Homochiral vs. heterochiral preference in chiral self-recognition of cyclic diols.

The structure and clustering propensity of a chiral derivative of cis-1,2-cyclohexanediol, namely, 1-phenyl-cis-1,2-cyclohexanediol (cis-PCD), has been studied under supersonic expansion conditions by combining laser spectroscopy with quantum chemistry calculations. The presence of the phenyl substituent induces conformational locking relative to cis-1,2-cyclohexanediol (cis-CD), and only one conformer of the bare molecule is observed by both Raman and IR-UV double resonance spectroscopy. The homochiral preference inferred for the dimer formation at low enough temperature is in line with the formation of a conglomerate in the solid state. The change in clustering propensity in cis-PCD relative to trans-1,2-cyclohexanediol (trans-CD), which shows heterochiral preference, is explained by the presence of the phenyl substituent rather than the effect of cis-trans isomerism. Indeed the transiently chiral cis-CD also forms preferentially heterodimers, whose structure is very close to that of the corresponding trans-CD dimer.

Conformer-Selective Photoelectron Circular Dichroism.

Conformational flexibility and chirality both play a key role in molecular recognition. It is therefore very useful to develop spectroscopic methods that simultaneously probe both properties. It has been theoretically predicted that photoelectron circular dichroism (PECD) should be very sensitive to conformational isomerism. However, experimental proof has been less forthcoming and only exists for a very few favorable cases. Here, we present a new PECD scheme based on resonance-enhanced two-photon ionization (RE2PI) using UV/Vis nanosecond laser excitations. The spectral resolution obtained thereby guarantees conformer-selectivity by inducing resonant conformer-specific ππ* S1←S0 transitions. We apply this experimental scheme to the study of chiral 1-indanol, which exists in two conformers linked by a ring inversion and defined by the position of the hydroxyl group, namely axial and equatorial. We show that the PECD of the equatorial and axial forms considerably differ in sign, magnitude and shape. We also discuss the influence of the total ionization energy, vibronic excitation of intermediate and final states, and relative polarization of the excitation and ionization lasers. Conformer-specificity adds a new dimension to the applications of PECD in analytical chemistry addressing now the general case of floppy systems.

Vibrational Circular Dichroism Spectroscopy with a Classical Polarizable Force Field: Alanine in the Gas and Condensed Phases.

Polarizable force fields are an essential component for the chemically accurate modeling of complex molecular systems with a significant degree of fluxionality, beyond harmonic or perturbative approximations. In this contribution we examine the performance of such an approach for the vibrational spectroscopy of the alanine amino acid, in the gas and condensed phases, from the Fourier transform of appropriate time correlation functions generated along molecular dynamics (MD) trajectories. While the infrared (IR) spectrum only requires the electric dipole moment, the vibrational circular dichroism (VCD) spectrum further requires knowledge of the magnetic dipole moment, for which we provide relevant expressions to be used with polarizable force fields. The AMOEBA force field was employed here to model alanine in the neutral and zwitterionic isolated forms, solvated by water or nitrogen, and as a crystal. Within this framework, comparison of the electric and magnetic dipole moments to those obtained with nuclear velocity perturbation theory based on density-functional theory for the same MD trajectories are found to agree well with one another. The statistical convergence of the IR and VCD spectra is examined and found to be more demanding in the latter case. Comparisons with experimental frequencies are also provided for the condensed phases.

Induced photoelectron circular dichroism onto an achiral chromophore.

An achiral chromophore can acquire a chiral spectroscopic signature when interacting with a chiral environment. This so-called induced chirality is documented in electronic or vibrational circular dichroism, which arises from the coupling between electric and magnetic transition dipoles. Here, we demonstrate that a chiroptical response is also induced within the electric dipole approximation by observing the asymmetric scattering of a photoelectron ejected from an achiral chromophore in interaction with a chiral host. In a phenol-methyloxirane complex, removing an electron from an achiral aromatic π orbital localised on the phenol moiety results in an intense and opposite photoelectron circular dichroism (PECD) for the two enantiomeric complexes with (R) and (S) methyloxirane, evidencing the long-range effect (~5 Å) of the scattering chiral potential. This induced chirality has important structural and analytical implications, discussed here in the context of growing interest in laser-based PECD, for in situ, real time enantiomer determination.

Does Chiral Sensitivity of a Structure Depend on the Metal Core? Alkali Ion Complexes of Cyclo(Tyr-Tyr).

Alkali metal complexes of cyclic dipeptide cyclo Tyr-Tyr have been studied under cryogenic ion trap conditions. Their structure was obtained by combining Infra-Red Photo-Dissociation (IRPD) and quantum chemical calculations. The structural motif strongly depends on the relative chirality of the tyrosine residues. For residues of identical chirality, the cation interacts with one amide oxygen and one of the aromatic rings only; the distance between the aromatic rings does not change with the nature of the metal. In contrast, for residues of opposite chirality, the metal cation is located in between the two aromatic rings and interacts with both of them. The distance between the two aromatic rings strongly depends on the metal. Electronic spectra obtained by Ultra Violet Photodissociation (UVPD) spectroscopy and analysis of the UV photo-fragments shed light on the excited state deactivation processes, which depend on both the chirality of the residue and that of the metal ion core. Na+ stands out by the presence of low-lying charge transfer states resulting in the broadening of the electronic spectrum.

Subtle hydrogen bond preference and dual Franck-Condon activity - the interesting pairing of 2-naphthol with anisole.

The hydrogen-bonded complexes between 2-naphthol (or ß-naphthol) and anisole are explored by detecting their IR absorption in the OH stretching range as well as their UV absorption by means of laser-induced fluorescence and resonance-enhanced two-photon UV ionisation. For the more stable cis and the metastable trans conformations of the OH group in 2-naphthol, hydrogen bonding to the oxygen atom of anisole is consistently detected in different supersonic jet expansions. Alternative hydrogen bonding to the aromatic ring of anisole remains elusive, although the majority of state-of-the-art hybrid DFT functionals with London dispersion correction and - less surprisingly - MP2 wavefunction theory predict it to be slightly more stable at zero-point level, unless three-body dispersion correction is added to the B3LYP-D3(BJ) approach. This changes at the CCSD(T) level, which forecasts an energy advantage of 1-3 kJ mol-1 for the classical hydrogen bond arrangement even after including (DFT) zero-point energy contributions. The UV and IR spectra of the cis complex exhibit clear evidence for intensity redistribution of the primary OH stretch oscillator to combination states with the same low-frequency intermolecular bending mode by Franck-Condon-type vertical excitation mechanisms. This rare case of dual (vibronic and vibrational) Franck-Condon activity of a low-frequency mode invites future studies of homologues where aromatic ring docking of the OH group may be further stabilised, e.g. through anisole ring methylation.

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.

Do Stereochemical Effects Overcome a Charge-Induced Perturbation in Isolated Protonated Cyclo(Tyr-Tyr)?

Two diastereomers of the protonated diketopiperazine (DKP) dipeptide cyclo(Tyr-Tyr), namely, cyclo(LTyr-LTyr)H+ and cyclo(LTyr-DTyr)H+, are studied in a cryogenic ion trap by means of IR photodissociation spectroscopy combined with quantum chemical calculations. The two diastereomers have similar structures in which one of the rings is folded over the DKP ring and the other one is extended in a trans geometry, allowing a strong OH+···π interaction to take place. This contrasts to the observation of a stacked geometry for neutral cyclo(LTyr-LTyr) only under supersonic expansion conditions that do not exist for cyclo(LTyr-DTyr). In the protonated form, the strength of the OH+···π interaction is different for the two diastereomers, resulting in a ∼110 cm-1 difference in the ν(OH+) frequency and a smaller but clearly identifiable difference in the protonated amide ν(NH) frequency. Stereochemical effects are therefore still evidenced despite the strong perturbation due to the excess charge.

How change in chirality prevents ß-amyloid type interaction in a protonated cyclic dipeptide dimer.

The protonated dimers of the diketopiperazine dipeptide cyclo (LPhe-LHis) and cyclo (LPhe-DHis) are studied by laser spectroscopy combined with mass spectrometry to shed light on the influence of stereochemistry on the clustering propensity of cyclic dipeptides. The marked spectroscopic differences experimentally observed in the hydride stretch region are well accounted for by the results of DFT calculations. Both diastereomeric protonated dimers involve a strong ionic hydrogen bond from the protonated imidazole ring of one monomer to the neutral imidazole nitrogen of the other. While this strong interaction is accompanied by a single NH⋯O hydrogen bond between the amide functions of the two moieties for the protonated dimer of cyclo (LPhe-DHis), that of cyclo (LPhe-LHis) involves two NH⋯O interactions, forming the motif of an antiparallel ß sheet. Therefore, a change in chirality of the residue prevents the formation of the ß sheet pattern observed in the amyloid type aggregation. These results emphasize the peculiar role of the histidine residue in peptide structure and interaction.

Photoelectron Circular Dichroism as a Signature of Subtle Conformational Changes: The Case of Ring Inversion in 1-Indanol.

Chirality plays a fundamental role in the molecular recognition processes. Molecular flexibility is also crucial in molecular recognition, allowing the interacting molecules to adjust their structures and hence optimize the interaction. Methods probing simultaneously chirality and molecular conformation are therefore crucially needed. Taking advantage of a possible control in the gas phase of the conformational distribution between the equatorial and axial conformers resulting from a ring inversion in jet-cooled 1-indanol, we demonstrate here the sensitivity of valence-shell photoelectron circular dichroism (PECD) to both chirality and subtle conformational changes, in a case where the photoelectron spectra of the two conformers are identical. For the highest occupied orbital, we observe a dramatic inversion of the PECD-induced photoelectron asymmetries, while the photoionization cross-section and usual anisotropy (ß) parameter are completely insensitive to conformational isomerism. Such a sensitivity is a major asset for the ongoing developments of PECD-based techniques as a sensitive chiral (bio)chemical analytical tool in the gas phase.

Competition between inter and intramolecular hydrogen bond evidenced by vibrational circular dichroism spectroscopy: The case of (1S,2R)-(-)-cis-1-amino-2-indanol.

The infrared (IR) absorption and vibrational circular dichroism (VCD) spectra of an intramolecularly hydrogen-bonded chiral amino-alcohol, (1S,2R)-(-)-cis-1-amino-2-indanol, are studied in DMSO-d6 . The spectra are simulated at the density functional theory (DFT) level within the frame of the cluster-in-the-liquid model. Both IR and VCD spectra show a clear signature of the formation of intermolecular hydrogen bonds at the detriment of the intramolecular OH … N interaction present in the isolated molecule. Two solvent molecules are necessary to reproduce the experimental spectra. Whereas the first DMSO molecule captures the main spectral modifications due to hydrogen bond formation between the solute and the solvent, the second DMSO molecule is necessary for a good description of the Boltzmann contribution of the different complexes, based on their Gibbs free energy.

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.

Assessing cluster models of solvation for the description of vibrational circular dichroism spectra: synergy between static and dynamic approaches.

Solvation effects are essential for defining the shape of vibrational circular dichroism (VCD) spectra. Several approaches have been proposed to include them into computational models for calculating VCD signals, in particular those resting on the "cluster-in-a-liquid" model. Here we examine the capabilities of this ansatz on the example of flexible (1S,2S)-trans-1-amino-2-indanol solvated in dimethyl sulfoxide (DMSO). We compare cluster sets obtained from static calculations with results from explicit molecular dynamics (MD) trajectories based on either force field (FF) or first-principles (FP) methods. While the FFMD approach provides a broader sampling of configurational space, FPMD and time-correlation functions of dipole moments account for anharmonicity and entropy effects in the VCD calculation. They provide a means to evaluate the immediate effect of the solvent on the spectrum. This survey singles out several challenges associated with the use of clusters to describe solvation effects in systems showing shallow potential energy surfaces and non-covalent interactions. Static structures of clusters involving a limited number of solvent molecules satisfactorily capture the main effects of solvation in the bulk limit on the VCD spectra, if these structures are correctly weighted. The importance of taking into consideration their fluxionality, i.e. different solvent conformations sharing a same hydrogen bond pattern, and the limitations of small clusters for describing the solvent dynamics are discussed.

Chiral discrimination between tyrosine and ß-cyclodextrin revealed by cryogenic ion trap infrared spectroscopy.

Complexes of permethylated ß-cyclodextrin (ß-MCD) with the two enantiomers of protonated tyrosine (l- and d-TyrH+) are studied by cryogenic ion trap infrared photo-dissociation spectroscopy. The vibrational spectra in the OH/NH stretch and fingerprint regions are assigned based on density functional theory calculations. The spectrum of both l- and d-TyrH+ complexes contains features characteristic of a first structure with ammonium and acid groups of the amino acid simultaneously interacting with the ß-MCD, the phenolic OH remaining free. A second structure involving additional interaction between the phenolic OH and the ß-MCD is observed only for the complex with d-TyrH+. The larger abundance of the d-TyrH+ complex in the mass spectrum is tentatively explained in terms of (1) better insertion of d-TyrH+ within the cavity with the hydrophobic aromatic moiety less exposed to hydrophilic solvent molecules and (2) a stiff structure involving three interaction points, namely the ammonium, the phenolic OH and the carboxylic acid OH, which is not possible for the complex with l-TyrH+. The recognition process does not occur through size effects that induce complementarity to the host molecule but specific interactions. These results provide a comprehensive understanding of how the cyclodextrin recognises a chiral biomolecule.

Solid-state synthesis of cyclo LD-diphenylalanine: A chiral phase built from achiral subunits.

The solid-state structure of LL/DD or LD/DL diphenylalanine diluted in KBr pellets is studied by infrared (IR) absorption and vibrational circular dichroism (VCD) spectroscopy. The structure depends on the absolute configuration of the residues. The natural LL diphenylalanine exists as a mixture of neutral and zwitterionic structures, depending on the humidity of the sample, while mostly the zwitterion is observed for LD diphenylalanine whatever the experimental conditions. The system undergoes spontaneous cyclization upon heating at 125°C, resulting to the formation of a diketopiperazine (DKP) dipeptide as the only product. The reaction is faster for LD than for LL diphenylalanine. As expected, LL and DD diphenylalanine react to form the LL and DD enantiomers of cyclo diphenylalanine. Interestingly, the DKP dipeptides formed from the LD or DL diphenylalanine show unexpected optical activity, with opposite VCD spectra for the products formed from the LD and DL reagents. This is explained in terms of chirality synchronization between the monomers within the crystal, which retain the symmetry of the reagent, resulting to the formation of a new chiral phase made from transiently chiral molecules.

Conformation control through concurrent N-H⋯S and N-H⋯O[double bond, length as m-dash]C hydrogen bonding and hyperconjugation effects.

In addition to the classical N-H⋯O[double bond, length as m-dash]C non-covalent interaction, less conventional types of hydrogen bonding, such as N-H⋯S, may play a key role in determining the molecular structure. In this work, using theoretical calculations in combination with spectroscopic analysis in both gas phase and solution phase, we demonstrate that both these H-bonding modes exist simultaneously in low-energy conformers of capped derivatives of Attc, a thietane α-amino acid. 6-Membered ring inter-residue N-H⋯S interactions (C6γ), assisted by hyperconjugation between the thietane ring and the backbone, combine with 5-membered ring intra-residue backbone N-H⋯O[double bond, length as m-dash]C interactions (C5) to provide a C5-C6γ feature that stabilizes a planar geometry in the monomer unit. Two contiguous C5-C6γ features in the planar dimer implicate an unprecedented three-centre H-bond of the type C[double bond, length as m-dash]O⋯H(N)⋯SR2, while the trimer adopts two C5-C6γ features separated by a Ramachandran α-type backbone configuration. These low-energy conformers are fully characterized in the gas phase and support is presented for their existence in solution state.

The reduced cohesion of homoconfigurational 1,2-diols.

By a combination of linear FTIR and Raman jet spectroscopy, racemic trans-1,2-cyclohexanediol is shown to form an energetically unrivalled S4-symmetric heterochiral dimer in close analogy to 1,2-ethanediol. Analogous experiments with enantiopure trans-1,2-cyclohexanediol reveal the spectral signature of at least three unsymmetric homochiral dimers. A comparison to signal-enhanced spectra of 1,2-ethanediol and to calculations uncovers at least three transiently homochiral dimer contributions as well. In few of these dimer structures, the intramolecular OHO contact present in monomeric 1,2-diols survives, despite the kinetic control in supersonic jet expansions. This provides further insights into the dimerisation mechanism of conformationally semi-flexible molecules in supersonic jets. Racemisation upon dimerisation is shown to be largely quenched under jet cooling conditions, whereas it should be strongly energy-driven at higher temperatures. The pronounced energetic preference for heterochiral aggregation of vicinal diols is also discussed in the context of chirality-induced spin selectivity.

Conformational Study of the Jet-Cooled Diketopiperazine Peptide Cyclo Tyrosyl-Prolyl.

The conformational landscape of the diketopiperazine (DKP) dipeptide built on tyrosine and proline, namely, cyclo Tyr-Pro, is studied by combining resonance-enhanced multiphoton ionization, double resonance infrared ultraviolet (IR-UV) spectroscopy, and quantum chemical calculations. Despite the geometrical constraints due the two aliphatic rings, DKP and proline, cyclo Tyr-Pro is a flexible molecule. For both diastereoisomers, cyclo LTyr-LPro and cyclo LTyr-DPro, two structural families coexist under supersonic jet conditions. In the most stable conformation, the aromatic tyrosine substituent is folded over the DKP ring (g+ geometry of the aromatic ring) as it is in the solid state. The other structure is completely extended (g- geometry of the aromatic ring) and resembles that proposed for the vapor phase. IR-UV results are not sufficient for unambiguous assignment of the observed spectra to either folded or extended conformations and the simulation of the vibronic pattern of the S0-S1 transition is necessary. Still, the comparison between IR-UV results and anharmonic calculations allows explanation of the minor structural differences between cyclo LTyr-LPro and cyclo LTyr-DPro in terms of different NH···π and CH···π interactions.

Effects of complexation with sulfuric acid on the photodissociation of protonated Cinchona alkaloids in the gas phase.

The effect of complexation with sulfuric acid on the photo-dissociation of protonated Cinchona alkaloids, namely cinchonidine (Cd), quinine (Qn) and quinidine (Qd), is studied by combining laser spectroscopy with quantum chemical calculations. The protonated complexes are structurally characterized in a room-temperature ion trap by means of infra-red multiple photon dissociation (IRMPD) spectroscopy in the fingerprint and the ν(XH) (X = C, N, O) stretch regions. Comparison with density functional theory calculations including dispersion (DFT-D) unambiguously shows that the complex consists of a doubly protonated Cinchona alkaloid strongly bound to a bisulfate HSO4- anion, which bridges the two protonated sites of the Cinchona alkaloid. UV excitation of the complex does not induce loss of specific photo fragments, in contrast to the protonated monomer or dimer, for which photo-specific fragments were observed. Indeed the UV-induced fragmentation pattern is identical to that observed in collision-induced dissociation experiments. Analysis of the nature of the first electronic transitions at the second order approximate coupled-cluster level (CC2) explains the difference in the behavior of the complex relative to the monomer or dimer towards UV excitation.

Vibrational circular dichroism as a probe of solid-state organisation of derivatives of cyclic ß-amino acids: Cis- and trans-2-aminocyclobutane-1-carboxylic acid.

Peptide models built from cis- and trans-2-aminocyclobutane-1-carboxylic acids (ACBCs) are studied in the solid phase by combining Fourier-transform infrared spectroscopy (FTIR) absorption spectroscopy, vibrational circular dichroism (VCD), and quantum chemical calculations using density functional theory (DFT). The studied systems are N-tert-butyloxycarbonyl (Boc) derivatives of 2-aminocyclobutanecarboxylic acid (ACBC) benzylamides, namely Boc-(cis-ACBC)-NH-Bn and Boc-(trans-ACBC)-NH-Bn. These two diastereomers show very different VCD signatures and intensities, which of the trans-ACBC derivative being one order of magnitude larger in the region of the ν (CO) stretch. The spectral signature of the cis-ACBC derivative is satisfactorily reproduced by that of the monomer extracted from the solid-state geometry of related ACBC derivatives, which shows that no long-range effects are implicated for this system. In terms of hydrogen bonds, the geometry of this monomer is intermediate between the C6 and C8 structures (exhibiting a 6- or 8-membered cyclic NH⋯O hydrogen bond) previously evidenced in the gas phase. The benzyl group must be in an extended geometry to reproduce satisfactorily the shape of the VCD spectrum in the ν (CO) range, which qualifies VCD as a potential probe of dispersion interaction. In contrast, reproducing the IR and VCD spectrum of the trans-ACBC derivative requires clusters larger than four units, exhibiting strong intermolecular H-bonding patterns. A qualitative agreement is obtained for a tetramer, although the intensity enhancement is not reproduced. These results underline the sensitivity of VCD to the long-range organisation in the crystal.