Amino Tautomeric Form Research Articles

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

Proton tautomerism in 5-dimethylaminomethylidene-4-(o-,m-,p-hydroxyphenyl)amino-1,3-thiazol-2(5H)-ones: synthesis, crystal structure and spectroscopic studies.

Three new 5-dimethylaminomethylidene-4-phenylamino-1,3-thiazol-2(5H)-ones with an hydroxyl group in the ortho-, meta- and para- positions on the phenyl ring were synthesized in order to deduce the structural changes occurring on prototropic tautomerism of the amidine system. The existence of all the title compounds solely in the amino tautomeric form has been established in the solid and liquid (dimethyl sulfoxide solution) phases. The title compounds are analyzed from the point of view of the electronic effects and conformational freedom of their molecules. The intermolecular interactions in the crystals and their supramolecular architecture are highlighted.

Spectroscopic characterization, crystallographic elucidation and DFT investigation of 5-fluoro-6-(4-methylpiperazin-1-yl)benzo[d]thiazol-2-amine

The spectroscopic features and molecular structure of 5-fluoro-6-(4-methylpiperazin-1-yl)benzo[d]thiazol-2-amine (2-ABT) have been determined. Single-crystal X-ray analysis and vibrational spectroscopy have revealed the existence of 2-ABT in the amino tautomeric form in the solid state. Properties of 2-ABT in solution have been investigated using 1H and 13C NMR spectroscopy along with electronic absorption spectroscopy. The experimental data are complemented by DFT and TD-DFT calculations at the B3LYP/6–311 + g(2d,p) level. TD-DTF-predicted spectroscopic and structural properties for both amino and imino tautomers of 2-ABT are compared with the measured data; no strong evidence for the presence of the imino tautomer is found within the experimental data. Calculated energy differences between the tautomers strongly favour the amino tautomer over the other. Indeed, X-ray crystallography has unequivocally shown the amino tautomer which co-crystallized with one water molecule in the orthorhombic space group Pnna. Analysis of the crystal packing reveals an interesting structural motif which comprises an assemblage of the 2-ABT molecules through π···π stacking interactions. Furthermore, there exist hydrogen-bonding interactions involving the lattice solvent and the amino group along with the benzothiazole nitrogen atom.

Supramolecular solid-state structure, potential energy surfaces and evaluation of antiproliferative effect of 2-benzothiazolylhydrazone derivatives in vitro

The in situ condensation reaction of 2-hydrazinobenzothiazole with salicylaldehyde, 3,4-dihydroxybenzaldehyde, 2,4-dihydroxybenzaldehyde, 2,5-dihydroxybenzaldehyde, 2,3-dihydroxybenzaldehyde, 2-hydroxy-1-naphthaldehyde, 2-methoxy-1-naphthaldehyde, 4-methoxy-1-naphthaldehyde and 6-methoxy-2-naphthaldehyde produced 9 hydrazone Schiff bases (L1–L9, respectively) which were identified and characterized by elemental analysis, IR and NMR spectroscopy. The crystal and molecular structures of four Schiff bases (L1, L7–L9) have been determined by the single-crystal X-ray diffraction method confirming the imino form of L1 and the amino tautomeric form of L7–L9 compounds. Molecular structure analysis also confirmed that reported compounds are E-isomers relative to exo C = N imino bond. The Nhydrazino–H group of amino tautomers forms Nhydrazino–H···Nthiazolyl intermolecular hydrogen bonds shaping molecules into R22(8) rings, while imino tautomer of L1 forms C(4) infinite helical chains via Nthiazolyl–H···Nhydrazino type of intermolecular hydrogen bond. The methoxy group (L7–L9) further shaped these primary supramolecular synthons into different supramolecular arrangements via C–H···O, C–H···N and C–H···S intermolecular hydrogen bonds. The role of aryl substituents in the shaping and stabilization of supramolecular architectures of L1, L7–L9 is supported by quantum chemical calculations. Strong antiproliferative effects on tumor cells and cytotoxic effects on fibroblasts are shown for all ligands L1–L9 with exception of L6 and L7 that had no effect on fibroblast cells.

Calculated tautomeric equilibria and X-ray structures of 2-substituted N-methoxy-9-methyl-9H-purin-6-amines

Density Functional Theory calculations of nine 2-substituted N-methoxy-9-methyl-9H-purin-6-amines in the amino and imino tautomeric forms, as well as the complexes of the same with dimethyl sulfoxide (DMSO), were performed using two functionals (BP86 and B3LYP) and two basis sets (SV(P) and def2-TZVP). Solid-state structures of two of the compounds were obtained from single-crystal X-ray diffraction techniques. It was found that the inclusion of both an explicit hydrogen-bonding partner (DMSO) as well as continuum solvation effects, and vibrational corrections to energy, were necessary for qualitative and reasonable quantitative agreement with observed tautomeric ratios. The solution-optimized geometries and X-ray structures were found to be in good agreement. NMR spectroscopy confirmed the dependence of the tautomeric ratios on hydrogen-bonding abilities, in addition to the dipole moment of the solvent in question. Natural Bond Orbital charges on the N-7 nitrogen, as well as the tautomeric ratios were used to explain the observed reactivities of the compounds toward N-7 alkylation.

Keto–enol tautomerism in asymmetric Schiff bases derived from p-phenylenediamine

Reaction of dehydroacetic acid and p-phenylenediamine afforded a monosubstituted Schiff base, I, with the other amino group free. In further reactions with various salicylaldehyde derivatives, I served as a precursor for synthesis of asymmetric bis-Schiff bases. The synthesized compounds are thus comprised of two subunits, dehydroacetic ( dha) and salicylidene ( sal), which are bridged by the phenylene linker. All products were investigated by means of elemental analysis, FT-IR and NMR spectroscopy, thermal methods, powder X-ray diffraction and, when possible, by single crystal X-ray crystallography. Structural and spectroscopic studies revealed that in the bis-products, the dha subunit adopts the keto–amino tautomeric form, while the sal subunit adopts the enol–imino form. Tautomeric forms were not affected if a methoxo group was introduced on the salicylidene ring. Both tautomeric subunits are stabilized by strong resonance-assisted hydrogen bonds, RAHB. The two subunits of the prepared bis-Schiff bases predominantly retain in solution the same tautomeric forms as found in the solid state.

Assignment of Absolute Configurations of the Enantiomeric Spiroiminodihydantoin Nucleobases by Experimental and Computational Optical Rotatory Dispersion Methods

The diastereomeric spiroiminodihydantoin (Sp) lesions are oxidation products of guanine and 8-oxo-7,8-dihydroguanine (8-oxoG) and have generated considerable interest because of their stereochemistry-dependent mutagenic properties in vivo (Henderson, P. T., et al. (2003) Biochemistry 42, 9257-9262). However, the absolute configurations of the two diastereomers have not yet been elucidated, and such information may prove valuable for understanding relationships between biological function and structure at the DNA level (Jia, L., Shafirovich, V., Shapiro, R., Geacintov, N. E., and Broyde, S. (2005) Biochemistry 44, 13342-13353). We have synthesized the two chiral Sp nucleobases by hydrolysis of the nucleosides denoted by dSp1 and dSp2 according to their elution order in HPLC experiments using a Hypercarb column, and determined their absolute configurations using a combination of experimentally measured optical rotatory dispersion (ORD) spectra in aqueous solutions and computed ORD specific rotations using density functional theory (DFT). Recent developments have shown that DFT methods are now sufficiently robust for predicting ORD values of chiral molecules (Polavarapu, P. L. (2002) Chirality 14, 768-781). The nucleobases Sp1 and Sp2 exhibit experimentally measured CD and ORD spectra that are very close to those of the respective precursor nucleosides dSp1 and dSp2 in shape and sign. The first nucleoside stereoisomer (dSp1) to elute from a typical Hypercarb HPLC column has (-)-S, while the second (dSp2) has (+)-R absolute configuration. The R and S assignments are applicable to the amino tautomeric forms in each case.

Cobalt hexammine induced tautomeric shift in Z-DNA: the structure of d(CGCGCA)*d(TGCGCG) in two crystal forms.

We report here the crystal structure of the DNA hexamer duplex d(CGCGCA)*d(TGCGCG) at 1.71 A resolution. The crystals, in orthorhombic space group, were grown in the presence of cobalt hexammine, a known inducer of the left-handed Z form of DNA. The interaction of this ion with the DNA helix results in a change of the adenine base from the common amino tautomeric form to the imino tautomer. Consequently the A:T base pair is disrupted from the normal Watson-Crick base pairing to a 'wobble' like base pairing. This change is accommodated easily within the helix, and the helical parameters are those expected for Z-DNA. When the cobalt hexammine concentration is decreased slightly in the crystallization conditions, the duplex crystallizes in a different, hexagonal space group, with two hexamer duplexes in the asymmetric unit. One of these is situated on a crystallographic 6-fold screw axis, leading to disorder. The tautomeric shift is not observed in this space group. We show that the change in inter-helix interactions that lead to the two different space groups probably arise from the small decrease in ion concentration, and consequently disordered positions for the ion.

Structure of 4,6-dimethylisothiazolo[5,4-b]pyridin-3(2H)-one and its 2-[4-(2-methylphenyl) piperazin-1-ylmethyl] derivative

The crystal and molecular structures of 4,6-dimethylisothiazolo[5,4-b]pyridin-3(2H)-one, C8H8N2OS, 1, and its 2-[4-(2-methylphenyl)piperazin-1-ylmethyl] derivative, C20H24N4OS, 2c, are described. These compounds crystallize in the monoclinic system in the space group P21/c. The cell constants for compound 1 are a = 5.049(1), b = 14.897(1), c = 11.330(1) A, β = 98.07(1)°, Z = 4, T = 293 K, and Dcal = 1.419 g cm−3, and for compound 2c are a = 15.525(1), b = 12.021(1), c = 10.911(1) A, β = 106.42(1)°, Z = 4, T = 293 K, and Dcal = 1.253 g cm−3 The structures were solved by direct methods and refined to R values of 0.0411 and 0.0380 for 1640 and 3504 reflections for 1 and 2c, respectively. The analysis of the geometry and difference electron density map reveal that the dimethylisothiazolopyridine 1 exists in the amino tautomeric form in the crystalline state. The conformation of the o-methylphenylpiperazine part of the molecule 2c strongly depends on the substituents effect in the phenyl ring and is very similar to those observed in crystals for other investigated arylopiperazine derivatives of the isothiazolopyridine.

Diiminoisoindoline: tautomerism, conformations, and polymorphism.

Two polymorphs of the industrially important compound diiminoisoindoline occur in the amino tautomeric form as a conformational isomorph with a 1 : 1 mixture of the syn- and anti-isomers, and a conformational polymorph containing only the syn-isomer.

The structure of N-allyl derivatives of (5-(2′-pyridyl)-[1,3,4]thiadiazol-2-yl) amine in solution and the solid state studied by the 1H, 13C, 15N NMR spectroscopy, X-ray crystallography and DFT computations

The 2-N-allyl- 1 and (3-phenyl-allyl)- 2 (5-(2′-pyridyl)-[1,3,4]thiadiazol-2-yl)-amines were examined by the 1H, 13C, 15N NMR spectroscopy, X-ray diffraction and B3LYP/6-31G(d, p) computations. It has been found that all compounds exist in the egzo–amino tautomeric form a in a solution and in a solid state. Two different positions of the H6 atom have been found in the crystals, enabling formation of the polar ribbons 1 and the centrosymmetric dimers 2. The DFT calculations have shown the egzo–amino tautomeric form to be more stable than the egzo–imino form by 35 kJ/mol.

The origin of the absorption band induced through the interaction between apotransketolase and thiamin diphosphate

It has long been known that formation of a catalytically active holotransketolase from the apoenzyme and coenzyme (thiamin diphosphate) is accompanied by the appearance of a new band, in both the absorption and CD spectra. Binding and subsequent conversion of the substrates bring about changes in this band's intensity. The observation of these changes allows the investigator to monitor the coenzyme-to-apoenzyme binding and the conversion of substrates during the transketolase reaction and thus to kinetically characterize its individual steps. The origin of the thiamin diphosphate induced absorption band has been postulated to be resulted from formation of a charge transfer complex or alternatively from an induced conformational transition of the enzyme. The latter brings aromatic amino acid residues into close proximity and generates the absorption. However, X-ray crystallographic and enzyme point mutation experiments cast doubts on both of these hypotheses. Here we show that the binding of thiamin diphosphate to the apotransketolase leads to the conversion of the 4 ′-amino tautomeric form of its aminopyrimidine ring into the N 1 ′ H-imino tautomeric form. This imino form emerges as a result of the coenzyme's aminopyrymidine ring incorporation into the hydrophobic pocket of the transketolase active center and is stabilized through the interactions with Glu418 and Phe445 residues. The N 1 ′ H-imino tautomeric form of thiamin diphosphate is thought to be the origin of the holotransketolase absorption band induced through the coenzyme binding.

9-(tert-Butylamino)acridine

The crystal structure of 9-(tert-butyl­amino)­acridine, C17H18N2, is composed of mol­ecules of the amino tautomeric form. The acridine moiety is slightly folded along the C⋯N line passing through opposite atoms of the central ring, and the orientation of the tert-butyl­amino group makes the conjugation between the lone pair of the N atom and the acridine π-system almost negligible. An intermolecular hydrogen bond, involving the exocyclic NH group as donor and the endocyclic N atom as acceptor, links the mol­ecules into infinite chains stretching along the b axis of the crystal.

The imino–amino tautomeric equilibrium in cyanoguanidine dissolved in several aprotic solvents; an FT-Raman spectroscopic study

The FT-Raman spectra of cyanoguanidine solutions in N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) and hexamethylphosphoric triamide (HMPA), in a range of concentrations between R=3 and R=10 (R=solvent/solute mole ratio), are studied. The intense doublet that appears in the spectral region of the nitrile stretching fundamental is attributed to the presence of the imino (2147cm−1) and amino (2186cm−1) tautomeric forms. Furthermore, a shoulder located in the higher frequency wing that could arise from cyanoguanidine molecules associated through hydrogen bonds affecting the nitrogen atom of the nitrile group. When the solute concentration is increased, the relative intensity of that band arising from the imino tautomer increases and a further increase of the associated species can also be observed. These observations are common for the three solvents studied. The concentration of the imino form strongly depends on the solvent, increasing in the order DMF<DMSO<HMPA, which qualitatively corresponds with the donor number ranking. The presence of associated species, however, seems to be controlled by the dielectric constant of the solvent, being scarce in DMSO, moderate in DMF and more important in HMPA.

Tautomeric investigations and crystal structure analysis of chlorzoxazone

The crystal structure and infrared spectra of the compound has been reported. Infrared spectra of the compound were examined in various solvents. The results of the crystal structure analysis and IR spectra assignments showed that the compound has the amino tautomeric form in the solid state and in studied solutions.

Conformatzonal Properties of a Novel Modified Nucleoside, 5-Formylcytidine, Found at the First Position of the Anticodon of Bovine Mitochondrial tRNAMet

Abstract Conformational properties of a novel modified nucleoside, 5-formylcytidine (f5C), which is found at the first position of the anticodon of bovine mitochondrial tRNAMet, were analyzed by 1H-NMR spectroscopy. f5C has a normal amino tautomeric form at position 4 of the base moiety. The results indicate the presence of an intramolecular hydrogen bond between the carbony1 of the 5-formyl group and the 4-amino function. f5C was found to exhibit the C3′-endo conformation exclusively and the enthalpy difference (ΔH) between the C2′-endo and C3′- endo forms was found to be 1.56 ± 0.13 kcal/mol, indicating f5C to be one of the most conformationally rigid nucleosides yet analyzed. The conformational rigidity of f5C may contribute to regulation of codon recognition by tRNAMet.

Reaction of benzylidenebenzocyclanones with dithiocarbamic acid and thiourea

Reaction of 2-benzylidene-1-benzocyclanones1 with dithiocarbamic acid afforded open-chain addition products2A–4B. Dehydration of the adducts yielded tricyclic 1,3-thiazine-2-thiones5 and6. Treatment of1 with thiourea under acid conditions gave tricyclic 2-amino-1,3-thiazines7–9. IR and1H NMR spectroscopic investigations showed7–9 to exist predominantly in the amino tautomeric form both in the solid state and in solution.

Structure of 1-aryl-3-alkyl-5-(2-benzothiazolyl)formazans

The isomeric and tautomeric structures of 1-aryl-3-alkyl-5-(2-benzothiazolyl)formazans in solutions were investigated by means of NMR, IR, and electronic spectroscopy. It is shown that the nature of the solvent and the alkyl substituent in the 3 position affects the ratio of the Z and E isomers relative to the C=N bond of the azohydrazone chain. An increase in the length of the alkyl substituent in the 3 position leads to preponderance of the Z isomer in solution, while branching stabilizes the Z configuration with an N2...HN5 intramolecular hydrogen bond (IMHB), regardless of the solvent. The nature of the solvent has a significant effect on the ratio of the amino and imino tautomeric forms of the E isomers. The benzothiazolylhydrazone form predominates in CHCl3, while the tautomer with a benzothiazolidene fragment is the major form in DMSO.

Structure of 2-benzothiazolylhydrazones of aromatic and aliphatic aldehydes

On the basis of data of 13C and 1H NMR and IR spectroscopy, it was shown that 2-benzothiazolylhydrazones of aliphatic aldehydes were in solution as a mixture of E and Z isomers, and hydrazones of aromatic aldehydes were in solution only as E isomers. All investigated compounds existed in solution mainly in an amino tautomeric form, and the content of the imino form did not depend on the nature of the aldehyde fragment.

Structure and conformation of N4-hydroxycytosine and N4-hydroxy-5-fluorocytosine. A theoretical ab initio study

Optimal molecular geometries and molecular energies were obtained for N 4-hydroxycytosine and its 5-fluoro congener with the use of the theoretical ab initio quantum mechanical calculations within the Self Consistent Field method corrected for the electron correlation effects by the second-order Many Body Perturbation Theory (SCF + MBPT(2)). The 6–31G Gaussian basis set was employed. Several tautomeric and rotameric forms were considered. For N 4-hydroxycytosine and N 4-hydroxy-5-fluorocytosine the imino tautomer (in the conformation syn relatively to the N3-nitrogen atom) appeared to be the most stable form. The imino tautomer of N 4-hydroxy-cytosine in the anti rotameric form is by 12.8 kJ mol −1 less stable than the imino- syn form. The 5-fluoro substituent raises the energy difference between the syn and anti rotamers up to 38.5 kJ mol −1. The potential energy barrier for the syn-anti rotation in the imino form of N 4-hydroxycytosine is estimated to be about 180 kJ/mol. The results presented in this paper suggest that the syn-imino and anti-imino forms can be treated as two structural isomers that do not interconvert at temperatures relevant to biochemical conditions. The theoretical results also show that the amino tautomeric forms do not compete with the imino forms in the gas-phase and in non-polar and weakly-polar environment. In a polar environment (e.g., in aqueous solutions), however, one may expect an increased population of the amino forms. Qualitatively, the results of the present study agree well with the available experimental and theoretical data for N 4-hydroxycytosine and some of its derivatives. The implications of the present study are discussed in relation to the molecular mechanisms of mutagenesis caused by NH 2OH and of enzyme (thymidylate synthase) inhibition by N 4-hydroxydeoxycytidine monophosphate.