Theoretical study of the stability of myrsinone in vacuo and in solution

The stability of various conformers of myrsinone (2,3-dihydroxy-5-undecyl-1,4-benzoquinone) and its tautomer [2,3-dihydroxy-5-(undec-1-ene)-cyclohex-2-ene-1,4-dione] has been studied in vacuo and in solution on model systems with the long alkyl side chains replaced with ethyl and eth-1-ene groups, respectively. Ab initio Hartree–Fock (HF) calculations in vacuo and free-energy calculations either in chloroform or in water solution, in the framework of the polarizable continuum model, have been carried out on the 6-31G* optimized geometries obtained in vacuo and in solution (water or chloroform). The nature of the stationary points found was investigated using normal mode analysis. The energy gap between the two tautomeric forms turns out to be about 1.3 kcal/mol in vacuo and becomes about 0.3 kcal/mol in chloroform solution, whereas in water the second tautomer is favored by about 1.2 kcal/mol. The effect of second-order M?ller–Plesset (MP2) correlation corrections has been considered on both the energy and the geometry of the tautomers in vacuo, whereas in solution only their effect on the energy was taken into account. The contribution to the stability in the gas phase and in solution of the intramolecular hydrogen bonds between the hydroxy hydrogen and the quinonoid oxygen is larger at the MP2 level than at the HF one. The directionality of the hydrogen bonds between the hydroxy groups affects considerably only the stability of the isomer with the exocyclic double bond. The computed chemical shifts for the two tautomers were compared to the experimental ones. In addition the solvation properties of 2,5-dihydroxy-3-ethyl-1,4-benzoquinone and of an ortho-quinonoid system were considered in order to evaluate the effect of the repulsion between vicinal hydroxy or quinonoid groups. Received: 14 September 1999 / Accepted: 3 February 2000 / Published online: 2 May 2000     

Photochemical syn-anti isomerization reactions in N2-hydroxyisocytosines--an experimental matrix isolation and theoretical study

N2-hydroxyisocytosine and 1-methyl-N2-hydroxyisocytosine were studied using a matrix isolation technique combined with infrared absorption spectroscopy. For N2-hydroxyisocytosine isolated in an Ar matrix (at 10 K), two imino-oxo isomers, one with the hydroxyimino =N-OH group directed toward the N1-H group (the form called further anti) and the second with the =N-OH group directed toward N3-H (syn), were observed in the ratio 1.4:1. The syn isomer is converted totally to the anti form after UV (lambda > 295 nm) irradiation of the matrix. A small amount of the N(3)H-hydroxy-amino tautomer of N2-hydroxyisocytosine was also detected in the matrix. This form did not react photochemically. For 1-methyl-N2-hydroxyisocytosine, only the syn form of the imino-oxo tautomer was observed after deposition of the matrix. UV (lambda > 295 nm) irradiation induced a photoreaction converting this isomer into the anti form. After 15% of the starting material had been converted into the product, a photostationary state was achieved, and no further progress of the reaction was observed. Subsequent UV irradiation (lambda > 335 nm) caused a back reaction, leading to a disappearance of the anti form and to the recovery of the initial syn isomer. All isomers were identified by comparing their experimental IR spectra with the spectra theoretically calculated at the DFT(B3LYP)/6-31G(d,p) level, where DFT is the density functional theory. Good agreement between the observed and predicted patterns of the spectral lines allowed for reliable identification. The experimental IR spectra were interpreted and discussed. The relative energies of the 12 isomers of N2-hydroxyisocytosine were calculated at the MP2/6-31G(d,p) and MP4//MP2/6-31G(d,p) levels. For six isomers of 1-methyl-N2-hydroxyisocytosine, the calculations were carried out at the MP2/6-31G(d,p) level. The anti form of the imino-oxo tautomer of N-hydroxyisocytosine and the syn form of the imino-oxo tautomer of 1-methyl-N2-hydroxyisocytosine were predicted to be the most stable.     

Reaction of dialuric acid with hydrazine derivatives

In the condensation of dialuric, thiodialuric, and acetyldialuric acids with hydrazine derivatives, the ketone character of the CO group in the 2 position is manifested only in the case of acetyldialuric acid; the hydroxy or mercapto group in dialuric and thiodialuric acids is substituted to form 5-substituted derivatives of these acids.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 267–269, February, 1973.     

Heterocycles from aroylacetic aldehydes and SH-containing hydrazides

Condensation products of aroylacetic aldehydes with hydrazides of thioglycolic, 3-mercaptopropionic and 2-mercaptobenzoic acids exist in cyclic 1,3,4-thiadiazine, 1,3,4-thiadiazepine, or 1,3,4-benzothiadiazepine forms arising at the intramolecular addition of the mercapto group to the C=N bond of the initially formed hydrazone tautomer. The appearance of an alternative 5-hydroxy-2-pyrazoline form is favored by introduction of a strong electron-acceptor substituent into the aromatic ring of the 1,3-ketoaldehyde or by going over to benzoylacetone derivatives. In solutions the derivatives of aroylacetic aldehydes and of benzoylacetone show no tendency to tautomeric transition into linear hydrazine or enhydrazine forms.

     

Oxo-hydroxy tautomerism of 5-fluorouracil: water-assisted proton transfer

Post-Hartree-Fock ab initio quantum chemical calculations were performed for 5-fluorouracil in the gas phase and in a three-water cluster. Full geometry optimizations of the 5-fluorouracil-water complexes were carried out at the MP2/6-31+G(d,p) level of theory. MP4/6-31+G(d,p)//MP2/6-31+G(d,p) and MP4/6-31++G(d,p)//MP2/6-31+G(d,p) single-point calculations were performed to obtain more accurate energies. In water solution, 5-fluorouracil exists mainly in the 2,4-dioxo form (A). We propose that the populations of the 2-hydroxy-4-oxo (B) and 4-hydroxy-2-oxo (D) tautomers are 1 x 10(-4)% and 3.9 x 10(-8)%, respectively, on the basis of the relative stabilities of the tautomers calculated at the MP4/6-31++G(d,p)//MP2/6-31+G(d,p) level of theory. A profound difference between isolated and hydrated 5-fluorouracil is noted for the height of the tautomerization barrier. In the absence of water, the process of proton transfer is very slow. The addition of water molecules decreases the barrier by 2.3 times, making the process much faster. The minimum energy path (MP2/6-31+G(d,p)) for water-assisted proton transfer in trihydrated 5-fluorouracil was followed. CNDO/S-CI calculations predict singlet pi-pi(*) electron transitions at 312 nm for B and at 318 nm for D. The fluorescence spectrum of 5-fluorouracil in water confirms the presence of the hydroxy tautomer.     

A thermochemistry and kinetic study on the thermal decomposition of ethoxyquinoline and ethoxyisoquinoline

Quantum chemical calculations were used to study the production of ethylene and keto/enol tautomers from ethoxyquinoline (2‐EQ) and ethoxyisoquinoline (1‐EisoQ and 3‐EisoQ) in the gas phase and ethanol at the MP2/6‐311++G(2d,2p)//BMK/6‐31+G(d,p) level. The obtained data indicate that the elimination of ethylene from 1‐EisoQ and 2‐EQ is slightly more favorable than from 3‐EisoQ. Formation of quinolone and isoquinolone (2‐EQO, 1‐EisoQO, and 3‐EisoQO) is kinetically favored compared to their enols. Decomposition of 2‐EQ and 1‐EisoQ to ethylene and keto forms is thermodynamically and kinetically preferable more stable than the corresponding enols. However, the hydroxy form of 3‐EisoQ is more stable than its keto tautomer in the gas phase and ethanol. The enol tautomers cost less energy when formed from their keto forms rather than from the parent ethoxyquinolone and ethoxyisoquinoline.     

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.     

CNDO/2 study on tautomerism in monosubstituted pyridines and pyrimidines

A molecular orbital calculation in the CNDO/2 approximation has been used to discuss the tautomeric stability of pyridine and pyrimidine substituted by amino, mercapto and hydroxy groups, respectively. The results of the calculations predict the stability of the amino and mercapto compounds, while the results for hydroxy substituted molecules are less satisfactory. A tentative calculation has been performed for the barrier of the proton motion in the intramolecular hydrogen bond of 2-substituted pyridines.     

Molecular structures of benzoic acid and 2-hydroxybenzoic acid, obtained by gas-phase electron diffraction and theoretical calculations

The structures of benzoic acid (C6H5COOH) and 2-hydroxybenzoic acid (C6H4OHCOOH) have been determined in the gas phase by electron diffraction using results from quantum chemical calculations to inform restraints used on the structural parameters. Theoretical methods (HF and MP2/6-311+G(d,p)) predict two conformers for benzoic acid, one which is 25.0 kJ mol(-1) (MP2) lower in energy than the other. In the low-energy form, the carboxyl group is coplanar with the phenyl ring and the O-H group eclipses the C=O bond. Theoretical calculations (HF and MP2/6-311+G(d,p)) carried out for 2-hydroxybenzoic acid gave evidence for seven stable conformers but one low-energy form (11.7 kJ mol(-1) lower in energy (MP2)) which again has the carboxyl group coplanar with the phenyl ring, the O-H of the carboxyl group eclipsing the C=O bond and the C=O of the carboxyl group oriented toward the O-H group of the phenyl ring. The effects of internal hydrogen bonding in 2-hydroxybenzoic acid can be clearly observed by comparison of pertinent structural parameters between the two compounds. These differences for 2-hydroxybenzoic acid include a shorter exocyclic C-C bond, a lengthening of the ring C-C bond between the substituents, and a shortening of the carboxylic single C-O bond.     

Crystal structure and ab initio calculations of a cyano-carbamimidic acid ethyl ester

The structure of one tautomer (amine form) of cyano-carbamimidic acid ethyl ester or (amino-ethoxy-methylidene)aminoformonitrile (CAS: 13947-84-7) was determined by single crystal X-ray diffraction. Ab initio quantum chemical calculations at the B3LYP, MP2 and G3 levels were performed to investigate the stability and the formation of the different tautomers and conformers. The calculations indicate that the amine form is the more stable tautomer, showing a high degree of electron conjugation. The most stable amine conformer located by the calculations corresponds to the crystallized structure. On the contrary, in the less stable imine form, the conjugation is separated by a N2–C2 single bond.     

DFT and MP2 Calculations on Tautomers and Water-Assisted Proton Transfer on 1,2,5-Oxadiazol-4,3-diamine

In this work a detailed quantum-chemical comparison of the relative stability of six tautomers of 1,2,5-oxadiazol-4,3-diamine studied in the gas phase and solution. Theoretical calculations are carried out by the density functional theory (DFT/B3LYP) and MP2 methods using the standard 311++G(d,p) basis set. The results indicate that A is the most stable form in the gas phase and also is the predominant tautomer in solution at the DFT and MP2 methods. The transition states of proton transfer reaction are calculated. The variation of dipole moments and charges on atoms are studied in various solvent. Specific solvent effects with addition of one water molecule near the electrophilic centers of tautomer investigated. Also the transition state of proton transfer assisted by a water molecule was investigated.     

Systematic effect of benzo-annelation on oxo-hydroxy tautomerism of heterocyclic compounds. Experimental matrix-isolation and theoretical study

Oxo-hydroxy tautomerism and phototautomerism of 2-quinolinone, 1-isoquinolinone, 3-hydroxyisoquinoline, 2-quinoxalinone, and 4-quinazolinone were studied using the matrix-isolation technique. These compounds contain a benzene ring fused with a heterocyclic ring of 2-pyridinone, 2-pyrazinone, or 4-pyrimidinone. It turned out that direct attachment of a benzene ring to a heterocycle leads to a very pronounced increase of the relative stability of oxo tautomers (in comparison with the tautomerism of the parent compounds 2-pyridinone, 2-pyrazinone, and 4-pyrimidinone). The only exception concerns 3-hydroxyisoquinoline, where fusion with a benzene ring enforces rearrangement of the double- and single-bond system in the oxo tautomer. This destabilizes substantially the oxo form with respect to the hydroxy tautomer. The ratios of population of the oxo and hydroxy tautomers observed in Ar matrixes correspond to the tautomeric equilibria of the compounds in the gas phase. These equilibria were well reproduced by theoretical calculations carried out at the QCISD and QCISD(T) levels. The combined experimental and theoretical results reveal links between aromaticity and tautomerism. Moreover, a UV-induced phototautomeric reaction transforming the oxo forms into the hydroxy tautomers was observed for all (except 3-hydroxyisoquinoline) studied compounds. This photoeffect allowed separation of the IR spectra of the tautomers in question.     

Theoretical study of the excited singlet and triplet states of alloxan

The possibility of excited‐state protomeric shifts in the biologically important molecule, alloxan, is investigated. We have focused on the S₁ and T₁ excited states of alloxan and its hydroxy tautomers. Modifications brought in by excitation on the relative stabilities, activation barriers, and optimized geometries, computed at the MNDO, AM1, and PM3 levels of approximation, have been discussed for both excited electronic states. The absorption and fluorescence spectra for the three tautomers are also discussed. Results show significant changes in the geometries on excitation, although the changes are similar for the singlet and triplet excited states. Though the relative stability orders do not change, the 2‐hydroxy tautomer is stabilized, while the 4‐hydroxy tautomer gets destabilized on excitation. The excited states are (n,π*) states, involving the promotion of a nonbonding oxygen lone pair from the CO? CO? CO moiety, which explains why the oxygens of this group become less basic and the 4‐hydroxy tautomer gets destabilized on excitation. However, the activation barriers do not reduce significantly on excitation, and this precludes the possibility of ground‐ or excited‐state proton transfer in the gas phase. © 2001 John Wiley & Sons, Inc. Int J Quantum Chem, 2001     

Conjugation and hyperconjugation in conformational analysis of cyclohexene derivatives containing an exocyclic double bond

The equilibrium geometry, ring-inversion pathway barriers for analogues of cyclohexene with an exocyclic double bond have been studied using the MP2/6-311 G(d,p) level of theory. The equilibrium conformation of the ring depends on conjugation between the endocyclic and exocyclic double bonds. Interactions between conjugated double bonds include the pi-pi conjugation and interactions between the lone pair of the heteroatom of the exocyclic double bond and the sigma-antibonding orbital of the endocyclic single bond. In the case of the tetrahydrocycles with double bonds separated by a methylene group the balance between the pi --> sigma* hyperconjugation interactions between the exocyclic double bond and the neighboring methylene group and the n --> sigma* interaction between the lone pair of the heteroatom and the sigma-antibonding orbitals of the C(sp(2))-C(sp(3)) bond determine the geometrical parameters of the ring. The character of the potential-energy surface around the saddle point depends on the position of the exocyclic double bond and the orientation of the hydrogen atom attached to the heteroatom of the V group of the periodic table in the tetrahydrocycles with double bonds separated by a methylene group.     

Conformation and tautomerism of the cimetidine molecule: a theoretical study

The cimetidine molecule conformation and tautomer stability was studied at the ab initio HF/6-31G** level and for single point energies at the MP2/6-31G** level. The most stable N3-H cimetidine tautomer was found to be more stable than the most stable N1-H tautomer by ca. 3.7 and 5.0 kcal/mol, at the HF/6-31G** and MP2/6-31G**//HF/6-31G** level, respectively. At the HF/6-31G** level, the most stable N3-H and 1-H forms are stabilized by the intramolecular N3′-H?N1 hydrogen bond and N1-H?N4′, respectively. However, when the correlation effects are included at the MP2/6-31G**//HF/6-31G** level, the most stable N3-H and N1-H tautomers appeared to be folded forms without hydrogen bonds.     

Tautomeric and conformational equilibrium of 2-nitrosophenol and 9,10-phenanthrenequinonemonooxime: ab initio and NMR study

The tautomeric and conformational equilibrium of 2-nitrosophenol and 9,10-phenanthrenequinonemonooxime was studied by ab initio methods. The geometry optimizations of the structures investigated were done without any geometrical restrictions at HF/6-31G** and MP2/6-31G** levels of theory. The transition structures for tautomeric and rotameric conversions were located. To correct for electron correlation, single-point calculations were carried out up to MP4/6-311G*//MP2/6-31G* level of theory.

Ab initio calculations for 2-nitrosophenol in agreement with the available experimental data define the nitroso form as more stable. It was found that the influence of the correlation energy on the relative stabilities is smaller for the rotamers of the nitroso tautomer but substantially (4–6 kcal/mol) for the oxime forms. It was found that the barrier height of tautomerization reaction is 10.24 kcal/mol.

The structure of the 9,10-phenanthrenequinonemonooxime was studied by solid and liquid state NMR spectroscopy. Ab initio calculations in agreement with our experimental data predict that the compound exists as oxime tautomer and the syn-oxime is most stable. It was found that the solvent influence on the relative stabilities of both isomers: syn- and anti-oxime. While in chloroform solution the syn-oxime is preferred but in DMSO anti-oxime is more stable in energy.

At the MP4/6-311G*//MP2/6-31G**+ZPE level of theory the barrier of tautomerization was predicted to be 10.96 kcal/mol and the rotational barrier around the single C–O bond in the syn-oxime was found to be 7.57 kcal/mol. The rotation is facile and this explains the absence of nitroso tautomers in solution.     

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.     

Chemoselectivity in reactions of esterification

This review is devoted to the problem of chemoselective formation of ester functions in polyfunctional molecules. The review covers most typical approaches to chemoselective acylation of hydroxy groups in molecules containing an amino, mercapto, or another hydroxy functionality as well as chemoselective esterification of di- and polycarboxylic acids.     

Remarkably strong polarization of amidine fragment in the crystals of 1-imino-1H-isoindol-3-amine

Results of the X-ray diffraction studies of 1-imino-1H-isoindol-3-amine and its derivatives reveal unusual distribution of bond lengths within the NH₂–C=N amidine fragment in the considered crystals. In the crystal phase, single C–N bond is shorter or at most has the same length as double C=N bond, while in isolated molecules both these bonds have expected lengths, according to the calculations by MP2/6-311G(d,p) and MP2/cc-pvtz methods. It is demonstrated that so unusually strong polarization of the amidine fragment is induced by polar environment in solid state. This effect stabilizes the amino-imino tautomer of 1-imino-1H-isoindol-3-amine, which becomes more stable than the diimino tautomer possessing the lowest energy in the gas phase.     

Quantum chemical investigation of the molecular structure of some 2,3-dihydro-1,4-diazepines and related molecules

Accurate ab-initio and semi-empirical molecular orbital calculations with full geometry optimization were performed on the various tautomeric forms of some 2,3-dihydro-1,4-diazepines and related molecules. The highly accurate ab-initio calculations at the HF/6–31G7 level with Möller-Plesset Second-Order Perturbation Theory (MP2) refinement clearly established the higher stability of the enamine tautomer of the 1,4-diazepine ring over the di-imine form by 27.786 kJ/mol, whereas the semi-empirical calculations at the NDDO level (AM1 and PM3) predicted comparable energies within reported errors of the two methods. However, both ab-initio and semi-empirical NDDO methods predicted similar geometries in agreement with observed geometrical parameters. The AM1 calculations predicted small energy differences among the three tautomeric forms of 2,3-dihydro-5-methyl 7-phenyl 1,4-diazepine with the more polar enamine tautomer being the more stable tautomer in the half-chair conformation which is likely to predominate in polar media through stabilizing intermolecular solute-solvent interactions.