Differentiation and identification of enantiomers by nuclear magnetic resonance spectroscopy with support of quantum mechanical computations.

We report nuclear magnetic resonance studies of two chiral building blocks of solifenacin, phenyltetrahydroisoquinoline and quinuclidinol, in which chiral solvating agents, Mosher's acid, and Pirkle's alcohol were used for spectral discrimination between enantiomers of solifenacin constituents. Based on the constraints following from measurements of the nuclear Overhauser effect, structures of phenyltetrahydroisoquinoline and Pirkle's alcohol solvates were found. Next, shifts of nuclear magnetic resonance signals of phenyltetrahydroisoquinoline due to the application of Pirkle's alcohol were computed using density functional theory methods. The computed carbon-13 shifts reproduce those determined experimentally, allowing us to attribute the absolute configuration to phenyltetrahydroisoquinoline enantiomers without the need for the use of empirical rules.

Adjusting the Structure of ß-Cyclodextrin to Improve Complexation of Anthraquinone-Derived Drugs.

ß-Cyclodextrin (CD) derivatives containing an aromatic triazole ring were studied as potential carriers of the following drugs containing an anthraquinone moiety: anthraquinone-2-sulfonic acid (AQ2S); anthraquinone-2-carboxylic acid (AQ2CA); and a common anthracycline, daunorubicin (DNR). UV-Vis and voltammetry measurements were carried out to determine the solubilities and association constants of the complexes formed, and the results revealed the unique properties of the chosen CDs as effective pH-dependent drug complexing agents. The association constants of the drug complexes with the CDs containing a triazole and lipoic acid (ßCDLip) or galactosamine (ßCDGAL), were significantly larger than that of the native ßCD. The AQ2CA and AQ2S drugs were poorly soluble, and their solubilities increased as a result of complex formation with ßCDLip and ßCDGAL ligands. AQ2CA and AQ2S are negatively charged at pH 7.4. Therefore, they were less prone to form an inclusion complex with the hydrophobic CD cavity than at pH 3 (characteristic of gastric juices) when protonated. The ßCDTriazole and ßCDGAL ligands were found to form weaker inclusion complexes with the positively charged drug DNR at an acidic pH (pH 5.5) than in a neutral medium (pH 7.4) in which the drug dissociates to its neutral, uncharged form. This pH dependence is favorable for antitumor applications.

Gas-phase 21 Ne NMR studies and the nuclear magnetic dipole moment of neon-21.

Gas-phase 21 Ne nuclear magnetic resonance spectra were measured at the natural abundance of 21 Ne isotope for samples consisting of pressurized neon up to 60 bar at room temperature and applying the magnetic field of the strength B0 = 11.7574 T. It showed that the nuclear magnetic resonance frequency is linearly dependent on the density of gaseous neon. The resonance frequency was extrapolated to the zero-density point, and it permitted the determination of the 21 Ne nuclear magnetic moment, µ(21 Ne) = 0.6617774(10) µN . The present value of µ(21 Ne) is not influenced by the bulk magnetic susceptibility of neon and interactions between neon atoms; therefore, it is more precise and reliable than the previous result obtained for µ(21 Ne).

NMR shielding in helium-3 atoms modified by gaseous nitrogen and oxygen.

Helium-3 nuclear magnetic resonance (3 He NMR) measurements were carried out for the gaseous mixtures of helium-3 with pure nitrogen and synthetic air as the solvents. It was found that 3 He shielding is linearly dependent on solvent density up to approx. 6 mol/L. At higher density of the gaseous solvent, the change of 3 He shielding is nonlinear and especially distinct when helium-3 atoms can interact with two O2 molecules. The interaction with paramagnetic oxygen molecules can induce two kinds of 3 He shielding changes: (1) due to the isotropic Fermi contact interaction and (2) from the dipolar magnetic interaction between unpaired O2 electrons and 3 He nuclear magnetic dipole moment. The two paramagnetic effects in helium-3 shielding cannot be experimentally separated, although for such small molecular objects, they could be presumably modeled by advanced theoretical calculations.

Isotope Effects on Nuclear Magnetic Shielding in Molecular Hydrogen.

The secondary isotope shifts of six molecular hydrogen isotopologues (H2, D2, T2, HD, HT, and DT) were measured using gas-phase nuclear magnetic resonance spectroscopy. It was found that these isotope shifts are in satisfying agreement with performed ab initio quantum chemistry computations. However, there is a small systematic discrepancy between results of experiments and computations, i.e., the magnitudes of computed shifts are approximately 10% larger than those obtained from the experiments. This indicates that computations performed using the Born-Oppenheimer approximation are not sufficient for reproducing quantitatively the experimentally determined secondary isotope shifts of molecular hydrogen.

The Bloch equation with terms induced by an electric field.

The Bloch equation of the nuclear magnetization of spin-1/2 nuclei in molecules, which have permanent electric dipole moments µe that are placed simultaneously in a magnetic field B and an electric field E, is derived. It is shown that if the principal components of the nuclear magnetic shielding tensor σ and the dipole moment µe are known, then the measurement of the transverse component to the magnetic field B of the nuclear magnetization, which is induced by the application of the electric field oscillating at the half of the spin precession frequency, allows determining the orientation of the dipole moment µe with respect to the principal axis system of the symmetric part of the tensor σ. Four-component relativistic density functional theory computations, which have been performed for several molecules containing heavy nuclei, i.e., 207Pb, 205Tl, 199Hg, 195Pt, and 125Te, indicate that coefficients of the relaxation matrix perturbed by the electric field E are in favorable cases of the order of 1000 pm2 V-2 T-2. Therefore, the spin dynamics is perturbed at experimentally observable levels for the strengths of electric and magnetic fields E = 5 kV/mm and B = 10 T, respectively.

Indirect Spin-Spin Coupling Constants in the Hydrogen Isotopologues.

The results of experimental and theoretical studies of indirect spin-spin coupling constants for hydrogen deuteride (HD), hydrogen tritide (HT), and deuterium tritide (DT) are described. The reduced coupling constants obtained from the gas-phase NMR (nuclear magnetic resonance) experiment conducted at 300 K are 2.338(1), 2.334(3), and 2.316(1) × 10(20) T(2) J(-1), while the ab initio values computed at the full configuration interaction level of theory equal 2.349(3), 2.343(3), and 2.322(3) × 10(20) T(2) J(-1) for HD, HT, and DT, respectively. The agreement of the experimental and theoretical results is improved when proper treatment of the influence of nuclear relaxation on the NMR spectrum is applied. However, there is a minor discrepancy between experiment and theory, exceeding the estimated error bars; potential sources of this discrepancy are discussed.

Chirality-sensitive effects induced by nuclear relaxation in an electric field.

Two effects induced by the interaction between an electric field E and a permanent electric dipole moment 𝝁𝒆 of a chiral molecule placed in a magnetic field B are discussed as follows: (i) a spin-1/2 nucleus relaxes faster and the increase in the relaxation rate is the same for both enantiomers and (ii) in a two-spin system a cross correlation between the dipole-dipole relaxation mechanism and the interaction between nuclear magnetic shielding and the dipole moment 𝝁𝒆 enables the direct discrimination between the enantiomers. The former effect is too small in magnitude to be observed experimentally. For detection of the latter, an experimental procedure based on the application of an electric field oscillating at a frequency equal to the difference between the spin-precession frequencies of two heteronuclear spins is proposed.

A loop-gap resonator for chirality-sensitive nuclear magneto-electric resonance (NMER).

Direct detection of molecular chirality is practically impossible by methods of standard nuclear magnetic resonance (NMR) that is based on interactions involving magnetic-dipole and magnetic-field operators. However, theoretical studies provide a possible direct probe of chirality by exploiting an enantiomer selective additional coupling involving magnetic-dipole, magnetic-field, and electric field operators. This offers a way for direct experimental detection of chirality by nuclear magneto-electric resonance (NMER). This method uses both resonant magnetic and electric radiofrequency (RF) fields. The weakness of the chiral interaction though requires a large electric RF field and a small transverse RF magnetic field over the sample volume, which is a non-trivial constraint. In this study, we present a detailed study of the NMER concept and a possible experimental realization based on a loop-gap resonator. For this original device, the basic principle and numerical studies as well as fabrication and measurements of the frequency dependence of the scattering parameter are reported. By simulating the NMER spin dynamics for our device and taking the (19)F NMER signal of enantiomer-pure 1,1,1-trifluoropropan-2-ol, we predict a chirality induced NMER signal that accounts for 1%-5% of the standard achiral NMR signal.

A theoretical study of potentially observable chirality-sensitive NMR effects in molecules.

Two recently predicted nuclear magnetic resonance effects, the chirality-induced rotating electric polarization and the oscillating magnetization, are examined for several experimentally available chiral molecules. We discuss in detail the requirements for experimental detection of chirality-sensitive NMR effects of the studied molecules. These requirements are related to two parameters: the shielding polarizability and the antisymmetric part of the nuclear magnetic shielding tensor. The dominant second contribution has been computed for small molecules at the coupled cluster and density functional theory levels. It was found that DFT calculations using the KT2 functional and the aug-cc-pCVTZ basis set adequately reproduce the CCSD(T) values obtained with the same basis set. The largest values of parameters, thus most promising from the experimental point of view, were obtained for the fluorine nuclei in 1,3-difluorocyclopropene and 1,3-diphenyl-2-fluoro-3-trifluoromethylcyclopropene.

The NMR spin-spin coupling constant ¹J(³¹P,¹H) in an isolated PH3 molecule.

We present new experimental and calculated values of the indirect spin-spin coupling constant (1)J((31)P,(1)H) in the PH3 molecule. The line shape analysis of (1)H and (31)P gas-phase NMR spectra recorded at several densities of PH3, followed by extrapolation of the results to the zero-density limit, gives 176.18(2) Hz as the experimental value at 300 K. The coupled-cluster singles-and-doubles (CCSD) model used in the quantum chemical ab initio calculation gives 187.86 Hz as the nonrelativistic equilibrium geometry value; adding the relativistic and temperature corrections we obtain (1)J((31)P,(1)H) = 177.14 Hz at 300 K. The comparison of this ab initio result with the experimental value shows that proper analysis of nuclear relaxation in the gas phase is essential and leads to very good agreement between theory and experiment.

¹H NMR diffusion studies of water self-diffusion in supercooled aqueous sodium chloride solutions.

The physical properties of aqueous sodium chloride solutions have been studied theoretically, but so far no experimental diffusion data have been obtained under supercooled conditions. Here the results of (1)H NMR translational diffusion measurements of water in sodium chloride solutions in the temperature range 230 to 300 K and sodium chloride concentrations up to 4.2 mol/kg are presented. It was found that the diffusion data were well-described by the Vogel-Tamman-Fulcher relationship with concentration-dependent parameters D0, B, and T0. The results indicate that under supercooled conditions the influence of sodium chloride on water diffusion is much smaller than predicted by molecular dynamics simulations.

Experimental characterization of the hydride 1H shielding tensors for HIrX2(PR3)2 and HRhCl2(PR3)2: extremely shielded hydride protons with unusually large magnetic shielding anisotropies.

The hydride proton magnetic shielding tensors for a series of iridium(III) and rhodium(III) complexes are determined. Although it has long been known that hydridic protons for transition-metal hydrides are often extremely shielded, this is the first experimental determination of the shielding tensors for such complexes. Isolating the (1)H NMR signal for a hydride proton requires careful experimental strategies because the spectra are generally dominated by ligand (1)H signals. We show that this can be accomplished for complexes containing as many as 66 ligand protons by substituting the latter with deuterium and by using hyperbolic secant pulses to selectively irradiate the hydride proton signal. We also demonstrate that the quality of the results is improved by performing experiments at the highest practical magnetic field (21.14 T for the work presented here). The hydride protons for iridium hydride complexes HIrX2(PR3)2 (X = Cl, Br, or I; R = isopropyl, cyclohexyl) are highly shielded with isotropic chemical shifts of approximately -50 ppm and are also highly anisotropic, with spans (=δ11 - δ33) ranging from 85.1 to 110.7 ppm. The hydridic protons for related rhodium complexes HRhCl2(PR3)2 also have unusual magnetic shielding properties with chemical shifts and spans of approximately -32 and 85 ppm, respectively. Relativistic density functional theory computations were performed to determine the orientation of the principal components of the hydride proton shielding tensors and to provide insights into the origin of these highly anisotropic shielding tensors. The results of our computations agree well with experiment, and our conclusions concerning the importance of relativistic effects support those recently reported by Kaupp and co-workers.

Spin-rotation and NMR shielding constants in HCl.

The spin-rotation and nuclear magnetic shielding constants are analysed for both nuclei in the HCl molecule. Nonrelativistic ab initio calculations at the CCSD(T) level of approximation show that it is essential to include relativistic effects to obtain spin-rotation constants consistent with accurate experimental data. Our best estimates for the spin-rotation constants of (1)H(35)Cl are CCl = -53.914 kHz and C(H) = 42.672 kHz (for the lowest rovibrational level). For the chlorine shielding constant, the ab initio value computed including the relativistic corrections, σ(Cl) = 976.202 ppm, provides a new absolute shielding scale; for hydrogen we find σ(H) = 31.403 ppm (both at 300 K). Combining the theoretical results with our new gas-phase NMR experimental data allows us to improve the accuracy of the magnetic dipole moments of both chlorine isotopes. For the hydrogen shielding constant, including relativistic effects yields better agreement between experimental and computed values.

Lithium Transport Studies on Chloride-Doped Argyrodites as Electrolytes for Solid-State Batteries.

In this study, the activation energy and ionic conductivity of the Li6PS5Cl material for all-solid-state batteries were investigated using solid-state nuclear magnetic resonance (NMR) spectroscopy and electrochemical impedance spectroscopy (EIS). The results show that the activation energy values estimated from nuclear relaxation rates are significantly lower than those obtained from impedance measurements. The total ionic conductivities for long-range lithium diffusion in Li6PS5Cl calculated from EIS studies depend on the crystal size and unit cell parameter. The study also presents a new sample preparation method for measuring activation energy using temperature-dependent EIS and compares the results with the solid-state NMR data. The activation energy for a thin-film sample is equivalent to the long-range lithium dynamics estimated from NMR measurements, indicating the presence of additional limiting processes in thick pellets. Additionally, a theoretical model of Li-ion hopping based on results obtained using density-functional theory methods in comparison with experimental findings was discussed. Overall, the study emphasizes the importance of sample preparation methods in determining accurate activation energy and ionic conductivity values for solid-state lithium batteries and the significance of solid-state electrolyte thickness in new solid-state battery design for faster Li-ion diffusion.

Nuclear magnetic shielding for hydrogen in selected isolated molecules.

We present the results of gas-phase NMR measurements designed to yield a new experimental value for the absolute (1)H magnetic shielding for an isolated hydrogen molecule and its deuterium isotopomers. The results are based on the original method of direct shielding measurements (Jackowski et al., 2010) and the density dependence of (1)H, (2)H, and (3)He NMR frequencies for molecular hydrogen and atomic helium-3. The absolute isotropic magnetic shielding measured for molecular hydrogen, σ(0)(H(2)), is 26.293(5) ppm at 300 K, within experimental error of previous measurements based on spin-rotation data and quantum chemistry computations, 26.289(2) ppm (Sundholm and Gauss, 1997), and recent ab initio calculations. We also report isotope effects in shielding for H(2), HD, and D(2) molecules that are consistent with theoretical predictions. In addition, gas-phase (1)H chemical shifts extrapolated to zero density have been measured for numerous small molecules. Our results yield precise absolute shielding data that will be useful in establishing benchmark computational chemistry methods for calculating rovibrational averaged magnetic shielding.

Ground and excited state double hydrogen transfer in symmetric and asymmetric potentials: comparison of 2,7,12,17-tetra-n-propylporphycene with 9-acetoxy-2,7,12,17-tetra-n-propylporphycene.

Analysis of time-resolved anisotropy of transient absorption enabled determination of room temperature ground and excited state rate constants for intramolecular double hydrogen transfer in two similar porphycenes, one of them with symmetric and the other, with asymmetric character of a double minimum potential for hydrogen motion. The perturbation preserves a quasi-symmetric minimum in S(0), but the rate decreases approximately two times. In S(1), the perturbed potential becomes strongly asymmetric, and the downhill hydrogen transfer occurs with a rate higher than that observed for a symmetrical compound.

Weak intermolecular interactions in gas-phase nuclear magnetic resonance.

Gas-phase nuclear magnetic resonance (NMR) spectra demonstrating the effect of weak intermolecular forces on the NMR shielding constants of the interacting species are reported. We analyse the interaction of the molecular hydrogen isotopomers with He, Ne, and Ar, and the interaction in the He-CO(2) dimer. The same effects are studied for all these systems in the ab initio calculations. The comparison of the experimental and computed shielding constants is shown to depend strongly on the treatment of the bulk susceptibility effects, which determine in practice the pressure dependence of the experimental values. Best agreement of the results is obtained when the bulk susceptibility correction in rare gas solvents is evaluated from the analysis of the He-rare gas interactions, and when the shielding of deuterium in D(2)-rare gas systems is considered.

Direct enantiomeric discrimination through antisymmetric hyperfine coupling.

Chiral open-shell molecules possessing permanent electric dipole moments have an EPR signal at the difference frequency of the electron and nuclear resonances, allowing direct enantiomeric discrimination by signal phase. The effect depends on the vector antisymmetry of the hyperfine coupling. Quantum chemistry suggests chiral bisfluorene methyl radical derivatives as promising for experiments.