Jiří Kessler

Resolution of Organic Polymorphic Crystals by Raman Spectroscopy

Depending on crystallization conditions, many organic compounds can form crystals of different structure. Their proper characterization is important, for example, in the pharmaceutical industry. While the X-ray diffractometry established as a standard method, alternative techniques are desirable for broader application flexibility and economic reasons. In the present study, Raman spectroscopy combined with the density functional calculations is suggested as a complementary method to the X-ray and other higher resolution techniques. The potential to discriminate structural differences in polymorphic crystalline forms is documented on three model compounds of industrial importance. Methacrylamide, piracetam, and 2-thiobarbituric acid were crystallized under various conditions, and their Raman spectra were recorded using 532 and 1064 nm laser excitations. X-ray diffractometry and nuclear magnetic resonance spectroscopy were used as complementary techniques to verify sample composition and structure. To interpret the observed differences in Raman frequencies and intensities, three computational strategies were explored based on single molecule, a cluster model, and a plane-wave periodic boundary conditions calculation. The single-molecule modeling was found inadequate, whereas the plane-wave approach provides the most realistic spectra. For all compounds, the differences in the Raman spectra of polymorphic forms could be unambiguously assigned to the simulations. The modeling revealed that the spectral differences were caused by the molecular structure itself as well as by crystal packing. The relative importance of these factors significantly varied across the investigated samples. Owing to its simplicity, Raman spectroscopy appears to be a promising technique capable of reliable discriminating between organic crystal polymorphic states.

Parallel variable selection of molecular dynamics clusters as a tool for calculation of spectroscopic properties

Clusters of a solute and a few solvent molecules obtained from molecular dynamics (MD) are a powerful tool to study solvation effects by advanced quantum chemical (QC) methods. For spectroscopic properties strongly dependent on the solvation, however, a large number of clusters are needed for a good convergence. In this work, a parallel variable selection (PVS) method is proposed that in some cases efficiently reduces the number of clusters needed for the averaging. The mass, charge, or atomic density MD distributions are used as a secondary variable to preselect the most probable cluster geometries used for averaging of solute spectral properties. When applied to nuclear magnetic resonance chemical shift of a model alcohol, the method allowed one to significantly reduce the total computational time, by a factor of 10. Even larger savings were achieved for the modeling of Raman and Raman optical activity spectra of (S)‐lactamide molecule dissolved in water. The results thus suggest that the PVS method can be generally used for simulations of spectroscopic properties of solvated molecules and makes multiscale MD/QC computations more affordable.

Detection of Sugars via Chirality Induced in Europium(III) Compounds

Detection and resolution of simple monosaccharides are difficult tasks because their structure is quite similar. The present study shows that circularly polarized luminescence (CPL) induced in europium complexes provides very specific spectral patterns for fructose, mannose, glucose, and galactose. Differences were also observed between bare Eu(3+) ion and its complexes, when interacting with these sugars. The CPL spectra were measured on a Raman optical activity (ROA) spectrometer, which ensured high fluorescence intensity owing to the strong 532 nm laser excitation. The induced fluorescence was recorded in the same spectrum as the vibrational Raman bands. On the basis of the ligand field theory, most fluorescence spectral peaks could be assigned to f-shell europium transitions. Additional information on the interaction of the lanthanide with the sugar component was provided by measurement of time-dependent fluorescence, as formation of different complexes led to variations in fluorescence decay times. In nuclear magnetic resonance (NMR), the paramagnetic metal ion interacting with the sugars caused specific changes in (13)C chemical shifts. The spectroscopic data and molecular dynamics modeling showed that the interaction between the monosaccharides and Eu ion is rather weak due to the competition of the OH sugar groups with water molecules. However, multiple binding modes are possible, which contributes to the complexity and specificity of the spectra. The induced chirality and fluorescence spectra thus appear to be convenient means for monosaccharide detection and identification.

Arrangement of Fibril Side Chains Studied by Molecular Dynamics and Simulated Infrared and Vibrational Circular Dichroism Spectra

Highly ordered assemblies of β-sheet-forming peptide and protein fibrils have been the focus of much attention because of their multiple and partially unknown biological functions, in particular as related to degenerative neuronal disorders. Recently, vibrational circular dichroism (VCD) spectra have been shown to provide a unique means of detection for such extended structures utilizing modes of the peptide main chain backbone. In the case of poly-glutamic acid, surprising VCD responses were also found for side chain modes. In this study, in an attempt to explain this latter observation and obtain a link between fibrillar structure and its optical spectral properties, molecular dynamics (MD) methods are used to model the geometry and dynamics of assemblies containing repeating β-strands of Glu(n). A crystal-like model was adopted for the MD structure simulations. Infrared and VCD spectra for segments of MD modeled fibrillar geometries were first calculated using density functional theory (DFT), and then, those parameters were applied to larger structures by means of Cartesian coordinate transfer (CCT) of atomic tensors from the segments. The computations suggest the side chains exhibit residual conformational constraints, resulting in local coupling giving rise to non-negligible VCD intensity, albeit with an overall broad distribution. Calculated spectral distributions are qualitatively consistent with the experimental results but do differ in magnitude. The possibility of realistic modeling of vibrational spectra significantly broadens the potential for application of optical spectroscopies in structural studies of these aggregated biopolymers.

A new synthetic strategy to prepare throne and calix diastereoisomers of parallel tris-Tröger's bases

The calix diastereoisomers of the parallel tris-Trögers base (tris-TB) derivatives were suggested as potential cavitands in 2002, and the first members of this cavitand family were introduced in 2007. The synthetic strategy enabling the preparation of naphthalene and anthracene derivatives of parallel tris-TBs, i.e. preparation without any reduction step, is introduced. Naphthalene calix-tris-TB derivative having a cavity volume of about 0.113 nm3 (65% of α-CD cavity) is prepared by isomerisation in various acid conditions.

Determination of Absolute Configuration in Chiral Solvents with Nuclear Magnetic Resonance. A Combined Molecular Dynamics/ Quantum Chemical Study

Nuclear magnetic resonance (NMR) spectroscopy is omnipresent in chemical analysis. However, chirality of a molecule can only be detected indirectly by NMR, e.g., by monitoring its interaction with another chiral object. In the present study, we investigate the spectroscopic behavior of chiral molecules placed into a chiral solvent. In this case, the solvent-solute interaction is much weaker, but the application range of such NMR analysis is wider than for a specific chemical shift agent. Two alcohols and an amine were used as model systems, and differences in NMR chemical shifts dependent on the solute-solvent chirality combination were experimentally detected. Combined quantum mechanic/molecular mechanic (QM/MM) computations were applied to reveal the underlying solute-solvent interactions. NMR shielding was calculated using the density functional theory (DFT). While the experimental observations could not be reproduced quantitatively, the modeling provided a qualitative agreement and detailed insight into the essence of solvent-solute chiral interactions. The potentials of mean force (PMF) obtained using molecular dynamics (MD) and the weighted histogram analysis method (WHAM) indicate that the chiral interaction brings about differences in conformer ratios, which are to a large extent responsible for the NMR shifts. The MD results also predicted slight changes in the solvent structure, including the radial distribution function (RDF), to depend on the solvent/solute chirality combination. Apart from the conformer distribution, an effective average solvent electrostatic field was tested as another major factor contributing to the chiral NMR effect. The possibility to simulate spectral effects of chiral solvents from the first-principles opens up the way to NMR spectroscopic determination of the absolute configuration for a larger scale of compounds, including those not forming specific complexes.

Transfer of Frequency-Dependent Polarizabilities: A Tool To Simulate Absorption and Circular Dichroism Molecular Spectra

Absorption and circular dichroism spectra reveal important information about molecular geometry and electronic structure. For large molecules, however, spectral shapes cannot be computed directly. In the past, transition dipole coupling (TDC) and related theories were proposed as simplified ways of calculating the spectral responses of large systems. In the present study, an alternative approach better reflecting the chemical structure is explored. It is based on the transfer of complex frequency-dependent polarizabilities (TFDP) of molecular fragments. The electric dipole-electric dipole, electric dipole-electric quadrupole, and electric dipole-magnetic dipole polarizabilities are obtained separately for individual chromophores and then transferred to a larger system composed of them. Time-dependent density functional theory and the sum over states methodology were employed to obtain the polarizability tensors of N-methylacetamide, and porphyrin molecules were chosen for a numerical test. The TFDP fails for charge-transfer states and close chromophores; otherwise, the results suggest that this method is capable of reproducing the spectra of large systems of biochemical relevance. At the same time, it is sufficiently flexible to account for a wide range of transition energies and environmental factors instrumental in the modeling of chromophore properties. The TFDP approach also removes the need for diagonalization in TDC, making computations of larger molecular systems more time-efficient.

Molecular Dynamics with Helical Periodic Boundary Conditions

Helical symmetry is often encountered in nature and thus also in molecular dynamics (MD) simulations. In many cases, an approximation based on infinite helical periodicity can save a significant amount of computer time. However, standard simulations with the usual periodic boundary conditions (PBC) are not easily compatible with it. In the present study, we propose and investigate an algorithm comprising infinitely propagated helicity, which is compatible with commonly used MD software. The helical twist is introduced as a parametric geometry constraint, and the translational PBC are modified to allow for the helical symmetry via a transitional solvent volume. The algorithm including a parallel code was implemented within the Tinker software. The viability of the helical periodic boundary conditions (HPBC) was verified in test simulations including α‐helical and polyproline II like peptide structures. For an insulin‐based model, the HPBC dynamics made it possible to simulate a fibrillar structure, otherwise not stable within PBC.

Recognition of Oligosaccharides by Chirality Induced in Europium (III) Compounds

Identification of saccharides is difficult due to their similar chemical structure. However, they interact very selectively with lanthanide probes. To explore the potential for saccharide recognition, we compare circularly polarized luminescence induced by a variety of oligo- and polysaccharides in three europium compounds. Measurement on a standard Raman optical activity spectrometer made it possible to use high excitation powers and provided very distinct spectral patterns, which were sensitive both to the local structure and differences in molecular size. For example, α-, β- and γ-cyclodextrins provided unique spectroscopic responses. Titration data and molecular dynamics simulation confirmed that CPL spectra carry information about the binding mode and strength between the lanthanide probe and saccharide skeleton.

Circular Dichroism Is Sensitive to Monovalent Cation Binding in Monensin Complexes

Monensin is a natural antibiotic that exhibits high affinity to certain metal ions. In order to explore its potential in coordination chemistry, circular dichroism (CD) spectra of monensic acid A (MonH) and its derivatives containing monovalent cations (Li(+) , Na(+) , K(+) , Rb(+) , Ag(+) , and Et4 N(+) ) in methanolic solutions were measured and compared to computational models. Whereas the conventional CD spectroscopy allowed recording of the transitions down to 192 nm, synchrotron radiation circular dichroism (SRCD) revealed other bands in the 178-192 nm wavelength range. CD signs and intensities significantly varied in the studied compounds, in spite of their similar crystal structure. Computational modeling based on the Density Functional Theory (DFT) and continuum solvent model suggests that the solid state monensin structure is largely conserved in the solutions as well. Time-dependent Density Functional Theory (TDDFT) simulations did not allow band-to-band comparison with experimental spectra due to their limited precision, but indicated that the spectral changes were caused by a combination of minor conformational changes upon the monovalent cation binding and a direct involvement of the metal electrons in monensin electronic transitions. Both the experiment and simulations thus show that the CD spectra of monensin complexes are very sensitive to the captured ions and can be used for their discrimination. Chirality 28:420-428, 2016.