DOI:10.1139/cjc-2023-0076

An NMR experimental and theoretical study of pyrazagalloles, the gallium analogues of pyrazaboles

Five pyrazagalloles bearing H and CH3 substituents on the gallium atom and/or in the pyrazole ring have been calculated. The theoretical results have been compared with literature results concerning geometries from the Cambridge Data Base with very good agreement. 1H and 13C NMR results from the literature, scarce, and unpublished from our group are also well reproduced from GIAO calculations. The most important conclusion from this work is the assignment to a pz3Ga3 trimer as the isomer present in the 1H NMR spectra of dimeric pyrazagalloles. A mechanism connecting dimers and trimers has been found and the transition states identified.

DOI:10.1016/j.cplett.2024.141293  (OpenAccess)

Theoretical structure determination of a class of heterocyclic compounds: The pyrazolidines

Theoretical calculations at the B3LYP-D3(BJ)/6–311++G(d,p) level of a series of 35 neutral pyrazolidines and 3 protonated derivatives have been carried out for different conformers generated using the CREST program. Seven optimized geometries were compared with X-ray determined structures and their 1H and 13C GIAO calculated chemical shifts with experimental results. The remaining pyrazolidines were compared with the available NMR information. The core of the present paper is the use of the pseudorotational wheel of Cremer and Pople to discuss the experimental and calculated conformation of the five-membered ring.

DOI: 10.1007/s11224-024-02286-5   (OpenAccess)

Theoretical study of the formation of pyrazole and indazole carbamic acids

A theoretical study of the formation of carbamic acids of pyrazole and indazole has been carried out using DFT computational methods. The effects of the substituents and the solvent (using explicit and implicit solvent models) have been considered. In addition, the deprotonation of the carbamic acid and its influence on the stability of the system has been calculated. In the neutral systems, only the formation of indazole-1-carbamic acid derivatives is favored vs. the non-covalent complexes between pyrazole or indazole with CO2. The deprotonation of the carbamic acid highly stabilizes the system preventing its dissociation.

DOI: 10.24820/ark.5550190.p012.171   (OpenAccess)

Hydrogen and halogen rearrangements in imidazoles: Hydrogen, fluorine, chlorine and bromine shifts

The structures and energetics of the minima and the transition states corresponding to the migration of hydrogen and halogen atoms (F, Cl, Br) in imidazole and in cyclopentadiene rings have been calculated using the composite method Gaussian-4 (G4), a quantum chemical method for the calculation of energies of molecular species containing first-row, second-row, and third row main group atoms. The heats of formation obtained from the G4 values were found to be reliable by comparing them with the NIST Chemistry WebBook values of cyclopentadiene, imidazole and related compounds. The new G4 values thus obtained have been discussed using correlation analyses. In summary, this work was carried out because there is no clear evidence for intramolecular halogen migrations in azoles.

DOI:10.1002/hlca.202300090  (OpenAccess)

Borotropy: The Mechanism of Boron Transfer Between Adjacent N-Atoms of Pyrazol-1-yl Rings

This work examines theoretically the problem of the migration of borane groups between the nitrogen atoms of pyrazolyl rings. We have studied as a model the BH2 pyrazol-1-yl derivatives to determine the effects of substituents on the pyrazole ring; also 1-(9-borabicyclo[3.3.1]nonan-9-yl)-1H-pyrazoles to compare the calculated barriers with the experimental ones as well as to determine steric effects, i. e., how the buttressing effect increases the rate. The interacting quantum atoms methodology has been used for partitioning the energy of the systems in their stationary points into the contribution of pyrazole and BH2 group and their mutual interaction.

DOI: 10.1139/cjc-2022-0175 

A theoretical study of the reactivity of pyrazaboles with nitrogen nucleophiles (amines and pyrazoles): the ring-opening mechanism

A theoretical study of the reactivity of pyrazaboles with amines and pyrazoles has been carried out at DFT level in gas phase, toluene and water media. The reaction with amines yields two molecules of pyrazolylboranes, while the reaction with pyrazoles allows to understand the interchange of such molecules in the pyrazaboles. The reaction of three pyrazaboles with two amines [NH₃ and NMe₃] and pyrazole itself has been considered. The S_N2 and S_N1 mechanisms have been analyzed. The S_N2 reaction is more favorable than the SN1 in the absence or presence of amines.

DOI: 10.1007/s00214-022-02936-z  (OpenAccess)

A theoretical study of dynamic processes observed in trimethylsilyl-1H-pyrazoles: prototropy and silylotropy

The ¹H, ¹³C, ¹⁵N and ²⁹Si chemical shifts of three trimethylsilyl-1H-pyrazoles were calculated and compared with literature results; the calculations were carried out at the GIAO/B3LYP/6–311++G(d,p) level resulting in a very good agreement that allows to predict with confidence the missing experimental values. The prototropic barrier of 4-trimethylsilyl-1H-pyrazole (1) as well as the silylotropic barriers of 1-trimethylsilyl-1H-pyrazole (2) and 1-trimethylsilyl-4-methyl-1H-pyrazole (3) were also calculated and the mechanism was established, the accordance with the experimental values being satisfactory.

DOI: 10.1007/s11224-022-01962-8 (OpenAccess)

A theoretical study of the valence tautomerism of 1H-pyrazolium-4-olates (X = O) and related compounds (X = S, Se, NH): relative stabilities, protonation effects, and tautomerization barriers

The valence isomerism of a series of heterocyclic mesomeric betaines (HMBs) belonging to class 5, called pseudo-semi-conjugated HMBs, has been studied theoretically both the neutral and the protonated species. These HMBs are 1H-pyrazol-2-ium-4-olates and related compounds where the oxygen atom has been replaced by S, Se atoms, and an NH group. The main conclusion of the present work is that the ring/open valence tautomerism is possible both for neutral and protonated although it has never been observed experimentally.

DOI: 10.1016/j.ccr.2022.214812   (OpenAccess)

Pyrazaboles and pyrazolylboranes

The synthesis, reactivity, and properties of pyrazaboles and pyrazolylboranes have been reviewed with special attention to the NMR properties and X-ray structures. 104 X-ray structures are presented and 150 references are cited, which is a significant expansion of previous reviews. It appears that several items are incomplete and others deserve further development indicating than the field of pyrazaboles and of pyrazolylboranes needs new research contributions in particular in the field of coordination chemistry, a field that is clearly underdeveloped.

DOI: 10.1021/acs.joc.2c00154   (OpenAccess)

Study of the Addition Mechanism of 1H-Indazole and Its 4-, 5-, 6-, and 7-Nitro Derivatives to Formaldehyde in Aqueous Hydrochloric Acid Solutions

The reaction of NH-indazoles with formaldehyde in aqueous hydrochloric acid has been experimentally studied by solution and solid-state nuclear magnetic resonance (NMR) and crystallography. The mechanism of the formation of N1-CH2OH derivatives was determined. For the first time, 2-substituted derivatives have been characterized by multinuclear NMR. Theoretically, calculations with gauge-invariant atomic orbitals (GIAOs) at the Becke three-parameter (exchange) Lee–Yang–Parr B3LYP/6-311++G(d,p) level have provided a sound basis for the experimental observations. The first X-ray structures of four (1H-indazol-1-yl)methanol derivatives are reported.

DOI: 10.24820/ark.5550190.p011.747  (OpenAccess)

1H-Benzo[de]cinnolines: an interesting class of heterocycles

DOI: 10.1007/s00214-022-02883-9  (OpenAccess)

A DFT study of the tautomerism of 1H‑benzo[de]cinnolines and their protonated forms

1H-Benzo[de]cinnolines and 1H-indeno[6,7,1-def]cinnolines have been studied theoretically at the B3LYP/6-311++G(d,p) level in the gas-phase and in water solution (PCM model); gas-phase geometries were used to calculate absolute shieldings (GIAO) that were transformed into chemical shifts using empirical equations. The annular tautomerism of neutral species and of protonated cations have been determined, and the most stable cations coincide with those determined experimentally.

DOI:10.1002/mrc.5242

The use of DOSY experiments to determine the solution structures of coinage metal pyrazolates: The case of {[3,5-(CF3)2Pz]Ag}3

A series of DOSY experiments have been carried out to determine the solution stoichiometry of silver(I) 3,5-bis (trifluoromethyl)pyrazolate species. This compound exists as a trimer in the solid state (n = 3) but in solutions of chlorinated solvents, the DOSY data suggest the presence of a mixture of solvent stabilized monomer (n = 1) and dimer (n = 2) in equilibrium. Different approximations have been used including the Stokes–Einstein and the Stokes–Einstein–Gierer–Wirtz equations. Some methodological problems are discussed.

DOI: 10.1016/j.tet.2021.132413

The mechanism of the reaction of hydrazines with α,β-unsaturated carbonyl compounds to afford hydrazones and 2-pyrazolines (4,5-dihydro-1H-pyrazoles): Experimental and theoretical results

The reaction of hydrazines with α,β-unsaturated carbonyl compounds to afford 2-pyrazolines was studied using a dissymmetric chalcone (phenyl/p-tolyl) and three hydrazines, hydrazine itself, phenylhydrazine and thiosemicarbazide. Several products were identified, and some reaction paths established thanks to the evolution of 1H and 13C NMR spectra with time. Theoretical calculations on energies and chemical shifts were of paramount importance to ascertain the structure of some products. For important steps, the transition states were calculated while IRCs proved necessary to find some unexpected intermediates.

DOI: 10.24820/ark.5550190.p011.521  (OpenAccess)

3-Pyrazolines (2,3-dihydro-1H-pyrazoles): synthesis, reactivity, and physical and biological properties

This account provides a summary of the current knowledge on 3-pyrazolines, an important but rather neglected field of heterocyclic chemistry. The review is divided into sections on the synthesis, reactivity, structure and biological properties and covers the literature from 1937 to 2020. In an effort to clarify some results, theoretical calculations were carried out anew.

DOI: 10.1002/jhet.4243

Conformational analysis of 2,5‐diaryl‐4‐methyl‐2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐ones: Multinuclear NMR and DFT calculations

Conformational exploration of five 2,5‐diaryl‐4‐methyl‐2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐ones has been carried out based on a combination of their NMR chemical shifts determined in CDCl₃ and the scrutiny of their computed relative energies and absolute shieldings calculated at the DFT/GIAO/B3LYP/6–311++G(d,p) level. The very flat potential energy curves corresponding to the three relevant single bond rotations were explored by calculating the energy of the rotational barriers and comparing the experimental chemical shifts with those theoretically calculated in each rotamer by statistical analysis.

DOI: 10.1007/s11224-021-01755-5

A ¹³C chemical shifts study of iodopyrazoles: experimental results and relativistic and non-relativistic calculations

This work reports the ¹³C chemical shifts of 49 iodopyrazoles and the ¹⁵N chemical shifts of 6 iodopyrazoles, most of them from the literature but a number of significant cases from the present work. Most experimental data were from solution studies but some of them correspond to the solid state (CPMAS). The calculations include non-relativistic calculations (nr-GIAO) and relativistic ones (ZORA, mDKS/B3LYP/VDZ and mDKS/B3LYP/VTZ). In the case of NH-pyrazoles, problems of tautomerism and desmotropy arise that have been also studied. The manuscript is dedicated to develop some equations containing corrections for heavy atoms to predict ¹³C and ¹⁵N chemical shifts.

DOI:10.1002/jhet.4235

A theoretical study of inversion barriers and NMR chemical shifts of 3‐pyrazolines (2,3‐dihydro‐1H‐pyrazoles)

A rather neglected family of heterocyclic compounds, the 3‐pyrazolines or 2,3‐dihydro‐1H‐pyrazoles, has been studied theoretically at the B3LYP/6–311++G(d,p) level to obtain geometries and energies and at the GIAO/B3LYP/6–311++G(d,p) level for NMR chemical shifts. The calculated barriers of inversion of the N‐substituents reproduce adequately the scarce experimental data. The calculated ¹H and ¹³C chemical shifts are consistent with those reported in the literature. A combination of both results, geometries, and ¹³C chemical shifts, shed light on the conformation of N‐phenyl groups.

DOI: 10.1002/mrc.5107

A structural analysis of 2,5‐diaryl‐4H‐2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐ones: NMR in the solid state, X‐ray crystallography, and GIPAW calculations

The 1H, 13C, 15N, and 19F nuclear magnetic resonance (NMR) spectra of 11 2,5‐diaryl‐2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐ones have been acquired in DMSO‐d6 solution and the 13C, 15N, and 19F NMR spectra have also been acquired in the solid state (solid‐state nuclear magnetic resonance [SSNMR] and magic angle spinning [MAS]). The X‐ray structures of Compounds 3, 5, and 6 have been determined by X‐ray diffraction. Theoretical calculations at the gauge‐independent atomic orbital (GIAO)/B3LYP/6‐311++G(d,p) level have provided a set of 321 chemical shifts that were compared with 310 experimental values in DMSO‐d6. To obtain good agreements, some effects need to be included. The SSNMR chemical shifts have been compared with gauge‐including projector‐augmented wave (GIPAW) calculations and with the heavy atom–light atom (HALA) effects.

DOI: 10.1002/mrc.5118

A static and dynamic NMR study of 10‐hydrazino‐BODIPY

10‐Hydrazino‐BODIPY, BoNHNH2, presents slow rotation about the C10–NH bond that results in anisochronous ¹H and ¹³C NMR signals. The assignment of the different signals has been made using traditional two‐dimensional methods as well as spin–spin coupling constants and confirmed by DFT calculations (B3LYP) using the 6‐311++G(d,p) basis set. The rotational barrier has been determined in three pairs of proton signals and compared with the calculated barrier.

DOI: 10.1007/s11224-020-01661-2

Multinuclear magnetic resonance studies of five silver(I) trinuclear pyrazolate complexes

Experimental multinuclear determination of the chemical shifts, especially 15N and 109Ag, of five silver(I) trinuclear pyrazolate complexes, (PzAg)3, coupled with ZORA (zeroth-order regular approximation) and GIAO (gauge-independent atomic orbital) calculations, has shed new light on these compounds. An almost complete collection of spin-spin coupling constants has been measured for the first time for several of these compounds. The aromaticity of (PzAg)3 was examined using NICS (nucleus-independent chemical shift) and ACID (anisotropy of the induced current density) approaches reaching the conclusion of its absence.

DOI:10.2174/1381612826666200818212846

Theoretical and Spectroscopic Characterization of API-Related Azoles in Solution and in Solid State

Azoles are a family of five-membered azacyclic compounds with relevant biological and pharmacological activity. Different subclasses of azoles are defined depending on the atomic arrangement and the number of nitrogen atoms present in the ring: pyrazoles, indazoles, imidazoles, benzimidazoles, triazoles, benzotriazoles, tetrazoles and pentazoles. The complete characterization of their structure and the knowledge about their crystal packing and physical and chemical properties are of vital importance for the advancement in the design of new azole-containing drugs. In this review, we report the latest recent contributions to azole chemistry, in particular, those in which theoretical studies have been performed.

DOI:10.3390/molecules25215108 (OpenAccess)

A Computational Study of Metallacycles Formed by Pyrazolate Ligands and the Coinage Metals M = Cu(I), Ag(I) and Au(I): (pzM)n for n = 2, 3, 4, 5 and 6. Comparison with Structures Reported in the Cambridge Crystallographic Data Center (CCDC)

The structures reported in the Cambridge Structural Database (CSD) for neutral metallacycles formed by coinage metals in their valence (I) (cations) and pyrazolate anions were examined. Depending on the metal, dimers and trimers are the most common but some larger rings have also been reported, although some of the larger structures are not devoid of ambiguity. M06-2x calculations were carried out on simplified structures (without C-substituents on the pyrazolate rings) in order to facilitate a comparison with the reported X-ray structures (geometries and energies). The problems of stability of the different ring sizes were also analyzed.

DOI:10.1021/acsomega.0c03843 (OpenAccess)

Regiospecific Synthesis and Structural Studies of 3,5-Dihydro‑4H‑pyrido[2,3‑b][1,4]diazepin-4-ones and comparison with 1,3-Dihydro‑2H‑benzo[b][1,4]diazepin-2-ones

Nine 3,5-dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-ones (17–25), some of which contain fluoro-substituents, have been regiospecifically prepared by reaction of 2,3-diaminopyridines with ethyl aroylacetates. In two cases, open intermediates have been isolated and these are related to the reaction pathway. The X-ray crystal structure of 1-methyl-4-phenyl-3,5-dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-one (23) has been solved (formula, C15H13N3O; crystal system, monoclinic; space group, C2/c). This is an asymmetric unit constituted by a single nonplanar molecule and its conformational enantiomer due to the presence of the seven-membered diazepin-2-one moiety, which introduces a certain degree of torsion in the adjacent pyridine ring. The 1H, 13C, 15N, and 19F NMR spectra were obtained and the chemical shifts, together with those of the previously published 1,3-dihydro-2H-benzo[b][1,4]diazepin-2-ones (1–16), i.e., a total of 544 values, were successfully compared with the chemical shifts calculated at the gauge invariant atomic orbital (GIAO)/Becke, three-parameter, Lee–Yang–Parr (B3LYP)/6-311++G(d,p) level. The seven-membered ring inversion barrier in 5-benzyl-2-phenyl-3,5-dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-one (25) was determined and, in conjunction with the data from the literature, compared with the B3LYP/6-311++G(d,p) computed values. This allowed the determination of several structural effects. The rotation about the exocyclic N1–CR bond was also calculated and its dynamic properties were discussed.

DOI: 10.1016/j.cplett.2020.137927

A relative energy gradient (REG) study of the nitrogen inversion in Nsubstituted aziridines

A computational study of the nitrogen inversion in four N-derivatives of aziridine was carried out using the M06-2X functional. The Interactive Quantum Atom (IQA) and the Relative Energy Gradient (REG) methods were used to identify the energy term explains the energy barrier, that is, which atom and which energy type. In all four cases the REG analysis shows that the nitrogen inversion is dominated by the steric destabilization of N (Eintra(N)). REG also shows that the electrostatic energy between C and N (Vcl(N-C)) opposes the barrier the most.

DOI: 10.1070/RCR4963

Perimidines: a Unique π-Amphoteric Heteroaromatic System

Data on the physicochemical characteristics, theoretical calculations, reactivity and synthetic methods for perimidines are summarized. Although perimidine and some of its simple 2-substituted derivatives were obtained by Sachs back in 1909, their chemistry and key physical properties remained unknown until the early 1970s. Subsequent studies revealed many fundamental features of the perimidine system, previously not encountered in the heterocyclic series. The first comprehensive review on perimidines was published forty years ago. The period that has passed since 1980 led to the emergence of new directions and trends. Several hundred new publications have appeared, the generalization of which has become the main purpose of this article. This primarily concerns the obtaining of highly nucleophilic and stable perimidine carbenes, new methods of electrophilic substitution and oxidation, establishment of a close relationship between perimidines and proton sponges, and modern theoretical calculations. Based on perimidines, many different polycondensed systems have been obtained. Applied research has developed especially rapidly in recent years. Many new compounds based on perimidines related to chemosensors, analytical reagents, dyes, metal catalysts, electronic devices, nanotechnology, and medical chemistry have been proposed. Some information under review is presented as Supplementary Material. It contains six tables, which include data on the basicity constants of perimidines, details of some synthetic methods for perimidines and fused analogs as well as a list of biological activities of perimidines.

DOI: 10.1016/j.tet.2019.130690

A structural study of new tetrakis(1H-pyrazol-1-yl)methanes

Tetrakis(1H-pyrazol-1-yl)methanes are very rare compounds of which only two are known: the unsubstituted 1 obtained classically by Hückel in 1937 from carbon tetrachloride and prepared again several times and the 3,5-dimethyl substituted 2 obtained serendipitously by Pombeiro in 2009. We have now extended this group to include four new derivatives 8, 9, 11 and 12 bearing methyl groups. The X-ray crystal structure of the four compounds has been determined. They have been studied by NMR both in solution (¹H, ¹³C, ¹⁵N) and in the solid state (¹³C and ¹⁵N). DFT calculations of the six compounds (geometries, energies and absolute shieldings) have been used to discuss the experimental observations.

DOI: 10.1039/c9cp03209f

The synergy of different solid-state techniques to elucidate the supramolecular assembly of two 1H-benzotriazole polymorphs

1H-Benzotriazole crystallizes as two different polymorphs, namely 4aα and 4aβ. One polymorph is chiral and it resolves spontaneously as conglomerates. The other polymorph crystallizes in a centrosymmetric space group and it is therefore achiral. In both polymorphs supramolecular structures are formed starting from achiral monomers. An analysis of these two polymorphs of 1H-benzotriazole has been carried out by a complete strategy involving different solid-state experimental techniques and quantum chemical calculations (DFT, Density Functional Theory). In particular, X-ray crystallography, NMR spectroscopy and vibrational spectroscopy techniques (FarIR, IR and Raman) that are not sensitive to chirality have been used to characterize the two polymorphs structurally. Vibrational spectroscopy (VCD, Vibrational Circular Dichroism) that is sensitive to chirality was employed to determine the absolute configuration (M or P helices) of the chiral supramolecular structure of 4aα.

DOI: 10.1007/s11224-019-01381-2

Prototropic tautomerism of the addition products of N-heterocyclic carbenes to CO₂, CS₂, and COS 

The energies of 62 minima and 6 transition states have been calculated with the M06-2x functional and the aug-cc-pVDZ basis set. They correspond to carbenes and neutral molecules related to the products obtained by addition of N-heterocyclic carbenes (NHCs) to CO₂, CS₂, and COS. The NHCs belong to two “classical” NHCs (imidazoles and benzimidazoles) and one “remote” NHC (pyrazole). Several of these structures in the same series are related by prototropic tautomerism. To compare these calculated energies with experimental X-ray structures, solvation effects by water, calculated with a continuous model (PCM), as well as some dihydrates and dimers, have also been calculated.

DOI: 10.3390/molecules24030568

An Example of Polynomial Expansion: The Reaction of 3(5)-Methyl-1H-Pyrazole with Chloroform and Characterization of the Four Isomers

The reaction in phase-transfer catalyzed conditions of 3(5)-methyl-1H-pyrazole with chloroform affords four isomers 333, 335, 355 and 555 in proportions corresponding to the polynomial expansion (a + b)³, with a = 0.6 and b = 0.4, a and b being 3-methyl and 5-methyl proportions. The up (u) and down (d) conformation of the pyrazolyl rings with regard to the Csp³–H atom was established by X-ray crystallography and by ¹H-, ¹³C- and ¹⁵N-NMR in solution combined with gauge-including atomic orbitals (GIAO)/B3LYP/6-311++G(d,p) calculations. A comparison with other X-ray structures of tris-pyrazolylmethanes was carried out.

DOI: 10.1002/hc.21441

A theoretical study of the properties of ninety‐two “aromatic” six‐membered rings including benzene, azines, phosphinines and azaphosphinines

Ninety‐two unsaturated hexagonal compounds (from benzene to hexaphosphinine, including azines and azaphosphinines) have been theoretically studied at DFT level, B3LYP/6‐311++G(d,p). Lone pair/lone pair repulsion between adjacent N atoms has been deduced using an empirical partition of the energy. Aromaticity based on magnetic criteria and on Bader analysis was studied finding that both criteria were almost orthogonal. The structure that are nonplanar or broken have been analyzed in function of their geometry or the fragments, respectively.

DOI: 10.1107/S2053229618004394

The tautomeric structures of 3(5),3′(5′)-azopyrazole [(E)-1,2-di(1H-pyrazol-3(5)-yl)diazene)]: The combined use of NMR and electronic spectroscopies with DFT calculations

An azo derivative of 1H-pyrazole has been chosen to study the information obtained from different techniques for determining the structure of a non-crystalline compound in the solid-state and in solution. Syn–antiisomerism of the azo group, prototropic tautomerism of the 1H-pyrazole and rotation about the pyrazole–azo group resulted in 20 structures that were analyzed. Energy calculations, ¹³C and ¹⁵N chemical shifts, ¹H–¹H coupling constants and electronic spectra reduced the 20 possible structures to only one, the 3,3′-Z,Z-anti-azopyrazole.

DOI: 10.1002/mrc.4674

A theoretical NMR study of selected benzazoles: Comparison of GIPAW and GIAO‐PCM (DMSO) calculations

This paper compares the absolute shieldings obtained by gauge-including-projected-augmented-wave (GIPAW) to those obtained by gauge-invariant atomic orbital/Becke, 3-parameter, Lee-Yang-Parr (GIAO/B3LYP)/6–311++G(d,p)-polarizable continuum model (PCM, dimethyl sulfoxide) for nine benzazoles (benzimidazoles, indazoles, and benzotriazoles) recorded in the solid-state. Three nuclei were explored, 13C, 15N, and 19F, and the gauge-including-projected-augmented-wave approach only proved better for 15N MAS NMR.

DOI: 10.1002/jhet.3026

The Structure of N-phenyl-pyrazoles and Indazoles: Mononitro, Dinitro, and Trinitro Derivatives

This review explores the heterocyclic family of N-nitrophenyl pyrazoles and indazoles covering mainly their structural aspects, with special emphasis on the X-ray diffraction data. NMR spectroscopy and the theoretical calculations will also be briefly summarized. The synthesis and reactivity aspects will be reported when they are specific to these compounds.

DOI: 10.1007/s11224-017-0994-z

The structure of 2,4,6-tris(1H–pyrazol-1-yl)-1,3,5-triazine in the solid state: on polymorphs, pseudopolymorphs and co-crystals

Three structures of 2,4,6-tris(1H–pyrazol-1-yl)-1,3,5-triazine (TPT) have been determined at 193 K: the isolated molecule (2a), a solvate containing molecules of water and acetonitrile (2b) and a complex of two molecules of TPT and three molecules of water (2c). To discuss the structures, B3LYP/6–311++G(d,p) calculations have been carried out, in particular, in what concerns hydrogen bonds.

DOI:10.3390/molecules22112003  OpenAccess

19F‐NMR Diastereotopic Signals in Two N-CHF2 Derivatives of (4S,7R)-7,8,8-Trimethyl-4,5,6,7-tetrahydro-4,7-methano-2H-indazole

In this paper, we report the anisochrony of the fluorine atoms of a CHF₂ group when linked to a pyrazole ring. The pyrazole is part of (4S,7R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-4,7-methano-2H-indazole also known as (4S,7R)-campho[2,3-c]pyrazole, which has two stereogenic centers. Gauge-Independent Atomic Orbital (GIAO)/Becke, 3-parameter, Lee-Yang-Parr (B3LYP)/6-311++G(d,f) calculated ¹⁹F chemical shifts of the minimum energy conformations satisfactorily agree with the experimental data. The energy differences between minima need to consider solvent effects (continuum model) to be satisfactorily reproduced.

DOI: 10.1021/acs.jpca.7b05220

The Curious Case of 2‑Propyl‑1H‑benzimidazole in the Solid State: An Experimental and Theoretical Study

2-Propyl-1H-benzimidazole (2PrBzIm) is a small molecule, commercially available, which displays a curious behavior in the solid state. 2PrBzIm, although devoid of chirality by fast rotation about a single bond of the propyl group in solution, crystallizes as a conglomerate showing chiroptical properties. An exhaustive analysis of its crystal structure and a wide range of experiments monitored by vibrational circular dichroism spectroscopy eliminated all possibilities of an artifact. What remains is a new example of the unexplained phenomenon of persistent supramolecular chirality.

DOI: 10.1002/slct.201700405

Curcumin Related 1,4-Diazepines: Regioselective Synthesis, Structure Analysis, Tautomerism, NMR Spectroscopy, X-ray Crystallography, Density Functional Theory and GIAO Calculations

The reaction of 1,2-ethylenediamine with seven fluorinated β-diketones affords two different 1,4-diazepine series depending on the experimental conditions. Their structures as well as tautomerism have been established by 1H, 13C, 15N and 19F nuclear magnetic resonance in solution supported by density functional theory calculations at the B3LYP/6-311++G(d,p) level. The two compounds obtained from (E)-5-(2-fluoro-4-hydroxyphenyl)-1-phenylpent-4-ene-1,3-dione were analyzed by X-ray crystallography and studied by solid-state NMR.

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Theoretical studies of the tautomerism of two azaphospholes: 5-tert-butyl-1,2,3,4-triazaphosphole and N,N-dimethyl-1,2,4,3-triazaphosphol-5-amine

Two isomeric triazaphospholes have been studied theoretically at the B3LYP//6-311++G(d,p) level. The main aspects that have been analyzed are the prototropic tautomerism and the NMR properties (chemical shifts and spin-spin coupling constants). These last properties are well reproduced but the relative stabilities show some discrepancies between experimental and calculated values.

DOI: 10.1107/S2053229616007385

The structures of two scorpionates: thallium tetrakis(3-phenyl-1H-pyrazol-1-yl)borate and potassium tetrakis(3-cyclopropyl-1H-pyrazol-1-yl)borate 

The introduction of poly(1H-pyrazol­yl)borate anions, better known as scor­pion­ates, as negatively charged ligands for a great diversity of metal cations has had a tremendous influence in coordination chemistry. The structures of two salts of tetra­kis­pyrazolylborate, namely [tetra­kis­(3-phenyl-1H-pyrazol-1-yl)borato]thallium(I), [Tl(C36H28BN8)], and catena-poly[potassium-[µ2-tetra­kis­(3-cyclo­propyl-1H-pyrazol-1-yl)borato]], [K(C24H28BN8)]n, have been determined at 296 K in the monoclinic P21/c and C2/c space groups, respectively. In their crystal structures, the thallium salt presents discrete mol­ecular motifs, while the potassium salt shows infinite polymeric chains. The 13C and 15N CPMAS (cross polarization magic angle spinning) NMR spectra of these compounds were recorded and the chemical shifts compared with theoretically calculated ones at the GIAO/B3LYP/6-311++G(d,p) level. Both techniques are complementary and mutually consistent.

DOI: 10.1016/j.jfluchem.2016.10.013

The structure of 4,5,6,7-tetrafluoro-1H-benzotriazole in solid state and in solution

This work reports the behavior in solution and in the solid-state of the title compound, a known but neglected benzotriazole. In solution, we have measured the prototropic barrier corresponding to the N1H/N3H tautomerism. In the solid-state, we have determined the X-ray molecular structure and the NMR chemical shifts. For both states and both properties (geometry and chemical shifts), theoretical calculations at the B3LYP/6-311++G(d,p) level proved invaluable.

A theoretical study of the structure of 6,6-dimethyl-7-nitroso-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine

DFT calculations have been carried out on 6,6-dimethyl-7-nitroso-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine concerning energies, absolute shieldings (GIAO) and molecular graphs (AIM) to determine the molecular structure of the compound (tautomerism and conformation of the nitroso group).

DOI: 10.2174/1570178613666160815163117

A Proof of Concept: 2-Pyrazolines (4,5-Dihydro-1H-pyrazoles) Can Be Used as Organocatalysts via Iminium Activation

Background: In the field of asymmetric aminocatalysis, chiral catalysts derived from azoles (five-membered heterocycles containing exclusively N atoms) play an important role. Surprisingly, all the catalysts used for enamine and/or iminium ion activation derive from pyrrole or imidazole. We decided to test if other reduced azole derivatives could be used as organocatalysts and particularly in aminocatalysis via iminium ion activation. The azole derivatives that came naturally to mind are the 3,5-disubstituted 2-pyrazolines (also called 4,5-dihydro-1H-pyrazoles).

Methods: We synthesized racemic 3,5-diphenyl-2-pyrazoline, separated both enantiomers by chiral-HPLC on a Lux-Cellulose-4 column (heptane/ethanol 70:30 as mobile phase), determined the absolute configuration of their hydrochloride salts (pyrazolinium) by the combined use of experimental rotatory power and B3LYP/6-311++G(d,p) theoretical calculations and use one the enantiomers, the R, as the catalyst.

Results: We have demonstrated that the enantiopure (R)-3,5-diphenyl-2-pyrazoline is able to catalyze the Michael addition of 1-(4-nitrophenyl)propan-2-one to cinnamaldehyde and crotonaldehyde via iminium activation.

Conclusion: This is the first example of activation of both types of enals, aliphatic and aromatic, via pyrazolinium salts and opens new possibilities to the design of other type of chiral organocatalysts than the traditional pyrrole and imidazole derivatives.

DOI:10.1007/s11224-016-0780-3

A computational study of azaphospholes: anions and neutral tautomers

One hundred and eleven azaphospholes (31 anions and 80 neutral compounds) have been studied theoretically at the B3LYP/6-311++G(d,p) level. Among the analyzed properties, there are the geometries, mainly the non-planarity of the PH tautomers, the isomerism of the anions, the NH/PH tautomerism of neutral compounds, the chemical shifts and spin–spin coupling constants. The aromaticity has been assessed through Schleyer’s NICS values, preferably NICS(1). Finally, we have compared our calculations with previous ones as well as with the available experimental data for the calculated compounds and for related ones

DOI: 10.1002/slct.201600167

Static and Dynamic Properties of Fluorinated 4-Aryl-1,5-Benzodiazepinones

Six 4-aryl-6,7,8,9-tetrafluoro-1,5-benzodiazepine-2-ones have been synthesized and fully characterized by ¹H, ¹³C, ¹⁵N and ¹⁹F NMR in solution and in the solid state. In addition, the structures of three of them have been determined by X-ray crystallography. The imine/enamine tautomerism has been experimentally studied by NMR in solution (in the solid state, only the imino tautomer is present). Three barriers corresponding to the inversion of the seven-membered ring have been determined (N1-unsubstituted derivatives). Both for the tautomerism and for the conformational aspects, theoretical calculations at the B3LYP/6-311++G(d,p) level including GIAO calculations of the NMR chemical shifts have been carried out with satisfying results. Different energy profiles have been considered and several transition states located.

DOI:10.1016/j.molstruc.2016.02.020

Researchgate

The structure and properties of 5,6-dinitro-1H-benzotriazole

5,6-Dinitro-1H-benzotriazole crystallizes in the monoclinic system, space group P21/c. The asymmetric unit contains the planar 1H-tautomer together with a water molecule of crystallization. Each water molecule is hydrogen bonded to three adjacent 5,6-dinitrobenzotriazoles forming a tape along the b-axis of the crystal. These tapes stack along the c-axis through hydrogen bonds involving the water molecules and one of the nitro groups leading to a bidimensional structure. Solid-state 13C and 15N CPMAS NMR allow to confirm that the tautomer present is the 1H one. In DMSO-d6 solution the results are quite different and, based on GIAO/B3LYP/6-311++G(d,p) calculations, lead us to conclude that the major tautomer is the 5,6-dinitro-2H-benzotriazole, a surprising result that contradicts the rule that the major tautomer in solution coincides with the one present in the crystal. An anhydrous pseudopolymorph of 5,6-dinitro-1H-benzotriazole has been obtained as a non-crystalline form and from solid-state NMR and theoretical calculations, we conclude that it is an 1H-tautomer.

DOI: 10.4067/S0717-97072015000200022

The tautomerism of pyrazolines (dihydropyrazoles)

The exception to the rule that Δ³-pyrazolines are not stable unless both nitrogen atoms are substituted that has been recently published,Tetrahedron Lett. 55, 2208, (2014), has been proved false. By means of GIAO/B3LYP/6-311++G(d,p) calculations, it has been shown that the product is a pyrazole formed by rearrangement.

DOI:10.1016/j.molstruc.2015.07.055

Synthesis, structure and biological activity of 3(5)-trifluoromethyl-1H-pyrazoles derived from hemicurcuminoids

Six new 3(5)-trifluoromethyl-5(3)-substituted-styryl-1H-pyrazoles have been synthesized and their tautomerism studied in solution and in the solid state. The determination of their structures has been based on multinuclear NMR spectroscopy together with GIAO/B3LYP/6–311++G(d,p) theoretical calculations of eight structures for each pyrazole (two tautomers and four conformations). Five out of the six compounds present inhibition percentages of the iNOS isoform higher than 50%. With regard to the nNOS inhibitory activity, only two of the studied compounds show an inhibition of about 50%. Finally, concerning the eNOS, there is a compound presenting a low percentage of inhibition (40.2%) attaining in the other cases 50%.

DOI: 10.1002/cphc.201500317

Computational Study of Proton Transfer in Tautomers of 3- and 5-Hydroxypyrazole Assisted by Water

The tautomerism of 3- and 5-hydroxypyrazole is studied at the B3LYP, CCSD and G3B3 computational levels, including the gas phase, PCM–water effects, and proton transfer assisted by water molecules. To understand the propensity of tautomerization, hydrogen-bond acidity and basicity of neutral species is approached by means of correlations between donor/acceptor ability and H-bond interaction energies. Tautomerism processes are highly dependent on the solvent environment, and a significant reduction of the transition barriers upon solvation is seen. In addition, the inclusion of a single water molecule to assist proton transfer decreases the barriers between tautomers. Although the second water molecule further reduces those barriers, its effect is less appreciable than the first one. Neutral species present more stable minima than anionic and cationic species, but relatively similar transition barriers to anionic tautomers.

DOI:10.1515/zkri-2015-0004

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 3aand 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.

DOI:10.1002/mrc.4203

A theoretical and experimental study of the NMR spectra of 4,5,6,7-tetrafluorobenzazoles with special stress on PCM calculations of chemical shifts

The chemical shifts and several ¹⁹F–¹⁹F, ¹³C–¹⁹F and ¹H–¹⁹F spin-spin coupling constants (SSCSs) of eight 4,5,6,7-tetraflurobenzazoles (three benzimidazoles, three benzimidazolinones and two indazoles) have been determined. The chemical shifts were discussed using gauge including atomic orbital-density functional theory calculations taking into account solvent effects (polarizable continuum model) and, for the solid state, hydrogen bonds (clusters up to three molecules). 

DOI:10.1039/c4nj02201g

A theoretical study of the gas phase (proton affinity) and aqueous (pKa) basicity of a series of 150 pyrazoles

This study deals with the basicity, both in the gas phase and in an aqueous solution, of a set of 150 pyrazoles covering a range of about 200 kJ mol⁻¹ in proton affinity and 10–15 pK_a units. There are 63 NH-pyrazoles, in many cases, with two different tautomers and 87 N-substituted pyrazoles. The gas phase results are well reproduced by DFT theoretical calculations when the less stable tautomers are removed. For the pK_a values to be reproduced adequately by calculations, some of the tautomers need to be removed, and the use of dummy variables accounting for the protonation on exocyclic amine groups is required and the conformation of the 5-phenyl groups need to be considered. Using these restrictions a large number of unknown pK_as can be predicted and a few errors corrected.

DOI:10.1002/jhet.1955

An NMR and Computational Study of Azolo[a]pyrimidines with Special Emphasis on Pyrazolo[1,5- a]pyrimidines

The reaction of 3(5)-amino-5(3)-hydrazinopyrazole, a bifunctional compound, with 3-oxo-3-phenylpropanenitrile and two of its p-substituted derivatives affords 2,5-diaryl-7-aminopyrazolo[1,5-a]pyrimidines. A mechanism for this unexpected reaction involving the formation of hydrazine is proposed. The position of the aryl substituents on the bicyclic ring has been established by the combined use of NMR and DFT calculations. Moreover, the chemical shifts have been calculated, and some general rules have been withdrawn.

DOI:10.1016/j.ssnmr.2014.12.005

Diazole-based powdered cocrystal featuring a helical hydrogen-bonded network: Structure determination from PXRD, solid-state NMR and computer modeling

We present the structure of a new equimolar 1:1 cocrystal formed by 3,5-dimethyl-1H-pyrazole (dmpz) and 4,5-dimethyl-1H-imidazole (dmim), determined by means of powder X-ray diffraction data combined with solid-state NMR that provided insight into topological details of hydrogen bonding connectivities and weak interactions such as C─H···π contacts. The use of various 1D/2D ¹³C, ¹⁵N and ¹H high-resolution solid-state NMR techniques provided structural insight on local length scales revealing internuclear proximities and relative orientations between the dmim and dmpz molecular building blocks of the studied cocrystal. Molecular modeling and DFT calculations were also employed to generate meaningful structures. DFT refinement was able to decrease the figure of merit R(F²) from ~11% (PXRD only) to 5.4%. An attempt was made to rationalize the role of N─H···N and C─H···π contacts in stabilizing the reported cocrystal. For this purpose four imidazole derivatives with distinct placement of methyl substituents were reacted withdmpz to understand the effect of methylation in blocking or enabling certain intermolecular contacts. Only one imidazole derivative (dmim) was able to incorporate into the dmpz trimeric motif thus resulting in a cocrystal, which contains both hydrophobic (methyl groups) and hydrophilic components that self-assemble to form an atypical 1D network of helicoidal hydrogen bonded pattern, featuring structural similarities with alpha-helix arrangements in proteins. The 1:1 dmpz···dmim compound I is the first example of a cocrystal formed by two different azoles.

DOI:  10.1016/j.tet.2014.09.018

A theoretical and experimental study of the racemization process of hexaaza[5]helicenes

A dynamic ¹H NMR study, together with DFT calculations, of bis-([1,2,3]triazolo)[1,5-a:5′,1′-k][1,10]phenanthroline 2 has allowed to identify the ring and open forms of a new example of ring/chain tautomerism, as well as their interconversion barriers (ring/ring and ring/open). The barrier of the exchange process between the chain forms and the ring form was found higher than the ‘racemization’ process in the closed form, so the ring opening does not contribute to the ‘racemization’. The di-1,10-methyl and di-1,10-iodo derivatives have been prepared and their properties calculated.shifts, ¹H–¹H coupling constants and electronic spectra reduced the 20 possible structures to only one, the 3,3′-Z,Z-anti-azopyrazole.

DOI: 10.1016/j.molstruc.2014.07.020

The origin of the splitting of ¹³C and ¹⁵N NMR signals of 3(5)-phenyl-5(3)-methylpyrazolium chloride and bromide in the solid state: Quantum Espresso calculations

A combination of ¹³C and ¹⁵N CPMAS NMR spectroscopy and theoretical methods (DFT and DFT-D) was used to discuss the observation of large splittings affecting some atoms in 3(5)-phenyl-5(3)-methylpyrazolium chloride and bromide. Conventional calculations using fully optimized structures with C₂symmetry reproduce solution spectra, but the large splitting observed for the signals of several pyrazolium carbon and nitrogen atoms in the solid-state can only be explained by calculations employing the experimental P2₁/n geometry and periodic boundary calculations.

DOI: 10.1021/jo501061z

Open Bis(triazolium) Structural Motifs as a Benchmark To Study Combined Hydrogen- and Halogen-Bonding Interactions in Oxoanion Recognition Processes

We have designed a series of triazolium-pyrene-based dyads to probe their potential as fluorescent chemosensors for anion recognition through combinations of hydrogen and halogen bonding. Cooperation between the two distinct noncovalent interactions leads to an unusual effect on receptor affinity, as a result of fundamental differences in the interactions of halogen and hydrogen bond donor groups with anions. Absorption, emission spectrophotometries and proton and phosphorus NMR spectroscopies indicate that the two interactions act in concert to achieve the selective binding of the hydrogen pyrophosphate anion, a conclusion supported by computational studies. Hence, as clearly demonstrated with respective halogen- and hydrogen-bonding triazolium receptors, the integration of a halogen atom into the anion receptor at the expense of one hydrogen-bonding receptor greatly influences the anion recognition affinity of the receptor. The association constant values of the halogen-bonding complexes are larger than the hydrogen-bonding counterpart. Thus, halogen bonding has been exploited for the selective fluorescent sensing of hydrogen pyrophosphate anion. Halogen bonding has been demonstrated to increase the strength of hydrogen pyrophosphate binding, as compared to the hydrogen-bonded analogue. Grimme’s PBE-D functional, which adequately reproduces the pyrene stacking energies, has been successfully applied to model the affinity for anions, especially hydrogen pyrophosphate, of the new receptors.

DOI: 10.3762/bjoc.10.168

An experimental and theoretical NMR study of NH-benzimidazoles in solution and in the solid state: proton transfer and tautomerism

This paper reports the 1H, 13C and 15N NMR experimental study of five benzimidazoles in solution and in the solid state (13C and 15N CPMAS NMR) as well as the theoretically calculated (GIAO/DFT) chemical shifts. We have assigned unambiguously the "tautomeric positions" (C3a/C7a, C4/C7 and C5/C6) of NH-benzimidazoles that, in some solvents and in the solid state, appear different (blocked tautomerism). In the case of 1H-benzimidazole itself we have measured the prototropic rate in HMPA-d18.

DOI: 10.1007/s11224-014-0396-4

Tautomerism, structure in solution and in the solid state of 1:9,5:10-anthradipyrazole

By means of DFT calculations [B3LYP/6-311++G(d,p), GIAO], the properties of the three tautomers of 1:9,5:10-anthradipyrazole were analyzed and compared with Maspero’s crystal structures and NMR results. The agreement is fairly good and in agreement with indazole tautomers. Besides, the aromaticity of these interesting five-membered ring systems was explored.

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Preparation of 2,2-dimethylchroman-4-ones from 5-alkyl-substituted resorcinols: microwave-assisted synthesis and theoretical calculations

The influence of different 5-alkyl-substituted resorcinols on the formation of 2,2-dimethyl-chroman-4-ones is examined experimentally and theoretically. Structures are fully assigned by means of experimental and theoretical 13C and 1H NMR chemical shifts. Based on experimental and theoretical calculations of Friedel-Crafts acylation, it is possible to explain the formation of 2,2-dimethyl-5-hydroxychroman-4-ones and/or 2,2-dimethyl-7-hydroxychroman-4-ones. Evaluation of their biological activity as cannabinoid receptor ligands is also reported. 

DOI: 10.3762/bjoc.9.253

Structure of 1,5-benzodiazepinones in the solid state and in solution: Effect of the fluorination in the six-membered

Two novel tetrafluorinated 1,5-benzodiazepinones were synthesized and their X-ray structures determined. 6,7,8,9-Tetrafluoro-4-methyl-1,3-dihydro-2H-1,5-benzodiazepin-2-one crystallizes in the monoclinic P21/c space group and 6,7,8,9-tetrafluoro-1,4-dimethyl-1,3-dihydro-2H-1,5-benzodiazepin-2-one in the triclinic P−1 space group. Density functional theory studies at the B3LYP/6-311++G(d,p) level were carried out on these compounds and on four non-fluorinated derivatives, allowing to calculate geometries, tautomeric energies and ring-inversion barriers, that were compared with the experimental results obtained by static and dynamic NMR in solution and in solid state.

DOI: 10.1002/cphc.201300503

Self-Assembly Structures of 1H-Indazoles in the Solution and Solid Phases: A Vibrational (IR, FIR, Raman, and VCD) Spectroscopy and Computational Study

1H-indazoles are good candidates for studying the phenomena of molecular association and spontaneous resolution of chiral compounds. Thus, because the 1H-indazoles can crystallize as dimers, trimers, or catemers, depending on their structure and the phase that they are in, the difficulty in the experimental analysis of the structure of the family of 1H-indazoles becomes clear. This difficulty leads us to contemplate several questions: How can we determine the presence of different structures of a given molecular species if they change according to the phase? Could these different structures be present in the same phase simultaneously? How can they be determined? To shed light on these questions, we outline a very complete strategy by using various vibrational spectroscopic techniques that are sensitive (VCD) and insensitive (IR, FIR, and Raman) towards the chirality, together with quantum chemical calculations.

DOI: 10.1107/S0108270113018969

A tris(pyrazol-1-yl)methane bearing carboxylic acid groups at position 4: {1-[bis(4-carboxy-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-3,5-dimethyl-1H-pyrazole-4-carboxylato}sodium dihydrate

 A low-resolution X-ray molecular structure of the title hydrated salt, Na(C₁₉H₂₁N₆O₆)]·2H₂O, displays scorpionate character and resolves apparent ambiguities between solution and solid-state NMR spectroscopies. The ¹³C NMR CPMAS spectrum is consistent with this structure showing some splittings, which have been rationalized using GIAO/B3LYP/6-311++G(d,p) theoretical calculations.

DOI: 10.1016/j.comptc.2013.07.002

A theoretical study of the conformation and dynamic properties of 1,5-benzodiazepines and their derivatives

The geometries of eighteen 1,5-benzodiazepines including their oxo and thioxo derivatives have been calculated and compared with experimental geometries determined by X-ray crystallography using as property the methylene flip angle. Protonation of 3H-1,5-benzodiazepine lead to a planar quasi-aromatic cation. For the non-planar structures we have calculated ring inversion barriers that are well correlated with ten experimental values determined by Dynamic NMR allowing the establishment of an empirical equation for predicting new values.

DOI: 10.1039/C3NJ00186E

The reaction of NH-indazoles with 1-fluoro-2,4-dinitrobenzene: the unusual formation of benzotriazole-N-oxides

When N-unsubstituted indazoles, like indazole itself, reacted with 1-fluoro-2,4-dinitrobenzene or 1-chloro-2,4,6-trinitrobenzene, three products were obtained whose structures were determined by X-ray diffraction. Besides the two N-substituted nitroaryl derivatives, a third compound was obtained with the same molecular formula (C₁₃H₈N₄O₄) to which was assigned the structure of a derivative of benzotriazole N-oxide. With the combined use of crystallography, NMR and DFT calculations this reaction was studied with special stress on the mechanism of formation of the benzotriazole-N-oxide.

DOI: 10.1007/s10593-013-1237-x

Structure of NH-benzazoles (1H-benzimidazoles, 1H- and 2H-indazoles, 1H- and 2H-benzotriazoles)

The structure and properties (crystallography, NMR, theoretical calculations) of the three N-unsubstituted benzazoles (1H-benzimidazoles, 1H- and 2H-indazoles, 1H- and 2H-benzotriazoles) have been reviewed for the period 2000–2012 with some results from previous years. The study of these compounds will greatly increase in the coming years and it is expected that the present review will contribute to it.

Arkivoc, ii, 19-35 (2014)

A theoretical study of the mechanism of oxidation of 1H-pyrazolines to 1H-pyrazoles by molecular bromine

The bromine oxidation of NH-pyrazolines to pyrazoles involves a bromo substituted 2- or 1-pyrazoline. The present paper explores theoretically the different possibilities comparing the published NMR results to the experimental ones. Besides, geometries and energies are reported and discussed.

DOI:10.1007/s11224-012-0091-2

Theoretical studies of parent 1-, 2-, 3-pyrazolines and their methylated derivatives

A theoretical study of the minima of 1-, 2-, and 3-pyrazolines as well as some methyl derivatives was performed using B3LYP/6-311++G(d,p) and CCSD(T) calculations. Conformation, tautomerism, basicity, protonation as well as NMR properties have been computationally studied. In general, the agreement with the available experimental results is excellent, highlighting the predictive potential of this type of study in the consideration of new compounds.

DOI: 10.1002/mrc.3926

The structure of azines derived from C-formyl-1H-imidazoles in solution and in the solid state: tautomerism, configurational and conformational studies

The structures of three azines derived from 2-formylimidazole, 4(5)-formylimidazole, and 4(5)-formyl-5(4)-methylimidazole have been determined in solution and in the solid state. Density Functional Theory (DFT) Polarizable Continuum Model (PCM) calculations (geometries, energies, and chemical shifts), NMR [solution and cross polarization magic-angle spinning (CPMAS)], and X-ray crystallography [azine of 4(5)-formylimidazole] have been used. The configuration around the central C = N bonds has been determined and some insights about prototropic tautomerism and conformation have been gained.

DOI: 10.1016/j.tet.2013.01.096

Synthesis and structural study of 2-arylbenzotriazoles related to Tinuvins

A total number of nineteen 2-arylbenzotriazoles related to the UV absorber Tinuvin P have been studied. Moreover, besides those bearing a 2′-hydroxy substituent, known to experience ESIPT (Excited-State Intramolecular Proton Transfer), we have also prepared three compounds having another ortho-hydroxy group at position 6′. The X-ray molecular structures of five key representatives have been determined and some important features related to their behavior discussed on the basis of solution and solid-state NMR, as well as B3LYP/6-311++G(d,p) computational results.

 The structure of NH-benzazoles (1H-benzimidazoles, 1H- and 2H-indazoles, 1H- and 2H-benzotriazoles)

The structure and properties (crystallography, NMR, theoretical calculations) of the three  N-unsubstituted benzazoles (1H-benzimidazoles, 1H- and 2H-indazoles, 1H- and 2H-benzotriazoles) have been reviewed for the period 2000–2012 with some results from previous years. The study of these compounds will greatly increase in the coming years and it is expected that the present review will contribute to it

DOI: 10.1002/jhet.1076

Multinuclear NMR Characterization of Cyanuric Fluoride (2,4,6-Trifluoro-1,3,5-triazine)

Although 2,4,6-trifluoro-1,3,5-triazine, C₃F₃N₃, is a highly symmetrical molecule, its NMR parameters can be obtained by reducing its symmetry through the introduction of ¹⁴N/¹⁵N and ¹²C/¹³C isotopomers. Experimental and computed chemical shifts of cyanuric fluoride have been obtained for ¹³C, ¹⁵N, and ¹⁹F. Spin-spin coupling constants have been measured and compared with previous experimental data and with the complete set of computed EOM-CCSD coupling constants.

DOI:10.1016/j.molstruc.2012.02.013

The tautomeric structures of 3(5),3′(5′)-azopyrazole [(E)-1,2-di(1H-pyrazol-3(5)-yl)diazene)]: The combined use of NMR and electronic spectroscopies with DFT calculations

An azo derivative of 1H-pyrazole has been chosen to study the information obtained from different techniques for determining the structure of a non-crystalline compound in the solid-state and in solution. Syn–antiisomerism of the azo group, prototropic tautomerism of the 1H-pyrazole and rotation about the pyrazole–azo group resulted in 20 structures that were analyzed. Energy calculations, ¹³C and ¹⁵N chemical shifts, ¹H–¹H coupling constants and electronic spectra reduced the 20 possible structures to only one, the 3,3′-Z,Z-anti-azopyrazole.

DOI:10.1016/j.molstruc.2012.02.013

The tautomeric structures of 3(5),3′(5′)-azopyrazole [(E)-1,2-di(1H-pyrazol-3(5)-yl)diazene)]: The combined use of NMR and electronic spectroscopies with DFT calculations

An azo derivative of 1H-pyrazole has been chosen to study the information obtained from different techniques for determining the structure of a non-crystalline compound in the solid-state and in solution. Syn–antiisomerism of the azo group, prototropic tautomerism of the 1H-pyrazole and rotation about the pyrazole–azo group resulted in 20 structures that were analyzed. Energy calculations, ¹³C and ¹⁵N chemical shifts, ¹H–¹H coupling constants and electronic spectra reduced the 20 possible structures to only one, the 3,3′-Z,Z-anti-azopyrazole.

DOI:10.1016/j.molstruc.2012.02.013

The tautomeric structures of 3(5),3′(5′)-azopyrazole [(E)-1,2-di(1H-pyrazol-3(5)-yl)diazene)]: The combined use of NMR and electronic spectroscopies with DFT calculations

An azo derivative of 1H-pyrazole has been chosen to study the information obtained from different techniques for determining the structure of a non-crystalline compound in the solid-state and in solution. Syn–antiisomerism of the azo group, prototropic tautomerism of the 1H-pyrazole and rotation about the pyrazole–azo group resulted in 20 structures that were analyzed. Energy calculations, ¹³C and ¹⁵N chemical shifts, ¹H–¹H coupling constants and electronic spectra reduced the 20 possible structures to only one, the 3,3′-Z,Z-anti-azopyrazole.

DOI: 10.1016/j.molstruc.2011.07.031

Tautomerism of hydroxychromenopyrazoles

Annular tautomerism (OH⋯N and/or NH⋯O) of hydroxychromenopyrazoles was studied by NMR-spectroscopy and B3LYP/6-311++G(d,p) theoretical calculations. The experimental chemical shifts of 4,4-dimethyl-7-pentyl-2,4-dihydrochromeno[4,3-c]pyrazol-9-ol have been compared with absolute shieldings calculations performed using the GIAO approximation. This study shows that the title compound exists mainly as an OH⋯N tautomer in solution.

DOI: 10.1039/C2NJ20820B

The chiral structure of 1H-indazoles in the solid state: a crystallographic, vibrational circular dichroism and computational study

A survey of the Cambridge Crystallographic Database reveals that there are 17 1H-indazoles forming dimers (7), trimers (4) and catemers or chains (6). Amongst the catemers there is one centrosymmetric compound and five non-centrosymmetric ones that crystallize in chiral helices, either M or P, including indazole itself, whose structure has been determined anew. An explanation will be provided for how an achiral molecule crystallizes in a chiral space group. The second part of the paper is devoted to the use of Vibrational Circular Dichroism (VCD) for determining the absolute configuration of a crystal of indazole. This previously needs the complete assignment of its IR and Raman spectra in solution and in the solid-state based on B3LYP/6-31G(d) calculations of indazole dimers and trimers, which are already chiral.

DOI: 10.1016/j.tet.2012.05.056

A theoretical NMR study of the structure of benzynes and some of their carbocyclic and heterocyclic analogs

This work reports the theoretical study of the aromaticity of a series of carbocycles (benzene, cyclohexane, bent and planar cyclooctatetraene) and heterocycles (pyridine, furan, thiophene, pyrrole) and their didehydro forms (arynes and hetarynes). As aromaticity probe Schleyer's NICS were used and represented in two 3D isosurfaces of the electron density. The spatial 3D representation of the NICS is shown to be a powerful tool to visualize the aromaticity (or its absence) of different molecules

DOI: 10.1016/j.molstruc.2012.04.049

The tautomerism of fluorinated indazolinones in the solid state

The structure of three fluorinated NH-indazolinones, two oxo derivatives and one 3-hydroxyindazole, has been determined by ¹³C and ¹⁵N solid state NMR. For two of them, X-ray crystallography confirmed the results on the tautomeric forms, 4,5,6,7-tetrafluoroindazolin-3-one crystallizing in P2₁/c monoclinic space group and 6,7-difluoroindazolin-3-one in P2₁/n monoclinic space group, proving once more the efficiency of the combined use of both techniques in structural determination. DFT theoretical calculations, gas phase, water-PCM and one explicit water molecule, support the results.

http://www.arkat-usa.org/get-file/45154/

A theoretical study of the parent NH-benzazoles (benzimidazoles,indazoles and benzotriazoles): geometries, energies, acidity and basicity, NMR properties and molecular electrostatic potentials

The three parent N H-benzazoles, benzimidazole, indazole and benzotriaz ole, have been studied theoretically at the B3LYP/6-311++G(d,p) level. Opt imized geometries have been compared with those obtained by X-ray crystallography, energ ies with studies about tautomerism, acidbase properties with p Kas, and chemical shifts with those reported in the l iterature. As aromaticity probe, Schleyer's Nuclear Independent C hemical Shifts (NICS) were used and represented in two 3D isosurfaces of the electron density

DOI: 10.1016/j.tet.2011.09.083

Oxazolidinone cross-alkylation during Evans' asymmetric alkylation reaction

Starting from Evans’ imidazolidin-2-one (1) two compounds were obtained by trans-N-acylation: the expected one 3 with S,R configuration and a second compound 5, that is, related to 3 by the loss of a CH(CH₃)C═O fragment. The stereochemistry of 3 was established by NMR spectroscopy, mainly NOE experiments, as expected, the new center has an S configuration, the compound being thus S,R. The structure of compound 5was determined by X-ray crystallography. A mechanism of formation of 5 was proposed.

DOI: 10.1016/j.tet.2011.09.027

A theoretical study of the effect of copper(I) chloride on the azido/tetrazole isomerism

B3LYP/6-31G(d), B3LYP/6-311++G(d,p), and CBS-QB3 calculations on the effect of CuCl on the azido/tetrazole isomerism have been performed. The cases of 2-azidopyridine and 2-azido-1H-imidazole have been selected as examples of heteroaromatic six- and five-membered rings. All minima and transition states have been characterized.

DOI: 10.1007/s11224-011-9799-7

Conformational analysis of N,N'-dinaphthyl heterocyclic carbenes: imidazol-2-ylidenes and imidazolin-2-ylidenes

The paths connecting the stationary points of tesseract (four-dimensional hypercube) have been explored. The minimum energy conformations and the different transition states of N,N′-dinaphthyl imidazol-2-ylidenes and imidazolin-2-ylidenes have been calculated. The available experimental results were conveniently reproduced. The dimerization of carbenes to enetetramines has also been calculated.

DOI: 10.1016/j.tetasy.2011.06.003

Determination of the absolute configuration of 1,3,5-triphenyl-4,5-dihydropyrazole enantiomers by a combination of VCD, ECD measurements, and theoretical calculations

The enantiomers of 1,3,5-triphenyl-4,5-dihydropyrazole (an intense blue fluorescent compound) have been separated for the first time and their absolute configuration was established by a combination of VCD and ECD measurements and theoretical calculations. The enantiomers of 1,3,5-triphenyl-4,5-dihydropyrazole which are highly fluorescent both in solution (CH₂Cl₂) and in the solid state may find application in the very active field of enantioselective fluorosensors.

DOI: 10.1142/S1088424611002994

Atropisomerism and conformational aspects of meso-tetraarylporphyrins and related compounds

This review provides a comprehensive description of the atropisomerism of meso-di- and tetraarylporphyrins with substituents in ortho-positions of the aryl ring, as well as in corroles and in conveniently substituted phthalocyanines. Different methods of study were examined: X-ray crystallography, NMR spectroscopy (both static and dynamic aspects), classical kinetics, HPLC and theoretical calculations. Then the four atropisomers, the tautomerism of the inner protons, the 'picket fence' concept, conformationally restricted meso-tetraarylporphyrins and the influence of the metal on the conformation were discussed based on 250 references.

DOI: 10.1016/j.ejmech.2011.01.027

Synthesis and biological evaluation of indazole derivatives

The inhibition of neuronal and inducible nitric oxide synthases (nNOS and iNOS) by a series of 36 indazoles has been evaluated, showing that most of the assayed derivatives are better iNOS than nNOS inhibitors. A parabolic model relating the iNOS inhibition percentage with the difference, E_rel, between stacking and apical interaction energies of indazoles with the active site of the NOS enzyme has been established.

DOI: 10.1016/j.comptc.2010.11.030

A computational study of the conformation of heterocyclic systems related to biphenyl

The conformation of nine N,N′-linked heterocycles including pyrrole, carbazole, 4H-1,2,4-triazole, pyrazole, pyridinium and 4-pyridone has been explored (minima and transition states) at the B3LYP/6-31G(d) level. Besides, six conformationally restricted molecules belonging to the same series have been calculated.

DOI: 10.1016/j.molstruc.2010.11.054

Synthesis of [1,2,4]-triazolo[1,5-a]pyrimidines by Dimroth rearrangement of [1,2,4]-triazolo[4,3-a]pyrimidines: A theoretical and NMR study

DOI: 10.1039/C0DT01183E

[1,2,3]Triazolo[1,5-a]pyridyl phosphines reflecting the influence of phosphorus lone pair orientation on spectroscopic properties

A series of new triazolopyridine-based phosphines has been prepared. These compounds revealed unexpected spectroscopic patterns. In particular, the NMR spectra are highly dependent on the relative conformational preference of the phosphine substituent at C7. Here, we report on their complete NMR analysis, X-ray structures and DFT calculations that confirm the particular arrangement of the phosphorus lone pair orbital related to the substituent pattern of the chosen phosphine.

http://www.arkat-usa.org/get-file/37461/

High resolution NMR of free radicals: 13C magic angle spinning of two solid organic free radicals derived from 4,5-dihydro-1H-imidazol-3-oxide-1-oxyl and theoretical calculation of their NMR properties

The 13C CPMAS NMR spectra of  two 4,4,5,5-tetramethyl-2-(1H- and 2H-pyrazol-3-yl)-2-imidazoline-1-oxyl-3-oxides have been recorded and their signals assigned, through unrestricted density functional theory (UDFT) calculations of their absolute shieldings, with satisfactory results. 

DOI: 10.1016/j.molstruc.2010.10.023

Crystal and molecular structure of three biologically active nitroindazoles

3-Bromo-1-methyl-7-nitro-1H-indazole (1), 3-bromo-2-methyl-7-nitro-2H-indazole (2) and 3,7-dinitro-1(2)H-indazole (3) have been synthesized and characterized by X-ray diffraction, ¹³C and ¹⁵N NMR spectroscopy in solution and in solid-state. The dihedral angles obtained in the crystal structures are in good agreement with the molecular parameters calculated using DFT B3LYP calculations employing the 6-311++G(d,p) basis set. Compounds 1 and 2 present intermolecular halogen bonds between the bromine and the oxygen atoms of the nitro group and in compound 3 inter- and intramolecular hydrogen bonding exists.

http://www.arkat-usa.org/get-file/37295/

Pyridinium-N-(2-pyridyl)aminides and related compounds: a theoretical study. 

Seven families of pyridinium-N-(heteroaryl)aminides, both azinyl and azolyl, have been studied. For each family, three structures have been considered, the "classical" and two radicals. The transition states corresponding to the rotation  of the pyridinium and  the heterocycle were calculated at the B3LYP/6-31G* level.

DOI: 10.1515/HC.2010.008

A theoretical multinuclear NMR study of pyrazolylborates

The experimental chemical shifts and coupling constants of five borates of general formula BH_nPz_4–n [from the borohydride to tetrakis(pyrazol-1-yl)borate] anions were compared with calculations carried out at the B3LYP/6-311++G(d,p) level (GIAO for absolute shieldings), in general with satisfying results. The most stable conformations of pyrazolylborate anions are similar to those of neutral pyrazolylmethanes.

http://www.arkat-usa.org/get-file/33911/

N-substituted-1,2,3-triazoles: synthesis, characterization and evaluation as cannabinoid ligands 

A series of new N1-, N2- and N3-substituted 1,2,3-triazole derivatives has been synthesized by cycloaddition of butyltin azide with substituted alkynes followed by a N-alkylation reaction. The regioisomers have been isolated and characterized using NMR techniques. GIAO/B3LYP calculations of the absolute shieldings have been performed to verify the assignments and so the structures have been unequivocally identified. The proportion in which the three isomers are obtained corresponds with the relative order of stability indicated by the energy values calculated at the B3LYP level.  CB1 cannabinoid receptor binding assays have been performed but none of the compounds showed significant activity

DOI: 10.1002/jhet.377

Six pyrazolo[1,5-a]pyrimidines bearing a 7-trifluoromethyl (three compounds), a 7-trichloromethyl (two compounds), and a 7-ethoxycarbonyl (one compound) have been structurally characterized. The new X-ray structures of 2-methyl-5-(p-bromophenyl)-7-trifluoromethylpyrazolo[1,5-a]pyrimidine (3) and 2-methyl-7-trichloromethylpyrazolo[1,5-a]pyrimidine (4) are reported. The combined use of GIAO/B3LYP/6-311++G(d,p) calculations with NMR spectroscopy in solution and in the solid state allows to establish some general rules that can be useful for characterizing related compounds. Compounds 3 and 4 present in the solid-state interesting intra- and intermolecular halogen bonds. 

DOI: 10.1039/C0CE00249F

Fast degenerate double proton transfer in the solid state between two indazolinone tautomers

The neutral dimer formed by 4,6-difluoro-1H,2H-indazolin-3-one and 3-hydroxy-4,6-difluoro-1H-indazole linked by two hydrogen bonds presents a very fast intermolecular double proton transfer in the solid state (ISSPT). The combined use of crystallography, solid state NMR and DFT [B3LYP/6-311++G(d,p)] calculations supports this interesting observation and allows us to estimate a barrier of about 20 kJ mol⁻¹.

DOI: 10.1142/S1088424610002409

A theoretical study of the conformation of meso-tetraphenylporphyrin (TPPH2), its anions, cations and metal complexes (Mg2+, Ca2+ and Zn2+)

A theoretical study has been carried out on TPPH₂ (both tautomers), its deprotonated and protonated forms, as well as complexes of TPP containing Mg²⁺, Ca²⁺ and Zn²⁺ ions. Two properties have been analyzed. The first one considers the conformation of the meso-phenyl rings and the deformation of the porphyrin macrocycle, the second one relates to the barriers of rotation of the meso-phenyl rings (atropisomerism). In the case of the Zn complex (ZnTPP), the coordination effects with the N3 of 1H-imidazole have been calculated.

DOI: 10.1007/s11224-010-9625-7

Conformational analysis of dibenzo[a,e]cyclooctadiene and three related heterocyclic compounds

A theoretical B3LYP/6-311++G(d,p) study of four derivatives of cyclooctadiene bearing two aromatic or heteroaromatic rings is reported. The conformational analysis reproduces well the experimental results (minima and transition states). The GIAO calculated ¹H and ¹³C chemical shifts proved useful in solving some stereochemical questions.

DOI: 10.1016/j.tet.2010.04.119

The azido-tetrazole tautomerism in azoles and its relationships with aromaticity and NMR properties

The properties of 41 neutral molecules (azoles) together with 13 transition states as well as of 16 anions (azolates) with seven transition states belonging to the series of azido/azoles, have been calculated at the B3LYP/6-31G(d) and at the G3B3 levels. Energies, NICS, and bond critical points are used to discuss the ring-chain tautomerism of these compounds in relation with the magnetic aromaticity of the azoles (imidazoles, benzimidazoles, pyrazoles, indazoles, 1,2,4-triazoles, 1,2,3-triazoles and tetrazoles). The removal of the N–H proton has a considerable effect on the azido/tetrazole equilibrium and corresponds to a large stabilization (73 kJ mol⁻¹ in average) of the tetrazoles. Cioslowski’s exothermicity is related to the energy barriers (TSs). A study of the E/Z isomerism of the azides, determination of NICS(1) values and AIM analysis were also carried out.

DOI: 10.1016/j.tetasy.2010.02.023

A theoretical analysis of the conformational space of tris(2-methylbenzimidazol-1-yl)methane

The conformation surface of tris(2-methylbenzimidazol-1-yl)methane has been explored locating four minima (uuu, uud, udd and ddd, each one corresponding to two enantiomers, the P and the M) and seven transition states. The known experimental barrier to racemization (119 kJ mol⁻¹) was calculated to be about 110 kJ mol⁻¹ (uuu or uud stereoisomers). GIAO calculations of absolute shieldings correlate very well with¹H and ¹³C NMR chemical shifts. Finally, the specific rotation of the four minima was calculated allowing us to identify the absolute configuration of the first eluted enantiomer.

DOI: 10.1016/j.tet.2010.02.035

The azido-tetrazole and diazo-1,2,3-triazole tautomerism in six-membered heteroaromatic rings and their relationships with aromaticity: Azines and perimidine

The properties of 28 molecules together with 12 transition states belonging to the series of azido-azines, tetrazolo-azines, diazo-azines, and 1,2,3-triazolo-azines have been studied at the B3LYP/6-31G(d), B3LYP/6-311++G(d,p) and, for 26 cases, at the G3B3 level. Energies, NICS and bond critical points were used to discuss the ring-chain tautomerism of these compounds in relation with the aromaticity of the azines (pyridine, pyrimidine, quinazoline, 1,3-diazapyrene, and perimidine) and the azoles (tetrazoles and 1,2,3-triazoles).

DOI: 10.1016/j.theochem.2009.11.024

A theoretical comparison of the chemical shifts of three related heterocycles: 1H-pyrazoles, 1H-1,2,4-triazoles and 1H-1,2,4-diazaphospholes

Seventeen derivatives of 1H-pyrazoles, 1H-1,2,4-triazoles and 1H-1,2,4-diazaphospholes (three of them existing in two tautomeric forms, thus forming 20 families of compounds) were studied theoretically. At the GIAO/B3LYP/6-311++G(d,p) level, the calculations reproduce fairly well the available experimental chemical shifts. The completeness of the calculated absolute shieldings allows to discuss the relationships between the 4-position (CH, C, N and P) chemical shifts. There are noticeable differences due to the different contributions of the substituents at positions 3 and 5.

DOI: 10.1016/j.molstruc.2009.11.041

The structures of chiral and racemate campho[2,3-c]pyrazole: A combined crystallographic, solid-state NMR and computational study

Crystallographic and solid CPMAS NMR studies were performed on the (4S,7R)-enantiomer as well as on the (4S,7R)- and (4R,7S)-7,8,8-trimethyl-4,5,6,7-tetrahydro-4,7-methano-2H-indazole racemate. Both crystallize with six independent molecules forming two trimers. Assignment of the ¹³C chemical shifts to the six molecules, slighting differing in geometry, was carried out by comparison with GIAO/B3LYP/6-31G(d) calculations.

Doi: 10.1016/j.molstruc.2008.11.027

A theoretical and experimental NMR study of (+)-biotin methyl ester

Doi: 10.1016/j.molstruc.2008.10.020

Structural study of diarylazoles related to Rimonabant

The structures of three diarylazoles (two pyrazoles and one 1,2,4-triazole) related to Rimonabant have been determined by X-ray crystallography. The conformation of both aryl groups in the new structures is discussed with regard to other related compounds reported in the Cambridge Structural Database. The secondary structure of the three compounds is very different. Compound 2 forms a helix, compound 3 forms a structure with the hydrocarbon layers parallel and compound 4 crystallizes forming a double chain. In the solid state, the conformation of both aryl groups, the N-aryl and the C-aryl, was compared with similar compounds reported in the literature. GIAO calculations afford absolute shieldings that were compared with experimental chemical shifts.

DOI: 10.1002/ejoc.200900818

3-(Pyridin-2-yl)[1,2,3]triazolo[1,5-a]quinoline: A Theoretical and Experimental Analysis of Ring-Chain Isomerisation

In the course of the synthesis of new fluorophores for molecular recognition an experimental (¹H NMR) and theoretical (DFT) study of the ring-chain isomerism of 3-(pyridin-2-yl)[1,2,3]triazolo[1,5-a]quinoline derivatives (A) into 2-([1,2,3]triazolo[1,5-a]pyridin-3-yl)quinoline derivatives (B) has been carried out. The rearrangement is influenced by steric and electronic effects of the substituents present on the quinoline ring. 

DOI: 10.1016/j.molstruc.2009.08.018

The structure of two pyrazole esters related to Rimonabant

Two 1,5-diarylpyrazoles related to the antiobesity agent Rimonabant have been synthesized and their structure determined by X-ray crystallography. Compound 2, 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate, forms strange crystals but its only peculiarity involves Cl⋯Cl and Cl⋯π interactions, that were modeled theoretically at the M05-2x/6-31+G(d,p) level. ¹³C NMR results were rationalized through GIAO calculations at the B3LYP/6-311+G(d,p) computational level.

DOI: 10.1002/poc.1512

N-sigma versus pi configuration in mono- and bis-pyrrole and imidazole derivatives of alkaline earth metals

A theoretical study of the preferred N-σ or π configuration of the mono- and bis-pyrrole and imidazole derivatives of alkaline earth metals has been carried by means of DFT and ab initio methods, up to G2 computational level. The energetic results show that the beryllium derivatives prefer the N-σ configuration while the calcium ones prefer the π one. In the case of magnesium, both configurations present similar stability. The calculated dissociation enthalpies correspond to the fact that the metallic atom is strongly bonded to the azoles in both configurations. The NBO analysis shows that the systems can be considered as formed by the azolates interacting with the charged metallic atom and thus the Natural Energy Decomposition Analysis (NEDA) indicates that the main attractive force is the electrostatic. 

DOI: 10.1016/j.tet.2009.05.018

Theoretical studies of azapentalenes. Part 5: Bimanes

The properties of 21 molecules related to azapentalenes and their conjugated acids have been calculated: energies, dipole moments, natural bond orders, bond lengths, bond critical points, HOMA, and NICS. The ring-opening processes of dioxopyrazolo[1,2-a] pyrazolium and pyrazolo[1,2-a][1,2,4]triazol-4-ium into ketenes and isocyanates have been studied. The calculations were carried out at the B3LYP/6-311++G(d,p) level.

DOI: 10.1016/j.tet.2009.05.017

Theoretical studies of azapentalenes. Part 4: Theoretical study of the properties of 3a,6a-diazapentalene

A theoretical study of the properties of the isolated 3a,6a-diazapentalene by means of DFT, B3LYP/6-311++G(d,p) and ab initio methods, MP2/6-311++G(d,p), has been carried out. In addition, the complexes formed with hydrogen bond donor, acceptors, cations, and anions have been studied and analyzed. Ring opening into 1,5-diazocine as well as basicity and acidity properties of 3a,6a-diazapentalene have been explored. Their ability to form HB complexes and the complexes formed with anions and cations have been studied.

DOI: 10.1002/chem.200900867

1,2,4-Diazaphospholide Complexes of Tin(II): From Nitride Stannylene to Stannylenated Ammonium Ions 

An unusual nitride tetrastannylene and a stannylenated ammonium ion stabilized by a samarium tetradiazaphospholido counterion are the first examples of a tris(organostannylenyl)amine derivative and a divalent tin coordinate onium ion that incorporates 1,2,4-diazaphospholide ligand.

DOI:10.1007/7081_2008_1

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How Aromaticity Affects the Chemical and Physicochemical Properties of Heterocycles: A Computational Approach

Our publications dealing with problems related to aromatic heterocycles are discussed with the appropriate references from the literature. The three main topics are theoretical calculations, tautomerism, and NMR spectroscopy but other aspects are also discussed, such as crystal structures, proton transfer, hydrogen bonds, IR, etc.

DOI: 10.1039/b803855d

A theoretical and experimental NMR study of the tautomerism of two phenylene-bis-C-substituted pyrazoles

Two bis-pyrazolylbenzenes, one meta- and the other para-substituted, have been studied by multinuclear magnetic resonance both in solution and in the solid state, including ¹³C CP-MAS NMR variable temperature experiments. The tautomerism in DMSO-d₆ solution has been studied and the most stable tautomers (the 3,3 and the 3,5) identified. In the solid state themeta derivative exists as the 3,3-tautomer while the tautomer of the para derivative is the 3,5 one. This latter tautomer exists in a dynamic equilibrium with the 5,3 one, representing a new and original example of proton transfer in the solid state (SSPT).

DOI: 10.1016/j.tet.2008.09.064

[1,2,3]Triazolo[1,5-a]pyridines. A theoretical (DFT) study of the ring-chain isomerization

The ring opening isomerization of [1,2,3]triazolo[1,5-a]pyridines to the corresponding 2-pyridyl derivatives has been studied by means of DFT calculations at the B3LYP/6-31+G(d,p) computational level. The effect of the substitution as well as those of protonation, deprotonation, and lithiation on different positions has been studied. The electronic characteristics of the optimized structures have been analyzed by means of the Atoms In Molecules (AIM), Electron Localization Function (ELF), Molecular Electrostatic Potential (MEP), and Natural Bond Orbital (NBO) methodologies.

DOI: 10.1016/j.tetlet.2008.09.131

The use of a molecular balance derived from 5,5'-bipyrazole to calculate pi-pi stacking interactions

Theoretical calculations have been carried out on 3,3′-dimethyl-1,1′-diphenyl-5,5′-bi-1H-pyrazole to evaluate its usefulness as a molecular balance to measure π−π stacking. After removing the methyl groups (1,1′-diphenyl-5,5′-bi-1H-pyrazole), the N-phenyl groups have been replaced by a series of aromatic rings, and the energy difference between the syn and anti forms is discussed in terms of π−π stacking and dipole–dipole interactions.

DOI: 10.1002/chem.200800911

Synthesis and Preferred All-syn Conformation of C3-Symmetrical N-(Hetero)arylmethyl Triindoles

A new series of C₃-symmetrical N-(hetero)arylmethyl triindoles has been synthesized in a straightforward procedure. The structure and conformation in the solid state have been determined for three derivatives (3, 4, and 6) by X-ray crystallographic analysis. In all three cases, the molecules adopt a tripodal conformation with all of the flexible arms directed towards the same side, thereby delimiting an inner cavity. Compound 6 crystallizes and forms C₃-symmetric dimeric cagelike complexes. Guest molecules of chloroform and water are confined within the resulting cavities with stabilization by different intermolecular interactions; this highlights the potential of these compounds in the construction of supramolecular systems. A computational analysis has been performed to predict the most stable conformers. As a general trend, a preference for a conformation with all branches directed to the same side has been predicted. Comparison between theoretical and experimental results indicates that the computational level selected for the present study, B3LYP/6-31G*, is able to reproduce both the minimum energy conformations and the rotation barriers about the NCH₂ bond.

DOI: 10.1021/jp801936v

The Structure of Alkali Metal Derivatives of Azoles: N-sigma versus pi Structures

High level ab initio calculations have been used to study the relative stability of N−σ and π configurations of the neutral alkaline derivatives of azoles. The N−σ structure is the one normally expected for nonionized azolate salts. However, the results show that in the case of the pyrrole and imidazole the π configuration is more stable than the N−σ one. The preference of the N−σ vs π configurations is related to the presence or the absence of two contiguous nitrogen atoms in the azole ring. A search in the CSD shows that some pyrrolate and imidazolate salts exist in solid phase in the π configuration.

DOI: 10.1007/s11224-007-9271-x

Proton transfer in C-halogen pyrazole cyclamers. A theoretical study

Four monomers and twelve pyrazole cyclamers unsubstituted or bearing fluoro, chloro, or bromo substituents at positions 3 and 5 have been studied at the B3LYP/6-31+G** theoretical level. Two mechanisms of proton transfer, stepwise and synchronous, have been studied for dimers, trimers, and tetramers. Even though some values of the barriers have not been determined, the set of values of energies and geometries provide useful insights about the dynamics of NH-pyrazoles in the solid state.

DOI: 10.1016/j.tet.2008.01.141

Application of Free-Wilson matrices to the analysis of the tautomerism and aromaticity of azapentalenes: a DFT study

The tautomerism and aromaticity of 44 neutral and the corresponding 60 protonated azapentalenes were studied. The tautomerism was based on the calculated relative energies of the different tautomers, from two to three and nine nitrogen atoms. The aromaticity was estimated from the NICS values of both rings of azapentalenes. The possible relationship between both properties was assessed. The calculation was carried out at the B3LYP/6-311++G^∗∗ computational level. MEP and NBO analysis were carried out on the studied compounds.

DOI: 10.1021/cg0702939

The Boat Conformation in Pyrazaboles. A Theoretical and Experimental Study

Experimental data are combined with theoretical calculations to study the stability of the boat conformation of the pyrazabole ring. For the experimental studies, new BH₂- and BF₂-pyrazaboles disubstituted with iodo or ethynyl groups at the 2- and 6-positions have been prepared and structurally characterized. We have found different molecular structures and crystal packings depending on the substituents. The iodo derivatives have a bent molecular shape due to the boat conformation of the pyrazabole ring, and the molecules are arranged in stacks with the same conformation (all-up or all-down boat conformation) along the crystallographic b axis. Stacks of molecules with the same conformation interact in a plane by means of iodo−iodo short contacts. However, the ethynyl derivatives are formed by bent-shaped molecules for BH₂ and planar structures for BF₂. Density functional theory and ab initio calculations have been performed on these compounds and on unsubstituted analogues to understand the effect of substituents on the conformation, inversion barrier, and NMR chemical shifts. The results of these calculations were compared with the experimental results. Theoretically, the boat conformation is an energy minimum, with the planar and chair conformations as transition states in an energy diagram. In solution, the compounds are in a boat conformation (with a boat-to-boat dynamic equilibrium) irrespective of their crystal structures.

DOI: 10.1016/j.theochem.2007.10.037

Heteropentalenes aromaticity: A theoretical study

Theoretical calculations at the B3LYP/6-311++G^∗∗ level including GIAO and NICS chemical shifts have been carried out on seven simple heterocycles (furan, thiophene, pyrrole, 1H-imidazole, 1H-pyrazole, 1H-1,2,3-triazole, 2H-1,2,3-triazole) and 28 heteropentalenes (22 of them being azapentalenes). The relative energies are discussed in function of the heteroatoms and of the topology ([2,3-b] vs. [3,2-b]) for isomers and tautomers. Schleyer’s NICS(0) and NICS(1) are used to discuss the aromaticity of these compounds.

DOI: 10.1002/chem.200701542

Synthesis, Characterization, Molecular Structure and Theoretical Studies of Axially Fluoro-Substituted Subazaporphyrins

A new and general synthetic method for the preparation of fluoro-substituted subazaporphyrins is reported that involves the treatment of the corresponding chloro- or aryloxy-substituted subazaporphyrins (SubAPs) with BF₃⋅OEt₂. The strategy has been applied to both subphthalocyanines (SubPcs) and subporphyrazines (SubPzs). The yields were high for the latter, although low yields were obtained for the benzo derivatives. In contrast to the corresponding chloro derivatives, fluorosubazaporphyrins are quite robust towards hydrolysis. All of the new compounds were characterized by several spectroscopic techniques, which included ¹H, ¹³C, ¹⁹F, ¹⁵N, and ¹¹B NMR spectroscopy, IR spectroscopy, UV/Vis spectrophotometry, and mass spectrometry (both high and low resolution). In addition, DFT calculations provided theoretical NMR spectroscopy values that are in good agreement with the experimental ones. The high dipole moments exhibited by the fluorosubazaporphyrins as a result of the presence of a fluorine atom in an axial position are responsible for the spontaneous and singular supramolecular aggregation of the macrocycles in the crystalline state. The molecular and crystal structures of two one-dimensional fluorine SubAPs, namely, a SubPc and a SubPz, are discussed. Molecules of the same class stack in alternating configurations along the c axis, which gives rise to columns that contain large numbers of monomers. SubPz 3 c forms aggregates with the macrocycles arranged in a parallel fashion with the BF bonds perfectly aligned within a column, whereas with SubPc 3 b the neighboring columns cause a commensurate sinusoidal distortion along the columns in the c direction, which prevents the alignment of the BF bonds. However, the most remarkable feature, common to both crystalline architectures, is the extremely short and unusual intermolecular F⋅⋅⋅N distances of the contiguous molecules, which are shorter than the sum of the corresponding van der Waals radii. Theoretical calculations have shown that these short distances can be explained by the existence of a cooperativity effect as the number of monomers included in the cluster increases.

Doi: 10.1007/s11224-007-9237-z

Substitution effects in N-pyrazole and N-imidazole derivatives along the periodic table

A theoretical study of the monosubstitution effects of all the atoms of the second and third row of the periodic table on the pyrazole and imidazole rings has been carried out by means of B3LYP/6-31+G(d,p) DFT calculations. The geometric and electronic properties, calculated using the atoms in molecules methodology, electrostatic potential, and frontier orbitals have been analyzed. Some of the results have been rationalized based on the electronegativity of the substituents. In addition, the different parameters obtained have been compared with aromaticity indexes (HOMA and NICS). A comparison with the results obtained for the corresponding N-pyrrole derivatives has been carried out.

Doi: 10.1007/s11224-007-9245-z

Substitution effects in phenyl and N-pyrrole derivatives along the periodic table

A theoretical study of the monosubstitution effects of all the atoms of the second and third row of the periodic table on the phenyl and pyrrole rings has been carried out by means of B3LYP/6-31 + G(d,p) DFT calculations. The geometric and electronic properties, calculated using the Atoms In Molecules methodology, have been analyzed. Some of the results have been rationalized based on the electronegativity of the substituents. In addition, the different parameters obtained have been compared with different aromaticity indexes (HOMA, NICS, and ASE), as well as with Taft’s σ⁰ _Rparameter.

DOI:10.1071/CH07268

Synthesis of 4-Aryl-3(5)-(2-hydroxyphenyl)pyrazoles by Reaction of Isoflavones and their 4-Thio Analogues with Hydrazine Derivatives

4-Aryl-3(5)-2-(hydroxyphenyl)pyrazoles have been prepared by the reaction of isoflavones and their 4-thio analogues with hydrazine hydrate and phenylhydrazine in hot pyridine. The reaction mechanism for the formation of these pyrazoles is discussed. All the new compounds have been fully characterized by NMR spectroscopy. In [D₆]DMSO, a ¹H NMR study allows observation of the presence of both pyrazole annular tautomers, due to the presence of intramolecular hydrogen bonds in each tautomer (OH···N and NH···O). Theoretical calculations have been carried out on tautomers and conformers of compounds 20(3(5)-(2-hydroxy-4-methoxyphenyl)-5(3)-methyl-4-phenylpyrazole) and 21 (3(5)-(2-hydroxy-4-methoxyphenyl)-4-(2-methoxyphenyl)-5(3)-methylpyrazole), including the absolute shieldings (GIAO/B3 LYP/6–311++G**) of 21.

Doi: 10.1007/s11224-007-9208-4

The use of chemical shifts vs. coupling constants for studying tautomerism: a combined experimental and theoretical approach

When observing average NMR signals originated from a rapid equilibrium, the procedure to estimate the composition of the mixture is to use interpolation. To illustrate the difficulties of this approach, the much-studied case of the NH and OH tautomers of pyrazolinones will be reexamined. Calculated absolute shieldings and coupling constants were compared with experimental data. Although the large predominance of the OH tautomer in DMSO was confirmed, the result is a little disappointing because no consistency in the percentages was achieved using chemical shifts and coupling constants.

DOI: Not available

Review: A simple approach to the tautomerism of aromatic heterocycles

This Lead Article describes in a simple way the universe of the tautomerism of aromatic heterocyles. The most frequent errors are described and, at the same time, some general rules about how to proceed in tautomeric studies are provided.

Doi: 10.1016/j.tet.2007.06.069

The structural and theoretical study of 1H-3,5-di-phenyl-1,2,4-diazaphosphole in the solid state

The N-, P-containing five-membered heterocyclic compound 1H-3,5-di-phenyl-1,2,4-diazaphosphole (1) was prepared in good yield and has been structurally characterized. 1H-3,5-Di-phenyl-1,2,4-diazaphosphole (1), crystallizing in two unexpected cyclic dimers with N–H⋯N hydrogen bonds, presents in the solid state a dynamic proton disorder implying a dynamic equilibrium within both dimers. The conformations of the phenyl rings, the disorder of the NH protons, and the intermolecular hydrogen bond of several 1,2,4-diazaphospholes (1–5) in the solid state have been rationalized by DFT [B3LYP/6-311++G(d,p)] calculations.

Doi: 10.1016/j.tet.2007.06.007

Structure and tautomerism of 4-bromo substituted 1H-pyrazoles

The tautomerism in the solid state and in solution of five 4-bromo-1H-pyrazoles has been studied by multinuclear magnetic resonance spectroscopy and, for one of them, by X-ray crystallography (3,4-dibromo-5-phenyl-1H-pyrazole). When there is a bromine atom at position 3(5), in all cases, the tautomer present in the solid state is the 3-bromo one. In solution, the same tautomer is the major one. DFT calculations justify the predominance of 3-bromo tautomers over 5-bromo ones and provide some useful chemical shifts obtained through GIAO calculations.

Doi: 10.1039/b617988f

The structure of fluorinated indazoles: the effect of the replacement of a H by a F atom on the supramolecular structure of NH-indazoles

The structures of three NH-indazoles (3-methyl, 3-trifluoromethyl and 3-trifluoromethyl-4,5,6,7-tetrafluoroindazoles) have been determined by X-ray crystallography. These three compounds, together with 3-methyl-4,5,6,7-tetrafluoroindazole, whose X-ray structure could not be determined, have been studied using multinuclear magnetic resonance spectroscopy, including solid-state CPMAS. They all are 1H-tautomers. In the crystal, 3-methyl-1H-indazole forms hydrogen bonded dimers, whereas 3-trifluoromethyl-1H-indazole and 3-trifluoromethyl-4,5,6,7-tetrafluoro-1H-indazole crystallize as catemers. These catemers are chiral space groupP3₂. They are the first examples of indazoles crystallizing in the form of helices of three-fold screw axis. Attempts at rationalizing this behavior on the basis of supramolecular interactions (hydrogen bonds and aromatic interactions) and GIAO calculations are discussed.

Doi: 10.1021/cg0701527

Cocrystals of 3,5-Dimethyl-1H-pyrazole and Salicylic Acid: Controlled Formation of Trimers via O-H···N Hydrogen Bonds

Solid-state reactions of 3,5-dimethyl-1H-pyrazole (dmpz) and salicylic acid (sa) in different stoichiometries afford two different trimers whose structures have been determined by X-ray diffraction and analyzed by ¹³C and ¹⁵N solid-state nuclear magnetic resonance spectroscopy. GIAO absolute shieldings at the B3LYP/6-311++G** level have been calculated and compared with the experimental chemical shifts. Hydrogen-bond interactions between dmpz and saprovide sufficient driving force to direct molecular recognition and crystal packing.

http://www.arkat-usa.org/get-file/18756/

Double addition of azoles to glyoxal: characterization of the bis-adducts and theoretical study of their structure

We have studied the structure (isomerism and conformation) of the products resulting from the double addition of four NH-azoles, benzotriazole, pyrazole, imidazole and benzimidazole, on glyoxal and on DODO ([1,4]-dioxane-2,3-diol). The reactions result in the formation of meso and d,l diastereoisomers, although in all cases a significant amount of unreacted azole remains. The four component mixtures were analyzed by 1H and 13C NMR. DFT calculations (B3LYP/6-31G*) were carried out to determine the relative stabilities of the different structures. 

DOI: 10.1002/mrc.1992

Pyrazolo[1,5-a]pyrimidines. A combined multinuclear magnetic resonance (¹H, ¹³C, ¹⁵N, ¹⁹F) and DFT approach to their structural assignment.

Multinuclear magnetic resonance spectroscopy together with GIAO-DFT calculations allowed establishment of the structure of the products obtained by condensation of 3(5)-amino-4-phenyl-1H-pyrazole and β-dicarbonyl compounds bearing a trifluoromethyl group. They are 3-phenyl-5-(R)-7-trifluoromethylpyrazolo[1,5-a]pyrimidines. 

DOI: 10.1039/b607871k

Theoretical models of directional proton molecular transport 

The important topic of proton transport through molecular wires is usually associated with the Grotthuss mechanism. In this paper we propose an alternative conductor based on chains of lone pairs. B3LYP/6–31+G** and PW91 DFT calculations on model compounds (1,2,3,4-tetrasubstituted benzenes) show that these compounds could play the role of proton conductors.

Doi: 10.1002/ejoc.200600043

Synthesis of Pyrazoles by Treatment of 3-Benzylchromones, 3-Benzylflavones and Their 4-Thio Analogues with Hydrazine

The synthesis of pyrazoles 13–24 has been accomplished by treatment of 3-benzylchromones 1–5, 3-benzylflavones 6–12 and their 4-thio analogues 25–29 with hydrazine hydrate in hot pyridine. A plausible reaction mechanism for the formation of pyrazoles 13–24 is discussed. A ¹H NMR study in [D₆]DMSO allowed the presence of both pyrazole annular tautomers to be observed, due to the presence of intramolecular hydrogen bonds in each tautomer (OH--N and NH--O). GIAO/B3LYP/6-311++G** calculations were carried out on some model pyrazoles to provide a theoretical basis for the NMR experimental observations.

Doi: 10.1002/mrc.1897

The structure of ammonium pyrazolates in the solid state

The crystals obtained by mixing equimolar amounts of diethyl 1H-pyrazole-3,5-dicarboxylate and the primary amines phenethylamine and homoveratrylamine are ammonium pyrazolate salts as determined by ¹³C and ¹⁵N CPMAS NMR.

Doi: 10.1007/s11224-006-9065-6

The annular tautomerism of imidazoles and pyrazoles: the possible existence of non-aromatic forms

DFT (B3LYP/6-31G^*) and G3//B3LYP (usually referred as G3B3 in the literature) calculations have been carried out on annular tautomers of C- and/or N-functionalized imidazoles (both the aromatic 1H- and nonaromatic 2H-) and pyrazoles (the aromatic 1H- and 2H-, and nonaromatic 3H- and 4H-). The aromaticity of 1H-imidazole and 1H- and 2H-pyrazole results in these species being more stable than their nonaromatic tautomers. However, this stability is reversed when the hydrogen on the azole nitrogen or methylene carbon is substituted by OH or by F, e.g., in increasing order of stability we find 1-fluoro-1H-imidazole <2-fluoro-2H-imidazole (<2-fluoro-1H-imidazole). These results are related to a recent report of a highly substituted imidazole that exists in the “nonaromatic” 2H-tautomeric form, and discussed subsequently in a purely thermochemical context.

Doi: 10.1016/j.tet.2006.07.002

The calculated enthalpies of nine pyrazole anions, cations, and radicals: a comparison with experiment

Enthalpies of 12 pyrazole species including neutral, anions, cations, and radicals have been calculated at the G3B3 level. The main conclusions are: (i) there are ten equilibria between species of which six have been measured experimentally and the agreement is excellent; (ii) two structures, cyclic and chain, have been found for the pyrazolium-radical 8 that are able to explain the electrochemistry of pyrazolium salts; (iii) the aromaticity, calculated as the NICS indexes, is related to the unexpected stability of the pyrazole anion 3.

Doi: 10.1007/s11224-006-9031-3

Phosphole, pyrrole, and their tetrahydro derivatives: A theoretical study of their properties

A theoretical analysis of four molecules (phosphole, phospholane, pyrrole, and pyrrolidine) in their ground and transition states has been carried out. The transition state of phosphole is highly aromatic and a partition of its energy into atomic contributions reveals that it is the phosphorus atom that is responsible for this observation.

Doi: 10.1016/j.tet.2006.01.059

Regioselectivity in the formation of norbornene-fused pyrazoles: preparation of 1-substituted derivatives of 4,5,6,7-tetrahydro-1H-4,7-methanoindazole.

The structural characteristics of (±)-(exo,exo)-3-(hydroxymethylene)-5,6-(isopropylidenedioxy)bicyclo[2.2.1]heptan-2-one make the reactions between this β-diketone and hydrazines particularly interesting for elucidating the mechanism of pyrazole formation. The isolation and X-ray structure determination of two 5-hydroxy substituted Δ²-pyrazolines [(±)-(3aR*,4R*,5R*,6S*,7R*,7aR*)-7a-hydroxy-5,6-(isopropylidenedioxy)-3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-indazole] and [(±)-(3aS*,4R*,5R*,6S*,7R*,7aR*)-7a-hydroxy-5,6-(isopropylidene-dioxy)-1-phenyl-3a,4,5,6,7,7a-hexa-hydro-4,7-methano-1H-indazole] has been determinant for proposing a mechanism. Besides B3LYP/6-31G* calculations have been carried out on all intermediate dihydroxypyrazolidines and 5-hydroxypyrazolines. Finally, the annular tautomerism of the NH-methanotetrahydroindazoles has been studied both experimentally (¹³C NMR) and theoretically: the Mills–Nixon effect favours the 2H-tautomer.

http://www.arkat-usa.org/get-file/23558/

The structure of 2,3-dihydro-3-(2,4-dioxo-6-methylpyran-3-ylidene)-2-(2-nitrobenzyl)-1,4-benzothiazine and the problem of orthogonal interactions

The structure of the title compound has been determined. The compound crystallizes in the P21/n space group with 4 molecules in the unit cell.  The structure is consistent with previous conclusions based on NMR spectroscopy; moreover it provides new information about the conformation of the thiazine  ring, the nature of the intramolecular hydrogen bond and the sulfur/nitro "orthogonal interaction". This last aspect has been examined through the use of DFT calculations on a simplified model system.

Doi: 10.1007/s11224-005-4550-x

A Theoretical Study on the Tautomerism of C-Carboxylic and Methoxycarbonyl Substituted Azoles.

DFT calculations (B3LYP/6-31+G^**) have been carried out on 106 tautomers and conformers of NH-azoles bearing CO₂H and CO₂CH₃ groups. The following azoles systems have been studied: 2-substituted pyrroles, 2-substituted indoles, 2-substituted imidazoles, 2-substituted benzimidazoles, 4(5)-substituted imidazoles, 3(5)-substituted pyrazoles, 3-substituted indazoles (1H and 2H), 3,4(5)-substituted-1,2,3(5)-triazoles, 2,3(5)-substituted-1,2(3),4-triazoles, 4(5)-1,2,3,4(5)-tetrazoles. In the case of pyrazole, 3,5-disubstituted derivatives have also been computed, including four dimers.

Doi: 10.1039/b510535h

3-(2-Pyridyl)-[1,2,3]triazolo[1,5-a]pyridines. An experimental and theoretical (DFT) study of the ring-chain isomerization

An experimental (¹H NMR) and theoretical (DFT) study of the ring–chain–ring isomerization of 3-(2-pyridyl)-[1,2,3]triazolo[1,5-a]pyrid-7-yl derivatives (A) into 6-{[1,2,3]triazolo[1,5-a]pyrid-3-yl}-2-pyridyl derivatives (B) has been carried out. Based on the calculations, a mechanism of several steps will be proposed. The experimental results as well as the calculations lead to the conclusion that the A–B ratio depends on the electronic properties of the substituents.

DOI:10.1071/CH05238

The X-Ray Molecular Structure of 1-(2',4'-Dinitrophenyl)-1,2,3-triazole and the Problem of the Orthogonal Interaction Between a 'Pyridine-Like' Nitrogen and a Nitro Group

The structure of the title compound serves for a discussion about the topic of orthogonal interactions. This interaction, although weak, is important due to its peculiar geometry. Other examples from the Cambridge Crystallographic Database, together with theoretical calculations are reported.

Doi: 10.1002/hc.20163

Barriers to the intramolecular N- to N-transfer of different groups in pyrazoles: Prototropy vs. Elementotropy

Barriers to the N- to N- transfer of different groups in pyrazole have been calculated at different levels (B3LYP and MP2 with 6-31G*, 6-311G*, and CEP-121 basis sets). Ten groups studied were H, BH₂, CH₃, CHO, AlH₂, SiH₃, GaH₂, GeH₃, SnH₃, and HgH. Two types of different transition states were found: The most common is a triangular situation with the group symmetrically linked to both N atoms. For metals M of the group 13 (B, Ga, Al) that situation is a second minimum while the TS corresponds to a rotation about the NM bond plus a displacement of the migrating group to yield a nonsymmetric TS. A relationship between the barrier and the geometry has been found. 

Doi: 10.1002/mrc.1676

The structure of the products of condensation of hydroxylamine with trifluoromethyl-b-diketones: assignments of the diastereotopic protons of the 4-methylene group in 5-hydroxy-5-trifluoromethyl-D2-isoxazolines

The combined use of ¹H NMR spectroscopy with theoretical calculations of chemical shifts (GIAO) and coupling constants (B3LYP/6-311 ++G**) of a 5-hydroxy-5-trifluoromethyl-Δ²-isoxazoline has enabled solving the problem of the assignments of the diastereotopic protons in this compound. This result has been extended to 5-hydroxy-5-trifluoromethyl-Δ²-pyrazolines and the corresponding 5-trichloromethyl derivatives. 

Doi: 10.1002/poc.923

Theoretical estimation of the annular tautomerism of indazoles

heoretical calculations at semi-empirical AM1 and density functional B3LYP/6–31G* levels were carried out on 52 NH-indazoles. Although in most cases the 1H-tautomer is the most stable, we found several indazoles for which the 2H-tautomer is more stable than the 1H-tautomer. The differences in energy between the 1H- and 2H-tautomers were interpreted in terms of substituent effects with the use of a Free–Wilson (presence–absence) matrix. 

Doi: 10.1016/j.tet.2005.03.035

Study of the reaction of chalcone analogs of dehydroacetic acid and o-aminothiophenol: synthesis and structure of 1,5-benzothiazepines and 1,4-benzothiazines

Treatment of α,β-unsaturated carbonyl compounds, obtained by the reaction of DHA and aromatic (or heteroaromatic) aldehydes, with o-aminothiophenol results in the formation of 1,5-benzothiazepines and/or 1,4-benzothiazines depending upon the reaction conditions and structure of the aldehydes. The products were characterized by the combined use of multinuclear 1D and 2D NMR and GIAO/DFT calculations of ¹H,¹³C and ¹⁵N chemical shifts. The tautomerism of these compounds in solution was determined, they have an exocyclic CC double bond.

Doi: 10.1002/mrc.1481

The tautomerism of 1H-pyrazole-3(5)-(N-tert-butyl)carboxamide in the solid state and in solution

The X-ray crystal structure of 1H-pyrazole-3-(N-tert-butyl)-carboxamide was determined. In the solid state, the ¹³C and ¹⁵N CP/MAS NMR spectra correspond to this tautomer. In solution, both tautomers are present in a ratio that depends on the temperature (at 293 K, 90% 3-substituted/10% 5-substituted). Some unusual ¹H, ¹H couplings involving the NH proton were observed. DFT (GIAO) calculations were carried out. 

DOI: 10.1002/jhet.5570410223

Study of the Structure of 1-Hydroxymethylindazole and 1-Hydroxymethylbenzotriazole by X-ray crystallography, Multinuclear NMR in Solution and DFT Calculations

1-Hydroxymethylindazole and 1-hydroxymethylbenzotriazole have been studied in solution by ¹H, ¹³C and ¹⁵N NMR spectroscopy and the X-ray structure of the second compound determined. DFT and GIAO calculations have been used to discuss geometries, energies (comparatively with 2-substituted isomers) and NMR chemical shifts.

DOI:10.1016/j.tet.2004.06.005

Synthesis, experimental and theoretical NMR study of 2'-hydroxychalcones bearing a nitro substituent on their B ring

The synthesis of several 2′-hydroxynitrochalcones has been accomplished by an aldol reaction of equimolar amounts of the appropriate 2′-hydroxyacetophenones with nitrobenzaldehydes in alkaline medium. The reaction of 2′-hydroxyacetophenones bearing a 6′-methoxy with 2- or 4-nitrobenzaldehydes gave the expected 2′-hydroxynitrochalcones and also 4-methoxynitroaurones, being the latter ones the unique reaction products when using 2 molar equiv of nitrobenzaldehydes. The reaction mechanisms for the formation of both products are discussed. The ¹³C NMR chemical shifts have been discussed first by means of an empirical additive model and then by comparison with GIAO/B3LYP calculated absolute shieldings.

DOI:10.1016/j.tet.2004.06.039

On the tautomerism of pyrazolones: the geminal 2J[pyrazole C-4,H-3(5)] spin coupling constant as a diagnostic tool

The tautomerism of pyrazolones unsubstituted at position 3(5) has been investigated by ¹³C- and ¹H NMR spectroscopic methods. Apart from chemical shift considerations and NOE effects the magnitude of the geminal ²J[pyrazole C-4,H3(5)] spin coupling constant permits the unambiguous differentiation between 1H-pyrazol-5-ol (OH) and 1,2-dihydro-3H-pyrazol-3-one (NH) forms. Whereas 1H-pyrazol-5-ols and 2,4-dihydro-3H-pyrazol-3-ones (CH-form) exhibit ²J values of approximately 9–11 Hz, in 1,2-dihydro-3H-pyrazol-3-ones this coupling constant is considerably reduced to 4–5 Hz. This can be mainly attributed to the removal of the lone-pair at pyrazole N−1 in the latter due to protonation or alkylation. According to the data obtained, 2-substituted 4-acyl-1,2-dihydro-3H-pyrazol-3-ones exist predominantly as pyrazol-5-ols in CDCl₃ or benzene-d₆ solution, whereas in DMSO-d₆ also minor amounts of NH tautomer may contribute to the tautomeric composition. 2,4-Dihydro-2-phenyl-3H-pyrazol-3-one (1-phenyl-2-pyrazolin-5-one) exists in benzene-d₆ solely in the CH-form, in CDCl₃ as a mixture of CH and OH-form, whereas in DMSO-d₆ a fast equilibrium between OH and NH isomer (with the former far predominating) is probable. For 11 compounds, including neutral and protonated molecules, we have calculated at the B3LYP/6-311++G** level, the²J(¹H,¹³C) coupling constants which are in good agreement with those measured experimentally.

Doi: 10.1002/ejoc.200400465

Synthesis of Pyrazolyl-2-pyrazolines by Treatment of 3-(3-Aryl-3-oxopropenyl)-chromen-4-ones with Hydrazine and Their Oxidation to Bis(pyrazoles)

The synthesis of several 1-acetyl-3-aryl-5-[3-(2-hydroxyphenyl)pyrazol-4-yl]-2-pyrazolines 3a−3h has been accomplished by treatment of the 3-(3-aryl-3-oxopropenyl)chromen-4-ones 1a−h with hydrazine hydrate in hot acetic acid. The 1-acetyl-3-aryl-5-(3-chromonyl)-2-pyrazolines 2a−2f were also obtained as by-products. Oxidation of the 1-acetyl-4-pyrazolyl-2-pyrazolines 3a−3f with DDQ gave the 3(5)-aryl-5(3)-[3-(2-hydroxyphenyl)pyrazol-4-yl]pyrazoles 5a−5f. The oxidation of the 2-pyrazoline rings was accompanied by N-deacylation. The reaction mechanisms of both transformations are discussed, the first one being supported by experimental results. The structures of all new derivatives were established by NMR and the evidence of prototropic tautomerism is carefully discussed. Theoretical calculations of energies and of the ¹H and ¹³C NMR chemical shifts of the possible tautomeric forms of 5(3)-[3-(2-hydroxyphenyl)pyrazol-4-yl]-3(5)-(4-methoxyphenyl)pyrazole (5c), by B3LYP and GIAO, showed that compounds of this type probably exist as mixtures of two tautomers.

Doi: 10.1071/CH04142

The structure of two 1-(nitrophenyl)-D2-pyrazolines: A crystallographic and theoretical study

The crystal and molecular structures of two nitrophenylpyrazolines have been determined. The geometries have been used as starting geometries for density functional theory (DFT) calculations. The differences in conformation between both molecules and between the solid state and gas phase are explained in terms of steric effects. An attractive intramolecular N···N interaction between the nitro group and the pyrazoline N2 nitrogens has been found. Absolute shieldings have been calculated (GIAO) and compared with experimental ¹H and ¹³C chemical shifts.

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The structure of 1,1,3-trimethyl-D2-pyrazolinium perchlorate: an X-ray crystallographic and GIAO/DFT multinuclear NMR study

The crystal and molecular structure of 1,1,3-trimethyl-Δ²-pyrazolinium perchlorate has been determined and compared with those of other pyrazolinium salts (both 1,1 and 1,2-substituted). Reported ¹³C and ¹⁵N chemical shifts for a series of related pyrazolines have been compared with GIAO/DFT calculations, with excellent agreement. The combination of the biological properties of pyrazolines with those of the perchlorate anion in the same molecule will be discussed.

Doi:10.1016/j.theochem.2003.10.019

A theoretical study of the tautomerism and ionization of 5-substituted NH-tetrazoles

The energies, geometries and charge distributions of the five more stable forms (anion, 1H- and 2H-neutral tautomers, 1,3-H,H⁺- and 1,4-H,H⁺-cation tautomers) of a series of 5-R tetrazoles [R=H, CH₃, C(CH₃)₃, Ph, Cl, CF₃, NO₂] in the gas phase have been calculated with the DFT/B3LYP method at the 6-31G* level. For tetrazolate anions, a shortening of the 1–2 bond and a simultaneous elongation of the 2–3 bond is observed when the value of the σ_p constant of the substituent increases. A considerable ring aromaticity is exhibited by tetrazolate anions, and also by the 2H-form of neutral tetrazoles and 1,3-H,H⁺-form of cations and it somewhat depends on the nature of the substituent. The calculated values of the dipole moments of 2H- and 1H-forms of neutral tetrazoles correlate well with the σ_p constants of substituents. The relative thermodynamic stability of 2H-forms as compared with 1H-ones does not practically depend on the nature of the substituent R. In contrast, in the case of tetrazolium cations, the most stable form is the 1,4-H,H⁺—for the electron-donating substituents and the 1,3-H,H⁺—for the electron-withdrawing ones. Good correlations have been observed between the energies of protonation of anions and neutral tetrazoles and the experimental pK_aand pK_BH+ values.

DOI: 10.1039/B314742H

Homoheteroaromaticity: the case study of azepine and dibenzazepine

Azepine and dibenzazepines are antiaromatic compounds that by protonation afford homoheteroaromatic compounds. GIAO and NICS/DFT calculations have been used to calculate NMR properties and energies.

http://www.arkat-usa.org/get-file/19834/

Theoretical study of cyameluric acid and related compounds

DFT calculations (B3LYP/6-31G*) have been carried out on the seventeen tautomers of cyameluric acid. The C3h trioxo tautomer 258 is the most stable. Some energies and absolute NMR shieldings (GIAO) were calculated for 258 and other tri-s-triazines, including cyamelurine and Pauling mystery molecule.

Doi:10.1016/j.molstruc.2004.04.019

The structure of p-nitrophenylhydrazones of aldehydes: the case of the p-nitro-phenylhydrazone of 2-diethylamino-5-methoxy-2H-indazole-3-carboxaldehyde

The ¹H and ¹³C NMR spectroscopic study of four p-nitrophenylhydrazones of aldehydes is reported. The data have been analysed using theoretically calculated absolute shieldings (GIAO/DFT). Tautomerism, isomerism and signal anisochrony are described.

Doi:10.1016/j.ejmech.2003.10.003

Tetrahydroacridin-9-ones, 9-chlorotetrahydroacridines, 9-amino- tetrahydroacridines and 9-(pyrazol-1-yl)-tetrahydroacridinines derived from chiral cyclanones

A series of tetrahydroacridines related to tacrine have been synthesized starting from 3-methylcyclohexananone, menthone, pulegone, carvone and dihydrocarvone (both racemic and chiral). In many cases, the yields and purity of the compounds have been improved by the use of a microwave oven. These compounds have been characterized by (1)H and (13)C NMR data. To establish their relative configuration, the structure of (1R,4R)-(+)-9-chloro-1-methyl-4-isopropyl-1,2,3,4-tetrahydroacridine (cis-10b), derived from (2S,5R)-(-)-menthone, has been determined by X-ray. The chemical shifts of cis-10b and trans-10b have been calculated at the GIAO/B3LYP/6-31G* level and compared successfully with the experimental data.

http://www.arkat-usa.org/get-file/18680/

The behavior of 5H-dibenz[b,f]azepine dissolved in sulfuric acid 

When 5H-dibenz[b,f]azepine is dissolved in pure sulfuric acid it experiments an oxidative dismutation into two acridine derivatives: 9-formylacridine and 9,9'-ethene-1,2-diyl-bis-acridine.

DOI:10.1248/cpb.51.929

Fentanyl and Its Analogue N-(1-Phenylpyrazol-3-yl)-N-[1-(2-phenylethyl)-4-piperidyl] propanamide: 1H- and 13C-NMR Spectroscopy, X-Ray Crystallography, and Theoretical Calculations.

The oxalate salts and free bases of fentanyl and N-[1-(2-phenylethyl)-4-piperidyl]-N-(1-phenyl-4-pyrazolyl)propanamide, a new lead compound for long-acting analgesia, have been characterized by ¹H- and ¹³C-NMR spectroscopy. The crystal structure of the hydrochloride of N-[1-(2-phenylethyl)-4-piperidyl]-N-(1-phenyl-4-pyrazolyl)propanamide monohydrate has been determined. Two centrosymmetrically related cations, joined through C(phenyl)-H…π contacts, encapsulate a large void that contains pairs of anions and bridged water molecules into a zero-dimensional (0D) supramolecular motif. The cations are linked to this framework via N⁺H…Cl⁻ contacts. GIAO/B3LYP calculations have been carried out to compare the experimental ¹³C chemical shifts with the absolute shieldings thus calculated. The protonation of both molecules takes place on the piperidine ring (axial protonation), as has been verified both in the solid state (X-ray) and in solution (NMR).

DOI: 10.1021/jo034833u

The structure of a 4-Nitroso-5-aminopyrazole and Its Salts: Tautomerism, Protonation and E/Z Isomerism

The structures of 1-benzyl-4-nitroso-5-aminopyrazole (1) and its hydrochloride (1H⁺) have been determined in the solid state and in solution in DMSO, methanol, and ethanol. The free base exists in solution as a mixture of amino/nitroso tautomers 2a and 2b rather than in the imino/oxime tautomers 3. The conjugated cation 1H⁺ results from the protonation of the nitroso group. X-ray crystallography showed that both amino hydrogen atoms of 2a form NH···O═N hydrogen bonds:  one is intramolecular, the other links adjacent molecules in an infinite chain.

Doi:10.1002/hlca.200390091

The Structure of N1-Hydroxylophine N3-Oxide (=1-Hydroxy-2,4,5-triphenyl-1H-imidazole 3-Oxide) in the Solid State

The crystal structure of 1-hydroxy-2,4,5-triphenyl-1H-imidazole 3-oxide (1) has been determined from laboratory X-ray powder-diffraction data. The two independent molecules in the asymmetric unit form chains via OH⋅⋅⋅O hydrogen bonds related by a twofold screw axis. One of the O⋅⋅⋅O distances is extremely short (2.32(1) and 2.43(1) Å). Solid-state NMR spectroscopy (CPMAS) combined with calculation of absolute shieldings (GIAO/B3LYP/6-31G*) allowed us to determine that the compound behaves as if the OH⋅⋅⋅O hydrogen bond has the proton in the middle (single-well potential), resulting in the near identity of both ¹⁵N-NMR signals.

DOI: 10.1039/B210251J

Protonation and phase effects on the NMR chemical shifts of imidazoles and pyrazoles: experimental results and GIAO calculations

The effects produced on ¹H, ¹³C and ¹⁵N chemical shifts by protonation and by hydrogen-bonding solvents on five azoles have been determined experimentally. The following compounds have been studied: imidazole, 4,5-dimethylimidazole, pyrazole, 3,5-dimethylpyrazole and 4,5-dihydro-3-methyl-2H-benz[g]indazole. Phase effects on the ¹³C chemical shifts of the C-4 atom of pyrazole are discussed based both on empirical models and on GIAO calculations of absolute shieldings in different complexes. The special case of the chemical shifts of pyrazoles in the solid state, where they form multiple N–H⋅⋅⋅N hydrogen bonds, has also been studied theoretically.

Doi:10.1016/S0040-4020(02)01157-2

An experimental (NMR) and theoretical (GIAO) study of the tautomerism of benzotriazole in solution

The ¹H, ¹³C and ¹⁵N chemical shifts of benzotriazole and its adducts with acetone have been measured. Using dynamic ¹³C NMR spectroscopy in the +30/−90°C range, the barrier to prototropy in benzotriazole has been determined (10.8 kcal mol⁻¹ at 294 K). The thermodynamic parameters corresponding to the equilibria between benzotriazole and its two acetone adducts have been measured. GIAO calculations (B3LYP/6-311++G^∗∗) have been carried out on 1H-benzotriazole tautomer: they provide a sound basis for signal assignment of all the nuclei.

Doi:10.1016/S0022-2860(01)00759-1

1-Benzoylazoles: an experimental (NMR and crystallography) and theoretical study.

Five N-benzoylazoles (imidazole, pyrazole, indole, benzimidazole and carbazole) have been prepared following modified literature procedures. Their NMR spectra in solution (¹H, ¹³C and ¹⁵N) have been measured. The crystal structures of 1-benzoylindole and 9-benzoylcarbazole have been determined by X-ray crystallography and the corresponding ¹³C NMR spectra in the solid state have been measured by the CPMAS technique. Whereas 1-benzoylindole presents a standard behaviour, 9-benzoylcarbazole shows an unexpected ¹³C CPMAS spectrum with additional splittings. In order to understand this fact, the ¹H and ¹³C NMR spectra in dimethylether at −143°C (130 K) have been recorded and ab initio calculations (RHF/6-311G**) carried out. The corresponding absolute shieldings (GIAO/ RHF/6-311G**) together with the X-ray structure and the ¹³C chemical shifts at low temperature have been used to discuss the CPMAS spectrum. We propose that the supplementary splittings of this spectrum are due to its conglomerate structure.

DOI: 10.3987/COM-01-9407

Synthesis, 1H and 13C NMR study of pyrazoles derived from chiral cyclohexanones (3-methylcyclohexanone, menthone, pulegone, dihydrocarvone and carvone)

The ¹H and ¹³C chemical shifts of four tetrahydroindazoles (two of them existing as diastereomeric mixtures) and one aldazine were measured and assigned. These compounds were obtained from monoterpenic ketones (R)-(+)-3-methylcyclohexanone, (2S,5R)-(-)-menthone, (R)-(+)-pulegone, (5R)-(+)-dihydrocarvone, and (R)-(-)-carvone in a two-step procedure. The annular tautomerism in CDCl₃solution was calculated and compared with ab initio calculations (B3LYP/6-31G*).

DOI:Access this article

¹³C and ¹⁵N NMR shieldings of 1,2,4-diazaphospholes in the solid state and in solution

The solid state ¹³C and ¹⁵N CPMAS NMR spectra of 3,5-di-tert-butyl-1,2,4-diazaphosphole 4 and 3,5-diphenyl-1,2,4-diazaphosphole 5 have been recorded. The X-ray structure of the first compound was already known (it is a cyclic dimer with localized N–H protons) while the structure of the second cannot be determined due to the difficulty to grow suitable single crystals. NMR results pointed out that 4 is a “classical” compound while 5 is probably a tetramer showing Intermolecular Solid-State Proton Transfer (ISSPT). GIAO/ab initio calculations have been carried out to estimate the absolute ¹H, ¹³C and ¹⁵N shieldings. The agreement with the experimental chemical shifts is good enough to assign the signals of carbons C-3 and C-5.

DOI: 10.1039/B103405G

The structure of halogeno-1,2,4-triazoles in the solid state and in solution

The X-ray molecular structures of two halogenotriazoles, 3-chloro- and 3-bromo-1H-1,2,4-triazole, have been determined, thus ending a controversy that made these compounds an exception to a general rule concerning their annular tautomerism. ¹³C and ¹⁵N NMR experiments in the solid state are complex because of the dipolar couplings with the halogens. The complex signal of the carbon atom bearing the halogen has been analysed and the residual ¹³C–X dipolar couplings determined. However, since the tautomeric structures are known, the spectra can be analysed. Solution NMR, at low temperatures (178 K) at which the tautomerism of triazoles is blocked, and using as models 1,2,4-triazole itself and its 1-methyl derivative, allowed us to determine that the same tautomers, 3-halo-1H-1,2,4-triazole, are present in methanol.

DOI: 10.1002/jhet.5570380221

Ab initio study of azolides: energetics and spectroscopic properties

We report the ab initio study of twenty-four azolides derived from pyrrole, imidazole, pyrazole, both triazoles, tetrazole, pentazole, indole and carbazole bearing at the nitrogen atom the groups COMe, CHO, COCF₃ and CO₂Me. Theoretical values (isomerism, barriers, dipole moments, C=O stretching) are compared with experimental ones, when available, and also internally compared. A special effort has been devoted to the calculation of the absolute shieldings for the different nuclei present in azolides. At the level of calculation used (RHF/6-311G**) the results are satisfactory. To complete the nmr data from the literature, some ¹H, ¹³C, ¹⁵N, ¹⁷O and 19F chemical shifts have been determined.

DOI: 10.1002/jhet.5570380622

A Density Functional Theoretical Study of the Influence of Cavities and Water Molecules on Tautomerism: the Case of Pyridones and 1,2,4-Triazoles Linked to Crown Ethers and Esters

The tautomerism of pyridones and 1,2,4-triazoles related to two crown ethers and two crown esters derived from these heterocycles was studied theoretically. For the four macrocycles, Bradshaw identified a single tautomer by X-ray crystallography. To rationalize these findings, a series of calculations from simple models to crown derivatives have been carried out. The most interesting case concerns the observation, for the first time, of a 4H-1,2,4-triazole tautomer. To explain this result it was necessary to calculate the whole crown ester plus a caged water molecule was necessary.

DOI: 10.1002/1099-0690(200108)2001:16<3013::AID-EJOC3013>3.0.CO;2-Y

Basicity of N-H and N-Methyl-1,2,3-triazoles in the Gas Phase, Solution and Solid State: An Experimental and Theoretical Study.

The gas-phase and aqueous basicities of six 1,2,3-triazoles have been determined, the former by FT-ICR and the latter by spectrophotometry and ¹H NMR. The gas-phase experiments agree very well with the Gibbs free energies calculated at the B3LYP/6-31G* level. In contrast, only semiquantitative ascertainments are possible when basicities in the gas phase and in solution are compared. It is possible, with the aid of calculations, to obtain a complete picture of the complex equilibria involved in C-substituted N-H-1,2,3-triazoles. The crystal structures of 4(5)-phenyl-1,2,3-triazole (4) and 4(5)-nitro-1,2,3-triazole (15) have been determined. In the gas phase, 2Htautomers b always predominate, while in aqueous solution, both 1H and 2H tautomers − a and b − are present. Finally, in the solid state,1 exists as a 1:1 mixture of 1a and 1b, while 4 is in the 4b tautomeric form and 15 is a 1H tautomer 15a. These conclusions − a in the gas phase, a + b in solution, and equal probabilities of finding either a or b in the crystal − are probably general for all 1,2,3-triazoles.

DOI: 10.1021/ja002688l

A Solid-State NMR, X-ray Diffraction, and ab Initio Computational Study of Hydrogen-Bond Structure and Dynamics of Pyrazole-4-Carboxylic Acid Chains

Using high-resolution solid-state ¹⁵N CMAS NMR, X-ray crystallography, and ab initio calculations, we have studied the structure of solid pyrazole-4-carboxylic acid (1). The crystal structure was determined at 295 and 150 K. Molecules of 1 are located on a two-fold axis, implying proton disorder of the NH and OH groups; no phase transition was observed between these two temperatures. The compound forms quasi-linear ribbons in which the molecules are linked by cyclic hydrogen bonds between pyrazole and carboxylic acid groups with disordered hydrogen-bonded protons. Crystallography is unable to decide whether the disorder is dynamic or static. NMR shows that this disorder is dynamic, that is, consisting of very fast degenerate double proton transfers between two rapidly interconverting O−H···N and O···H−N hydrogen bridges. However, at low temperature, NMR shows a proton disorder−order transition where the protons are preferentially localized on given nitrogen and oxygen atoms. An amorphous phase exhibiting proton order is observed when the compound is precipitated rapidly. In this case, the defects are annealed by moderate heating. Ab initio calculations performed on oligomers of 1 show that the O−H···N hydrogen bridge is about 0.064 Å shorter and less bent (∼171°) than the O···H−N hydrogen bridge (∼150°). For an isolated ribbon, this result leads to structures with localized protons, either to a cycle with about 200 molecules, or to a quasi-linear ribbon involving an undulated structure, or to a combination of both motifs. Only the undulated structure is compatible with the linear ribbon observed by X-ray crystallography, where the fast proton transfer in the high-temperature phase is assisted by the motions of the undulated chain. A disordered structure is assigned to the amorphous phase, which exhibits the combination of the curved and the undulated motifs.

doi:10.1107/S0108768100008752

Supramolecular structure of 1H-pyrazoles in the solid state: a crystallographic and ab initio study

 The secondary structure of 1H-unsubstituted pyrazole derivatives bearing only one hydrogen donor group and one or more acceptor groups has been analyzed in terms of some descriptors representing the substituents at C3 and C5. The substituent at C4 appears to affect mainly the tertiary or quaternary structure of these compounds. The proposed semi-quantitative model, which explains most hydrogen-bonded motifs as a combination of the effects of substituents at C3 and C5, has also been examined as a function of the steric and polarizability effects of these substituents represented by molar refractivity. The model also applies to other five-membered rings (1,2,4-triazoles, 1,2,4-diazaphospholes and 1,2,4-diazaarsoles). Furthermore, ab initio calculations at RHF/6-31G* have been performed to discover the relative stability of three of the four hydrogen-bond patterns displayed by several symmetrical pyrazoles (dimers, trimers, tetramers). The fourth motif, catemers, has only been discussed geometrically.

DOI:N/A

Vibrational spectra of 3,5-dimethylpyrazole and deuterated derivatives

The infrared (IR) and Raman spectra of 3,5-dimethylpyrazole have been recorded in the vapor, liquid (melt and solution) and solid states. Two deuterated derivatives, C5H7N-ND and C5D7N-NH, were also studied in solid state and in solutions. Instrumental resolution was relatively low, 2.0 cm(-1) in the IR and approximate to 2.7 cm(-1) in the Raman spectra, The solids are made of cyclic hydrogen-bonded trimers. These trimers, present also in chloroform and acetone solutions, give rise to characteristic high absorption IR spectra in the 3200-2500 cm(-1) region, related to Fermi resonance involving nu(NH) vibrations. Bands from trimers are not present in water solutions but these solutions show spectral features similar in several ways to thoseof the trimer, attributable to solvent-bonded complexes. Evidence of H-bonding interactions with the other solvents is also visible in the high-frequency region. The two very intense bands in the Raman spectra of the solids appearing at 115 and 82 cm(-1) in the parent compound are also connected with a trimer formation. To interpret the experimental data, ab initio computations of the harmonic vibrational frequencies and IR and Raman intensitieswere carried out using the Gaussian 94 program package after full optimization at the RHF/6-31G* level for the three monomeric compounds as well as for three models of the trimer, with C-3h, C-3 and C-1 symmetry. The combined use of experiments and computations allow a firm assignment of most of the observed bands for all the systems. In general, the agreement between theory and experiment: is very good, with the exception of the IR and Raman intensities of some transitions. Particularly noticeable is the failure of the theoretical calculation in accounting for the high intensity of the Ramanbands of the solid about 115 and 82 cm(-1)

DOI: 10.1002/1099-1395(200007)13:7<372::AID-POC261>3.0.CO;2-L

Basicity of 1-nitroaryl-4,5-dihydropyrazoles: pKa measurements and theoretical calculations

The basicity of simple 4,5-dihydropyrazoles (Δ²-pyrazolines) was previously discussed on the basis of protonation at position 1 in the case of 1-unsubstituted, 1-methyl and 1-phenyl derivatives. The pK_a of 15 4,5-dihydropyrazoles substituted at position 1 by p-nitrophenyl, 2,4-dinitrophenyl and 2,4,6-trinitrophenyl groups have now been determined. After examining some linear free energy relationships, to discuss these pK_a values further, DFT theoretical calculations, including temperature effects, were carried out on the parent compounds (no C-substituents) for the 1-unsubstituted, 1-methyl, 1-phenyl, 1-p-nitrophenyl and 1-(2′,4′,6′)trinitrophenyl series. These calculations predict an inversion of N-1 and N-2 basicity between 1-phenyl and 1-p-nitrophenyl-4,5-dihydropyrazoles. Since there were no experimental data for the protonation of 4,5-dihydropyrazoles in the gas phase, chemical ionization mass spectrometry was used to try to determine the structure of protonated 1-methyl- and 1,3-dimethyl-5-phenyl-4,5-dihydropyrazoles (3 and 7, respectively). In both cases, it appears that these pyrazoles are protonated on N1, but the production of another isomeric species cannot be completely ruled out for 7H⁺. 

DOI: 10.3987/COM-99-S23

A theoretical Study of the 1,2,3-Triazolo-Iminodiazomethane Isomerism in the Gas Phase

The ring opening reactions of the 1,2,3-triazolate anion, of the three tautorners of NH-1,2,3-triazole, and of different 1,2,3-triazolium cations, to give the corresponding iminodiazomethanes, have been studied by means of ab initio calculations at the HF/6-31 ** level. The 1,5-electrocyclization reactions of 1,2,3-triazolate and 1H-1,2,3-triazole proceed through planar transition states with high and medium energy barriers, respectively. In both cases the cyclic forms are thermodynamically more stable than the open-ring ones. In contrast, the decomposition of the 1,2-H-1,2,3-triazolium cation into protonated iminodiazo-methane is an exothermic process. In the last case, the preferable way of the reaction proceeds via non-aromatic intermediates (1,4H₂- and 1,1H₂-1,2,3-triazolium ions) which have a very low activation energy towards the ring opening. It has been found that there is a high ππ-conjugation between diazornethyl and imine fragments in the chain forms.

DOI: 10.3987/COM-98-8381

Fluoropyrazoles: an ab initio study

Quantum mechanic calculations have been done at the RHF and MP2 levels with the STO-3G, 6-31G**, 6-311G** basis sets on pyrazole itself and seven N-unsubstituted C-fluoropyrazoles. These calculations have been used to discuss the molecular structure of these compounds in relation to their aromaticity. The corresponding ¹H, ¹³C, ¹⁵N and ¹⁹F chemical shifts were calculated using the GIAO perturbation method.

Doi:10.1016/S0040-4020(99)00013-7

Synthesis and Structural Studies of Some [1₄]Paracyclo-bis-(1,2)pyrazolium- and (1,3)imidazolium-phanes 

The crystal and molecular structure of [1₄]paracyclo-bis-(1,2)pyrazoliumphane dibromide (1a) has been determined. The compound exists in the solid state in the chair (C) conformation while both chair (C) and boat (B) conformations are present in solution in comparable amounts. The barrier to the C ⇌ B interconversion has been determined by ¹H NMR spectroscopy (). AM1 semiempirical calculations conveniently reproduce the difference in stability between the chair (C) and the boat (B) conformations.

[1₄]Paracyclo-bis-(1,2)pyrazolium-phane dibromide exists in the solid state in the chair conformation (X-ray crystallography) while both chair and boat conformations are present in solution in comparable amounts. The barrier to the chair boat interconversion has been determined by¹H NMR spectroscopy ().

DOI: 10.1039/A807669C 

An experimental (Flash Vacuum Pyrolisis) and theoretical study of the tautomerism of pyrazolinones at high temperatures

Flash vacuum pyrolysis experiments were carried out between 500 and 800 °C on 3(5)-phenyl- and 3(5)-methyl-pyrazolinones and on 3(5)-methoxy-5(3)-phenylpyrazole. The origin of the isolated products (mainly indanone, hydroxyalkynes and α,β-unsaturated aldehydes) can be explained as arising from the hydroxy tautomers of pyrazolinones. Temperature effects on the tautomeric equilibrium of 1-phenyl-3-methylpyrazolinone in solution show that the percentage of the CH tautomer increases with the temperature. MP2 ab initio calculations on the model compound, pyrazolinone itself, have been used to rationalize these findings. The problem of the aromaticity of the four tautomers of pyrazolinone has been examined through Schleyer’s NICS (nuclear independent chemical shifts) calculations.

Doi:10.1016/S1093-3263(99)00006-6

Similarity Studies on Guanidinium, Imidazolinium and Imidazolium Cations: Towards New Bradykinin Antagonists

Bradykinin (BK) is a potent nociceptive agent and its antagonists show analgesic activity. In the search for new antagonists of BK, the design of nonpeptidic derivatives with different terminal cations has been considered. Among these new antagonists, the guanidinium cations, which appear not only in the terminal arginine residues of BK but also in several nonpeptidic antagonists, will be substituted by groups with characteristics similar in terms of electrostatic potential, electron density, shape, etc. Several similarity indexes have been calculated for guanidinium, 2-aminoimidazolinium, and 2-aminoimidazolium cations and their corresponding neutral species to design new nonpeptidic BK antagonists. The geometric and electronic characteristics of the molecules were compared by means of: (1) the Carbo index, (2) the Hodgkin index, and (3) a shape similarity index based on the volume of each molecule as defined by a certain electron density. Molecular geometries and energies were optimized by ab initio calculations at the B3LYP/6-311++G∗∗ level. The molecular electrostatic potential (MEP) and the electron density (ρ) were then computed in a cubic grid of points around each molecule. These molecular properties were used to calculate similarity indexes with the guanidinium cation or guanidine as the reference molecule in each family. In addition, three-dimensional similarity maps were generated to localize those molecular areas more alike in each of the sets.

DOI: 10.1039/A805415K

Tautomerism of 1-(2',4'-dinitrophenyl)-3-methyl-2-pyrazolin-5-one: Theoretical calculations, solid and solution NMR studies and X-ray crystallography

To gain a better understanding of the tautomerism of 1-(2′,4′-dinitrophenyl)-3-methyl-2-pyrazolin-5-one, 2, different studies were performed. In order to simulate the gas phase, several MO calculations at the semiempirical (AM1 and PM3) and abinitio (HF/6-31G* and B3LYP/6-31G*) levels were carried out on the different tautomers of this compound and on those of the corresponding 1-phenyl derivative 4. The ¹H and ¹³C NMR spectra were recorded in solution for compound 2. Finally, to investigate the solid state, ¹³C CPMAS NMR studies and the crystal structure analysis of this pyrazolinone and that of its isomer [1-(2′,4′-dinitrophenyl)-3-hydroxy-5-methylpyrazole, 3, whose chemical structure was incorrectly reported in the literature] were performed. In solution, the most abundant tautomer for both pyrazolinones, 2 and 4, depends on the solvent used. For compound 2 it was found that the CH tautomer was the most stable in the gas and solid states as opposed to its 1-phenyl analogue, which appears as the CH form in the gas phase and as NH and OH tautomers in the crystal.

Doi:10.1016/S0022-2860(98)00305-6

Tautomerism of NH-pyrazolinones in the solid state: the case of 3(5)-ethoxycarbonyl-5(3)-hydroxypyrazole

The molecular and crystal structure of the title compound, as determined by X-ray analysis, shows that the tautomeric form present in the solid state is 5-ethoxycarbonyl-3-hydroxypyrazole, 3. Dimers with crystallographic symmetry centres are formed through O-HżN hydrogen bonds. The relative stability of the 3(5)-hydroxypyrazole tautomers and the disposition of the ethoxycarbonyl groups with respect to the pyrazole ring have been studied by ab initio methods.

DOI:10.1039/A804086I

1,2-Proton shifts in pyrazole and related systems: a computational study of [1,5]-sigmatropic migrations of hydrogen and related phenomena

Three different approaches are used to discuss the possible analogy between the [1,5] hydrogen shift in cyclopentadiene and the prototropy in 1H-pyrazole. In the first, a series of NH→HN hydrogen shifts in cyclic conjugated molecules are considered demonstrating that the case of pyrazole is not intrinsically different from the other systems which are unrelated to [1,5] H shifts. The second approach compares pyrazole and cyclopentadiene with their open-ring structures, pentadiene and aminoazadiene, proving that the N–N bond is essential to describe pyrazole while the C(sp³)–C(sp²) bond in cyclopentadiene can be considered as a perturbation. Finally, the third approach is a study of cyclopentadienide and pyrazolide anions as hydrogen-bond acceptors, the first one being a π-acceptor while the second one is a σ-acceptor through the nitrogen lone pair. The conclusion is that N(sp²)–N(sp²) migrations of hydrogen in aromatic azoles are outside the Woodward–Hoffmann domain of application.

Doi:10.1016/S0040-4020(96)01052-6

The Mills-Nixon effect on enol-enol tautomerism in beta-dicarbonyl compounds and on annular tautomerism in NH-pyrazoles: a semi-empirical study

Doi:10.1007/BF02263506

Tautomerism and Mills-Nixon-like effect in pyrazols

Theoretical calculations on a wide variety of NH-pyrazoles clearly show a relationship between ring strain and annular tautomerism, i.e., the most stable tautomer is that having the largest singleond character in the C3-C4 bond.

Doi:10.1016/S1386-1425(97)00050-4

Vibrational spectra of N-methylpyrazole: an experimental and theoretical study

The gas-phase infrared spectrum of N-methylpyrazole was measured in the range 5000–500 cm⁻¹ and with a resolution of 0.5 cm⁻¹. Its Raman spectrum was obtained in the condensed-phase in the range 3500–100 cm⁻¹ and with a resolution of 2.7 cm⁻¹. The corresponding depolarization ratios were also measured. Theoretical information on harmonic vibrational frequencies, infrared and Raman intensities and depolarization ratios was obtained by means of ab initio and density functional theory approaches. The former were performed at the MP2/6-31G** level and the latter at the B3LYP/6-31G** level. This information was useful in the assignment of the different fundamentals. In general the agreement theory-experiment was very good, with the only exception of the infrared and Raman intensities of some transitions.

DOI: 10.1002/(SICI)1099-1395(199708)10:8<637::AID-POC930>3.0.CO;2-P

Structure of 3-nitropyrazole in solution and in the solid state 

The molecular and crystal structure of 3-nitropyrazole was determined by X-ray analysis. The triclinic unit cell contains 12 molecules which form four hydrogen-bonded (N—H···N) trimers. Each trimer comprises of pseudo-ring in a flattened envelope distorted towards a chair conformation. The crystal packing consists of layers formed by centrosymmetric related trimers joined through C—H···O interactions. Ab initio calculations were performed on 3(5)-nitro- and 4-nitropyrazole and their corresponding protonated forms up to the MP2/6–31G** level of theory. The origin of the difference in aqueous basicities between both nitropyrazoles is discussed.

DOI: 10.1039/A603035A

Theoretical study of the structure and tautomerism of N1-unsubstituted pyrazoles in the solid state

Ab initio theoretical calculations have been performed on the pyrazole cyclic dimer, trimer and tetramers as well as on linear oligomers, assuming that there is no relaxation of the geometry during the proton transfer. The ground state and a wide variety of transition states, corresponding to different pathways for intermolecular proton transfer, have been explored and the results compared with experimental data from crystallography and solid state NMR spectroscopy. For the simplest case of the dimer, the reaction path corresponding to a double proton transfer has been explored as well as the effect of relaxing the geometry. 

DOI: 10.1039/P29960000057

Importance of aromaticity on the relative stabilities of indazole annular tautomers: an ab initio study. 

MP2-6-31G** calculations on both indazole annular tautomers, the 1H and the 2H, show that the first one is more stable than the second one by 3.6 kcal mol-1. In the case of 1H-indazole, the excellence of MP2-6-31G** results is confirmed by the fact that its microwave rotational constants are reproduced with great accuracy. The addition of the thermal energy correction and entropy effects to DE(MP2-6-31G**) led to the following thermodynamic values: DH²⁹⁸(1H->2H) = 3.9 kcal mol-1 and DG₀²⁹⁸(1H->2H) = 4.1 kcal mol-1. Electronic spectra recorded at 80ºC provided experimental evidence for the clear predominance of 1H-indazole in the gas phase.

DOI: 10.1021/ci950066r

Molecular lipophilic potential on van der Waals surfaces as a tool in the study of 4-alkylpyrazoles

A new method for the calculation and analysis of lipophilic properties on molecular surfaces is presented. In this method, both, the concept of molecular lipophilic potential developed by Audry and co-workers and the approach of Ghose and Crippen implying that the hydrophobicity of a molecule can be obtained as the sum of certain atomic contributions, are combined. Then, shape analysis methodology is applied to characterize the interrelation between this molecular lipophilic potential and the van der Waals surfaces of a family of pyrazoles, which are known inhibitors of the enzyme liver alcohol dehydrogenase. In this study graphical representations and analytical methods are used. The mentioned topological analysis provides certain codes which combine lipophilic and steric information and are unique and characteristic of each pyrazole. These three-dimensional codes were correlated with the inhibitory activity of this series of pyrazoles. The inhibitory power of 4-isopentylpyrazole was not known experimentally before this study was carried out. Thus, by using these combined codes, the inhibitory activity of the isopentyl derivative was suggested to be lower than that of its linear isomer. This hypothesis was confirmed after the synthesis of 4-isopentylpyrazole and its enzymatic evaluation.

Doi:10.1016/0040-4020(95)00335-6

Ab initio study of the effect of N-substituents on the properties of pyrazoles

A series of fourteen derivatives of pyrazole have been calculated at the MP2-6-31G^∗∗ level. 1. N-H; 2. N-BH₂;3. N-BH₃⁻; 4. N-CH₃; 5. N-CHO; 6. N-CF₃; 7. N-NH₂; 8. N-NO₂; 9. N-OH; 10. N-AlH₂; 11. N-SiH₃; 13. N-SO₂H; 14. N-oxide. The first thirteen are derivatives of the parent pyrazole nitrogen N(1) and the last one is pyrazole N-oxide. The substituents have been selected to cover a wide range of electronic effects. The theoretical results are discussed in relation with geometries, energies, vibrational spectra, Bader analysis and tautomerism (in the case 1-hydroxypyrazole/pyrazole N-oxide).

DOI: 10.1039/P29950000379

Theoretical calculations on pyrazole derivatives. Part 2. Effect of cationic C-Substituents (NH3+ and N2+) on the basicity and tautomerism of pyrazoles

Semiempirical and ab initio calculations have been performed on pyrazoles with 3- or 5-cationic substituents, e.g. NH₃⁺ and N₂⁺, with the aim of discovering if these substituents were able to shift the tautomeric equilibrium towards one of the tautomers. The ammonium substituent is not amenable to the experiment since 3(5)-aminopyrazoles protonate on the pyrazole ring; however, pyrazole-3(5)-diazonium is stable and has been studied. The conclusion is that these equilibria are strongly shifted towards the 3-substituted tautomer. The azide substituent behaves normally in the sense that both tautomers are of similar stability.

Doi:10.1016/0022-2860(94)08434-J

Microwave spectra and ab initio calculations of 1-nitropyrazole

The microwave (MW) spectrum of 1-nitropyrazole obtained at room temperature is presented, together with ab initio MP2/6-31G∗∗ calculations on its structure and harmonic vibrational frequencies. The initial assignment of the spectrum was carried out using a radio frequency—microwave double resonance (RFMWDR) technique. Both experimental and theoretical results indicate that 1-nitropyrazole is a planar molecule. The structure obtained from the MW spectrum agrees fairly well with that obtained at the MP2(FULL)/6-31G∗∗ level.

DOI: 10.1002/jcc.540160302

The geometry of pyrazole: a test for ab initio calculations

Ab initio calculations on the structure of pyrazole have been carried out at different levels of accuracy. At the Hartree-Fock (HF) level, the performance of several basis sets, namely 3-21G, 6-31G, 6-31G**, and 6–311G** was investigated. The influence of electron correlation effects also was studied by carrying out geometry optimizations at the MP2, MP4, and QCISD levels. The performance of a density functional method also was evaluated. We have also investigated the possible influence of the frozen core approximation on the final optimized geometry. Three different statistical analyses were considered in determining which geometry is closest to the experimental microwave geometry—namely Paul Curtin's diagrams, cluster analysis, and multidimensional scaling. From these analyses, we conclude that there is no asymptotic approach to the experimental geometry by increasing the quality of the theoretical model, although, as expected, the more reliable structures are those obtained at the MP2, MP4, and QCISD levels, as well as those obtained by the B3LYP density functional method. We have also found that the values of the rotational constants are a tight criterion to define the quality of a molecular geometry.

DOI:N/A

Theoretical calculations on pyrazole derivatives. Part 1. the effect of c-substituents on the protonation enthalpies of 102 NH-pyrazoles and 54 N-methylpyrazoles

AM1 calculations performed on a wide variety of C-substituted NH and N-methyl pyrazoles as well as on their protonated forms have been used to calculate their intrinsic (gas phase) proton affinities and the molecular dipole moments of the neutral species; proton affinities were also successfully analysed by means of the Taft-Topsom formalism.

Doi/10.1016/0263-7855(94)80103-7

Effect of branching in 4-alkylpyrazoles on liver alcohol dehydrogenase inhibition

Shape analysis methodology is applied to the study of 4-alkylpyrazoles which are known inhibitors of liver alcohol dehydrogenase. Elongation of the alkyl chain increases the inhibitory power, whereas branching of the chain diminishes the activity. These two counterpoised effects are studied simultaneously in a selected set of 4-alkylpyrazoles. A systematic conformational analysis followed by topological characterization of the van der Waals surfaces of all the local minima restricts the conformational space to potential bioactive structures. The analysis of the interrelation between the molecular electrostatic potential and van der Waals surfaces provides certain shape codes characteristic of each 4-alkylpyrazole. In both topological analyses van der Waals surfaces and molecular electrostatic potential van der Waals surface interrelations) graphical representations and analytical methods were used. A good correlation between the shape codes and the inhibitory activity is found for the linear derivatives. For branched pyrazoles, a tendency in their inhibitory power is predicted. Isopentylpyrazole is suggested to have the same inhibitory profile as 4-butylpyrazole, the linear derivative with one less carbon atom.