Molecular Structure of Pyrazinamide: A Critical Assessment of Modern Gas Electron Diffraction Data from Three Laboratories.

Accuracy and precision of molecular parameters determined by modern gas electron diffraction have been investigated. Diffraction patterns of gaseous pyrazinamide have been measured independently in three laboratories, in Bielefeld (Germany), Ivanovo (Russia), and Moscow (Russia). All data sets have been analyzed in equal manner using a highly controlled background elimination procedure and flexible restraints in molecular structure refinement. In detailed examination and comparison of the obtained results we have determined the average experimental precision of 0.004 Å for bond lengths and 0.2° for angles. The corresponding average deviations of the refined parameters from the ae-CCSD(T)/cc-pwCVTZ theoretical values were 0.003 Å and 0.2°. The average precision for refined amplitudes of interatomic vibrations was determined to be 0.005 Å. It is recommended to take into account these values in calculations of total errors for refined parameters of other molecules with comparable complexity.

Structure of C60F36: A Gas-Phase Electron Diffraction and Quantum Chemical Computational Study of a Remarkably Distorted Fluorofullerene.

The equilibrium molecular structure of the gaseous fluorofullerene C60F36 has been determined for the first time by the electron diffraction method with the use of quantum chemical calculations up to the RI-MP2/def2-TZVPP level of theory. Vibrational amplitudes and quadratic and cubic force constants were calculated by density functional theory methods. It was found that the sample under study consists of the isomer of C1 symmetry, 81(4)%, with a small amount of the isomer of C3 symmetry, in good accordance with HPLC-MS (atmospheric pressure photoionization), HPLC-UV/vis, and NMR spectroscopic data. The presence of the isomer of T symmetry, up to 5%, cannot be completely excluded. Theoretical structural parameters of the C60F36 molecule were compared with those of the C60F48 molecule. Relative to C60, the C60F36 molecule has a remarkably distorted carbon cage because of steric, electrostatic, and orbital interactions. This results in the longest carbon-carbon bond (1.671 Å) found in free molecules. In particular, about the longest FC-CF bond, the dihedral angle is only around 20°, which leads to the very short nonbonded distance between electronegative vicinal fluorine atoms (2.531 Å) that is much shorter than the sum of van der Waals radii of fluorine atoms (2.94 Å). A natural bond orbital analysis revealed that strong nπ(F) → σ*(FC-CF) interactions delocalize the lone pair of π-type at the fluorine atoms into the antibonding orbital of the FC-CF bond. This hyperconjugation results in additional elongation of FC-CF bonds.

Experiment and theory at the convergence limit: accurate equilibrium structure of picolinic acid by gas-phase electron diffraction and coupled-cluster computations.

The accurate molecular structure of picolinic acid has been determined from experimental data and computed at the coupled cluster level of theory. Only one conformer with the O[double bond, length as m-dash]C-C-N and H-O-C[double bond, length as m-dash]O fragments in antiperiplanar (ap) positions, ap-ap, has been detected under conditions of the gas-phase electron diffraction (GED) experiment (Tnozzle = 375(3) K). The semiexperimental equilibrium structure, rsee, of this conformer has been derived from the GED data taking into account the anharmonic vibrational effects estimated from the ab initio force field. The equilibrium structures of the two lowest-energy conformers, ap-ap and ap-sp (with the synperiplanar H-O-C[double bond, length as m-dash]O fragment), have been fully optimized at the CCSD(T)_ae level of theory in conjunction with the triple-ζ basis set (cc-pwCVTZ). The quality of the optimized structures has been improved due to extrapolation to the quadruple-ζ basis set. The high accuracy of both GED determination and CCSD(T) computations has been disclosed by a correct comparison of structures having the same physical meaning. The ap-ap conformer has been found to be stabilized by the relatively strong NH-O hydrogen bond of 1.973(27) Š(GED) and predicted to be lower in energy by 16 kJ mol-1 with respect to the ap-sp conformer without a hydrogen bond. The influence of this bond on the structure of picolinic acid has been analyzed within the Natural Bond Orbital model. The possibility of the decarboxylation of picolinic acid has been considered in the GED analysis, but no significant amounts of pyridine and carbon dioxide could be detected. To reveal the structural changes reflecting the mesomeric and inductive effects due to the carboxylic substituent, the accurate structure of pyridine has been also computed at the CCSD(T)_ae level with basis sets from triple- to 5-ζ quality. The comprehensive structure computations for pyridine as well as for carbon dioxide have been used to examine the convergence with respect to the basis set size.

Nitroxoline Molecule: Planar or Not? A Story of Battle between π-π Conjugation and Interatomic Repulsion.

The conformational properties of the nitro group in nitroxoline (8-hydroxy-5-nitroquinoline, NXN) were investigated in the gas phase by means of gas electron diffraction (GED) and quantum chemical calculations, and also with solid-state analysis performed using terahertz time-domain spectroscopy (THz-TDS). The results of the GED refinement show that in the equilibrium structure the NO2 group is twisted by angle ϕ = 8 ± 3° with respect to the 8-hydroxyoquinoline plane. This is the result of interatomic repulsion of oxygen in the NO2 group from the closest hydrogen, which overcomes the energy gain from the π-π conjugation of the nitro group and aromatic system of 8-hydroxyoquinoline. The computation of equilibrium geometry using MP2/cc-pVXZ (X = T, Q) shows a large overestimation of the ϕ value, while DFT with the cc-pVTZ basis set performs reasonably well. On the other hand, DFT computations with double-ζ basis sets yield a planar structure of NXN. The refined potential energy surface of the torsion vibration the of nitro group in the condensed phase derived from the THz-TDS data indicates the NXN molecule to be planar. This result stays in good agreement with the previous X-ray structure determination. The strength of the π-system conjugation for the NO2 group and 8-hydroxyoquinoline is discussed using NBO analysis, being further supported by comparison of the refined semiexperimental gas-phase structure of NXN from GED with other nitrocompounds.

Molecular structure of clonidine: gas-phase electron diffraction, single-crystal X-ray diffraction and quantum chemical studies.

This study presents the first determination of the molecular structure of the antihypertensive drug clonidine in the gas phase using gas electron diffraction (GED). The refinement was supported by quantum chemical calculations (QCs). The tautomeric and conformational distribution was investigated theoretically, providing an explanation for the presence of the single conformer in the gas phase. The molecular conformation of clonidine has been shown to have a nearly perpendicular arrangement of the phenyl and imidazolidine rings as described by the torsion angle C2-N6-C7-C8 = -72(6)°. The following structural parameters were obtained (bond lengths in Angstroms and bond angles in degrees with 3σ in parentheses): r(CHH-CHH) = 1.549(7), r(CHH-NH)av = 1.470(7), r(NH-C)av = 1.388(2), r(C[double bond, length as m-dash]N) = 1.286(7), r(C-N) = 1.388(2), r(C[partial double bond, bottom dashed]C)av = 1.403(2), r(C-Cl)av = 1.737(2); ∠(NH-C-NH) = 108.1(11), ∠(CHH-NH-C)av = 109.7(12), ∠(CHH-CHH-NH)av = 100.9(12), ∠(C-N[double bond, length as m-dash]C) = 122.5(12), ∠(CCl[partial double bond, bottom dashed]C[partial double bond, bottom dashed]CCl) = 114.9(2), and ∠(CH[partial double bond, bottom dashed]CCl[partial double bond, bottom dashed]C)av = 123.1(2). The standard enthalpy of formation of clonidine in the gas phase was calculated using G4 theory with both atomisation and isodesmic reaction approaches, yielding the corresponding value of . The molecular structure of clonidine in the solid phase was determined using X-ray diffraction (XRD). Clonidine crystallizes in the monoclinic space group P21/c as a twinned crystal. The imino-tautomer, as an equimolar mixture of the two conformers with geometries close to the enantiomeric pair, is present in the solid phase. The identical conformers are linked into centrosymmetric dimers by paired N-HN hydrogen bonds. The geometries of gaseous and solid clonidine differ especially in the immediate vicinity of the intermolecular hydrogen bonds formed in the crystal.

Gas phase equilibrium structure of histamine.

The first gas electron diffraction (GED) experiment for histamine was carried out. The equilibrium structure of histamine in the gas phase was determined on the basis of the data obtained. The refinement was also supported by the rotational constants obtained in previous studies [B. Vogelsanger, et al., J. Am. Chem. Soc., 1991, 113, 7864-7869; P. Godfrey, et al., J. Am. Chem. Soc., 1998, 120, 10724-10732] and quantum chemical calculations. The proposed mechanism of tautomerization by simultaneous intermolecular transfer of hydrogens in a histamine dimer helps to explain the distribution of tautomers in different experiments. The estimations of the conformational interconversion times provided the explanation for the absence of some conformers in the rotational spectroscopy experiments.

From the determination of the accurate equilibrium structure of 1-methylthymine by gas electron diffraction and coupled cluster computations to the observation of methylation and flexibility effects in pyrimidine nucleobases.

1-Methylthymine is of particular interest because it can be considered as a simple model of thymidine, in which deoxyribose attaches to thymine precisely at the N1 atom. The structure of this molecule is still unknown and so far has been experimentally studied for the first time in this work. The semiexperimental equilibrium structural parameters (r(e)(se)/∠(e)(se)) of 1-methylthymine have been determined by the gas electron diffraction (GED) method, taking into account vibrational corrections calculated with the use of the anharmonic (cubic) MP2/cc-pVTZ force constants. The methyl torsion around the C­N bond has been treated as a large-amplitude motion. For the first time, the structure of this molecule has been optimized by the very time-consuming coupled-cluster method (CCSD(T)(ae)) with the triple-ζ (cc-pwCVTZ) basis set. The obtained results have been extrapolated to the quadruple-ζ basis set at the MP2 level. It has been revealed that the methylation of uracil, especially at the nitrogen atom, leads to an increase in the flexibility of the nucleobase as well as a noticeable deformation of the pyrimidine ring.

Conformational and Bonding Properties of 3,3-Dimethyl- and 6,6-Dimethyl-1,5-diazabicyclo[3.1.0]hexane: A Case Study Employing the Monte Carlo Method in Gas Electron Diffraction.

Gas-phase structures of two isomers of dimethyl-substituted 1,5-diazabicyclo[3.1.0]hexanes, namely, 3,3-dimethyl- and 6,6-dimethyl-1,5-diazabicyclo[3.1.0]hexane molecules, have been determined by gas electron diffraction method. A new approach based on the Monte Carlo method has been developed and used for the analysis of precision and accuracy of the refined structures. It was found that at 57 °C 3,3-dimethyl derivative exists as a mixture of chair and boat conformers with abundances 68(8)% and 32(8)%, respectively. 6,6-Dimethyl-1,5-diazabicyclo[3.1.0]hexane at 50 °C has only one stable conformation with planar 5-ring within error limits. Theoretical calculations predict that the 6,6-dimethyl isomer is more stable in comparison to the 3,3-dimethyl isomer with energy difference 3-5 kcal mol(-1). In order to explain the relative stability and bonding properties of different structures the natural bond orbitals (NBO), atoms in molecules (AIM), and interacting quantum atoms (IQA) analyses were performed.

Interplay of experiment and theory: determination of an accurate equilibrium structure of 1-methyluracil by the gas electron diffraction method and coupled-cluster computations.

As far as fundamental knowledge is concerned, the methyl derivatives of uracil can be considered as the simplest objects for studying the structural effects due to the substitution in the pyrimidyne nucleobases. From this point of view, 1-methyluracil is of special importance in biochemistry because uracil attaches ribose in ribonucleic acid (RNA) just precisely at the N1 atom. The semi-experimental equilibrium structure (r(e)(se)) of 1-methyluracil has been determined for the first time by the gas electron diffraction (GED) method taking into account rovibrational corrections to the thermal-average internuclear distances calculated with harmonic and anharmonic (cubic) MP2/cc-pVTZ force constants with consideration of the methyl torsion as a large-amplitude motion. For the first time, the structure of the molecule has been optimized by the very time-consuming coupled-cluster method with single and double excitations and perturbative treatment of connected triples using the correlation-consistent polarized weighted core-valence triple-ζ basis set with all electrons being correlated (CCSD(T)(all)/cc-pwCVTZ) and extrapolated to the complete basis set (CBS) with the help of the MP2 calculations. Small differences between similar bond lengths of equilibrium configurations were assumed in the GED analysis at the CCSD(T)(all)/CBS values. A remarkable agreement between the semi-experimental and computed equilibrium structures points out the high accuracy of both the GED determination and the coupled-cluster computations. The effect of methylation on the structure of uracil has been analyzed.

Structure and bonding nature of the strained Lewis acid 3-methyl-1-boraadamantane: a case study employing a new data-analysis procedure in gas electron diffraction.

Base-free 3-methyl-1-boraadamantane was synthesized by starting from its known THF adduct, transforming it to a butylate-complex with n-butyllithium, cleaving the cage with acetyl chloride to give 3-n-butyl-5-methyl-7-methylene-3-borabicyclo[3.3.1]nonane and closing the cage again by reacting the latter with dicyclohexylborane. The identity of 3-methyl-1-boraadamantane was proven by (1) H, (11) B and (13) C NMR spectroscopy and elemental analysis. The experimental equilibrium structure of the free 3-methyl-1-boraadamantane molecules has been determined at 100 °C by using gas-phase electron diffraction. For this structure determination, an improved method for data analysis has been introduced and tested: the structural refinement versus gas-phase electron diffraction data (in terms of Cartesian coordinates) with a set of quantum-chemically derived regularization constraints for the complete structure under optimization of a regularization constant, which maximizes the contribution of experimental data while retaining a stable refinement. The detailed analysis of parameter errors shows that the new approach allows obtaining more reliable results. The most important structural parameters are: r(e) (B-C)(av) =1.556(5) Å, angle(e) (C-B-C)(av) =116.5(2)°. The configuration of the boron atom is pyramidal with ∑ angle (C-B-C)=349.4(4)°. The nature of bonding was analyzed further by applying the natural bond orbital (NBO) and atoms in molecules (AIM) approaches. The experimentally observed shortening of the B-C bonds and elongation of the adjacent C-C bonds can be explained by the σ(C-C)→p(B) hyperconjugation model. Both NBO and AIM analyses predict that the B-C bonds are significantly bent in the direction out of the cage.

Molecular structure of 9H-adenine tautomer: gas-phase electron diffraction and quantum-chemical studies.

Molecular geometry of 9H-adenine tautomer was calculated by MP2 method using several basis sets (up to cc-pVQZ). According to the results of all quantum-chemical calculations, the molecule has an essentially planar heavy-atom skeleton and a quasi-planar amino group. Since the bond lengths of adenine are of similar magnitude, the structural problem could not be solved by the gas-phase electron diffraction (GED) method alone. Therefore the differences between similar bond lengths derived from ab initio geometry and rotational constants from microwave (MW) spectroscopic study (Brown, R. D.; et al. Chem. Phys. Lett. 1989, 156, 61) were used as supplementary data. To bring the data of the different experimental methods to the same basis (equilibrium structure), GED internuclear distances r(a) and MW rotational constants B(0)((i)) (i = A, B, C) were corrected for vibrational effects. Harmonic and anharmonic corrections were estimated using quadratic and cubic force constants from MP2/cc-pVTZ calculations. Anharmonic corrections to r(a) distances were calculated using improved theoretical approximation. The molecular structure of 9H-adenine is determined experimentally for the first time. Since the GED intensities are not sensitive to hydrogen positions, and small deviations of skeleton cannot be determined with appropriate uncertainty, the molecular configuration of adenine was assumed to be planar (C(s) symmetry) in the GED analysis. The main equilibrium structural parameters determined from GED data supplemented by rotational constants and results of MP2/cc-pVTZ calculations are the following (bond lengths in angstroms and bond angles in degrees with 3sigma in parentheses): r(e)(C2-N1) = 1.344(3), r(e)(C2-N3) = 1.330(3), r(e)(C4-N3) = 1.333(3), r(e)(C4-C5) = 1.401(3), r(e)(C5-C6) = 1.409(3), r(e)(C6-N1) = 1.332(3), r(e)(C5-N7) = 1.380(4), r(e)(C8-N7) = 1.319(3), r(e)(C8-N9) = 1.371(4), r(e)(C4-N9) = 1.377(4), r(e)(C6-N10) = 1.357(4), angle(e)(N1-C2-N3) = 129.0(1), angle(e)(C2-N3-C4) = 111.0(1), angle(e)(N3-C4-C5) = 127.2(1), angle(e)(C4-C5-N7) = 111.9(2), angle(e)(C5-N7-C8) = 103.4(2), and angle(e)(C5-C6-N10) = 121.9(2). The determined experimental bond lengths of adenine are in good agreement with those from MP2 calculations and with experimental bond lengths of pyrimidine and 1H-imidazole (except for the C-C double bond in imidazole). Being close to typical aromatic internuclear distances, the obtained C-C and C-N bond lengths indicate the aromatic nature of this molecule. The calculated aromaticity indexes (GIAO-MP2/cc-pVTZ) confirm this statement.

Study of the thymine molecule: equilibrium structure from joint analysis of gas-phase electron diffraction and microwave data and assignment of vibrational spectra using results of ab initio calculations.

Thymine is one of the nucleobases which forms the nucleic acid (NA) base pair with adenine in DNA. The study of molecular structure and dynamics of nucleobases can help to understand and explain some processes in biological systems and therefore it is of interest. Because the scattered intensities on the C, N, and O atoms as well as some bond lengths in thymine are close to each other the structural problem cannot been solved by the gas phase electron diffraction (GED) method alone. Therefore the rotational constants from microvawe (MW) studies and differences in the groups of N-C, C=O, N-H, and C-H bond lengths from MP2 (full)/cc-pVQZ calculations were used as supplementary data. The analysis of GED data was based on the C(s) molecular symmetry according to results of the structure optimizations at the MP2 (full) level using 6-311G (d,p), cc-pVTZ, and cc-pVQZ basis sets confirmed by vibrational frequency calculations with 6-311G (d,p) and cc-pVTZ basis sets. Mean-square amplitudes as well as harmonic and anharmonic vibrational corrections to the internuclear distances (r(e)-r(a)) and to the rotational constants (B(e)(k)-B(0)(k), where k = A, B, C) were calculated from the quadratic (MP2 (full)/cc-pVTZ) and cubic (MP2 (full)/6-311G (d,p)) force constants (the latter were used only for anharmonic corrections). The harmonic force field was scaled using published IR and Raman spectra of the parent and N1,N3-dideuterated species, which were for the first time completely assigned in the present work. The main equilibrium structural parameters of the thymine molecule determined from GED data supplemented by MW rotational constants and results of MP2 calculations are the following (bond lengths in Angstroms and bond angles in degrees with 3sigma in parentheses): r(e) (C5=C6) = 1.344 (16), r(e) (C5-C9) = 1.487 (8), r(e) (N1-C6) = 1.372 (3), r(e) (N1-C2) = 1.377 (3), r(e) (C2-N3) = 1.378 (3), r(e) (N3-C4) = 1.395 (3), r(e) (C2=O7) = 1.210 (1), r(e) (C4=O8) = 1.215 (1), angle e (N1-C6=C5) = 123.1 (5), angle e (C2-N1-C6) = 123.7 (5), angle e (N1-C2-N3) = 112.8 (5), angle e (C2-N3-C4) = 128.0 (5), angle e (N3-C4-C5) = 114.8 (5), angle e (C6=C5-C9) = 124.4 (9). The experimental structural parameters are in good agreement with those from MP2 (full) calculations with use of cc-pVTZ and cc-pVQZ basis sets.

Molecular structure of 1,5-diazabicyclo[3.1.0]hexane as determined by gas electron diffraction and quantum-chemical calculations.

The equilibrium molecular structure and conformation of 1,5-diazabicyclo[3.1.0]hexane (DABH) has been studied by the gas-phase electron-diffraction method at 20 degrees C and quantum-chemical calculations. Three possible conformations of DABH were considered: boat, chair, and twist. According to the experimental and theoretical results, DABH exists exclusively as a boat conformation of C s symmetry at the temperature of the experiment. The MP2 calculations predict the stable chair and twist conformations to be 3.8 and 49.5 kcal mol(-1) above the boat form, respectively. The most important semi-experimental geometrical parameters of DABH (r(e), A and angle)e), deg) are (N1-N5) = 1.506(13), (N1-C6) = 1.442(2), (N1-C2) = 1.469(4), (C2-C3) = 1.524(7), (C6-N1-C2) = 114.8(8), (N5-N1-C2) = 107.7(4), (N1-C2-C3) = 106.5(9), and (C2-C3-C4) = 104.0(10). The natural bond orbital (NBO) analysis has shown that the most important stabilization factor in the boat conformation is the n(N) --> sigma*(C-C) anomeric effect. The geometry calculations and NBO analysis have been performed also for the bicyclohexane molecule.

Molecular structure and conformational composition of 1,3-dihydroxyacetone studied by combined analysis of gas-phase electron diffraction data, rotational constants, and results of theoretical calculations. Ideal gas thermodynamic properties of 1,3-dihydroxyacetone.

The molecular structure of 1,3-dihydroxyacetone (DHA) has been studied by gas-phase electron diffraction (GED), combined analysis of GED and microwave (MW) data, ab initio, and density functional theory calculations. The equilibrium re structure of DHA was determined by a joint analysis of the GED data and rotational constants taken from the literature. The anharmonic vibrational corrections to the internuclear distances (re-ra) and to the rotational constants (B(i)e-B(i)0) needed for the estimation of the re structure were calculated from the B3LYP/cc-pVTZ cubic force field. It was found that the experimental data are well reproduced by assuming that DHA consists of a mixture of three conformers. The most stable conformer of C2v symmetry has two hydrogen bonds, whereas the next two lowest energy conformers (Cs and C1 symmetry) have one hydrogen bond and their abundance is about 30% in total. A combined analysis of GED and MW data led to the following equilibrium structural parameters (re) of the most abundant conformer of DHA (the uncertainties in parentheses are 3 times the standard deviations): r(C=O)=1.215(2) A, r(C-C)=1.516(2) A, r(C-O)=1.393(2) A, r(C-H)=1.096(4) A, r(O-H)=0.967(4) A, angleC-C=O=119.9(2) degrees, angleC-C-O=111.0(2) degrees, angleC-C-H=108.2(7) degrees, angleC-O-H=106.5(7) degrees. These structural parameters reproduce the experimental B(i)0 values within 0.05 MHz. The experimental structural parameters are in good agreement with those obtained from theoretical calculations. Ideal gas thermodynamic functions (S degrees (T), C degrees p(T), and H degrees (T)-H degrees (0)) of DHA were calculated on the basis of experimental and theoretical molecular parameters obtained in this work. The enthalpy of formation of DHA, -523+/-4 kJ/mol, was calculated by the atomization procedure using the G3X method.