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.

An Artificial Intelligence Approach for Tackling Conformational Energy Uncertainties in Chiroptical Spectroscopies.

Determination of the absolute configuration of chiral molecules is a prerequisite for obtaining a fundamental understanding in any chirality-related field. The interaction with polarised light has proven to be a powerful means to determine this absolute configuration, but its application rests on the comparison between experimental and computed spectra for which the inherent uncertainty in conformational Boltzmann factors has proven to be extremely hard to tackle. Here we present a novel approach that overcomes this issue by combining a genetic algorithm that identifies the relevant conformers by accounting for the uncertainties in DFT relative energies, and a hierarchical clustering algorithm that analyses the trends in the spectra of the considered conformers and identifies on-the-fly when a given chiroptical technique is not able to make reliable predictions. The effectiveness of this approach is demonstrated by considering the challenging cases of papuamine and haliclonadiamine, two bis-indane natural products with eight chiral centres and considerable conformational heterogeneity that could not be assigned unambiguously with current approaches.

Photonically active bowtie nanoassemblies with chirality continuum.

Chirality is a geometrical property described by continuous mathematical functions1-5. However, in chemical disciplines, chirality is often treated as a binary left or right characteristic of molecules rather than a continuity of chiral shapes. Although they are theoretically possible, a family of stable chemical structures with similar shapes and progressively tuneable chirality is yet unknown. Here we show that nanostructured microparticles with an anisotropic bowtie shape display chirality continuum and can be made with widely tuneable twist angle, pitch, width, thickness and length. The self-limited assembly of the bowties enables high synthetic reproducibility, size monodispersity and computational predictability of their geometries for different assembly conditions6. The bowtie nanoassemblies show several strong circular dichroism peaks originating from absorptive and scattering phenomena. Unlike classical chiral molecules, these particles show a continuum of chirality measures2 that correlate exponentially with the spectral positions of the circular dichroism peaks. Bowtie particles with variable polarization rotation were used to print photonically active metasurfaces with spectrally tuneable positive or negative polarization signatures for light detection and ranging (LIDAR) devices.

Molecule-like and lattice vibrations in metal clusters.

We report distinct molecule-like and lattice (breathing) vibrational signatures of atomically precise, ligand-protected metal clusters using low-temperature Raman spectroscopy. Our measurements provide fingerprint Raman spectra of a series of noble metal clusters, namely, Au25(SR)18, Ag25(SR)18, Ag24Au1(SR)18, Ag29(S2R)12 and Ag44(SR)30 (-SR = alkyl/arylthiolate, -S2R = dithiolate). Distinct, well-defined, low-frequency Raman bands of these clusters result from the vibrations of their metal cores whereas the higher-frequency bands reflect the structure of the metal-ligand interface. We observe a distinct breathing vibrational mode for each of these clusters. Detailed analyses of the bands are presented in the light of DFT calculations. These vibrational signatures change systematically when the metal atoms and/or the ligands are changed. Most importantly, our results show that the physical, lattice dynamics model alone cannot completely describe the vibrational properties of ligand-protected metal clusters. We show that low-frequency Raman spectroscopy is a powerful tool to understand the vibrational dynamics of atomically precise, molecule-like particles of other materials such as molecular nanocarbons, quantum dots, and perovskites.

Raman Spectroscopic Fingerprints of Atomically Precise Ligand Protected Noble Metal Clusters: Au38 (PET)24 and Au38-x Agx (PET)24.

Distinct Raman spectroscopic signatures of the metal core of atomically precise, ligand-protected noble metal nanoclusters are reported using Au38 (PET)24 and Au38-x Agx (PET)24 (PET = 2-phenylethanethiolate, -SC2 H4 C6 H5 ) as model systems. The fingerprint Raman features (occurring <200 cm-1 ) of these clusters arise due to the vibrations involving metal atoms of their Au23 or Au23-x Agx cores. A distinct core breathing vibrational mode of the Au23 core has been observed at 90 cm-1 . Whereas the breathing mode shifts to higher frequencies with increasing Ag content of the cluster, the vibrational signatures due to the outer metal-ligand staple motifs (between 200 and 500 cm-1 ) do not shift significantly. DFT calculations furthermore reveal weak Raman bands at higher frequencies compared to the breathing mode, which are associated mostly with the rattling of two central gold atoms of the bi-icosahedral Au23 core. These vibrations are also observed in the experimental spectrum. The study indicates that low-frequency Raman spectra are a characteristic fingerprint of atomically precise clusters, just as electronic absorption spectroscopy, in contrast to the spectrum associated with the ligand shell, which is observed at higher frequencies.

Revisiting an old concept: the coupled oscillator model for VCD. Part 1: the generalised coupled oscillator mechanism and its intrinsic connection to the strength of VCD signals.

Motivated by the renewed interest in the coupled oscillator (CO) model for VCD, in this work a generalised coupled oscillator (GCO) expression is derived by introducing the concept of a coupled oscillator origin. Unlike the standard CO expression, the GCO expression is exact within the harmonic approximation. Using two illustrative example molecules, the theoretical concepts introduced here are demonstrated by performing a GCO decomposition of the rotational strengths computed using DFT. This analysis shows that: (1) the contributions to the rotational strengths that are normally neglected in the standard CO model can be comparable to or larger than the CO contribution, and (2) the GCO mechanism introduced here can affect the VCD intensities of all types of modes in symmetric and asymmetric molecules.

Revisiting an old concept: the coupled oscillator model for VCD. Part 2: implications of the generalised coupled oscillator mechanism for the VCD robustness concept.

Using two illustrative examples it is shown that the generalised coupled oscillator (GCO) mechanism implies that the stability of the VCD sign computed for a given normal mode is not reflected by the magnitude of the ratio ζ between the rotational strength and dipole strength of the respective mode, i.e., the VCD robustness criterium proposed by Góbi and Magyarfalvi. The performed VCD GCO analysis brings further insight into the GCO mechanism and also into the VCD robustness concept. First, it shows that the GCO mechanism can be interpreted as a VCD resonance enhancement mechanism, i.e. very large VCD signals can be observed when the interacting molecular fragments are in favourable orientation. Second, it shows that the uncertainties observed in the computed VCD signs are associated to uncertainties in the relative orientation of the coupled oscillator fragments and/or to uncertainties in the predicted nuclear displacement vectors, i.e. not uncertainties in the computed magnetic dipole transition moments as was originally assumed. Since it is able to identify such situations easily, the VCD GCO analysis can be used as a VCD robustness analysis.

The importance of large-amplitude motions for the interpretation of mid-infrared vibrational absorption and circular dichroism spectra: 6,6'-dibromo-[1,1'-binaphthalene]-2,2'-diol in dimethyl sulfoxide.

Using the 6,6'-dibromo-[1,1'-binaphthalene]-2,2'-diol molecule and its vibrational absorption (VA) and vibrational circular dichroism (VCD) spectra measured in deuterated dimethyl sulfoxide as example, we present a first detailed study of the effects induced in VCD spectra by the large-amplitude motions of solvent molecules loosely bound to a solute molecule. We show that this type of perturbation can induce significant effects in the VA and VCD spectra. We also outline a computational procedure that can effectively model the effects induced in the spectra and at the same time provide detailed structural information regarding the relative orientations of moieties involved in a solute-solvent molecular complex.

Importance of C*-H based modes and large amplitude motion effects in vibrational circular dichroism spectra: the case of the chiral adduct of dimethyl fumarate and anthracene.

The role played by the C*-H based modes (C* being the chiral carbon atom) and the large amplitude motions in the vibrational absorption (VA) and vibrational circular dichroism (VCD) spectra is investigated. The example of an adduct of dimethyl fumarate and anthracene, i.e., dimethyl-(+)-(11R,12R)-9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboxylate, and two deuterated isotopomers thereof specially synthesized for this goal, are considered. By comparing the experimental and DFT calculated spectra of the undeuterated and deuterated species, we demonstrate that the C*-H bending, rocking, and stretching modes in the VA and VCD spectra are clearly identified in well defined spectroscopic features. Further, significant information about the conformer distribution is gathered by analyzing the VA and VCD data of both the fingerprint and the C-H stretching regions, with particular attention paid to the band shape data. Effects related to the large amplitude motions of the two methoxy moieties have been simulated by performing linear transit (LT) calculations, which consists of varying systematically the relative positions of the two methoxy moieties and calculating VCD spectra for the partially optimized structures obtained in this way. The LT method allows one to improve the quality of calculated spectra, as compared to experimental results, especially in regard to relative intensities and bandwidths.

On the complementarity of ECD and VCD techniques.

An unprecedented complementarity of electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectroscopic techniques is demonstrated by showing that each technique reveals the structure of a different molecular segment. Using a flexible molecule of biological significance we show that the synergetic use of ECD and VCD yields more complete structural characterization as it provides improved and more reliable conformer resolution.

Understanding solvent effects in vibrational circular dichroism spectra: [1,1'-binaphthalene]-2,2'-diol in dichloromethane, acetonitrile, and dimethyl sulfoxide solvents.

We present a combined experimental and computational investigation of the vibrational absorption (VA) and vibrational circular dichroism (VCD) spectra of [1,1'-binaphthalene]-2,2'-diol. First, the sensitive dependence of the experimental VA and VCD spectra on the solvent is demonstrated by comparing the experimental spectra measured in CH(2)Cl(2), CD(3)CN, and DMSO-d(6) solvents. Then, by comparing calculations performed for the isolated solute molecule to calculations performed for molecular complexes formed between solute and solvent molecules, we identify three main types of perturbations that affect the shape of the VA and VCD spectra when going from one solvent to another. These sources of perturbations are (1) perturbation of the Boltzmann populations, (2) perturbation of the electronic structure, and (3) perturbation of the normal modes.

On the equivalence of conformational and enantiomeric changes of atomic configuration for vibrational circular dichroism signs.

We study systematically the vibrational circular dichroism (VCD) spectra of the conformers of a simple chiral molecule, with one chiral carbon and an "achiral" alkyl substituent of varying length. The vibrational modes can be divided into a group involving the chiral center and its direct neighbors and the modes of the achiral substituent. Conformational changes that consist of rotations around the bond from the next-nearest neighbor to the following carbon, and bond rotations further in the chain, do not affect the modes around the chiral center. However, conformational changes within the chiral fragment have dramatic effects, often reversing the sign of the rotational strength. The equivalence of the effect of enantiomeric change of the atomic configuration and conformational change on the VCD sign (rotational strength) is studied. It is explained as an effect of atomic characteristics, such as the nuclear amplitudes in some vibrational modes as well as the atomic polar and axial tensors, being to a high degree determined by the local topology of the atomic configuration. They reflect the local physics of the electron motions that generate the chemical bonds rather than the overall shape of the molecule.

On the origin dependence of the angle made by the electric and magnetic vibrational transition dipole moment vectors.

The concept of robustness of rotational strengths of vibrational modes in a VCD spectrum has been introduced as an aid in assignment of the absolute configuration with the help of the VCD spectrum. The criteria for robustness have been based on the distribution around 90° of the angles ξ(i) between electric and magnetic transition dipoles of all the modes i of a molecule. The angles ξ(i) (not, of course, the rotational strengths) are, however, dependent on the choice of origin. The derived criteria are for the center of mass chosen as the origin of the coordinate system. We stress in this note that application of the derived criteria assumes that excessive translation of the coordinate origin is not applied. Although the ξ(i) angles are not very sensitive to the position of the origin, very small displacements (a few Å) are not a problem, excessive translation of the origin does have considerable effect on the ξ(i) angles. In this note we quantify this effect and demonstrate how the distribution of ξ(i) angles is affected. Although it is possible to recalibrate the robustness criteria for the angles for a specific (large) displacement, we recommend that such displacement simply be avoided. It is to be noted that some modeling software does yield output with excessively displaced coordinate origin; this should be checked and corrected.

Signatures of counter-ion association and hydrogen bonding in vibrational circular dichroism spectra.

We study the effect of counter-ion complexation on the example of Cl(-) ions interacting with the [Co(en)(3)](3+) complex. The H-bonding of the N-H groups of the ethylenediamine (en) ligands with the Cl(-) ions may lead to giant enhancement of the VCD intensity for the N-H stretches, but may also lead to VCD sign changes in the finger print region of N-H wagging, twisting and scissoring motions. Such sign changes should not be mistaken for signatures of the presence of the other enantiomer. We elucidate the mechanism for the sign changes and give a recommendation on how to deal with this problem. We also show that the experimental spectrum is only in good accord with the calculations if complexation of 5 Cl(-) ions (two axial, three equatorial) is assumed, but not with two (axial) or three (equatorial) Cl(-) ions, thus showing the potential of VCD to be used as an experimental probe for complexation.

Robust normal modes in vibrational circular dichroism spectra.

The use of calculations of the rotational strengths of normal modes in order to determine the absolute configuration (AC) of a molecule, by comparing a calculated vibrational circular dichroism (VCD) spectrum to an experimental one, can be made much more reliable when the vibrational modes are classified as either robust or non-robust. The robust modes are the ones with a robust sign of the rotational strength in the sense that it will not change by small perturbations in either experiment or calculation. The signs of non-robust modes may change. Clearly only robust modes should be used to establish the AC. We recommend that programs which calculate VCD spectra should provide, per normal mode, information that indicates the robustness of a mode, and therefore its usefulness for the AC determination. Such information consists of the angle xi between the electric and magnetic dipole transition moments, and the magnitudes of these dipole transition moments.

Enhancement of IR and VCD intensities due to charge transfer.

Donor-acceptor interactions such as the one between the Cl(-) base and the N-H sigma* acceptor orbitals encountered in the complexation of Cl(-) counterions to the [Co(en)(3)](3+) transition metal complex, have been shown to cause huge enhancement (between 1 and 2 orders of magnitude) of the VCD intensities of N-H stretching modes. This effect has been fully analyzed, and could be attributed to increased charge flow from the Cl(-) donors when the N-H bonds become stretched. The transfer of charge counteracts the movement of negative electronic charge that happens along with the motion of the H nuclei, effectively reversing the electronic part of the electric dipole transition moment (EDTM) in the direction of the charge flow (z, say), and of the magnetic transition dipole moment (MDTM) in the perpendicular direction. The consequences for the IR and VCD intensity follow: IR intensity is strongly increased if the EDTM is polarized in the z direction, e.g. in A(2) modes, but not so much if it is polarized in the xy plane (E modes), the VCD is strongly enhanced if the EDTM and MTDM are polarized in the xy plane (in E modes), but less so when they are polarized in the z direction (in A(2) modes). The explanation holds generally for complexation phenomena of this sort, including the donor-acceptor part of hydrogen bonding interactions, e.g. with solvent molecules.

A VCD robust mode analysis of induced chirality: the case of pulegone in chloroform.

Vibrational modes in an achiral molecule may acquire rotational strength by complexation to a chiral molecule, as happens for achiral solvent molecules complexed to a chiral solute. We investigate this transfer of chirality in vibrational circular dichroism for the pulegone molecule in CDCl(3) solvent from the point of view of the robustness concept introduced recently. It turns out that the transfer of chirality yields nonrobust modes, which means that, although they are observed in vibrational circular dichroism (VCD) experiments, the sign of these modes cannot be predicted reliably with standard (Density Functional Theory) VCD calculations. This limits the usefulness of the induced chirality phenomenon for obtaining information on the intermolecular interactions that give rise to it.

Effects of complex formation on vibrational circular dichroism spectra.

The determination of absolute configurations of chiral compounds using VCD is performed by comparing measured vibrational circular dichroism (VCD) spectra with calculated spectra. The process is based on two facts: the two enantiomers have rotational strengths of opposite sign, and the absolute configuration of the molecule used in the calculation is known. However, calculations on isolated molecules very often predict VCD intensities of very different magnitude or even different signs compared to the spectra measured in solution. Therefore, we have carefully analyzed what type of changes are induced by complexation of a solvent molecule to a solute. In the theoretical example of benzoyl-benzoic acid (in a particular chiral conformation) hydrogen bonded to the achiral NH3, we distinguish six cases, ranging from no or very small changes in the rotational strengths of solute modes (case A) to changes of sign of rotational strengths (case B), changes in magnitude (case C), nonzero rotational strengths for modes of the achiral solvent ("transfer of chirality", case D), large frequency shifts accompanied by giant enhancements of the IR and VCD intensities of modes involved in hydrogen bonding (case E), and emergence of new peaks (case F). In this work, all of these situations will be discussed and their origin will be elucidated. On the basis of our analysis, we advocate that codes for VCD rotational strength calculation should output for each mode i the angle xi(i) between the electric and magnetic transition dipole moments because only "robust modes" with xi far from 90 degrees should be used for the determination of the absolute configuration.