Open-chain Tautomer Research Articles

Anomerization reaction of bare and microhydrated d-erythrose via explicitly correlated coupled cluster approach. Two water molecules are optimal.

We present a comprehensive benchmark computational study which has explored a complete path of the anomerization reaction of bare d-erythrose involving a pair of the low-energy α- and β-furanose anomers, the former of which was observed spectroscopically (Cabezas et al., Chem. Commun. 2013, 49, 10826). We find that the ring opening of the α-anomer yields the most stable open-chain tautomer which step is followed by the rotational interconversion of the open-chain rotamers and final ring closing to form the β-anomer. Our results indicate the flatness of the reaction's potential energy surface (PES) corresponding to the rotational interconversion path and its sensitivity to the computational level. By using the explicitly correlated coupled cluster CCSD(T)-F12/cc-pVTZ-F12 energies, we determine the free energy barrier for the α-furanose ring-opening (rate-determining) step as 170.3 kJ/mol. The question of the number of water molecules (n) needed for optimal stabilization of the erythrose anomerization reaction rate-determining transition state is addressed by a systematic exploration of the PES of the ring opening in the α-anomer-(H2 O)n and various β-anomer-(H2 O)n (n = 1-3) clusters using density functional and CCSD(T)-F12 computations. These computations suggest the lowest free energy barrier of the ring opening for doubly hydrated α-anomer, achieved by a mechanism that involves water-mediated multiple proton transfer coupled with the furanose CO bond breakage. Among the methods used, the G4 performed best against the CCSD(T)-F12 reference at estimating the ring-opening barrier heights for both the hydrated and bare erythrose conformers. Our results for the hydrated species are most relevant to an experimental study of the anomerization reaction of d-erythrose to be carried out in microsolvation environment. © 2016 Wiley Periodicals, Inc.

Magnetically driven nanoparticles: 18 FDG-radiolabelling and positron emission tomography biodistribution study.

Superparamagnetic iron oxide nanoparticles (SPIONs) have received increasing interest as contrast media in biomedical imaging and innovative therapeutic tools, in particular for loco-regional ablative treatments and drug delivery. The future of therapeutic applications would strongly benefit from improving the capability of the nanostructured constructs to reach the selected target, in particular beyond the intravascular space. Besides the decoration of SPIONs surface with ad hoc bioactive molecules, external magnetic fields are in principle able to remotely influence SPIONs' physiological biodistribution and concentrate them to a specific anatomical region or portion of a tissue. The reduction of SPIONs administered to the body and the need for defining the effective SPIONs local concentration suggest that PET/CT may be a method to quantitatively detect the nanoparticles accumulation in vivo at low concentration and assess their tridimensional distribution in response to an external magnetic field and in relation to the local anatomy highlighted by CT imaging. Here, we report on the possibility to assess the spatial distribution of magnetically-driven radiolabelled SPIONs in a peripheral tissue (mouse thigh) with microPET/CT imaging. To this aim we labelled SPIONs using 18 F-2-fluoro-2-deoxyglucose as a synthon, by chemoselective oxime formation between its open-chain tautomer and nanoparticle amino-groups, and employed microPET/CT imaging to measure the radiolabelled construct biodistribution in a small animal model, following intravenous administration, with and without the application of a permanent magnet onto the skin. The in vivo and ex vivo results showed that micro-PET/CT was able to demonstrate the localizing action of the magnet on SPIONs and provide information, in a multimodal 3D data set, about SPIONs biodistribution taking into account the local anatomy. Copyright © 2017 John Wiley & Sons, Ltd.

Tautomerism of Warfarin: Combined Chemoinformatics, Quantum Chemical, and NMR Investigation.

Warfarin, an important anticoagulant drug, can exist in solution in 40 distinct tautomeric forms through both prototropic tautomerism and ring-chain tautomerism. We have investigated all warfarin tautomers with computational and NMR approaches. Relative energies calculated at the B3LYP/6-311G++(d,p) level of theory indicate that the 4-hydroxycoumarin cyclic hemiketal tautomer is the most stable tautomer in aqueous solution, followed by the 4-hydroxycoumarin open-chain tautomer. This is in agreement with our NMR experiments where the spectral assignments indicate that warfarin exists mainly as a mixture of cyclic hemiketal diastereomers, with an open-chain tautomer as a minor component. We present a diagram of the interconversion of warfarin created taking into account the calculated equilibrium constants (pK(T)) for all tautomeric reactions. These findings help with gaining further understanding of proton transfer and ring closure tautomerization processes. We also discuss the results in the context of chemoinformatics rules for handling tautomerism.

Synthesis, characterisation, and equilibrium studies of 1-(2-ethyl-1,2,3,4-tetrahydro-quinazolin-2-yl)-ethanone oxime and the copper(II) complex of its open-chain tautomer

1-(2-ethyl-1,2,3,4-tetrahydro-quinazolin-2-yl)-ethanone oxime (ETQX, HL) and the Cu(II) complex of its open-chain tautomer were synthesised and characterised by elemental analysis, magnetic susceptibility, molar conductance, thermal analyses, and spectral (IR, NMR, AAS, LC-MS, and UV-Vis) studies. The accumulated data exhibited that the ligand underwent a ring-opening reaction upon formation of a mononuclear Cu(II) complex in which the chain tautomer acted as an N,N,N-donor. The Cu(II) complex was formed in a 1 : 1 (M : HL′) ratio, as indicated by analytical results and the general formula was elucidated to be [Cu(HL′)Cl]Cl. The protonation constants of ETQX and the stability constants of the complex species formed with the Cu(II) of ETQX were studied by the potentiometric method at 25°C in 0.1 M KCl ionic medium. A complexation model for the Cu(II)-ETQX system was established with the software program “BEST” based on the potentiometric data. The concentration distribution curves of ETQX and Cu(II)-ETQX complex species in solution were evaluated by the SPE software program. The stoichiometry of the Cu(II) complex in solution was observed to be similar to that of the solid state Cu(II) complex.

Syntheses, Structural Characterization, and Thermal Properties of New 1,2,3,4-Tetrahydroquinazoline Ligands and Their Co(III) Complexes

In this study, new heterocyclic ligands, 2-(3-chloro-phenyl)-1,2,3,4-tetrahydro-quinazoline-2-carbaldehyde oxime,(HL1) and 2-(3-bromo-phenyl)-1,2,3,4-tetrahydro-quinazoline-2-carbaldehy- de oxime,(HL2), and Co(III) complexes of their open-chain tautomer,(HL1′ and HL2′), containing oxime, imine, and amine donor groups resulting from the reactions with Co(II) ion have been synthesized and characterized by spectral methods, elemental analysis, magnetic susceptibility, and thermal analysis (TG, DTG, and DTA) techniques. The obtained results show that the ligands undergo a ring-opening reaction upon complexation with Co(III) ion. The analyses confirmed the following molecular formulae: [Co(L1′)2]Cl.H2O and [Co(L2′)2]Cl.H2O.

A New Cyclic Ligand and Complexes of Its Open-Chain Tautomer With Co(III) and Ni(II) Ions: Synthesis, Characterization and Thermal Properties

A new ligand, 2−(p−tolyl)−1,2,3,4−tetrahydroquinazoline−2 −carbaldehyde oxime, was synthesized from a condensation reaction of oxo−p−tolyl−acetaldehyde oxime with 2−aminobenzyl- amine and then amine−imine−oxime complexes of this compound that formed with Co(III) and Ni(II) ions were obtained. All structures were characterized by spectral methods, elemental analysis, magnetic susceptibility, molar conductivity, and thermal analyses. The results that were obtained show that the cyclic ligand, HL, undergoes a ring−opening reaction upon complexation with metal ions. The Co(III) and Ni(II) complexes have a metal−ligand ratio of 1:2 and the imine ligand coordinates through the amine, imine, and oxime groups nitrogen atoms with metal ions.

Some novel observations on the reaction of 2-hydrazino-3-methylquinoxaline with trifluoromethyl-β-diketones

The reaction of 2-hydrazino-3-methylquinoxaline 1 with trifluoromethyl-β-diketones 2 not only yields the expected 5-trifluoromethyl-5-hydroxy-Δ 2-pyrazolines 3a– 3f and/or 3-trifluoromethylpyrazoles 4c– 4f but also the unexpected products 1,2,4-triazolo[4,3- a]quinoxalines 5a– 5f and/or 3(5)-trifluoromethyl-1 H-pyrazoles 6c– 6f. Furthermore, the acid-catalyzed dehydration of 5-hydroxypyrazolines 3a– 3b resulted in the formation of unexpected 5a– 5b along with the expected corresponding pyrazoles 7a– 7b. These unprecedented observations provide evidence for the existence of equilibrium between the hydroxypyrazoline 3 and its open chain tautomer, ketoimine 9 in the mechanistic path leading to the formation of pyrazoles 7 and triazoles 5.

Triosmium clusters with bridging terpenic thioureato-like ligands

The reaction of acetone-4-(2-methoxy-phenyl)thiosemicarbazone with triosmium cluster Os 3(CO) 11(NCMe) results in the formation of the cluster with the μ 2 chelate-bridging ligand coordinated by S and N 1 atoms, which was studied by X-ray diffraction analysis. Reaction of ( 3aR, 3bR, 4aR, 5aS)-5a-hydroxy-3,4,4-trimethyl-3a,3b,4,4a,5,5a-hexahydrocyclopropa[3, 4]cyclopenta[1,2-c]pyrazole-1-carbothioic acid amide with Os 3(CO) 11(NCMe) gives rise to the complex with the bridging ligand coordinated by sulphur atom. Further transformation of the complex in hot benzene results in tautomeric rearrangement of the organic ligand and the cleavage of the pyrazolinol cycle to form an open chain tautomer. Unusual silica gel induced oxidative cleavage of the cyclopropane ring in the open chain derivative and epoxidation of cycloalcane C–C bond are observed on the air.

Identification of adducts formed by pyridyloxobutylation of deoxyguanosine and DNA by 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone, a chemically activated form of tobacco specific carcinogens.

The tobacco specific carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are metabolically activated to 4-oxo-4-(3-pyridyl)-1-butanediazohydroxide (7), which is known to pyridyloxobutylate DNA. A substantial proportion of the adducts in this DNA releases 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB, 11) under various hydrolysis conditions, including neutral thermal hydrolysis. These HPB-releasing DNA adducts have been detected in target tissues of animals treated with NNK and NNN as well as in lung tissue from smokers. Although their presence in pyridyloxobutylated DNA was conclusively demonstrated 15 years ago, their structures have not been previously determined. We investigated this question in the present study by determining the structures of products formed in reactions with dGuo and DNA of 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKCH(2)OAc, 3), a stable precursor to 7. Reaction mixtures from NNKCH(2)OAc and dGuo were analyzed by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) with selected ion monitoring at m/z 415. A major peak was detected and identified as 7-[4-oxo-4-(3-pyridyl)but-1-yl]dGuo (37) by its ESI-MS fragmentation pattern and by neutral thermal hydrolysis, which converted it to 11 and 7-[4-oxo-4-(3-pyridyl)but-1-yl]Gua (26). The latter was identified by comparison to synthetic 26 using LC-ESI-MS with selected ion monitoring at m/z 299, M + 1 of 26. Further evidence was obtained by NaBH(4) reduction of 26 to 7-[4-hydroxy-4-(3-pyridyl)but-1-yl]Gua, which was also matched with a standard. Adduct 37 was similarly identified in enzyme hydrolysates of DNA reacted with NNKCH(2)OAc, accounting for 30-35% of the HPB-releasing adducts in this DNA. Several other adducts resulting from pyridyloxobutylation of the N(2)- and O(6)-positions of Gua were also identified as products in the dGuo or DNA reactions by comparison to standards; their concentrations were considerably less than that of 37. These adducts were N(2)-[4-oxo-4-(3-pyridyl)but-1-yl]dGuo (23), N(2)-[4-oxo-4-(3-pyridyl)but-2-yl]dGuo (25), N(2)-[2-(3-pyridyl)tetrahydrofuran-2-yl]dGuo (31a) (or its open chain tautomer 31b), and O(6)-[4-oxo-4-(3-pyridyl)but-1-yl]dGuo (10). Adducts 23, 25, and 10 did not release HPB upon neutral thermal hydrolysis. The results of this study provide the first structural identification of an HPB-releasing DNA adduct of the tobacco specific nitrosamines NNK and NNN.

Characterization of 3,4-dihydroxy-3-hexen-2,5-dione as the first open-chain caramel-like smelling flavor compound

3,4-Dihydroxy-3-hexen-2,5-dione (DHHD) was identified in a thermally treated mixture of cysteamine and fructose. GC/MS and 13C-NMR measurements revealed that its flavor activity is present only in the open chain form, while the cyclic species was shown to be completely odorless. The flavor quality of DHHD was similar to that of 4-hydroxy-2,5-dimethyl-3(2H)-furanone (furaneol) and its odor threshold was determined to be 10 µg/l in sunflower oil. NMR measurements, however, showed that the odor-active open chain tautomer is present only in aprotic solvents, such as oils, while the cyclic, odorless tautomer (diacetylformoin) is immediately formed in aqueous solution.

A theoretical study of hydrogen bonding, proton transfer and kinetic isotope effects in the dimers of 2-tetrahydropyranol and in the 2-tetrahydropyranol–H2O adductsElectronic Supplementary Information available. See http://www.rsc.org/suppdata/cp/b1/b104613f/

The catalysed isomerisation of the model sugar 2-tetrahydropyranol (2-THP) was investigated by means of DFT and ab initio calculations in vacuum. This reaction may be promoted by a second 2-THP molecule (self-catalysed process) or by a H2O molecule in the framework of hydrogen bonded adducts. Activation energies of ca. 30 and 25 kcal mol−1 respectively were calculated, so that the above processes are not considered to play a significant role at room temperature. A third type of reaction may take place, namely the ring opening of 2-THP catalysed by an open-chain 2-THP tautomer. This reaction displays an activation energy of ca. 16 kcal mol−1 but requires the presence of a third catalytic species, capable of yielding an initial amount of open-chain tautomer. Kinetic isotope effects (KIE) associated with H/D substitution were calculated for all considered adducts, resulting in higher effects for the H2O-catalysed reaction and for the reaction catalysed by an open-chain monomer than for the self-catalysed process. Normal-coordinate decomposition analysis performed on the vibrational modes of the transition states showed that the calculated KIEs increase with the contribution of O–H stretching modes to the reaction coordinate and decrease with the contribution of the stretching of the C–O bond in the sugar ring. The analysis also showed how such contributions affect the different terms which give rise to the KIE.

Ab initio and Density Functional Calculations on the Ring-Chain Tautomerism of γ-Oxocarboxylic Acids

The results of ab initio (HF, MP2) and density functional (B3LYP) calculations on a series of γ-oxocarboxylic acids [(Z)-3-acetyl or benzoylacrylic and 2-acetyl or benzoylbenzoic acids] A and their cyclic tautomers B are presented. For the open-chain tautomers, different rotamers were considered. Bulk solvent effects were considered by using the polarised continuum model (PCM) and were found to be essential for a proper description of the ring-chain tautomeric equilibrium. Acetyl derivatives generally prefer the cyclic form, whereas for benzoyl derivatives the preference depends on the nature of the link. Introduction of substituents (methyl, phenyl) at C2 and/or C3 for acrylic acid derivatives substantially shifts the equilibrium towards the cyclic form B.

An ab initio and density functional study on the ring-chain tautomerism of (Z)-3-formyl-acrylic acid

Ab initio (HF and MP2) and density functional (B3LYP) calculations with different basis sets (6-31G ∗, 6-311+G ∗∗, 6-311+G(2df,p)) on the various conformers of (Z)-3-formyl-acrylic acid and the corresponding ring-closed tautomer 5-hydroxy-furan-2(5H)-one are performed. At all levels of theory the ring tautomer is predicted to be the most stable one. Inclusion of bulk solvent effects (H 2O) by the self-consistent isodensity surface polarized continuum model (SCIPCM) further shifts the ring-chain tautomeric equilibria towards the furanone form. Among the open chain tautomers, the s- cis–s- trans conformation is the most stable.

A unique urinary constituent, 6-hydroxy-6-methyl-3-heptanone, is a pheromone that accelerates puberty in female mice

Olfactorily mediated puberty acceleration in female mice (measured by an increase in uterine weight) has been observed since the 1960s without the active chemosignal being structurally identified. There are many controversies in the literature as to whether this male-originated pheromone is a volatile substance. We investigated the chemical nature of the urinary fractions that are responsible for the characteristic uterine weight increases. The active pheromone was identified as 5,5-dimethyl-2-ethyltetrahydrofuran-2-ol and/or its open-chain tautomer (6-hydroxy-6-methyl-3-heptanone). A series of cyclic vinyl ethers were isolated from chromatographically active fractions of the urine. Because these compounds did not accelerate puberty, we postulated that these ethers were degradation products of a lactol (5,5-dimethyl-2-ethyltetrahydrofuran-2-ol). The lactol was then detected directly in the mouse urine extract using a silylation agent. Synthetic 6-hydroxy-6-methyl-3-heptanone had strong biological activity, whereas its close structural analogs did not. The male house mouse excretes into its urine a large quantity of a volatile substance that has a unique lactol/hydroxyketone structure. This substance is capable of binding to the less volatile urinary constituents, such as proteins or peptides, and is active in puberty-acceleration bioassays. The controversies regarding the volatility of the puberty-accelerating pheromones can now be explained by considering a complex of volatile lactol/hydroxyketone and urinary proteins.

Electron Ionization Mass Spectra of Some Diexo Norbornane- and Norbornene-fused Phenyl-substituted 1,3-Oxazines and Related Systems. Competitive retro-Diels-Alder Fragmentations in 4-Phenyl-4a,5,8,8a-tetrahydro-5,8-methano-4H-benzo[e]1,3-oxazines

The electron ionization spectra of seven diexo norbornane- and norbornene-fused six- and seven-membered heterocycles containing O and N in positions 1 and 3 are reported. Molecular ions of norbornane-fused oxazines, especially the 2-anilino derivative, underwent retro-Diels-Alder fragmentation leading to a cleavage of the heterocyclic ring whereas, in norbornene-fused compounds, two concurrent retro-Diels-Alder fragmentations occurred. Fragmentation patterns of norbornane-fused oxazin-2-ones(or -thiones) are closely related to each other and, in some cases, provide evidence for the presence of minor amounts of the ionized open-chain tautomers in the gas phase. The ionized molecular ions of the 2-anilino derivatives appear to exist as mixtures of 2-phenylimino and 2-anilino isomers with exo- and endocyclic C = N bonds, respectively. © 1997 John Wiley & Sons, Ltd.

Electron Ionization Mass Spectra of Some Diexo Norbornane- and Norbornene‐fused Phenyl‐substituted 1,3-Oxazines and Related Systems. Competitive retro‐Diels–Alder Fragmentations in 4-Phenyl-4a,5,8,8a‐tetrahydro-5,8-methano-4H-benzo[e]1,3-oxazines

The electron ionization spectra of seven diexo norbornane- and norbornene-fused six- and seven-membered heterocycles containing O and N in positions 1 and 3 are reported. Molecular ions of norbornane-fused oxazines, especially the 2-anilino derivative, underwent retro-Diels-Alder fragmentation leading to a cleavage of the heterocyclic ring whereas, in norbornene-fused compounds, two concurrent retro-Diels-Alder fragmentations occurred. Fragmentation patterns of norbornane-fused oxazin-2-ones(or -thiones) are closely related to each other and, in some cases, provide evidence for the presence of minor amounts of the ionized open-chain tautomers in the gas phase. The ionized molecular ions of the 2-anilino derivatives appear to exist as mixtures of 2-phenylimino and 2-anilino isomers with exo- and endocyclic C = N bonds, respectively. © 1997 John Wiley & Sons, Ltd.

Reaction of N-vinylpyrazolium and N-vinylindazolium salts with cyanide ion: formation of 1,2-dihydropyrimidines, 3,4-dihydroquinazolines, and quinolines

The reaction of 1-aryl-2-vinylpyrazolium tetrafluoroborates with potassium cyanide affords 2-hydroxy-1,2-dihydropyrimidines 3, which exist as open-chain tautomers 4, both in the solid state and in solution. The X-ray structure of the p-chlorophenyl derivative 4b has been determined (ClC 14 N 2 O 3 H 15 , P2 1 /c,a=11.433 (3) A, b=16.086 (4) A, c=1.813 (4) A, β=94.22 (5) o , V=1433.0 (9), Z=4, R=0.06 for 1334 observed reflections). Protonation of these vinylogous amidines 4 results in their cyclization and dehydration to pyrimidinium salts 6

Structural and electronic properties of MX compounds related to TA100 mutagenicity. A semi-empirical molecular orbital QSAR study

The structural and electronic properties of chlorofuranones including MX and its anhydride were calculated using the semi-empirical AM1 method to elucidate the key features related to the strong mutagenic activity of MX. Significant correlations were found between Ames TA100 mutagenicity and the following electronic parameters of chlorofuranones: LUMO energy ( r = 0.9607, n = 17), electron affinity ( r = 0.9557), LUMO electron density at the α-carbon ( r = 0.8855) and partial charge of the α-carbon ( r = 0.8812). Based on these results, a molecular orbital QSAR model for the mutagenic activity of 17 MX analogues is presented. The controversial role of the open-chain tautomers of MX compounds, chlorinated butenoic acids, is discussed briefly.

Ring-chain tautomerism in 1,3-thiazolidines

NMR spectroscopy was applied to study ring-chain tautomeric equilibria in several substituted 1,3-thiazolidines. The system highly prefers the ring form and only in the case of 2-(2 '-hydroxy,5 '-bromophenyl)-l,3-benzothiazo-line ( 2d) 1H and 13C NMR spectra revealed a detectable amount of the openchain tautomer. The relative stability of the 1,3-thiazolidine ring was estimated to be more than 10 4 times higher than that of the 1,3-oxazolidine ring.

Studies on the benzoxazine series. Part 1. Preparation and 1H and 13C nuclear magnetic resonance structural study of some substituted 3,4-dihydro-2H-1,3-benzoxazines

In addition to the parent compounds nine methyl-substituted 3,4-dihydro-2H-1,3-benzoxazines with and without N-methyl substitution were prepared. The former contain usually but minor amounts of the open-chain tautomer, too. The conformations and configurations of the oxazine rings were solved on the basis of 1H and 13C n.m.r. data which were best explained by assuming the N-methyl group predominantly axial in 3,4-dihydro-3-methyl-2H-1,3-benzoxazines. The oxazine ring prefers a half-chair form where the 4ax′-and 4eq′-methyl groups are practically equally stable. Hence, 3,4-dihydro-4-methyl-2H-benzoxazine is a 54 : 46 and the corresponding 3-methyl derivative an 8 : 92 mixture of the 4eq′ and 4ax′ forms. The 2,2,3,4-tetramethyl derivative is not conformationally homogeneous either. Substituent effects on 13C n.m.r. chemical shifts were found to be especially useful in configurational and conformational analysis and gave an excellent fit between observed and calculated shift values.