, second-order geometries and frequencies are computed using the larger 6-311G(3df) basis, and single-point MP2 calculations are performed at these geometries using the Aug-cc-pVTZ and Aug-cc-pVQZ basis sets. At the highest levels of theory considered, the cyclic isomer lies within 17 kJ/mol of the symmetric cis global minimum and is more stable than the often-studied symmetric trans conformation.     

Berberine alkaloid: Quantum chemical study of different forms by the DFT and MP2 methods

The stable structures and electronic properties for the berberine cation as well as possible ammonium, carbinol and amino-aldehyde forms of protoberberine salts in the presence of hydroxyl ions were investigated by the B3LYP/6-31G(d,p) and MP2/6-31++G(d,p) methods. The geometry optimizations by both methods lead to the nonplanar propeller-twisted and buckled structure for the all forms. The obtained bond lengths and bond angles agree with the experimental values. The comparison of total energies elucidates that the amino-aldehyde form is the most preferable tautomer in gas phase, while the carbinol form is less stable. The least stable tautomer is the ammonium form.     

Hydrogen bonding in 4‐nitrobenzene‐1,2‐diamine and two hydrohalide salts

The structures of 4‐nitrobenzene‐1,2‐diamine [C₆H₇N₃O₂, (I)], 2‐amino‐5‐nitroanilinium chloride [C₆H₈N₃O₂⁺·Cl⁻, (II)] and 2‐amino‐5‐nitroanilinium bromide monohydrate [C₆H₈N₃O₂⁺·Br⁻·H₂O, (III)] are reported and their hydrogen‐bonded structures described. The amine group para to the nitro group in (I) adopts an approximately planar geometry, whereas the meta amine group is decidedly pyramidal. In the hydrogen halide salts (II) and (III), the amine group meta to the nitro group is protonated. Compound (I) displays a pleated‐sheet hydrogen‐bonded two‐dimensional structure with R₂²(14) and R₄⁴(20) rings. The sheets are joined by additional hydrogen bonds, resulting in a three‐dimensional extended structure. Hydrohalide salt (II) has two formula units in the asymmetric unit that are related by a pseudo‐inversion center. The dominant hydrogen‐bonding interactions involve the chloride ion and result in R₄²(8) rings linked to form a ladder‐chain structure. The chains are joined by N—H...Cl and N—H...O hydrogen bonds to form sheets parallel to (010). In hydrated hydrohalide salt (III), bromide ions are hydrogen bonded to amine and ammonium groups to form R₄²(8) rings. The water behaves as a double donor/single acceptor and, along with the bromide anions, forms hydrogen bonds involving the nitro, amine, and ammonium groups. The result is sheets parallel to (001) composed of alternating R₅⁵(15) and R₆⁴(24) rings. Ammonium N—H...Br interactions join the sheets to form a three‐dimensional extended structure. Energy‐minimized structures obtained using DFT and MP2 calculations are consistent with the solid‐state structures. Consistent with (II) and (III), calculations show that protonation of the amine group meta to the nitro group results in a structure that is about 1.5 kJ mol⁻¹ more stable than that obtained by protonation of the para‐amine group. DFT calculations on single molecules and hydrogen‐bonded pairs of molecules based on structural results obtained for (I) and for 3‐nitrobenzene‐1,2‐diamine, (IV) [Betz & Gerber (2011). Acta Cryst. E 67 , o1359] were used to estimate the strength of the N—H...O(nitro) interactions for three observed motifs. The hydrogen‐bonding interaction between the pairs of molecules examined was found to correspond to 20–30 kJ mol⁻¹.     

Vibrational analysis,conformational stability,force constants,internal rotation barriers,MP2=full and DFT calculations of 1,3-dimethyluracil tautomers

The molecular structure of 1,3-dimethyluracil (C₆H₈N₂O₂; 1,3-DMU) is studied theoretically and experimentally using Gaussian 98 calculations and different spectroscopic techniques. The vibrational spectrum for 1,3-DMU in the solid phase is recorded in the IR range 4000-400 cm^–1. Initially, in order to get the most stable structure, twelve structures were proposed for the titled compound as a result of the internal rotation of CH₃ around C–N bonds and keto-enol tautomerism. The single point energy and frequency calculations are obtained by MP2 (Full) and DFT/B3LYP methods with the 6-31G(d) basis set using the Gaussian 98 computation package. After the complete relaxation of twelve isolated isomers, the (diketo) tautomer was the only favored structure owing to its low energy relative to the other isomers and the prediction of real frequencies. This interpretation is supported by the recorded infrared spectrum that shows the presence of only the diketo tautomer. Aided by the normal coordinate analysis and potential energy distributions, a confident vibrational assignment of the fundamental frequencies is calculated. The results are discussed herein and compared with similar molecules whenever possible.     

Conformation and tautomerism of methoxy‐substituted 4‐phenyl‐4‐thiazoline‐2‐thiones: a combined crystallographic and ab initio investigation

4‐Phenyl‐4‐thiazoline‐2‐thiol is an active pharmaceutical compound, one of whose activities is as a human indolenamine dioxygenase inhibitor. It has been shown recently that in both the solid state and the gas phase, the thiazolinethione tautomer should be preferred. As part of both research on this lead compound and a medicinal chemistry program, a series of substituted arylthiazolinethiones have been synthesized. The molecular conformations and tautomerism of 4‐(2‐methoxyphenyl)‐4‐thiazoline‐2‐thione and 4‐(4‐methoxyphenyl)‐4‐thiazoline‐2‐thione, both C₁₀H₉NOS₂, are reported and compared with the geometry deduced from ab initio calculations [PBE/6‐311G(d,p)]. Both the crystal structure analyses and the calculations establish the thione tautomer for the two substituted arylthiazolinethiones. In the crystal structure of the 2‐methoxyphenyl regioisomer, the thiazolinethione unit was disordered over two conformations. Both isomers exhibit similar hydrogen‐bond patterns [R₂²(8) motif] and form dimers. The crystal packing is further reinforced by short S…S interactions in the 2‐methoxyphenyl isomer. The conformations of the two regioisomers correspond to stable geometries calculated from an ab initio energy‐relaxed scan.     

STO-3G study of uracil,thymine, 5-fluorouracil, 5-methoxyuracil,and their 4-hydroxytautomeric forms

Ab initio molecular orbital calculations with an STO -3G basis have been performed to investigate the energetics and electronic properties of some 5-substituted uracils and their 4-OH tautomer forms with R including F, CH₃, and OMe. In all cases, the diketo form is more stable. An excellent linear correlation between the calculated and experimental ionization potentials was found.