Tautomeric behavior of 3-(arylhydrazono)methyl-2-oxo-1,2-dihydroquinoxalines between the hydrazone imine and diazenyl enamine forms in acidic media. Solvent and substituent effects

The 3-(arylhydrazono)methyl-2-oxo-1,2-dihydroquinoxalines 1a-h and 2a-e showed tautomeric equilibria between the hydrazone imine A and diazenyl enamine B forms in a series of mixed trifluoroacetic acid/dimethyl sulfoxide media. The substituent and solvent effects on the tautomer ratios of A to B in a series of mixed media were studied for compounds 1a-h and 2a-e by the nmr spectroscopy. In compounds 1a-h and 2a-e , the ratios of the tautomer B gradually increased with elevation of acid concentration, and the tautomer B exclusively existed in trifluoroacetic acid media. The various acid concentrations (C v/v%, C' mol/1) giving the 1:1 tautomer ratios [C(A:B = 1:1), C'(A:B = 1:1)] were obtained from all compounds (Figures 1–13), and the linear correlation of the Hammett σ_p values with the log C'(A:B = 1:1) values were observed for compounds 1a-h. The larger Hammett σ_p values brought about the larger acid concentrations C(A:B = 1:1) in compounds 1a-h and 2a-e , indicating that the higher acid concentration was required for the stabilization of tautomer B possessing the electron-withdrawing p-substituents R¹, which weakened the basicity of the azo nitrogen atom. Moreover, the ester group R² of compounds 2a-e was found to decrease the electron density of the azo nitrogen atom, since the acid concentration C(A:B = 1:1) of compound 2c (R¹ = H, R² = COOMe, σ_p = O) was 52%, whose value was larger than that of compound 1b (R¹ = CN, R² = H, σ_p = 0.66) [C(A:B = 1:1) = 42%].     

Substituent effects on the tautomer ratios between the hydrazone imine and diazenyl enamine forms in side-chained quinoxalines

The 3-(arylhydrazono)methyl-2-oxo-1,2-dihydroquinoxalines 9–11 were synthesized by the reaction of the quinoxalines 6–8 with various p-substituted benzenediazonium salts. Compounds 9–11 showed the tautomeric equilibria between the hydrazone imine A and diazenyl enamine B forms in dimethyl sulfoxide media. The substituent effect on the tautomer ratios of A to B was studied by the nmr spectroscopy to clarify that the presence of the ester group R² on the hydrazone carbon and electron-donating p-substituent R¹ on the side chain benzene ring exhibited a tendency to increase the ratios of the tautomer A .     

Substituent and solvent effects on the tautomer ratios between the hydrazone imine and diazenyl enamine forms in p- and m-substituted 3-(arylhydrazono)methyl-2-oxo-1,2-dihydroquinoxalines

The p- and m-substituted 3-(arylhydrazono)methyl-2-oxo-1,2-dihydroquinoxalines 1a-i and 2a-d exhibited tautomeric equilibria between the hydrazone imine A and diazenyl enamine B forms in a series of mixed dimethyl sulfoxide/trifluoroacetic acid media. The substituent and solvent effects on the tautomer ratios of A to B in a series of mixed media were studied for compounds 1a-i and 2a-d by the nmr spectroscopy. The linear correlation of the Hammett σp and σm values with the tautomeric equilibrium constants K_T ([A]/[B]) was found in the dimethyl sulfoxide media of compounds 1a-i and 2b-d . On the other hand, the linear correlation of the Hammett σp and σm values with the log C'(A:B = 1:1) was also observed in a series of mixed media of compounds 1a-h and 2a-c , wherein C'(A:B = 1:1) indicated the concentrations of trifluoroacetic acid (mol/l) giving 1:1 tautomer ratios in a series of mixed media. The increase in the Hammett σp or σm values decreased the K_T values in dimethyl sulfoxide media and augmented the C'(A:B = 1:1) values in a series of mixed media. The Hammett σp or σm values controlled the electron density of the side chain nitrogen atom, which influenced the C'(A:B = 1:1) values. In the K_T value temperature dependence, the higher temperature provided the larger K_T values in dimethyl sulfoxide media regardless of the Hammett σp or σm values.     

13C-NMR study on the tautomerism of 3-(arylhydrazono)methyl-2-oxo-1,2-dihydroquinoxalines between the hydrazone imine and diazenylenamine forms

The ¹³C-nmr study was carried out for the tautomerism of the 3-(arylhydrazono)methyl-2-oxo-1,2-dihy-droquinoxalines 1a-g and 2a-e between the hydrazone imine A and diazenylenamine B forms, providing the carbon chemical shifts for the tautomers A and B of compounds 1a-g and 2a-e. The comparison of the carbon chemical shifts for the tautomer B of compounds 1d, 1f , and 2b in deuteriodimethyl sulfoxide with those in deuteriotrifluoroacetic acid showed that the C_4a, C₅, and diazenyl carbons were considerably shielded presumably due to the azo N-deuteration in deuteriotrifluoroacetic acid.     

1H-NMR study on the tautomer ratios between the hydrazone imine and diazenylenamine forms in 3-(arylhydrazono)-methyl-2-oxo-1,2-dihydroquinoxalines

The o-substituted 3-(arylhydrazono)methyl-2-oxo-1,2-dihydroquinoxalines 1a-c and 2a , c were synthesized to investigate the tautomeric behavior between the hydrazone imine A and diazenylenamine B forms in a series of mixed dimethyl sulfoxide/trifluoroacetic acid media. The chemical shifts of the hydrazone NH, N₄-H, hydrazone CH, and diazenyl CH protons for o-, m-, and p-substituted 3-(arylhydrazono)methyl-2-oxo-1,2-dihydroquinoxalines 1 and 2 synthesized so far are summarized in Tables 3 and 4, respectively, which are found to be useful for the specification of the proton signals due to the hydrazone imine form A (hydrazone NH, hydrazone CH) and diazenylenamine form B (N₄-H, diazenyl CH).     

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.     

Reactivity of 2-amino-1,3,4-thiadiazoles. Nucleophilic behaviour of some 2-amino-1,3,4-thiadiazoles: Model compounds

The ambident nucleophilic behaviour of some 2-amino-5-H-1,3,4-thiadiazoles in alkylation, acylation and nitrosation reaction has been verified. The structures assigned to the 2-amino-1,3,4-thiadiazoles ( 1a-i ) and to the Δ²-1,3,4-thiadiazolines ( 2a-e ) agree with the spectral data.     

A selective synthesis of 1-aryl-3-quinoxalinyl-1,2,4-triazole and furo[2,3-b]quinoxaline

The reaction of the ester 1 with ethyl benzoate-2-diazonium chloride gave the α-arylhydrazonoester 2b , whose reaction with hydrazine hydrate afforded the α-arylhydrazonoacylhydrazide 3b. The reaction of 3b with sodium nitrite in water/acetic acid under heating on a boiling water bath provided the 1-aryl-3-quin-oxalinyl-1,2,4-triazole 5b , presumably via the α-arylhydrazonoacylazide 4b , while the isolation of 4b and then its refluxing in dioxane/water furnished the furo[2,3-b]quinoxaline 6. The tautomeric behavior of 2b and 3b between the hydrazone imine and diazenyl enamine forms was described together with the tautomer ratio determined by the nmr spectral data.     

Crystal structure of a trinuclear complex of zinc(II) with 2,6-Di-tert-butyl-p-quinone 1′-phthalazinylhydrazone

2,6-Di-tert-butyl-p-quinone 1′-phthalazynylhydrazone (HL) is synthesized; the total energies and geometry of the possible hydrazone tautomeric forms are calculated by quantum chemical methods. The hydrazone phthalazone tautomer is shown to be the most stable, which is well consistent with the ¹H NMR spectroscopic data for hydrazone. An X-ray crystallographic analysis is performed of the hydrazone-based Zn(II) trinuclear complex, in which zinc atoms are linked by the diazine bridge of the phthalazine cycle and two pivalate bridges. The geometric properties of the monodeprotonated hydrazone residue in the complex are similar to the calculated data for the phthalazone hydrazone tautomeric form.     

Substituent effects on the tautomer ratios between the enamine and methylene imine forms in side-chained quinoxalines

The p- and m-substituted 3-arylcarbamoylmethylene-2-oxo-1,2,3,4-tetrahydroquinoxalines 3a-o showed the tautomeric equilibria between the enamine C and methylene imine D forms in dimethyl sulfoxide or dimethyl sulfoxide/trifluoroacetic acid media. The linear correlation of the Hammett σ_p and σ_m values with the log K_T values was observed in the dimethyl sulfoxide/trifluoroacetic acid (2:1) media of compounds 3a-o , wherein K_T meaned the tautomeric equilibrium constants ([D]/[C]).     

A study of the spectra and acidity of 4,5-dihydro-1H-benz[g]indazol-7-ol and 2,3a,4,5-tetrahydro-7-hydroxy-3a-methyl-3H-benz[g]indazol-3-one

The synthesis of 2,3a,4,5-tetrahydro-7-hydroxy-3H-benz[g]indazol-3-one is recorded for the first time. Infrared, pmr, and uv spectral analysis of this pyrazolone and of 4,5-dihydro-1H-benz[g]indazol-7-ol strongly support the presence of one tautomer in each case. Measurements of pK_a values are in agreement with the proposed tautomeric structures based upon comparisons with simpler model systems. The data are taken in aqueous solution since the compounds are soluble at 10^?5 M and the results may more closely approximate that for the structure under physiological conditions.     

Controlled Release of Volatile Aldehydes and Ketones from Dynamic Mixtures Generated by Reversible Hydrazone Formation

Delivery systems generated by reversible hydrazone formation from hydrazine derivatives (see Fig. 1) and carbonyl compounds in H₂O efficiently increase the long‐lastingness of volatile aldehydes and ketones (R¹R²C?O) in various perfumery applications. The hydrazones are usually obtained in an (E) configuration at the imine double bond (NHN?C) and, in the case of aliphatic acylhydrazones R′CO? NH? N?CR¹R² (R′=alkyl), as syn and anti conformers with respect to the amide bond (CO? NHN). An average free‐energy barrier of ca. 78 kJ/mol was determined for the amide‐bond rotation by variable‐temperature ¹H‐NMR measurements (Fig. 2). In the presence of H₂O, the hydrazone formation is entirely reversible, reaching an equilibrium composed of the hydrazine derivative, the carbonyl compound, and the corresponding hydrazone. Kinetic measurements carried out by UV/VIS spectroscopy showed that the same equilibrium was reached for the formation and hydrolysis of the hydrazone. Rate constants are strongly pH‐dependent and increase with decreasing pH (Table 1). The influence of the hydrazine structure on the rate constants is less pronounced than the pH effect, and the presence of surfactants reduces the rate of equilibration (Tables 1 and 3). The full reversibility of the hydrazone formation allows to prepare dynamic mixtures by simple addition of a hydrazine derivative to several carbonyl compounds. Dynamic headspace analysis on dry cotton showed that the presence of a hydrazine derivative significantly increased the headspace concentrations of the different carbonyl compounds as compared to the reference sample without hydrazine (Table 4). The release of the volatiles was found to be efficient for fragrances with high vapor pressures and low H₂O solubility. Furthermore, a special long‐lasting effect was obtained for the release of ketones. The simplicity of generating dynamic mixtures combined with the high efficiency for the release of volatiles makes these systems particularly interesting for practical applications and will certainly influence the development of delivery systems in other areas such as the pharmaceutical or agrochemical industry.     

4-{[(1E)-(2-Hydroxyphenyl)methyl­idene]amino}-1,5-dimethyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one

In the title compound, C₁₈H₁₇N₃O₂, a strong intramolecular O—H⃛N hydrogen bond [N⃛O 2.607 (3), O—H 0.97 (3) and H⃛N 1.71 (3) Å, and O—H⃛N 153 (2)°] was observed, which leads to a unique phenol–imine tautomerism in the solid state. The C=N imine bond distance and the C—N—C bond angle [1.287 (2) Å and 121.7 (1)°, respectively] indicate the existence of this phenol–imine tautomer. In solution, the phenol–imine tautomer of the title free Schiff base ligand is dominant in both polar and non-polar solvents, as supported by ¹H NMR and UV–visible spectroscopic data.     

Thermochemical properties from ab initio calculations: π- and σ-Free radicals of importance in soot formation: •C3H3 (propargyl), •C4H3, •C13H9 (phenalenyl), •C6H5 (phenyl), •C10H7 (naphthyl), •C14H9 (anthryl), •C14H9 (phenanthryl), •C16H9 (pyrenyl), •C12H7 (acenaphthyl), and •C12H9 (biphenylyl)

The calculated difference in the standard heat of formation Δ Δ_fH°(298.15) of n- and i-C₄H₃^• free radicals is 37.9 kJ mol⁻¹ for G3MP2B3 and 45.0 kJ mol⁻¹ for CCSD(T)-CBS (W1U) calculations, which seems to preclude the direct even-carbon radical pathway to benzene and higher PAH (polycyclic aromatic hydrocarbon) formation including soot in a hydrocarbon flame. For the phenyl-type σ-radicals listed in the title, absolute values of Δ_fH°(298.15) have been calculated using G3MP2B3-computed values of bond dissociation energies D°(298.15) and combined with experimental values of Δ_fH° (298.15) for the parent hydrocarbon because of a slight systematic overprediction of the thermodynamic stability of large PAHs by the applied computational G3MP2B3 method. Standard enthalpies of formation Δ_fH°(298.15) as well as absolute entropies S° and heat capacities C°_p are given for a series of π- and σ-free radicals important to combustion as a function of temperature. A spread of roughly 40 kJ mol⁻¹ in the average C H bond strength of PAH leading to σ-radicals has been calculated, the lowest leading to 4-phenanthryl (463.6 kJ mol⁻¹), the highest leading to 2-biphenylyl radical (502.5 kJ mol⁻¹). © 2008 Wiley Periodicals, Inc. Int J Chem Kinet 40: 395–415, 2008     

Potential Functions of Internal Rotation around the Csp2-S Bond and Intramolecular Interactions in Thioanisoles p-RC6H4SCH3

The potential functions of internal rotation around the Csp²-S bond in the compounds p-RC6H4S· CH3 (R = NH₂, OCH₃, CH₃, H, F, Cl, CN, NO₂) are studied by ab initio quantum-chemical calculations taking into account the correlation energy for all the electrons (MP2/6-31G*) and in the approximation of the density functional theory (B3LYP/6-31G*). As the electron-donor power of the p-substituents decreases and their electron-acceptor power grows, the molecular conformation changes in the sequence orthogonal-free rotation-planar. The interaction of the sulfur lone electron pairs with the aromatic ring is studied by the natural bond orbital method. The effect that the conformational changes occurring upon replacement of p-substituents exert on the electron density redistribution is demonstrated. The first Koopmans ionization potentials and the geometric parameters of the molecule are reported.     

NMR spectra of Δ3- and Δ4-pyrrolin-2-one

The spectra of Δ³- and Δ⁴-pyrrolin-2-one were analysed and the sign of all the coupling constants determined by tickling and triple resonance experiments. A positive allylic interaction (J_xz in 2 ) is reported and four-bond couplings are discussed in particular. Deuterium exchange affords evidence for the tautomeric equilibrium between 1 and 2 .     

Kinetics and mechanisms in carbocationic polymerization: The quest for true rate constants

This article is a critical analysis of kinetic dataavailable on carbocationic polymerizations. A survey of published propagation rate constant (k_p) data revealed several orders of magnitude differences. In this article, an explanation of this apparent discrepancy is offered with a case study involving the carbocationic polymerization of 2,4,6‐trimethylstyrene (TMS). With the polymerization mechanism originally proposed for this system, k_p = 1.35 × 10⁴ L mol^?1 s^?1 was extracted from experimental data with the Predici polyreaction package. The alternative mechanism yielded k_p = 1.01 × 10⁷ L mol^?1 s^?1, close to that predicted by Mayr's Linear Free Energy Relationship (LFER). We propose that true rate constants can only be obtained from direct competition experiments or from kinetic interpretation based on independently proven mechanisms. The second part of this review discusses critical analysis of the temperature and concentration dependence of various living IB systems. Comparison of the temperature dependence in systems initiated with 2‐ chloro‐2,4, 4‐ trimethylpentane (TMPCl)/TiCl₄ from various laboratories yielded of ΔH ～?25 and ?34.5 kJ/mol for high and low TMPCl/TiCl₄ ratios, respectively. Aromatic (cumyl‐type) initiators show ΔH ～ ?40 kJ/mol, whereas H₂O/TiCl₄ in the presence of the strong electron‐ pair donor dimethylacetamide gave ΔH = ?12 kJ/mol. The significant differences indicate different underlying mechanisms with complex elementary reactions. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5394–5413, 2005     

Tautomerism of aza cycles: I. Structure of 3(5)-butylsulfanyl-5(3)-methyl(phenyl)-1H-1,2,4-triazole tautomers in crystal. Preference of the 3-RA-5-RD-1H-tautomer of 3(5)-mono-and 3,5-disubstituted 1,2,4-triazoles

The X-ray diffraction study of potentially tautomeric 3(5)-butylsulfanyl-5(3)-methyl-1H-1,2,4-triazole and its 5(3)-phenyl-substituted analog showed that these compounds in crystal have the structure of 3-butylsulfanyl-5-methyl(phenyl)-1H-tautomers. Analysis of our experimental and published data indicated that 3(5)-monosubstituted 1,2,4-triazoles and 3,5-disubstituted derivatives having nonequivalent substituents in crystal as exist as a tautomer in which the electron-acceptor substituent (R_A) occupies the 3 position, while the electron-donor substituent (R_D) resides in the 5 position, i.e., as 3-R_A-5-R_D-1H-1,2,4-triazoles. Symmetric 3,5-disubstituted 1,2,4-triazoles could give rise to tautomeric equilibrium between the 1H-and 2H-structures even in crystal.     

Acyl- und Alkylidenphosphane. XXXII [1, 2]. Di-cyclo-hexoyl- und Diadamant-1-oylphosphan — Keto-Enol-Tautomerie und Struktur

Acyl- and Alkylidenephosphines. XXXII. Di-cyclohexoyl- and Diadamant-1-oylphosphine – Keto-Enol Tautomerism and Structure Lithium dihydrogenphosphide · DME (¹) [12] and cyclo-hexoyl or adamant-1-oyl chloride react in a molar ratio of 3:2 to give lithium di-cyclo-hexoylphosphide · DME and the corresponding diadamant-1-oylphosphide.2THF (¹) resp. Treatment of these two compounds with 85% tetrafluoroboric acid. diethylether adduct yields di-cyclo-hexoyl- ( 1b ) and diadamant-1-oylphosphine ( 1c ). In nmr spectroscopic studies 1b over a range of 203 to 343 K, a strong temperature dependence of the keto-enol equilibrium is found; thermodynamic data characteristic for the formation of the enol tautomer (ΔH⁰ = ?4.3 kJ. mol^?1; ΔS⁰ = ?9.2 J. mol^?1. K (^?1) are compared of 1,3-diketones. The enol tautomer of diadamant-1-oylphosphine ( E-1c ) as obtained from a benzene solution in thin colourless plates, crystallizes in the monoclinic space group P2₁/c {a = 722.2(2); b = 1085.5(4); c = 2434.8(5) pm; ß = 96.43(2)° at –100 ± 3°C; Z = 4}. An X- ray structure analysis (R_w = 0.033) shows bond lengths and angles to be almost identical within the enolic system (P? C 179/180; C? O 130/129; C? C(adamant-1-yl) 152/153 pm; C? P? C 99°; P? C? O 124°/124°; P? C? C 120°/120°; C? C? O 116°/116°. The geometry of the very strong, but probably asymmetric O‥H‥O bridge is discussed (O? H 120/130, O‥O 245 pm).     

Synthesis,Tautomerism, and Antiradical Activity of Novel Pteridinetrione Derivatives

Synthesis of 1‐methyl‐6‐((2‐(aryl‐(heteryl‐))‐2‐oxoethyl) pteridine‐2,4,7(1H,3H,8H)‐triones via [4 + 2]‐cycloaddition of 1‐methyl‐5,6‐diaminouracil with ethyl 4‐aryl(heteryl)‐2,4‐dioxobutanoates is described in presented work. It was established that the reaction occurs regioselectively and proceeds under refluxing of starting compounds in acetic acid for 60 min. The structures of synthesized compounds were proven by complex of physicochemical methods including infrared, ¹H‐, ¹³C‐NMR spectroscopy, liquid chromatography–mass spectrometry, and electron impact–mass spectrometry. Based on the detail analysis of the correlational NMR spectral data (correlation spectroscopy, heteronuclear single quantum coherence, heteronuclear multiple bond correlation, and Nuclear Overhauser effect spectroscopy), it was determined that in dimethyl sulfoxide solution, the 1‐methyl‐6‐((2‐(aryl‐(heteryl‐))‐2‐oxoethyl)pteridine‐2,4,7(1H,3H,8H)‐triones exist in two tautomeric forms: ketone (A) and enol (B). It was also found that tautomeric behavior of aforementioned compounds in hexadeuterated dimethyl sulfoxide is sensitive to the nature of the aryl or heteryl substituent at the position 6 of ring. The electron donating groups shift equilibrium to the tautomer A, while electron withdrawing – to the tautomer B. The synthesized compounds were tested on antiradical activity. It was found that obtained compounds reveal radical scavenging activity comparable or higher than ascorbic acid.