Conformations and intermolecular interactions pattern in solid chloroxylenol and triclosan (API of anti‐infective agents and drugs). A 35Cl NQR, 1H‐14 N NQDR,X‐ray and DFT/QTAIM study

Two antibacterial and antifungal agents, chloroxylenol (4‐chloro‐3,5‐dimethyl‐phenol) and triclosan (5‐chloro‐2‐(2’,4’‐dichlorophenoxy)‐phenol), were studied experimentally in solid state with an X‐ray, ³⁵Cl‐nuclear quadrupole resonance (NQR) and ¹⁷O‐nuclear quadrupole double resonance (NQDR) spectroscopies and, theoretically, with the density functional theory/quantum theory of atoms in molecules (DFT/QTAIM). The crystallographic structure of triclosan, which crystallises in space group P3₁ with one molecule in the asymmetric unit [a = 12.64100(10), b = 12.64100(10), c = 6.71630(10) Å], was solved with an X‐ray and refined to a final R‐factor of 2.81% at room temperature. The NQR frequencies of ³⁵Cl and ¹⁷O were detected with the help of the density functional theory (DFT) assigned to particular chlorine and oxygen sites in the molecules of both compounds. The NQR frequencies at ³⁵Cl sites in chloroxylenol and triclosan were found to be more differentiated than frequencies at the ¹⁷O site. The former better describes the substituent withdrawing effects connected to π‐electron delocalization within the benzene rings and the influence of temperature; whereas, those at the ¹⁷O site provide more information on O‐H bond and intermolecular interactions pattern. The conformation adopted by diphenyl ether of triclosan in solid state was found to be typical of diphenyl ethers, but the opposite to those adopted when it was bound to different inhibitors. According to an X‐ray study, temperature had no effect on the conformation of the diphenyl ring of triclosan, which was the same at 90 K and at room temperature (RT). The scattering of NQR frequencies reproduced by the DFT under assumption of the X‐ray data at 90 K and RT is found to be a good indicator of the quality of resolution of the crystallographic structure. Copyright © 2012 John Wiley & Sons, Ltd.     

Electronic and structural properties of borazine and related molecules

Ab initio SCF MO calculations are reported for benzene, s-triazine, borazine and boroxine. The Laplacian of the charge density and the Mulliken population analysis procedure demonstrate that the delocalization of the π electrons decreases and the polarity of the ring bonds increases substantially as the atoms in the ring become more dissimilar. Several other properties, including distortion of the ring angles, puckering of the ring and nuclear quadrupolar coupling constants, emphasize the different chemical properties within the isoelectronic series.     

Insight into Local Structure and Molecular Dynamics in Organic Solid‐State Ionic Conductors

Elucidating the rate and geometry of molecular dynamics is particularly important for unravelling ion‐conduction mechanisms in electrochemical materials. The local molecular motions in the plastic crystal 1‐ethyl‐1‐methylpyrrolidinium tetrafluoroborate ([C₂mpyr][BF₄]) are studied by a combination of quantum chemical calculations and advanced solid‐state nuclear magnetic resonance spectroscopy. For the first time, a restricted puckering motion with a small fluctuation angle of 25° in the pyrrolidinium ring has been observed, even in the low‐temperature phase (?45 °C). This local molecular motion is deemed to be particularly important for the material to maintain its plasticity, and hence, its ion mobility at low temperatures.     

Nuclear quantum effect and temperature dependency on the hydrogen‐bonded structure of base pairs

The structure of Watson–Crick‐type adenine‐thymine and guanine‐cytosine pairs has been studied by hybrid Monte Carlo (HMC) and path integral hybrid Monte Carlo (PIHMC) simulations with the use of semiempirical PM6‐DH+ method in the gas phase. We elucidated the nuclear quantum effect and temperature dependency on the hydrogen‐bonded moiety of base pairs. It was shown that the contribution of nuclear quantum effect on the hydrogen‐bonded structure is significant not only at low temperature 150 K but also at temperature as high as 450 K. The relative position of hydrogen‐bonded proton between two heavy atoms and the nuclear quantum nature of the proton are also shown. Furthermore, we have applied principal component analysis to HMC and PIHMC simulations to analyze the nuclear quantum effect on intermolecular motions. We found that the ratio of Buckle mode (lowest vibrational mode from normal mode analysis) decreases due to the nuclear quantum effect, whereas that of Propeller mode (second lowest vibrational mode) increases. In addition, nonplanar structures of base pairs were found to become stable due to the nuclear quantum effect from two‐dimensional free energy landscape along Buckle and Propeller modes. © 2013 Wiley Periodicals, Inc.     

The crystal structure of the CeNA:RNA hybrid ce(GCGTAGCG):r(CGCUACGC)

Cyclohexenyl nucleic acids (CeNA) are characterised by the carbon–carbon double bond replacing the O4′‐oxygen atom of the natural D ‐2′‐deoxyribose sugar ring in DNA. CeNAs exhibit a high conformational flexibility, are stable against nuclease activity and their hybridisation is RNA selective. Additionally, CeNA has been shown to induce an enhanced biological activity when incorporated in siRNA. This makes CeNA a good candidate for siRNA and synthetic aptamer applications. The crystal structure of the synthetic CeNA:RNA hybrid ce(GCGTAGCG):r(CGCUACGC) has been solved with a resolution of 2.50 Å. The CeNA:RNA duplex adopts an anti‐parallel, right‐handed double helix with standard Watson–Crick base pairing. Analyses of the helical parameters revealed the octamer to form an A‐like double helix. The cyclohexenyl rings mainly adopt the ³H₂ conformation, which resembles the C3′‐endo conformation of RNA ribose ring. This C3′‐endo ring puckering was found in most of the RNA residues and is typical for A‐family helices. The crystal structure is stabilised by the presence of hexahydrated magnesium ions. The fact that the CeNA:RNA hybrid adopts an A‐type double helical conformation confirms the high potential of CeNAs for the construction of efficient siRNAs which can be used for therapeutical applications.     

Pyramidal distortion of the NO<Subscript>2</Subscript> group in the radical anion of 2,4,6-trimethoxynitrobenzene

Electrochemical reduction in DMF is used to produce the radical anion of 2,4,6-trimethoxynitrobenzene with an EPR spectrum that shows hyperfine splitting for ¹⁵N nuclei of the nitro group and ¹³C nuclei of the benzene ring given the natural abundance of the isotopes. According to UB3LYP/6-31+G* quantum chemical calculations considering solvation in the PCM model, the nitro group in the equilibrium conformation of the RA of 2,4,6-trimethoxynitrobenzene is rotated relative to the benzene ring plane by an angle close to 90° and has a pyramidal structure. The calculated isotropic hyperfine coupling constants for this conformation are closest to the experimental results.     

Ring Reconstruction on a Trichalcogenasumanene Buckybowl: A Facile Approach to Donor–Acceptor‐Type [5‐6‐7] Fused Planar Polyheterocycles

The transformation of trichalcogenasumanene buckybowls into donor–acceptor‐type [5‐6‐7] fused polyheterocycles is disclosed. The strategy involves a highly efficient ring‐opening of the flanking benzene upon oxidation at room temperature, and facile ring closure by functional‐group transformation. Crystallographic studies indicate that the resulting [5‐6‐7] fused polyheterocycles possess a planar conformation owing to the release of ring strain by expansion of one of the six‐membered flanking rings to the seven‐membered one. Additionally, the [5‐6‐7] fused polyheterocycles bear electron‐withdrawing groups, which reduce the HOMO–LUMO energy gap, and display broad absorption bands extending to λ=590 nm. Consequently, these compounds show strong red emission with fluorescence quantum yields of up to 38 %.     

Synthesis and Crystal Structures of O‐2′,3′‐Cyclic Cyclopentanone and Cyclohexanone Ketals of the Cytostatic 5‐Fluorouridine

The synthesis of two O‐2′,3′‐cyclic ketals, i.e., 5 and 6 , of the cytostatic 5‐fluorouridine ( 2 ), carrying a cyclopentane and/or a cyclohexane ring, respectively, is described. The novel compounds were characterized by ¹H‐, ¹⁹F‐, and ¹³C‐NMR, and UV spectroscopy, as well as by elemental analyses. Their crystal structures were determined by X‐ray analysis. Both compounds 5 and 6 show an anti‐conformation at the N‐glycosidic bond which is biased from +ac to +ap compared to the parent nucleoside 2 . The sugar puckering is changed from ^2′E to _3′E going along with a reduction of the puckering amplitude τ_m by ca. 10–13° due to the ketalization. The conformation about the sugar exocyclic bond C(4′)? C(5′) of 5 and 6 remains unchanged, i.e., g⁺, compared with compound 2 .     

cis‐6‐Phenyl‐4bH,6H,11H,13H‐isoindolo[1,2‐c]benz[2,4]oxazepin‐13‐one

The title compound, C₂₂H₁₇NO₂, contains an isoindolinone moiety joined to a phenyl‐substituted benzoxazepine ring. The isoindolinone moiety is essentially planar and the oxazepine ring adopts a distorted chair conformation, with the phenyl substituent equatorial. Owing to the severe puckering of the central oxazepine ring, the mol­ecule as a whole is non‐planar; the benzene ring of the benzoxazepine fragment makes an angle of 67.7 (1)° with respect to the isoindoline ring.     

Quantum‐chemical approach to the solvatochromic transition in polysilane derivatives

We approached the solvatochromic transition observed in polysilane derivatives (poly[bis(4‐propoxybutyl)silylene] (PPBS)) from the standpoint of various quantum chemical treatments. It was found from conventional geometry optimizations at the levels of semiempirical and ab initio molecular orbital methods that a protonation to polysilane oligomers with side chain R = ? OCH₃ results in the conformational change of Si‐backbone to a trans‐zigzag structure. Using the Elongation method, which was developed for efficient calculations of huge systems, it was demonstrated that a protonation could change the conformation of Si‐backbone to a trans‐zigzag structure over 10–14 Si atoms. In addition, ab initio calculations showed that the positive charge of a proton can delocalize into the Si‐backbone through a long side chain in PPBS. Positively charged polysilane oligomers provide a rotational barrier that prefers a trans‐zigzag structure, whereas neutral oligomers have a barrier that results to a random structure. This unique behavior of the charged polysilane oligomers should not be disregarded in understanding the mechanism of the solvatochromic transition in PPBS. In ab initio configuration interaction/Mφller‐Plesset through‐space/bond interaction analysis, it was found that such a unique behavior of the rotational barrier in polysilane oligomers could be explained by the effect of orbital delocalization through σ‐conjugation on the Si‐backbone. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 44: 119–133, 2006     

Unexpected conformational properties of 1-trifluoromethyl-1-silacyclohexane, C5H10SiHCF3: gas electron diffraction, low-temperature NMR spectropic studies, and quantum chemical calculations

The molecular structure of axial and equatorial conformers of 1-trifluoromethyl-1-silacyclohexane, (C5H10SiHCF3), as well as the thermodynamic equilibrium between these species was investigated by means of gas electron diffraction (GED), dynamic nuclear magnetic resonance (DNMR) spectroscopy, and quantum chemical calculations (B3LYP, MP2, and CBS-QB3). According to GED, the compound exists as a mixture of two Cs symmetry conformers possessing the chair conformation of the six-membered ring and differing in the axial or equatorial position of the CF3 group (axial=58(12) mol%/equatorial=42(12) mol%) at T=293 K. This result is in a good agreement with the theoretical prediction. This is, however, in sharp contrast to the conformational properties of the cyclohexane analogue. The main structural feature for both conformers is the unusually long exocyclic bond length Si--C 1.934(10) A. A low-temperature 19F NMR experiment results in an axial/equatorial ratio of 17(2) mol%:83(2) mol% at 113 K and a DeltaG (not equal) of 5.5(2) kcal mol-1. CBS-QB3 calculations in the gas-phase and solvation effect calculations using the PCM(B3LYP/6-311G*) and IPCM(B3LYP/6-311G*) models were applied to estimate the axial/equatorial ratio in the 100-300 K temperature range, which showed excellent agreement with the experimental results. The minimum energy pathways for the chair-to-chair inversion of trifluoromethylsilacyclohexane and methylsilacyclohexane were also calculated using the STQN(Path) method.     

Less is more when simulating unsulfated glycosaminoglycan 3D‐structure: Comparison of GLYCAM06/TIP3P,PM3‐CARB1/TIP3P,and SCC‐DFTB‐D/TIP3P predictions with experiment

The 3D‐structure of extracellular matrix glycosaminoglycans is central to function, but is currently poorly understood. Resolving this will provide insight into their heterogeneous biological roles and help to realize their significant therapeutic potential. Glycosaminoglycan chemical isoforms are too numerous to study experimentally and simulation provides a tractable alternative. However, best practice for accurate calculation of glycosaminoglycan 3D‐structure within biologically relevant nanosecond timescales is uncertain. Here, we evaluate the ability of three potentials to reproduce experimentally observed glycosaminoglycan monosaccharide puckering, disaccharide 3D‐conformation, and characteristic solvent interactions. Temporal dynamics of unsulfated chondroitin, chondroitin‐4‐sulfate, and hyaluronan β(1→3) disaccharides were simulated within TIP3P explicit solvent unrestrained for 20 ns using the GLYCAM06 force‐field and two semi‐empirical quantum mechanics methods, PM3‐CARB1 and SCC‐DFTB‐D (both within a hybrid QM/MM formalism). Comparison of calculated and experimental properties (vicinal couplings, nuclear Overhauser enhancements, and glycosidic linkage geometries) showed that the carbohydrate‐specific parameterization of PM3‐CARB1 imparted quantifiable benefits on monosaccharide puckering and that the SCC‐DFTB‐D method (including an empirical correction for dispersion) best modeled the effects of hexosamine 4‐sulfation. However, paradoxically, the most approximate approach (GLYCAM06/TIP3P) was the best at predicting monosaccharide puckering, 3D‐conformation, and solvent interactions. Our data contribute to the debate and emerging consensus on the relative performance of these levels of theory for biological molecules. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

On the influence of nuclear fluctuations on calculated NMR shieldings of benzene and ethylene: a Feynman path integral–ab initio investigation*

The absolute magnetic shieldings of benzene and ethylene have been theoretically studied under the conditions of thermal equilibrium, i.e., under explicit consideration of the nuclear degrees of freedom. For this purpose we have combined the Feynman path integral quantum Monte Carlo (PIMC) formalism with the gauge‐including atomic orbital (GIAO) approach in the Hartree–Fock (HF) approximation. The HF operator has been employed to derive the NMR parameters of the two hydrocarbons via an ensemble averaging over large sets of molecular configurations that are populated in thermal equilibrium. The nuclear fluctuations are responsible for a deshielding of the nuclei relative to the shieldings at the vibrationless minimum of the potential energy surface (PES). The influence of the nuclear degrees of freedom is largest for the isotropic part of the ¹³C shielding tensor. The theoretical results can be explained on the basis of simple geometrical considerations. The bond lengths in thermal equilibrium are larger than the bond lengths at the minimum of the PES. This length enhancement is the prerequisite for a deshielding of the nuclei in thermal equilibrium. The vibrational corrections of the nuclear magnetic resonance (NMR) parameters of benzene and ethylene are quantum driven; classical thermal degrees of freedom of the nuclei are of minor importance. Conceptual problems of theoretical studies of NMR parameters on the basis of a single molecular geometry are emphasized. The influence of the spatial uncertainty of the nuclei becomes decisive in molecules with light atoms. It is pointed out that the combination of the PIMC formalism with electronic Hamiltonians of state‐of‐the‐art quality renders possible accurate determinations of NMR parameters. © 2002 John Wiley & Sons, Inc. Int J Quantum Chem 86: 280–296, 2002     

1‐[(1‐Ethoxypropylidene)amino]‐2‐ethyl‐4‐(4‐hydroxybenzyl)imidazol‐5(4H)‐one

The racemic title compound, C₁₇H₂₃N₃O₃, isolated from the reaction of l ‐(−)‐tyrosine hydrazide with triethyl orthopropionate in the presence of a catalytic quantity of p‐toluenesulfonic acid (p‐TsOH), crystallizes with Z′ = 1 in a centrosymmetric monoclinic unit cell. The molecule contains two planar fragments, viz. the benzene and imidazole rings, linked by two C—C single bonds. The dihedral angle between the two planes is 59.54 (5)° and the molecule adopts a synclinal conformation. The HOMA (harmonic oscillator model of aromaticity) index, calculated for the benzene ring, demonstrates no substantial interaction between the two π‐electron delocalization regions in the molecule. In the crystal structure, there is an O—H...N hydrogen bond that links the molecules along the c axis.     

Conformational equilibrium in 8-methyl-cis-2-thiahydrindane and 8-methyl-cis-2-oxahydrindane by 13C NMR spectroscopy

The preferred conformation of 8-methyl-cis-thiahydrindane has been both estimated by ¹³C NMR chemical shifts and determined by low temperature ¹³C NMR spectroscopy to be the conformer with the methyl group equatorial with respect to the cyclohexane ring. This result is in disagreement with the interpretation of the temperature dependence of the CD spectra of (+) and (?) 8-methyl-cis-2-thiahydrindane, whereby the conformation with the methyl group axial with respect to the cyclohexane ring was claimed to be the preferred conformation. The preferred conformation of the related oxygen heterocycle, 8-methyl-cis-2-oxahydrindane, has been estimated by ¹³C NMR chemical shifts to be the conformer with the methyl group axial with respect to the cyclohexane ring. Possible reasons for these observations are discussed.     

Two 1,4‐dihydropyridine derivatives with potential calcium‐channel antagonist activity

The title compounds, benzyl 4‐(3‐chloro‐2‐fluorophenyl)‐2‐methyl‐5‐oxo‐4,5,6,7‐tetrahydro‐1H‐cyclopenta[b]pyridine‐3‐carboxylate, C₂₃H₁₉ClFNO₃, (I), and 3‐pyridylmethyl 4‐[2‐fluoro‐3‐(trifluoromethyl)phenyl]‐2,6,6‐trimethyl‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carboxylate, C₂₆H₂₄F₄N₂O₃, (II), belong to a class of 1,4‐dihydropyridines whose members sometimes display calcium modulatory properties. The 1,4‐dihydropyridine ring in each structure has a shallower than usual shallow‐boat conformation and is nearly planar in (I). In each structure, the halogen‐substituted benzene ring is oriented such that the halogen substituents are in a synperiplanar orientation with respect to the 1,4‐dihydropyridine ring plane. The oxocyclopentene ring in (I) is planar, while the oxocyclohexene ring in (II) has a half‐chair conformation, which is less commonly observed than the envelope conformation usually found in related compounds. In (I), the frequently observed intermolecular N—H...O hydrogen bond between the amine group and the carbonyl O atom of the oxocyclopentene ring of a neighbouring molecule links the molecules into extended chains; there are no other significant intermolecular interactions. By contrast, the amine group in (II) forms an N—H...N hydrogen bond with the pyridine ring N atom of a neighbouring molecule. Additional C—H...O interactions complete a two‐dimensional hydrogen‐bonded network. The halogen‐substituted benzene ring has a weak intramolecular π–π interaction with the pyridine ring. A stronger π–π interaction occurs between the 1,4‐dihydropyridine rings of centrosymmetrically related molecules.     

Effects of the Presence of Cyclohexane or Methylcyclohexane on the Densities and Volumetric Properties of the Mixture (Benzene + Propionitrile)

Excess molar volumes, V_m^E, have been obtained as a function of composition for ternary-pseudobinary mixtures of [(benzene + cyclohexane or methylcyclohexane) + (propionitrile + cyclohexane or methylcyclohexane)] from the densities measured by means of a vibrating-tube densimeter at atmospheric pressure and a temperature of 298.15 K. The values of V_m^E have been correlated using the Redlich–Kister equation to estimate the coefficients and standard errors. The experimental and calculated quantities are used to discuss the mixing behavior of the components. The results show that the third component, cyclohexane or methylcyclohexane, has a significant effect on the interaction between benzene and propionitrile.     

A Nuclear Singlet Lifetime of More than One Hour in Room‐Temperature Solution

Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) are supremely important techniques with numerous applications in almost all branches of science. However, until recently, NMR methodology was limited by the time constant T₁ for the decay of nuclear spin magnetization through contact with the thermal molecular environment. Long‐lived states, which are correlated quantum states of multiple nuclei, have decay time constants that may exceed T₁ by large factors. Here we demonstrate a nuclear long‐lived state comprising two ¹³C nuclei with a lifetime exceeding one hour in room‐temperature solution, which is around 50 times longer than T₁. This behavior is well‐predicted by a combination of quantum theory, molecular dynamics, and quantum chemistry. Such ultra‐long‐lived states are expected to be useful for the transport and application of nuclear hyperpolarization, which leads to NMR and MRI signals enhanced by up to five orders of magnitude.     

Exploration of the electronic structure of dendrimerlike acetylene-bridged oligothiophenes by correlating Raman spectroscopy, electrochemistry, and theory

A series of radial thiophene-based structures consisting of a central benzene or thiophene ring surrounded by acetylene-bridged terthienyl arms has been investigated by physical and theoretical methods. Fourier transform Raman spectroscopy of the neutral solids shows that the terthiophene arms are weakly coupled across the core (benzene plus acetylene groups) likely due to cross-conjugation or meta-conjugation effects that may prevent full delocalization. By increasing the number of arms around the central ring, the electronic structure of the molecules seems to be affected only at the core, whereas the outer terthiophene arms remain almost unaltered. Raman spectroelectrochemistry and quantum chemical calculations provide further insight into the charge delocalization of the oxidized species. There is no evidence to suggest that these oxidized forms, obtained upon electrochemical doping of the molecules, show charge delocalization across the core.