Solid-state Vibrational Circular Dichroism Research Articles

Solid-state vibrational circular dichroism for pharmaceutical applications: Polymorphs and cocrystal of sofosbuvir

X-ray diffraction is a commonly used technique in the pharmaceutical industry for the determination of the atomic and molecular structure of crystals. However, it is costly, sometimes time-consuming, and it requires a considerable degree of expertise. Vibrational circular dichroism (VCD) spectroscopy resolves these limitations, while also exhibiting substantial sensitivity to subtle modifications in the conformation and molecular packaging in the solid state. This study showcases VCD’s ability to differentiate between various crystal structures of the same molecule (polymorphs, cocrystals). We examined the most effective approach for producing high-quality spectra and unveiled the intricate link between structure and spectrum via quantum-chemical computations. We rigorously assessed, using alanine as a model compound, multiple experimental conditions on the resulting VCD spectra, with the aim of proposing an optimal and efficient procedure. The proposed approach, which yields reliable, reproducible, and artifact-free results with maximal signal-to-noise ratio, was then validated using a set comprising of three amino acids (serine, alanine, tyrosine), one hydroxy acid (tartaric acid), and a monosaccharide (ribose) to mimic active pharmaceutical components. Finally, the optimized approach was applied to distinguish three polymorphs of the antiviral drug sofosbuvir and its cocrystal with piperazine. Our results indicate that solid-state VCD is a prompt, cost-effective, and easy-to-use technique to identify crystal structures, demonstrating potential for application in pharmaceuticals. We also adapted the cluster and transfer approach to calculate the spectral properties of molecules in a periodic crystal environment. Our findings demonstrate that this approach reliably produces solid-state VCD spectra of model compounds. Although for large molecules with many atoms per unit cell, such as sofosbuvir, this approach has to be simplified and provides only a qualitative match, spectral calculations, and energy analysis helped us to decipher the observed differences in the experimental spectra of sofosbuvir.

Differentiation of solvatomorphs of active pharmaceutical ingredients (API) by solid-state vibrational circular dichroism (VCD)

Here, we present the new application of solid-state Vibrational Circular Dichroism (VCD) spectroscopy to differentiate several dutasteride (DS) solvatomorphs – the model active pharmaceutical ingredient (API). Several crystalline DS hydrochloride hydrates solvated with methanol, ethanol, acetonitrile, acetone, and acetic acid were prepared. In contrast to almost identical IR spectra, the VCD ones were very sensitive to changes in the sample composition. We marked significant differences in the shape of VCD spectra of studied DS solvatomorphs, DS hydrates, and DS polymorphic forms. Our findings, supported by DFT calculations, show that VCD spectroscopy has the pronounced ability to distinguish their crystal arrangements. We believe that this contribution will extend the use of VCD in the pharmaceutical industry for developing and designing new chiral drug products for the identification, description, and in-depth probing of several pharmaceutical solvatomorphs in the future.

Solid-state vibrational circular dichroism: Methodology and application for amphetamine derivatives

Amphetamine derivatives are considered most seized substances worldwide. In this study, solid-state vibrational circular dichroism (VCD) measurements of enantiomerically pure substances were performed for spectroscopic discrimination between (S)- and (R)-enantiomers. First, we have developed a universal experimental approach to obtain reliable and reproducible solid-state VCD spectra. First, the samples were prepared as pellets composed of mixtures of camphor as a model compound and a crystalline matrix powder. In order to obtain the best results without artifacts and with a maximum signal-to-noise ratio, the following experimental conditions were optimized: pellet thickness and diameter and sample rotation speed. The optimized parameters were then used for the analysis of amphetamine and its derivatives (methamphetamine and 3,4-methylendioxymethamphetamine). Our high-quality spectra and results suggest that solid-state VCD spectroscopy represents a cost-effective and easy-to-use method for the analysis of conformation changes and molecular packing in solid-state with potential applications in pharmaceutical and forensic practice.

Synthesis of phenylalanine and tartaric acid intercalated layered double hydroxide (LDH): Investigation of two kinds of chiral molecules interaction in interlayer space of LDH using solid-state vibrational circular dichroism

Recently, the applicability of solid-state vibrational circular dichroism (SD-VCD) for the evaluation of organoclay nanohybrids has attracted much attention. Herein, the intercalation of two kinds of chiral molecules, phenylalanine (Phe) and tartaric acid (Tart), into Zn-Al layered double hydroxide (LDH) was carried out by a standard coprecipitation method. The Phe/Tart/LDH was characterized by XRD, FT-IR, TG-DTA, and SD-VCD. The chemical composition and interlayer distance expansion of Phe/Tart/LDH indicated that Phe and Tart were intercalated into the LDH. The VCD and theoretical calculation results showed that Phe and Tart coexisted in the same interlayer space of LDH with the formation of electrostatic interaction and hydrogen bonding between Phe-Tart, LDH-Phe, and LDH-Tart. The results demonstrated the utility of the SD-VCD method for determining the detailed conformation of chiral molecules in the LDH interlayer space.

How Crystal Symmetry Dictates Non-Local Vibrational Circular Dichroism in the Solid State.

Solid-State Vibrational Circular Dichroism (VCD) can be used to determine the absolute structure of chiral crystals, but its interpretation remains a challenge in modern spectroscopy. In this work, we investigate the effect of a twofold screw axis on the solid-state VCD spectrum in a combined experimental and theoretical analysis of P21 crystals of (S)-(+)-1-indanol. Even though the space group is achiral, a single proper symmetry operation has an important impact on the VCD spectrum, which reflects the supramolecular chirality of the crystal. Distinguishing between contributions originating from molecular chirality and from chiral crystal packing, we find that while IR absorption hardly depends on the symmetry of the space group, the situation is different for VCD, where completely new non-local patterns emerge. Understanding the two underlying mechanisms, namely gauge transport and direct coupling, will help to use VCD to distinguish polymorphic forms.

Vibrational Circular Dichroism Spectroscopy toward Intercalation Compounds of Sodium Montmorillonite: Evidences for Molecular Packing of Enantiopure Monovalent Ir(III) Complexes within Interlayer Spaces

Solid state vibrational circular dichroism (SD-VCD) spectra were recorded on the intercalation compounds of sodium montmorillonite with a chiral iridium(III) complex. The complex used was Δ- (or Λ-)[Ir(bzq)2(phen)]+ (bzqH = benzo[h]quinoline; phen = 1,10-phenanthroline). The complex formed mono- or bi-molecular layers in interlayer spaces, depending on the adsorption amount to 50% or 100% cation exchange capacity (CEC), respectively. Notably, the VCD signals were sensitive enough to reveal the detailed molecular interactions in adsorption layers. Signal enhancement was achieved by the coherent delocalization of vibrational motions over tightly bound associates. Models of molecular packing were proposed with the help of theoretical simulations.

Clay Column Chromatography for Optical Resolution: A Series of Derivatized Amino Acids

Abstract Chromatographic resolution of a series of derivatized amino acids was attempted on a column packed with an ion-exchange adduct of Δ-[Ru(phen)3]2+ (phen = 1,10-phenanthroline) and synthetic hectorite. An amino acid was modified to N-3, 5-dinitrobenzoyl amino acid methyl ester (denoted by DNB-aa-me). For aa = Ala, Phe, Leu, Ile, Ser, Val, Thr, Tyr, Asp and Glu, racemic DNB-aa-me was resolved nearly to baseline separation on being eluted with methanol. For aa = Trp and His, racemic DNB-aa-me was resolved partially. No resolution was achieved for Pro and Lys. The mechanism of chiral discrimination was investigated by means of solid-state vibrational circular dichroism spectroscopy.

Preparation and characterization of a new chiral metal-organic framework with spiranes

Herein we report the first homochiral IRMOF structure with chiral carbocyclic spirolinkers, basic Zn-(R)-spiro[3.3]heptane-2,6-dicarboxylate, named WIG-5. First, (R)-spiro[3.3]heptane-2,6-dicarboxylic acid was prepared involving a HPLC separation on chiral stationary phase, then further transformed into homochiral WIG-5 by the solvothermal reaction with zinc nitrate hexahydrate in dimethyl formamide (DMF). WIG-5 crystallizes in the P212121 space group and is built of two interpenetrated networks with pcu underlying network topology. The tetranuclear secondary building units (SBUs) of WIG-5 are coordinated to two DMF molecules and six (R)-spiro[3.3]heptane-2,6-dicarboxylic acid linkers, that results in the formation of a homochiral distorted MOF-5-like structure. Extensive characterization by single crystal X-ray diffraction, powder X-ray diffraction, polarized light microscopy, infrared microspectroscopy, solid-state vibrational circular dichroism spectroscopy and thermogravimetry/mass spectroscopy has been performed on the new material. Birefringence of large WIG-5 single crystals enables potential optical applications.

Chiral Discrimination of Dansylated Alanine Methyl Ester on a Modified Clay Surface: Vibrational Circular Dichroism Approach

Abstract Baseline separation was achieved when dansylated alanine methyl ester (denoted by dan-ala-me) was eluted with methanol on an HPLC (high performance liquid chromatography) column (5 cm × 4 mm (i.d.)) packed with an ion-exchange adduct of synthetic hectorite and Δ-[Ru(phen)3]2+ (phen = 1, 10-phenanthroline). In order to unravel the separation mechanisms, the adsorption state of R- or S-dan-ala-me on a modified clay surface was investigated by means of solid-state vibrational circular dichroism spectroscopy. It was deduced that a dan-ala-me molecule changed its conformation, depending on the chirality relation to a co-adsorbed Ru(II) complex. The theoretical simulation of an association between a Ru(II) complex and a dan-ala-me molecule supported the conclusion.

Computation of Solid-State Vibrational Circular Dichroism in the Periodic Gauge.

We introduce a new theoretical formalism to compute solid-state vibrational circular dichroism (VCD) spectra from molecular dynamics simulations. Having solved the origin-dependence problem of the periodic magnetic gauge, we present IR and VCD spectra of (1S,2S)-trans-1,2-cyclohexanediol obtained from first-principles molecular dynamics calculations and nuclear velocity perturbation theory, along with the experimental results. Because the structure model imposes periodic boundary conditions, the common origin of the rotational strength has hitherto been ill-defined and was approximated by means of averaging multiple origins. The new formalism reconnects the periodic model with the finite physical system and restores gauge freedom. It nevertheless fully accounts for nonlocal spatial couplings from the gauge transport term. We show that even for small simulation cells the rich nature of solid-state VCD spectra found in experiments can be reproduced to a very satisfactory level.

Solid Phase Nitrosylation of Enantiomeric Cobalt(II) Complexes

Accompanied by a change in color from red to black, the enantiomorphic phases of the cobalt complexes of a chiral salen ligand (L2−, Co(L)·CS2, and Co(L) (L = LS,S or LR,R)) chemisorb NO (g) at atmospheric pressure and rt over hours for the CS2 solvated phase, and within seconds for the desolvated phase. NO is installed as an axial nitrosyl ligand. Aligned but unconnected voids in the CS2 desorbed Co(LR,R)·CS2 structure indicate conduits for the directional desorption of CS2 and reversible sorption of NO, which occur without loss of crystallinity. Vibrational circular dichroism (VCD) spectra have been recorded for both hands of LH2, Zn(L), Co(L)·CS2, Co(L), Co(NO)(L), and Co(NO)(L)·CS2, revealing significant differences between the solution-state and solid-state spectra. Chiral induction enables the detection of the νNO band in both condensed states, and surprisingly also the achiral lattice solvent (CS2 (νCS at 1514 cm−1)) in the solid-state VCD. Solution-state spectra of the paramagnetic Co(II) complex shows a nearly 10-fold enhancement and more extensive inversion of polarity of the vibrations of dominant VCD bands compared to the spectra of the diamagnetic compounds. This enhancement is less pronounced when there are fewer polarity inversions in the solid state VCD spectra.

Solid-state Vibrational Circular Dichroism as Applied for Heterogenous Asymmetric Catalysis: Copper(II) Complexes Immobilized in Montmorillonite

Solid-state vibrational circular dichroism (SD-VCD) spectra were measured on the ion-exchange adducts of sodium montmorillonite and [Cu(RR- or SS-oxa)]2+ as prepared in the presence of a substrate in Michael additions, (E)-2-butenoyl-2-oxazolidinone. Here RR- or SS-oxa denotes RR- or SS-2,2′-isopropylidene-bis(4-phenyl-2-oxazoline), respectively. By comparing the observed and theoretical VCD spectra, it was deduced that the substrate was transformed to a chiral structure in association with the Cu(II) complex within a clay mineral.

Application of Solid-State Vibrational Circular Dichroism for Intercalation Compounds of Layered Double Hydroxide and Amino Acids: Conformation of an Intercalated Phenylalanine

Abstract Solid-state vibrational circular dichroism (SD-VCD) spectra were measured for the intercalation compounds of layered double hydroxide (LDH) and d- or l-phenylalanine (d- or l-Phe). The investigated LDH was composed of Zn(II) and Al(III) in 2:1 molar ratio. For comparison, the SD-VCD spectra were recorded for enantiopure crystalline samples of Phe. The measured spectra were analyzed with the help of a theoretical simulation calculated by the Gaussian16 program. It was concluded that Phe formed a tetramer in the crystalline state, forming intermolecular hydrogen bonds between –COO− and –NH3+ groups. In the intercalated states, the neighboring Phe molecules oriented vertically to the layer surface in an anti-parallel fashion, forming their –COO− groups hydrogen bonded individually with the OH groups on the surface of LDH. The results demonstrated the utility of the SD-VCD method for obtaining the detailed conformation of a molecule within an inorganic host.

Solid-state vibrational circular dichroism studies of L- and D-serine

d-Serine is considered a key endogenous substance involved in several enzymatic reactions in the human body. In this study, solid-state vibrational circular dichroism (VCD) measurements of enantiomeric serine were performed for spectroscopic distinction between d- and l-serine. The mirror-image VCD signals of the isomers in the KBr pellets were observed in the mid-infrared range of 1800–1250 cm−1. The calculated infrared (IR) and VCD spectra for the optimized serine structures were in good agreement with the corresponding observed spectra. In addition, the chemical shift values estimated from the shielding constants of the optimized structure of serine corresponded with the observed values in 13C and 15N solid-state nuclear magnetic resonance spectra, supporting the VCD assignments. Our results suggest the need for further study of VCD to develop a sensitive and high-resolution spectroscopic technique for the detection of d-amino acids.

Helicity and Topological Chirality in Hydrogen-Bonded Supermolecules Characterized by Advanced Graph Set Analysis and Solid-State Vibrational Circular Dichroism Spectroscopy

The applicability of advanced graph set analysis and solid-state vibrational circular dichroism (SD-VCD) spectroscopy to the characterization of supramolecular chirality has been demonstrated. Recrystallization of R-(+)-1-phenylethylammonium 1-naphthoate affords two polymorphic crystals: one is composed of hydrogen-bonded (HB) 2-fold helices with helicity, while the other contains HB clusters with topological chirality. Handedness and origins of the chirality were crystallographically characterized by advanced graph set analysis. SD-VCD measurements were then recorded for these polymorphic crystals using the VCD spectrometer PRESTO-S-2007, which we developed. Unique VCD spectra were observed because of the difference in features of the chiral supramolecular structures. Enhancement of VCD signals depending on dimensionality of the supermolecules is especially noteworthy. Generality of 2-fold helices, demonstrated by statistics from the Cambridge Structural Database, and geometrical characteristics and theo...

Solid state vibrational circular dichroism towards molecular recognition: chiral metal complexes intercalated in a clay mineral.

Vibrational circular dichroism (VCD) spectroscopy was applied to study chirality recognition in the interlayer space of a clay mineral. Clay intercalation compounds including two kinds of chiral molecules were prepared. Firstly a cationic metal complex, Δ- or Λ-[Ru(phen)3]2+ (phen = 1,10-phenanthroline), was ion-exchanged into sodium montmorillonite. Thereafter a neutral organic molecule, R- or S-1,1'-bi-2-naphthol (denoted as R- or S-BINOL), was co-adsorbed. The solid state VCD spectra were recorded on the hybrid compounds thus prepared. The intensity of VCD peaks in the region of 1300-1400 cm-1, which were assigned to the bending vibrations of OH groups in BINOL, was remarkably dependent on the chirality relation between the two intercalated species. This implied that BINOL took a different conformation in response to the chirality of co-existing [Ru(phen)3]2+.

Solid-state Vibrational Circular Dichroism Spectra of Isoleucine and Its Related Compounds: Effects of Interplay between Two Chiral Centers

The solid-state vibrational circular dichroism spectra were measured for isoleucine and its related compounds. These amino acids are characterized by the presence of two chiral centers (the asymmetric carbon in an alkyl chain and the one at the α-position). The couplet peaks were observed for the stretching vibrations of –COOH and the bending vibration of –NH2. The signs of the peaks due to –COOH were determined uniquely by the RS-chirality of the α-carbon, while those due to –NH2 were dependent on the combination of the chirality of the α-carbon and the carbon in an alkyl chain. The results implied that the asymmetric vibrational behavior of an –NH2 group was affected by the interplay between two chiral centers.

Synthesis of a Chiral Crystal Form of MOF-5, CMOF-5, by Chiral Induction.

Chiral variants of the prototypal metal-organic framework MOF-5, Λ-CMOF-5 and Δ-CMOF-5, have been synthesized by preparing MOF-5 in the presence of L-proline or D-proline, respectively. CMOF-5 crystallizes in chiral space group P213 instead of Fm3̅m as exhibited by MOF-5. The phase purity of CMOF-5 was validated by single-crystal and powder X-ray diffraction, infrared spectroscopy, thermogravimetric analysis, N2 adsorption, microanalysis, and solid-state vibrational circular dichroism. CMOF-5 undergoes a reversible single crystal-to-single crystal phase change to MOF-5 when immersed in a variety of organic solvents, although N-methyl-2-pyrrolidone (NMP) does not induce loss of chirality. Indeed, MOF-5 undergoes chiral induction when immersed in NMP, affording racemic CMOF-5.

Reversible transformation between chiral and achiral Dy6Mo4 clusters through a symmetric operation.

Three polynuclear lanthanide clusters: (NH4)2[Dy6Mo4O12(rac-L(3-))4(OOCCH3)8]·4CH3OH·6H2O (I), (Et3NH)2[Dy6Mo4O12(rac-L(3-))4(OOCCH3)8]·18H2O (II), and (Me4N)2[Dy6Mo4O12(rac-L(3-))4(OOCCH3)8]·CH3OH·14H2O (III) (H3L = (E)-2-((2,3-dihydroxypropylimino)methyl)-phenol) were synthesized. Single-crystal analysis reveals that cluster I crystallized in the centrosymmetric space group (P42/n), while clusters II and II crystallized in the chiral space group (P3121 or P3221), and cluster I can be transformed into clusters II and III, when Et3NH(+) and Me4N(+), respectively, are used to replace NH4(+). Investigation on the solid-state vibrational circular dichroism (VCD) spectra shows that the clusters II and III are homochiral crystallization. Powder X-ray diffraction study demonstrates that the transformation between chiral and achiral clusters is reversible.

A Facile Method to Determine the Absolute Structure of Achiral Molecules: Supramolecular-Tilt Structures

Achiral compounds 4-methoxy-4-(p-methoxyphenyl)cyclohexanoneethylene ketal (2), 4-hydroxy-4-(p-methoxy phenyl)cyclohexanoneethylene ketal (3), and 3,5-dimethyl-4-nitropyrazole (4) crystallized in chiral structures and the samples showed an enantiomeric excess. We have determined the absolute structures of these compounds by using X-ray diffraction with copper radiation at low temperatures. Moreover, we have also established the prevalent absolute structures in these samples, by comparing their calculated and solid-state vibrational circular dichroism (VCD) spectra. The consistency of this method was confirmed by using (R,R)-2,8-diiodo-4,10-dimethyl-6 H,12H-5,11-methano-dibenzo[b,f][1,5]diazocine, Tröger's base, (R,R)-1, as a chiral compound of known absolute configuration.