Substituent and ring effects on enthalpies of formation: 2-methyl- and 2-ethylbenzimidazoles versus benzene-and imidazole-derivatives

The enthalpies of combustion, heat capacities, enthalpies of sublimation and enthalpies of formation of 2-methylbenzimidazole (2MeBIM) and 2-ethylbenzimidazole (2EtBIM) are reported and the results compared with those of benzimidazole itself (BIM). Theoretical estimates of the enthalpies of formation were obtained through the use of atom equivalent schemes. The necessary energies were obtained in single-point calculations at the B3LYP/6-311+G(d,p) on B3LYP/6-31G* optimized geometries. The comparison of experimental and calculated values of benzenes, imidazoles and benzimidazoles bearing H (unsubstituted), methyl and ethyl groups shows remarkable homogeneity. The energetic group contribution transferability is not followed, but either using it or adding an empirical interaction term, it is possible to generate an enormous collection of reasonably accurate data for different substituted heterocycles (pyrazole-derivatives, pyridine-derivatives, etc.) from the large amount of values available for substituted benzenes and those of the parent (pyrazole, pyridine) heterocycles.We acknowledge the financial support of the DGI/MCyT (project nos. BQU-2003-00976, 01251 and 05827). This work has been partially supported by the DGI project no. BQU-2003-00894. A generous allocation of computational time at the CCC of the Universidad Auto´noma de Madrid is also gratefully acknowledged. Thanks are also due to Instituto de Cooperac¸a˜o Cientı´fica e Tecnolo´gica Internacional (ICCTI), Lisbon, Portugal, and Consejo Superior de Investigaciones Cientı´ficas (CSIC), Madrid, Spain, for a joint research project ICCTI/CSIC. MLPFA thanks Fundac¸a˜o para a Cieˆncia e Tecnologia (FCT), Lisbon, Portugal, for the award of a postdoctoral fellowship (PRAXIS XXI/BPD/16319/98) and MT thanks MECD/SEEU (AP 2002-0603), Spain, for financial support

Substituent effects on enthalpies of formation of nitrogen heterocycles: 2-substituted benzimidazoles and related compounds

The enthalpies of combustion, heat capacities, enthalpies of sublimation and enthalpies of formation of 2-tert-butylbenzimidazole (2tBuBIM) and 2-phenylimidazole (2PhIM) are reported and the results compared with those of benzene derivatives and a series of azoles (imidazoles, pyrazoles, benzimidazoles and indazoles). Theoretical estimates of the enthalpies of formation were obtained through the use of atom equivalent schemes. The necessary energies were obtained in single-point calculations at the B3LYP/6-311++G(d,p) on B3LYP/6-31G* optimized geometries. The comparison of experimental and calculated values of all studied compounds bearing H (unsubstituted), methyl (Me) ethyl (Et), propyl (Pr), isopropyl (iPr), tert-butyl (tBu), benzyl (Bn) and phenyl (Ph) groups show remarkable homogeneity. The remarkable consistency of both the calculated and experimental results allows us to predict with reasonable certainty the missing experimental values. The crystal and molecular structure of the 2-benzylbenzimidazole (2BnBIM) has been determined by X-ray analysis. The observed molecular conformation permits the crystal being built up through N−H···N hydrogen bonds and van der Waals contacts between the molecules. An attempt has been made to relate the crystal structure to the enthalpies of sublimation.Thanks are due to Instituto de Cooperac¸a˜o Cientı´fica e Tecnolo´gica International (ICCTI), Lisbon, Portugal, and Consejo Superior de Investigaciones Cientı´ficas (CSIC), Madrid, Spain. L.M.P.F.A. thanks Fundac¸a˜o para a Cieˆncia e Tecnologia (FCT), Lisbon, Portugal, for the award of a postdoctoral fellowship (PRAXIS XXI/BPD/16319/98). This work has also been financed by DGICYT (BQU-2003- 00894, -00976 and -01251)

Experimental thermochemical study of two 2-alkylbenzimidazole isomers (alkyl = propyl and isopropyl)

This paper reports the values of the standard (p∘=0.1 MPa) molar enthalpy of formation in the condensed, at T=298.15 K, for 2-R-benzimidazoles (R=propyl, isopropyl), derived from, the respective enthalpies of combustion in oxygen, measured by static bomb combustion calorimetry and the standard molar enthalpies of sublimation, at T=298.15 K, obtained using Calvet microcalorimetry in the case of 2-isopropylbenzimidazole and, by the variation of vapour pressures, determined by the Knudsen effusion technique, with temperatures between (344 and 365) K for 2-propylbenzimidazole. Heat capacities, in the temperature ranges from T=268 K to near their respective melting temperatures, T=421 K for 2-propylbenzimidazole and T=464 K for 2-isopropylbenzimidazole, were measured with a differential scanning calorimeter. These values were used to derive the standard molar enthalpies of formation, of the two 2-benzimidazole derivatives, in gaseous phase.Thanks are due to Instituto de Cooperação Cientı́fica e Tecnológica Industrial (ICCTI), Lisbon, Portugal, and Consejo Superior de Investigaciones Cientı́ficas (CSIC), Madrid, Spain for a joint research project CSIC/ICCTI; M.L.P.F.A. thanks Fundação para a Ciência e Tecnologia (FCT), Lisbon, Portugal, for the award of a postdoctoral fellowship (SRFH/BPD/5595/2001). The Spanish DGI/MCyT is acknowledged under projects BQU2000-0252, 0906 and 1497; M.T. thanks MECD/SEEU, AP2002-0603, Spain for financial support

Enthalpies of formation of N-substituted pyrazoles and imidazoles

Accurate experimental enthalpies of formation measured using static bomb combustion calorimetry, the “vacuum sublimation” drop calorimetry method, and the Knudsen-effusion method are reported for the first time for four azoles:  1-methylimidazole (1MeIMI), 1-methylpyrazole (1MePYR), 1-benzylimidazole (1BnIMI), and 1-benzylpyrazole (1BnPYR). These values and those corresponding to imidazole (1HIMI), pyrazole (1HPYR), 1-ethylimidazole (1EtIMI), 1-ethylpyrazole (1EtPYR), 1-phenylimidazole (1PhIMI), and 1-phenylpyrazole (1PhPYR) are compared with theoretical values using the G2(MP2) and the B3LYP/6-311*G(3df,2p)//6-31G(d) approaches. In general, there is a very good agreement between calculated and experimental values for the series of N-substituted imidazoles, while the agreement is less good for the series of the N-substituted pyrazoles. Experimentally, the gap between the enthalpies of formation of imidazoles and pyrazoles decreases significantly upon N-substitution, while the theoretical estimates indicate that this decrease is smaller.This work has been partially supported by the DGES Projects PB 96-0001-C03-03, PB96-0067, and PB96-0927-C02-01. A generous allocation of computational time at the Centro de Computacio´n Cientı´fica de la Facultad de Ciencias (CCCFC) de la UAM is also gratefully acknowledged. Thanks are due to Junta National de Investigac¸a˜o Cientı´fica e Tecnolo´gica (JNICT), Lisbon, Portugal and Consejo Superior de Investigaciones Cientı´ficas (CSIC), Madrid, Spain, for a joint research project CSIC/JNICT. Financial support from the Praxis XXI, Project 2/2.1/qui/54/94, is acknowledged. L.M.P.F.A. thanks Fundac¸aˆo para a Cieˆncia e Tecnologia, Lisbon, Portugal for the award of a postdoctoral fellowship (Praxis XXI/BDP/16319/98). J.F.L. acknowledges funding from “Dow Chemical Company” for partial support of his thermochemical studies

The annular tautomerism of the curcuminoid NH-pyrazoles

The structures of four NH-pyrazoles, (E)-3,5-bis[β-(4-hydroxy-3- methoxyphenyl)-ethenyl]-1H-pyrazole (3), (E)-3(5)-[β-(4-hydroxy-3- methoxyphenyl)-ethenyl]-5(3)-methyl-1H-pyrazole (4), (E)-3(5)-[β-(4- hydroxy-3-methoxyphenyl)-ethenyl]-4,5(3)-dimethyl-1H-pyrazole (5) and (E)-3(5)-[β-(3,4-dimethoxyphenyl)-ethenyl]-4-methyl-5(3) -phenyl-1H-pyrazole (8), have been determined by X-ray crystallography. Compounds that have a phenol residue crystallize forming sheets that are stabilized by a complex pattern of hydrogen bonds between a unique tautomer (4), or by a 2: 1 mixture of both tautomers (5) (these tautomers being identical in the case of 3). Pyrazole 8, which lacks OH groups, crystallizes in cyclic dimers that are stabilized by N-H⋯N hydrogen bonds. The tautomerism in solution and in the solid state was determined by 13C and 15N CPMAS NMR spectroscopy. For compounds 4, 5 and 8, the solid state results agree with those observed by crystallography; the most abundant tautomer in solution coincides with the tautomer present in the solid state (4 and 8) or with the most abundant tautomer in the crystal (5). © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.Peer Reviewe

Structures of Hemi-Curcuminoids in the Solid State and in Solution

Hemi-curcuminoids are derivatives of the antioxidant radical scavenger curcumin in which one styryl moiety is missing but the β-diketone functionality is maintained. Five such derivatives have been prepared, and the X-ray molecular structures for all of them have been determined. The tautomerism of the five compounds has been studied by NMR in the solid state and in solution. An enol–enol proton transfer barrier has been determined.This work was financed by the Spanish Ministerio de Ciencia e Innovación (MICINN) (CTQ2010-16122) and the Ministerio de Economía y Competitividad (MEC) (CTQ2012-35513-C02-02) and by the Comunidad Autónoma de Madrid (project MADRISOLAR2, ref. number S2009/PPQ-1533). The authors thank Dr. Ibon Alkorta for his help with the CSD and Dr. Ma Ángeles García for her assistance in recording the variable-temperature NMR spectra.Peer reviewe

Crystal and molecular structures of two 1H-2-substituted benzimidazoles

The X-ray molecular structure of two benzimidazoles unsubstituted on the nitrogen atoms (2-ethyl- 1H-benzimidazole and 2-propyl-1H-benzimidazole) has been determined and analysed in the context of crystallographic and solid-state NMR data of seven substituted benzimidazoles. The first compound presents polymorphism, and two polymorphs [forms 3a and 3c] were obtained from different solutions of dichloromethane/ hexane. Polymorph (3a) contains two independent molecules differing in the conformation of the ethyl group. Polymorph (3c) contains only one molecule in the asymmetric unit, with similar configuration as the ordered molecule of polymorph (3a). Another polymorphic form (3b) is obtained by cooling form (3a) below 179 K. The transition is related to an order-disorder process and involves a change in the hydrogen-bonding scheme. The second compound (4) presents enantiomorphism and its asymmetric unit contains four independent molecules that differ in the conformation of the 2-propyl group. For form (3a), the splitting of NMR signals is almost perfectly consistent with the features of the crystal structure, whereas not splitting is observed for compound (4). Agreements between NMR and X-ray crystallography techniques are also observed in other simple 2-R-1H-benzimidazoles (R = C4H9, CH2C6H5 and C6H5), but disagreements are found for R = H, CH3.Authors thanks to Prof. T. Breczewski for helping in DSC measurements. This work has been financed by Ministerio de Ciencia e Innovación (CTQ2010- 16122) and Ministerio de Economía y Competitividad of Spain (CTQ2012-35513-C02-02) and Comunidad Autónoma de Madrid (Project MADRISOLAR2, ref. S2009/PPQ-1533). This work was also supported by the Basque Government (project IT779-13)Peer Reviewe

The molecular structure of 2-phenylbenzimidazole: A new example of incommensurate modulated intramolecular torsion

Molecular crystals of 2-phenylbenzimidazole, C13H 10N2, exhibit a one-dimensional incommensurate structure. The structure has been solved by charge flipping and refined using the superspace formalism in the (3 + 1) D superspace group C2/c(0b0) s0 with modulation wave-vector q = 0.368b*. The unit cell contains 8 molecules, each one disorderly occupying two configurations related by inversion center. The refinement based on a molecular model with two rigid-body parts per molecule includes up to second order Fourier amplitudes for the modulation. The displacive modulation involves a significant intra-molecular twist between the phenyl and the benzimidazole parts. © by Oldenbourg Wissenschaftsverlag.Peer Reviewe

Synthesis and biological evaluation of curcuminoid pyrazoles as new therapeutic agents in inflammatory bowel disease: Effect on matrix metalloproteinases

Seven N-unsubstituted curcuminoid pyrazoles have been synthesized from the corresponding β-diketones (including curcumin). We evaluated the possibility of curcuminoid pyrazoles regulating the activity of matrix metalloproteinases (MMPs) by human intestinal epithelial cells in vitro. Zymographic analysis revealed that three compounds significantly down-regulated MMP-9 activity on inflammation-induced intestinal epithelial cells, making them original candidates for the treatment of inflammatory bowel disease (IBD). © 2008 Elsevier Ltd. All rights reserved.Peer Reviewe

Libration of phenyl groups detected by VT-SSNMR: Comparison with X-ray crystallography

The X-ray crystal structure of 2-benzyl-1H-benzimidazole, 2BnBzIm, was determined at 293 K showing no dynamic phenomena (disorder) of any class. On the other hand, some C NMR signals were absent in the CPMAS spectrum (100 MHz, 300 K). We decided to carry out variable-temperature SSNMR and discovered that the missing signals are ortho and meta carbons of the phenyl ring of the benzyl group. Line-shape analysis and the Eyring equation were used to determine the barrier, which was compared with the calculated DFT for the gas phase that it is much lower.This work was supported by Ministerio de Economía, Industria y Competitividad of Spain (CTQ2014‐56833‐R and CTQ2015‐63997‐C2‐2‐P) and Comunidad Autónoma de Madrid (Project FOTOCARBON, ref. S2013/ MIT2841). Carla I. Nieto is indebted to UNED for a predoctoral contract “FPI Grupos de Investigación.”Peer Reviewe