Vibrational Circular Dichroism Spectroscopy Research Articles

Matrix effects in MI-VCD spectra of two chiral oxiranes and their potential microscopic origin.

Combining vibrational circular dichroism (VCD) spectroscopy with the matrix isolation (MI) technique opens up interesting possibilities to study chiral molecules. MI involves the isolation of guest species in inert solid matrices at cryogenic temperatures. Hence, MI-VCD measures are solid-state VCD measurements, and as such, can suffer from mostly birefringance-related artefacts in the same way as common solid-state VCD measurements. In this contribution, we demonstrate that the sample preparation condition have tremendous impact on the quality and reliability of the recorded MI-VCD spectra. While MI-IR spectra are basically blind to these artefacts, the variation of deposition temperatures and host flow rates seem to control whether high quality MI-VCD spectra are obtained or if depolarization effects lead to completely obscured spectra. For two selected examples, styrene oxide (SO) and 1-phenyl propylene oxide (PPO), we discuss how the various experimental conditions may lead to the aforementioned effects and give a microscopic description of their origin.

Simplified and enhanced VCD analysis of cyclic peptides guided by artificial intelligence.

Cyclic peptides are privileged structures in medicinal chemistry; however, their solution-state structure characterization is difficult. Vibrational circular dichroism (VCD) spectroscopy is a powerful alternative to NMR, but requires challenging calculations. We present a VCD approach guided by a genetic algorithm, which is simple, more effective, and has a higher conformer resolution.

Modelling solute-solvent interactions in VCD spectra analysis with the micro-solvation approach.

Vibrational circular dichroism (VCD) spectroscopy has become an important part of the (stereo-)chemists' toolbox as a reliable method for the determination of absolute configurations. Being the chiroptical version of infrared spectroscopy, it has also been recognized as being very sensitive to conformational changes and intermolecular interactions. This sensitivity originates from the fact that the VCD spectra of individual conformers are often more different than their IR spectra, so that changes in conformational distributions or band positions and intensities become more pronounced. What is an advantage for studies focussing on intermolecular interactions can, however, quickly turn into a major obstacle during AC determinations: solute-solvent interactions can have a strong influence on spectral signatures and they must be accurately treated when simulating VCD and IR spectra. In this perspective, we showcase selected examples which exhibit particularly pronounced solvent effects. It is demonstrated that it is typically sufficient to model solute-solvent interactions by placing single solvent molecules near hydrogen bonding sites of the solute and subsequently use the optimized structures for spectra simulations. This micro-solvation approach works reasonably well for medium-sized, not too conformationally flexible molecules. We thus also discuss its limitations and outline the next steps that method development needs to take in order to further improve the workflows for VCD spectra predictions.

Pushing the boundaries of VCD spectroscopy in natural product chemistry.

Vibrational circular dichroism (VCD) is one of the most powerful techniques to assess the stereochemistry of chiral molecules in solution state. The need for quantum chemical calculations to interpret experimental data, however, has precluded its widespread use by non-experts. Herein, we propose the search and validation of IR and VCD spectral markers to circumvent the requirement of DFT calculations allowing for absolute configuration assignments even in complex mixtures. To that end, a combination of visual inspection and machine learning based methods is used. Monoterpene mixtures are selected for this proof-of-concept study.

Plakilactone J: Structure and absolute configuration

The chemical investigation of the Brazilian marine sponge Plakortis angulospiculatus led to the isolation of the new peroxide-derived polyketide plakilactone J (1). The structure of (−)-1 was established by means of HRMS and NMR analysis, while its absolute configuration was unambiguously determined as (4R,6R) by vibrational circular dichroism spectroscopy and density functional theory calculations.

Vibrational Circular Dichroism Unravels Supramolecular Chirality and Hydration Polymorphism of Nucleoside Crystals.

Vibrational circular dichroism (VCD) spectroscopy has been widely used to study (bio)molecules in solution. However, its solid-state applications have been restricted due to experimental limitations and artifacts. Having overcome some of them, the first VCD study of nucleoside crystals is now presented. A two-orders-of-magnitude enhancement of VCD signal was observed due to high molecular order in the crystals and resulting supramolecular chirality. This allowed to obtain high-quality VCD spectra within minutes using minute amounts of samples. The VCD technique is extremely sensitive in detecting changes in a crystal order and is able to distinguish different hydration states of crystals. This elevates it to a new level, as a fast and efficient tool to study chiral crystalline samples. This study demonstrates that VCD is capable of near-instantaneous detection of hydration polymorphs and crystal degradation, which is of substantial interest in pharmaceutical industry (quality and stability control).

Dynamic Stereochemistry of a Biphenyl-Bisprolineamide Model Catalyst and its Imidazolidinone Intermediates.

In this study, we characterize the dynamic stereochemistry of a biphenyl‐2,2’‐bis(proline amide) catalyst in chloroform and DMSO as representative weakly and strongly hydrogen bonding solvents. Using vibrational circular dichroism (VCD) spectroscopy and density functional theory (DFT) based spectra calculations, we show that the preferred axial stereochemistry of the catalyst is determined by solute‐solvent interactions. Explicitly considering solvation with DMSO molecules is found to be essential to correctly predict the conformational preferences of the catalyst. Furthermore, we investigate the stereochemistry of the corresponding enamines and imidazolidinones that are formed upon reaction with isovaleraldehyde. The enamines are found to rapidly convert to endo‐imidazolidinones and the thermodynamically favored exo‐imidazolidinones are formed only slowly. The present study demonstrates that the stereochemistry of these imidazolidinones can be deduced directly from the VCD spectra analysis without any further detailed analysis of NMR spectra. Hence, we herein exemplify the use of VCD spectroscopy for an in situ characterization of intermediates relevant in asymmetric catalysts.

Structure Elucidation of In Situ Generated Chiral Hypervalent Iodine Complexes via Vibrational Circular Dichroism (VCD).

The structure of in situ generated chiral aryl-λ3 -iodanes obtained under oxidative reaction conditions was not yet observable with experimental techniques and their proposed structures are purely based on DFT calculations. Herein, we establish vibrational circular dichroism (VCD) spectroscopy as an experimental technique to verify DFT-calculated chiral iodane structures. Based on a chiral triazole-substituted iodoarene catalyst, we were able to elucidate a yet undescribed cationic chiral iodane as the most populated intermediate under oxidative conditions with a significant intramolecular N-I-interaction and no significant interactions with tosylate or m-chlorobenzoic acid as potential anionic ligands. Instead, aggregation of these substrates was found, which resulted in the formation of a non-coordinating anionic hydrogen bonded complex. The importance of VCD as a crucial experimental observable is further highlighted by the fact that our initial structural proposal, that was purely based on DFT calculations, could be falsified.

Strukturaufklärung eines chiralen in situ erzeugten hypervalenten Iod‐Komplexes mittels VCD‐Spektroskopie

AbstractDie Struktur von in situ erzeugten chiralen Aryl‐λ3‐iodanen, die unter oxidativen Reaktionsbedingungen erhalten wurden, konnte bisher nicht mit experimentellen Techniken beobachtet werden. Deren vorgeschlagene Strukturen beruhen nahezu ausschließlich auf DFT‐Berechnungen. In diesem Beitrag etablieren wir die Schwingungszirkulardichroismus‐Spektroskopie (VCD) als eine experimentelle Technik zur Verifizierung von DFT‐berechneten chiralen Iodanstrukturen. Für einen chiralen Triazol‐substituierten Iodoaren‐Katalysator wird ein bisher unbeschriebenes kationisches chirales Iodan identifiziert, dass eine intramolekulare N‐I‐Wechselwirkung aber keine signifikanten Wechselwirkungen mit Tosylat oder m‐Chlorbenzoesäure als potenzielle anionische Liganden aufweist. Stattdessen wurde eine Aggregation dieser Substrate festgestellt, die zur Bildung eines nicht‐koordinierenden anionischen wasserstoffgebundenen Komplexes führte. Die Bedeutung der VCD‐Spektroskopie als entscheidende experimentelle Methode zum Nachweis der kationischen Spezies wird auch durch die Tatsache unterstrichen, dass unser ursprünglicher Strukturvorschlag, der rein auf DFT‐Berechnungen basierte, widerlegt werden konnte.

Chiroptical and potential in vitro anti-inflammatory properties of viniferin stereoisomers from grapevine (Vitis vinifera L.)

Determination of stereochemistry and enantiomeric excess in chiral natural molecules is a research of great interest because enantiomers can exhibit different biological activities. Viniferin stilbene dimers are natural molecules present in grape berries and wine but also, in larger amount, in stalks of grapevine. Four stereoisomers of viniferin stilbene dimers (7aS,8aS)-E-ε-viniferin (1a), (7aR,8aR)-E-ε-viniferin (1b), (7aS,8aR)-E-ω-viniferin (2a), and (7aR,8aS)-E-ω-viniferin (2b) were isolated from grapevine stalks of Cabernet Sauvignon, Merlot and Sauvignon Blanc, using a combination of centrifugal partition chromatography (CPC), preparative and chiral HPLC. The structure elucidation of these molecules was achieved by NMR whereas the absolute configurations of the four stereoisomers were investigated by vibrational circular dichroism spectroscopy in combination with density functional theory (DFT) calculations. This study unambiguously established the (+)-(7aS,8aS) and (+)-(7aR,8aS) configurations for E-ε-viniferin and E-ω-viniferin, respectively. Finally, we show that Cabernet Sauvignon provided the quasi enantiopure (+)-(7aS,8aS)-E-ε-viniferin compound which presents the best anti-inflammatory and anti-oxidant activities.

Structural Elucidation by NMR Analysis Assisted by DFT Calculations of a Novel Natural Product from Conchocarpus Mastigophorus (Rutaceae)

AbstractThe stem of Conchocarpus mastigophorus was solvent‐extracted and purified by silica‐gel column chromatography to afford eleven natural products, including one new compound. The structures of all compounds were fully elucidated by spectrometric methods. NMR analyses assisted by theoretical calculations were used to determine the structure of a novel natural product. The structure of the novel compound 2 (acridone alkaloid) was established as 1,3,6‐trihydroxy‐2,4,5‐trimethoxy‐10‐methylacridin‐9(10H)‐one. The absolute configuration of compound 1 was assigned by means of vibrational circular dichroism (VCD) spectroscopy. The structure of compound 1 was defined as (3S)‐(−)‐3‐hydroxy‐1‐methylpiperidin‐2‐one. Theoretical calculations were performed at the B3LYP/6‐311+G(2d,p)//M06‐2X/6‐31+G(d,p) level of theory and DP4 statistical tool was employed to compare the calculated and experimental NMR chemical shifts.

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.

Vibrational circular dichroism spectroscopy as a probe for the detection of collagen fibril and fibrillation in solution

The detection of collagen fibrils and fibrillation is crucial for tissue regeneration, biomedical applications of collagen, and for studying the interaction of small molecules with the collagen fibrils in the development of therapeutics for collagen-based diseases. At present, collagen fibrillation is probed by high-value microscopic techniques, which limits real-time monitoring of collagen fibril growth and measurement only in dry form. In this context, a quick sensing method is necessary for detecting these fibrils, especially monitoring fibril growth in solution. Herein, we show that vibrational circular dichroism (VCD), a growing spectroscopic technique, can probe collagen fibrils in aqueous solutions by generating an enhanced amide I VCD signal (intensity) compared to monomer. Unlike regular protein VCD measurements, VCD of collagen fibrils require a very low concentration (5 mg/mL) of collagen and can be probed in a very short time (∼10 min). Moreover, VCD responds to the diameter and height of collagen fibrils as evidenced by an increased VCD intensity (close to 103) with pH and NaCl, making VCD a sensitive tool for monitoring the growth of the fibril diameter and height. VCD was also found to be suitable for detecting the time-dependent increase in fibril diameter under fibrillation conditions. Because no other probe is presently available for rapid detection of collagen fibrils in solution form, the ability of VCD to rapidly probe collagen fibrillation in solution and in real-time opens a new way of studying collagen fibrillation in different fields and applications.

Chiral molecular nanosilicas.

Molecular nanoparticles including polyoxometalates, proteins, fullerenes and polyhedral oligosiloxane (POSS) are nanosized objects with atomic precision, among which POSS derivatives are the smallest nanosilicas. Incorporation of molecular nanoparticles into chiral aggregates either by chiral matrices or self-assembly allows for the transfer of supramolecular chirality, yet the construction of intrinsic chirality with atomic precision in discrete molecules remains a great challenge. In this work, we present a molecular folding strategy to construct giant POSS molecules with inherent chirality. Ferrocenyl diamino acids are conjugated by two or four POSS segments. Hydrogen bonding-driven folding of diamino acid arms into parallel β-sheets facilitates the chirality transfer from amino acids to ferrocene and POSS respectively, disregarding the flexible alkyl spacers. Single crystal X-ray structures, density functional theory (DFT) calculations, circular dichroism and vibrational circular dichroism spectroscopy clearly verify the preferential formation of one enantiomer containing chiral molecular nanosilicas. The chiral orientation and chiroptical properties of POSS show pronounced dependence on the substituents of α-amino acids, affording an alternative way to control the folding behavior and POSS chirality in addition to the absolute configuration of amino acids. Through the kinetic nanoprecipitation protocol, one-dimensional aggregation enables chirality transfer from the molecular scale to the micrometer scale, self-assembling into helices in accordance with the packing propensity of POSS in a crystal phase. This work, by illustrating the construction of chiral molecular nanosilicas, paves a new way to obtain discrete chiral molecular nanoparticles for potential chiroptical applications.

7-Azaindole breaks carboxylic acid dimers and simplifies VCD spectra analyses of natural products.

The determination of absolute configurations of carboxylic acids by vibrational circular dichroism (VCD) spectroscopy is often complicated by self-aggregation and the subsequent need to compute the spectra of the aggregates. We show that 7-azaindole effectively breaks up these aggregates by stronger complemental hydrogen bonding to the COOH moiety, enabling drastic simplification and acceleration of VCD spectra calculations.

Probing the non-bonding interaction of small molecules with graphene oxide using DFT based vibrational circular dichroism

This study explores the non-bonding interaction of graphene oxide with small molecules such as NO2, SO3, SO2, and CO2 by density functional theory-based vibrational circular dichroism (VCD) and Raman spectroscopies. Molecular dynamics (MD) simulation is used to generate all possible and stable cluster conformers of the GO and small molecules. The non-bonding interactions between GO and small molecules in the gas phase are calculated with the help of density functional theory (DFT). VCD and Raman spectra are computed using ωB97XD/6-31G+(d) level of theory. Vibrational mode of the O–H wagging, C–H twisting, O–H bending, C–H bending, C–H rocking, C–H stretching, O–H stretching demonstrate representative VCD signature band in the gas phase. The highest and the lowest VCD signal are noticed for GO-NO2 and GO-CO2 complex, respectively. The most intense negative VCD signal is observed for GO-NO2, and GO-CO2 complexes, whereas the most intense positive VCD signal, is detected for GO-SO3 and GO-SO2 complexes. Non-bonding interaction of GO with NO2, SO3, SO2, and CO2 influences the various vibrational modes in the conformers, thus significantly changing the VCD signals. However, the Raman signal shows no significant changes for the non-bonding interaction examined in the multiple conformers. These findings indicate that vibrational circular dichroism may be employed for detecting the non-bonding interactions of graphene oxide with small molecules.

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.

Stereochemistry of chiral pesticide uniconazole and enantioselective metabolism in rat liver microsomes

In this work, stereochemistry of uniconazole enantiomers and their metabolism behaviors in rat liver microsomes have been researched. Significance analysis has been applied in data processing. Absolute configurations of uniconazole enantiomers were identified through vibrational circular dichroism spectroscopy. According to their elution order from the chiral column using the CO2-methanol (80:20, v/v) mixture, two eluted fractions were determined to be (R)-uniconazole and (S)-uniconazole, respectively. A high-efficient and sensitive LC-MS/MS chiral analysis method was established for investigating the metabolism of uniconazole enantiomers in rat liver microsomes. The metabolic half-life of (R)-uniconazole (38.7 min) in rat liver microsomes was half that of (S)-enantiomer (74.5 min), and maximum velocity of metabolism, Michaelis constant of metabolism as well as the intrinsic metabolic clearance of (R)-uniconazole were significantly higher than (S)-enantiomer (p < 0.05), which indicated that (R)-uniconazole was preferentially metabolized in rat liver microsomes. By the virtue of molecular docking, (R)-uniconazole exhibited a higher binding affinity to cytochrome CYP2D2 than (S)-enantiomer, which corroborated well with the metabolism results. This work will shed light on the risk assessment of uniconazole toward human health and the ecological environment.

Mapping of Supramolecular Chirality in Insect Wings by Microscopic Vibrational Circular Dichroism Spectroscopy: Heterogeneity in Protein Distribution.

The supramolecular chirality of the hindwing of Anomala albopilosa (male) was investigated using a microscopic vibrational circular dichroism (VCD) system, denoted as MultiD-VCD. The source of intense infrared (IR) light for the system was a quantum cascade laser. Two-dimensional maps of IR and VCD spectra were taken by scanning the surface area (ca. 2 mm × 2 mm) of the insect hindwing tissue. The spectra ranged from 1500 to 1700 cm-1, and the maps have a spatial resolution of 100 μm. The distribution of proteins, including their supramolecular structures, was analyzed from the location-dependent spectral shape of the VCD bands assigned to amides I and II. The results revealed that the hindwing consists of segregated domains of proteins with different secondary structures: an α-helix (in one part of the membrane), a hybrid of α-helix and β-sheet (in another part of the membrane), and a coil (in a vein).