Methyl Group Reorientation Research Articles

Crystal structures, phase transitions, thermodynamics, and molecular dynamics of organic–inorganic hybrid crystal [NH(CH3)3]2ZnCl4

Understanding the physical properties of organic–inorganic hybrid [NH(CH3)3]2ZnCl4 is necessary for its potential application in batteries and fuel cells due to its environmentally-friendly, and highly stable character. Here, we determine its overall properties in detail, such as its orthorhombic crystal structure, and phase transition temperatures associated with five different phases. Structural geometry was studied by the chemical shifts caused by the local field around 1H. No changes were observed for the environment around 1H for CH3, whereas the 1H chemical shifts around NH in the cation were shown due to the change in the hydrogen bond N‒H···Cl. This is related to the change in Cl around Zn in the anion. In addition, the coordination geometry of 14N and 1H around 13C exhibited increased symmetry at high temperatures. Finally, we were able to understand its molecular dynamics by the significant change with temperature observed from the spin–lattice relaxation time T1ρ values, which represent the energy transfer for the 1H and 13C atoms of the cation. The activation energies obtained from the T1ρ results were 3–4 times large at phase I (> 348 K) than at phase V and IV (< 286 K). The relaxations show that the energy barriers in phases IV and V are related to the reorientation of methyl groups around the triple symmetry axis, while the reorientation of methyl groups of the cation in phase I is related to as a whole.

Different Dynamic Behavior of Methyl Groups in Crystalline Carbimazole as Revealed by a Multitechnique Experimental and Theoretical Approach

Dynamic properties of carbimazole (a drug used in hyperthyroidism treatment) were thoroughly investigated by combining solid-state nuclear magnetic resonance spectroscopy and quasielastic neutron scattering with periodic density functional theory (plane-wave DFT) and molecular dynamics simulations. These complementary methods allowed the full description of internal carbimazole motions. Particularly, in crystalline carbimazole, only the reorientations of the two methyl groups were found to be active in the explored timescale. The combination of different techniques allowed the quantitative characterization of the two methyl reorientations, which differ by almost 2 orders of magnitude in the timescale, in agreement with results previously reported in the literature for methyl groups in similar chemical environments. These results could also assume a particular relevance considering the role of methyl groups in determining the biochemical and biological activities of active pharmaceutical ingredients.

Exploring the molecular reorientations in amorphous rosuvastatin calcium.

Molecular reorientations in rosuvastatin calcium, a drug that is widely used to prevent cardiovascular disease, were explored thoroughly by means of solid state nuclear magnetic resonance (1H and 13C NMR) combined with calculations of steric hindrances. The experimental results reveal rich internal reorientational dynamics. All relaxation processes were tested in a broad range of temperatures and described in terms of their type and the associated energy barriers. The internal molecular mobility of rosuvastatin calcium can be associated with the reorientational dynamics of four methyl groups, accompanied by reorientation of the isopropyl group. The energy barriers of methyl and isopropyl group reorientation depended on the type of E/Z isomers, while the water content also had a strong influence on the dynamics of the isopropyl group. In the paper, a consistent picture of the molecular dynamics is provided, facilitating our understanding of molecular mobility in this important pharmaceutical solid.

Methyl quantum tunneling in ionic liquid [DMIm][TFSI] facilitated by Bis(trifluoromethane)sulfonimide lithium salt

We probe, for the first time, quantum tunneling in the methyl groups of the ionic liquid [DMIm][TFSI] facilitated by the presence of Bis(trifluoromethane)sulfonimide lithium salt. The observation of tunneling is made possible by crystallization, rather than vitrification, of [DMIm][TFSI] at low temperature. Neutron scattering measurements detect quantum tunneling excitations at ~27 μeV at temperatures below 30 K in the presence of LiTFSI at a concentration of 1 mol/kg, but not in salt-free [DMIm][TFSI]. This indicates that the methyl rotational potential barrier is reduced by the presence of LiTFSI, thus bringing the tunneling excitations into the measurable range. The salt-induced reduction of the rotational barrier is corroborated by quasi-elastic scattering data associated with stochastic re-orientation of methyl groups measured between 40 and 60 K.

Methyl group reorientation under ligand binding probed by pseudocontact shifts

Liquid-state NMR spectroscopy is a powerful technique to elucidate binding properties of ligands on proteins. Ligands binding in hydrophobic pockets are often in close proximity to methyl groups and binding can lead to subtle displacements of methyl containing side chains to accommodate the ligand. To establish whether pseudocontact shifts can be used to characterize ligand binding and the effects on methyl groups, the N-terminal domain of HSP90 was tagged with caged lanthanoid NMR probe 5 at three positions and titrated with a ligand. Binding was monitored using the resonances of leucine and valine methyl groups. The pseudocontact shifts (PCS) caused by ytterbium result in enhanced dispersion of the methyl spectrum, allowing more resonances to be observed. The effects of tag attachment on the spectrum and ligand binding are small. Significant changes in PCS were observed upon ligand binding, indicating displacements of several methyl groups. By determining the cross-section of PCS iso-surfaces generated by two or three paramagnetic centers, the new position of a methyl group can be estimated, showing displacements in the range of 1–3 Å for methyl groups in the binding site. The information about such subtle but significant changes may be used to improve docking studies and can find application in fragment-based drug discovery.

Laboratory Investigation of the Hydrophobicity Transfer Mechanism on Composite Insulators Aged in Coastal Service

Silicone rubber (SIR) insulators are known to maintain their surface hydrophobicity even under severe pollution conditions in contrast to the other composite insulator materials used at the last decades. This critical advantage of silicone rubber insulators has made them dominant in high voltage power systems despite the fact that there are other composite materials with better static hydrophobicity. In service conditions, priority is given to the dynamic performance of hydrophobicity due to the unpredictable environmental pollution conditions. This dynamic performance of silicone rubber insulators is also known as hydrophobicity transfer mechanism. In literature, the hydrophobicity transfer mechanism of silicone rubber is related to the reorientation of methyl-groups and the existence of low molecular weight components. However there are many parameters which can change the effectiveness of this mechanism. Some of them referred to the ageing effects on the material structure. Thus it is of great importance to investigate the hydrophobicity transfer mechanism of field aged composite insulators. For this reason a new experimental procedure is introduced based on Cigre TB 442. The results of field aged insulators are compared to that of a new SIR insulator revealing the superiority of silicone rubber even after 17 years of field ageing.

Analysis of the Distribution of Energy Barriers in Amorphous Diazepam on the Basis of Computationally Supported NMR Relaxation Data.

Crystalline and amorphous diazepam, a psychoactive drug, were investigated by employing spin-lattice relaxation 1H NMR along with atom-atom calculations of the landscape of energy barriers. The activation barriers for reorientation of the methyl group in amorphous diazepam were found to be in the range of 1.9-12.7 kJ/mol. Atom-atom calculations permitted determination of the distribution of energy barriers for reorientations of methyl groups, which was in a good agreement with that obtained on the basis of experimental data. The NMR relaxation combined with calculations provided a quantitative description of the distribution of energy barriers including intra- and inter-molecular interactions.

Ultrafast Reorientational Dynamics of Leucine at the Air-Water Interface.

Ultrafast dynamics of protein side chains are involved in important biological processes such as ligand binding, protein folding, and hydration. In addition, the dynamics of a side chain can report on local environments within proteins. While protein side chain dynamics have been probed for proteins in solution with nuclear magnetic resonance and infrared methods for decades, information about side chain dynamics at interfaces is lacking. At the same time, the dynamics and motions of side chains can be particularly important for interfacial binding and protein-driven surface manipulation. We here demonstrate that ultrafast reorientation dynamics of leucine amino acids at interfaces can be recorded in situ and in real time using polarization- and time-resolved pump-probe sum frequency generation (SFG). Combined with molecular dynamics simulations, time-resolved SFG was used to probe the reorientation of the isopropyl methyl groups of l-leucine at the air-water interface. The data show that the methyl units reorient diffusively at an in plane rate of Dφ = 0.07 rad(2)/ps and an out of plane rate of Dθ = 0.05 rad(2)/ps.

NMR and NQR Study of Above-Room-Temperature Molecular Ferroelectrics Diisopropylammonium Chloride and Diisopropylammonium Perchlorate

The phase transitions and molecular motions in organic ferroelectrics diisopropylammonium chloride and diisopropylammonium perchlorate have been studied by proton NMR and spin–lattice relaxation and by 14N NQR and spin–lattice relaxation. In diisopropylammonium chloride, proton T1 shows slowing of the reorientation of methyl groups and a discontinuous decrease at the ferroelectric to paraelectric phase transition. The 14N NQR frequencies are observed in the range characteristic for a C–NH2+–C ion. Diisopropylammonium perchlorate undergoes three phase transitions at varying temperatures. Proton and 14N T1 shows the presence of two slow motions: the reorientation of the methyl groups and a second slow motion in phases II and III which is most probably tumbling of diisopropylammonium ions. The discontinuous change of proton T1 and M2 at the ferroelectric to paraelectric phase transition is ascribed to exchange between two orientations of a diisopropylammonium ion in the paraelectric phase. The 14N quadrupole...

Dynamics of Methyl Groups in Membrane Proteins Studied by Deterium Solid State NMR Relaxation

NMR relaxation is a valuable tool to study membrane protein dynamics which are important for their functions. Dynamical parameters (correlation times and activation barriers) can provide important information about intra- and intermolecular interactions. Here we present our study of the dynamics of the rhodopsin-bound cofactor retinal and a high-affinity transducin peptide (GαCT2) bound to opsin. To observe how the NMR relaxation and molecular dynamics depend on the local environment, we introduced a deuterated methyl group at positions C5, C9, or C13 of retinal [1], and in GαCT2 (ILENLKDVGLF) at leucine positions 2, 5, and 10. Selectively labeled retinals were studied in the dark, preactive Meta-I, and active Meta-II states of rhodopsin. High-affinity peptides were studied as the dry powder, in water, and bound to the opsin apoprotein. We measured deuterium NMR relaxation rates of Zeeman and quadrupolar order (T1Z and T1Q) in a wide temperature range from −15 to −120 °C. The temperature dependences were fitted using two approaches: first, a model-free approach [2] and second by utilizing various models of molecular motion (3-site jump and rotational diffusion models). Jump rates (k) and rotational diffusion coefficients (corresponding to methyl group spinning and reorientation) showed site-specific methyl differences [1]. Plots of relaxation rates versus temperature for both retinal and the high-affinity GαCT2 peptide indicated that methyl group dynamics are mostly determined by intramolecular interactions. The protein environment can also affect the dynamics, either directly or through structural changes (e.g. changes of the torsion angle between the beta-ionone ring and the polyene chain) as shown by relaxation measurements. [1] A.V. Struts et al. (2011) PNAS 108, 8263. [2] X. Xu et al. (2014) eMagRes 3, 275-286.

In search of the mutual relationship between the structure, solid-state spectroscopy and molecular dynamics in selected calcium channel blockers

Three isostructural 1,4-dihydropyridines (DHPs), namely, nifedipine, nitrendipine and nimodipine were selected to characterize their structure, intermolecular interactions and molecular dynamics. The studied samples were analyzed using powder X-ray diffraction (XRD), neutron (INS) and infrared spectroscopy (FT-IR) as well as solid-state nuclear magnetic resonance (NMR), where each technique was supported by the state-of-the-art theoretical calculations for solid-state. By combining multiple experimental techniques with advanced theoretical calculations we were able to shed light on the mutual relation between the structure, stabilizing intermolecular interactions and their spectral response. For the first time, unambiguous computationally-supported assignment of the most prominent spectral features in DHPs is presented to give a valuable support for polymorph screening and drug control. Molecular motions were interpreted in details, revealing that a dynamic reservoir of each compound is dominated by intra-molecular reorientations of methyl groups and large-amplitude oscillations in terminal chains. Our study successfully validates the realm of applicability of first-principles solid-state calculations in search of the mutual relation between the structure and spectroscopy in this important class of drugs. Such approach gives a first necessary step to gather combined structure-dynamics data on functionalized DHPs, which are of importance to better understand crystallization and binding tendency. The NMR relaxation experiments reveal that nitro groups significantly hinder the reorientation of methyl rotors and provide the first evidence of low-temperature methyl-group tunneling in DHPs, an intriguing quantum-effect which is to be further explored.

Structure and Internal Dynamics of Acid K Salt of (E)-2-hydroxyimino-2-cyanoacetic Acid Ethyl Ester

Abstract An investigation of the internal dynamic of molecular groups existing in a molecule of acid K salt of (E)-2-hydroxyimino-2-cyanoacetic acid ethyl ester is the subject of the work. Using the NMR method we could find such types of motions which could well describe the experimental temperature dependences of spin lattice relaxation time, and the second moment of experimental 1H NMR line. Those techniques of the 1H NMR method allow one to draw conclusions on activation parameters of following motions: reorientation of methyl group, reorientation of ethyl group, H jump in the hydrogen bond bridge, anisotropic (axial) reorientation of the whole molecule around O⋯H–O chemical bonds.

Influence of the linkage type between the polymer backbone and side groups on the surface segregation of methyl groups during film formation.

Although poly(vinyl acetate) (PVAc) differs from poly(methyl acrylate) (PMA) only in the reversed position of the ester group, a large difference in the concentration dependence of the casting solution on the corresponding surface structure of the cast films of PVAc, PMA and poly(methyl methacrylate) (PMMA) was observed. The hydrophobicity of both PMA and PMMA films increased with increasing concentration of the corresponding polymer solution, whereas cast PVAc films showed the reverse trend. The surface structure of the cast films prepared with different concentrations of the casting solution, characterized by sum frequency generation (SFG) vibrational spectra, showed that the order of the methylene groups increased while that of the acetyl methyl group decreased on the surface of cast PVAc film with increasing concentration of casting solution. However, the order of the ester methyl group increased and that of methylene groups did not change for cast PMA films with increasing concentration of casting solution. The cast PMMA film showed a reverse trend compared with the corresponding PMA film. It is apparent that well-ordered ester or acetyl methyl groups on the surface, which are oriented away from the polymer film, rather than methylene groups, play an important role in determining surface hydrophobicity, as the latter shield the OC[double bond, length as m-dash]O groups of PVAc, PMA and PMMA film surfaces from being exposed, resulting in low surface free energy. The reason for this difference is attributed to the relatively low energy for ester methyl group reorientation, an ester group structure nearer to the trans state and more regular local configuration of segments in concentrated solutions of PMA and PMMA compared to that of PVAc.

Phase transition and cationic motion in the perovskite formate framework [(CH3)2NH2][Mg(HCOO)3

The dielectric phase transition of a metal–organic perovskite with a dimethylammonium cation, [(CH3)2NH2][Mg(HCOO)3], at Tc=270K was investigated using 1H nuclear magnetic resonance spectroscopy. The temperature dependence of the spin–lattice relaxation time T1, was measured to elucidate the methyl group reorientation and cation reorientation. The results was very similar to that of the zinc analog, [(CH3)2NH2][Zn(HCOO)3], previously reported. The cationic motion was expected to be the 120° reorientation of the dimethylammonium ion around the axis through the two carbon atoms of the cation. The activation energy for cationic motion was determined to be 22.7kJmol−1. The two methyl groups of the cation in the low-temperature phase become nonequivalent and have activation energies of 9.1 and 7.0kJmol−1 for reorientation about the methyl group C3-axis. The T1 measurements indicated that the Tc=270K phase transition is of first-order and another first-order phase transition was revealed at around 80K. The transition entropy was estimated to be ΔS=10±1JK−1mol−1 for the Tc=270K phase transition in agreement with the simple three fold order–disorder model of dimethylammonium ion.

Polymorphism of Paracetamol: A New Understanding of Molecular Flexibility through Local Methyl Dynamics

This study focuses on the interplay of molecular flexibility and hydrogen bonding manifested in the monoclinic (form I) and orthorhombic (form II) polymorphs of paracetamol. By means of incoherent inelastic neutron scattering and density functional theory calculations, the relaxation processes related to the methyl side-group reorientation were analyzed in detail. Our computational study demonstrates the importance of considering quantum effects to explain how methyl reorientations and subtle conformational changes of the molecule are intertwined. Indeed, by analyzing the quasi elastic signal of the neutron data, we were able to show a unique and complex motional flexibility in form II, reflected by a coupling between the methyl and the phenyl reorientation. This is associated with a higher energy barrier of the methyl rotation and a lower Gibbs free energy when compared to form I. We put forward the idea that correlating solubility and molecular flexibility, through the relation between pKa and methyl rotation activation energy, might bring new insights to understanding and predicting drug bioavailability.

EPR and ESE of CuS4 complex in Cu(dmit)2: g-Factor and hyperfine splitting correlation in tetrahedral Cu–sulfur complexes

Pseudotetrahedral CuS4 complexes of Cu(dmit)2 compound in DMF solution were studied by EPR, UV–Vis and electron spin echo methods. After rapid freezing at 77K a good glassy state is formed and the CuS4 complex has a D2d symmetry of a compressed tetrahedron with xy ground state and spin-Hamiltonian parameters g||=2.089, g⊥=2.026, A||=146×10−4cm−1 and A⊥=30×10−4cm−1. The complex is not deformed in the glassy state and is very rigid as indicated by the echo detected spectrum and by electron spin relaxation which is governed by reorientations of methyl groups of surrounding DMF molecules as shown by electron spin echo envelope modulation (ESEEM) spectrum. The g|| and A|| of Cu(dmit)2 and other CuS4 complexes collected in Peisach–Blumberg correlation diagram were analyzed using extended Molecular Orbital theory. We explain why the correlation line for copper–sulfur complexes has larger slope compared to the CuO4 and CuN4 tetrahedra. Along the correlation line the delocalization of unpaired electron density onto ligand is constant and varies from β=0.78–0.83 for g|| in the range 2.06–2.10 of correlation diagram. The slope of the line is determined by the product of MO-coefficients αc1, where α is a parameter characterizing delocalization of unpaired electron in x2–y2 and c1<1 is a mixing parameter decreasing when 4p contribution grows. We found, unexpectedly, that αc1≈0.7 for all CuS4 complexes suggesting a correlation between degree of tetrahedral deformation and MO-parameters. MO-coefficients for Cu(dmit)2 are α=0.753, β=0.752 and c1=0.930 confirming a strong delocalization of unpaired electron in xy and x2–y2 orbitals.

Phase Transition and Cationic Motion in a Metal–Organic Perovskite, Dimethylammonium Zinc Formate [(CH3)2NH2][Zn(HCOO)3

The antiferroelectric phase transition of a metal–organic perovskite with a dimethylammonium cation, [(CH3)2NH2][Zn(HCOO)3], at Tc = 156 K was investigated using 1H nuclear magnetic resonance spectroscopy. The temperature dependence of the spin–lattice relaxation time, T1, was measured to elucidate the methyl group reorientation and cation reorientation. The proton–proton distance of NH2 protons was estimated to be 1.71 ± 0.03 A from line-shape measurements of the deuterated compound, [(CD3)2NH2][Zn(DCOO)3], and the cationic motion was shown to be the 120° reorientation of the dimethylammonium ion around the axis through the two carbon atoms of the cation. The activation energy for cationic motion was determined to be 23 kJ mol–1. The two methyl groups of the cation in the low-temperature antiferroelectric phase become nonequivalent and have activation energies of 8 and 10 kJ mol–1 for reorientation about the methyl group C3 axis. The phase transition was revealed to be first-order from line-shape measure...

Comprehensive Solid-State NMR Analysis Reveals the Effects of N-Methylation on the Molecular Dynamics of Glycine

Molecular dynamics of metabolites are important for their interactions and functions. To understand the structural dependence of molecular dynamics for N-methylated glycines, we comprehensively measured the (13)C and (1)H spin-lattice relaxation times for sarcosine, N,N-dimethylglycine, betaine, and betaine hydrochloride over a temperature range of 178-460 K. We found that the reorientations of methyl groups were observed for all these molecules, whereas reorientations of whole trimethylamine groups were detected in betaines. While similar rotational properties were observed for methyl groups in N,N-dimethylglycine and those in betaine, three methyl groups in betaine hydrochloride had different motional properties (E(a) ≈ 20.5 kJ/mol, τ(0) ≈ 1.85 × 10(-13) s; E(a) ≈ 13.9 kJ/mol, τ(0) ≈ 2.1 × 10(-12) s; E(a) ≈ 15.8 kJ/mol, τ(0) ≈ 1.1 × 10(-12) s). N,N-Dimethylglycine showed a phase transition at 348.5 K with changed relaxation behavior for methyl groups showing distinct E(a) and τ(0) values. The DIPSHIFT experiments showed that CH(3) and CH(2) moieties in these molecules had dipolar-dephasing curves similar to these moieties in alanine and glycine. The activation energies for CH(3) rotations positively correlated with the number of substituted methyl groups. These findings provided useful information for the structural dependence of molecular dynamics for N-methylated glycines and demonstrated solid-state NMR as a useful tool for probing the structure-dynamics relationships.

1H NMR Study of Molecular Motion of Benzene and n-Decane Confined in the Nanocavities of Metal–Organic Frameworks

The molecular motion of benzene and n-decane confined in the nanocavities of [Zn4O(O2CC6H4CO2)3]n (IRMOF-1) was investigated in terms of the temperature dependence of the proton spin–lattice relaxation time (1H T1). Both substances exhibited two components of T1, below 216 K for benzene and 181 K for n-decane, indicating that the guest molecules are localized separately in large and small cavities. For n-decane below 181 K, methyl reorientation is excited although the rate of reorientation in large and small cavities differed, whereas the overall motion was frozen. A thermal anomaly accompanies the translational diffusion of n-decane and is associated with melting of the confined n-decane. For benzene, translational diffusion was also excited at the thermal anomaly at 216 K, indicating melting of benzene molecular assemblies in IRMOF-1. Below 216 K, the molecular motions in the large and small cavities differed. In the large cavities, benzene undergoes isotropic reorientation, which is unaffected by the t...

Understanding the Molecular Dynamics Associated with Polymorphic Transitions of dl-Norvaline with Solid-State NMR Methods

DL-Norvaline (NVA) is an important pharmaceutical intermediate and undergoes two polymorphic transitions between 140 and 300 K. To understand molecular dynamics of NVA accompanied with these transitions, we conducted a comprehensive study on its molecular motions at multiple time scales (10(-9)-1 s) with various solid-state NMR methods. (13)C CPMAS NMR spectra revealed four sets of clearly resolved signals for NVA carbons corresponding to at least three crystal modifications with two polymorphic transitions. Proton and (13)C relaxation results showed that, apart from the reorientations of methyl and amino groups, NVA had another relaxation process following the second transition with the activation energy of 16-21 kJ/mol corresponding to the side-chain motions. This was further confirmed with the data from dipolar and chemical shift experiments. No motions were detected at CODEX time scale (ms-s). These results provide essential information for understanding the mechanistic aspects of the polymorphic transitions in aliphatic α-amino acids with linear side-chains.