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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Stereochemistry-dependent hydrogen bonds stabilise stacked conformations in jet-cooled cyclic dipeptides: (LD) vs. (LL) cyclo tyrosine-tyrosine.

Tyrosine-containing cyclic dipeptides based on a diketopiperazine (DKP) ring are studied under jet-cooled conditions using resonance-enhanced multi-photon ionisation (REMPI), conformer-selective IR-UV double resonance vibrational spectroscopy and quantum chemical calculations. The conformational landscape of the dipeptide containing natural L tyrosine (Tyr), namely c-LTyr-LTyr strongly differs from that of its diastereomer c-LTyr-DTyr. A similar family of conformers exists in both systems, with one aromatic ring folded on the dipeptide DKP ring and the other one extended. Weak NHπ and CHπ interactions are observed, which are slightly different in c-LTyr-LTyr and c-LTyr-DTyr. These structures are identical to those of LL and LD cyclo diphenylalanine, which only differ from c-Tyr-Tyr by the absence of hydroxyl on the benzene rings. While this is the only conformation observed for c-LTyr-DTyr, c-LTyr-LTyr exhibits an additional form stabilised by the interaction of the two hydroxyls, in which the two aromatic rings are in a stacked geometry. Stereochemical effects are still visible in the radical cation, for which one structure is observed for c-LTyr-DTyr, while the spectrum of the c-LTyr-LTyr radical cation is explained in terms of two co-existing structures.

Effect of puckering motion and hydrogen bond formation on the vibrational circular dichroism spectrum of a flexible molecule: the case of (S)-1-indanol.

The influence of flexibility and hydrogen bond formation on the IR absorption and vibrational circular dichroism (VCD) spectrum of a floppy protic molecule, namely, (S)-1-indanol, is studied in both non-polar CCl4 and polar DMSO solvents. The experimental IR absorption and VCD spectra obtained by Fourier transform spectroscopy are interpreted using both static density functional theory (DFT) calculations and first principles molecular dynamics (FPMD) within DFT, using the nuclear velocity perturbation theory (NVPT). Simulation of the spectra based on static optimised geometries is not sufficient in CCl4 and going beyond static calculations is mandatory for satisfactorily reproducing the VCD spectra. The FPMD results obtained in DMSO indicate that (S)-1-indanol is hydrogen-bonded to one DMSO molecule. As a result, static "cluster-in-the-bulk" DFT calculations in which the solute-solvent interaction is modeled as the most stable (S)-1-indanol:DMSO complexes in a DMSO continuum yield satisfactory agreement with the experiment. Correspondence between experimental and simulated spectra is slightly improved when the VCD spectrum is calculated as the summed contributions of snapshots extracted from FPMD trajectories, due to better sampling of the potential-energy surface. Finally, NVPT calculations further improve the description of experimental spectra by taking into account higher-energy structures, which are not necessary local minima.

Stereochemistry-dependent structure of hydrogen-bonded protonated dimers: the case of 1-amino-2-indanol.

To understand the role of chirality in shaping biological supramolecular systems it is instructive to visualize the subtle effects of stereochemistry on the structure of model aggregates at the molecular level. Here, we apply conformer-specific IR-UV double-resonance laser spectroscopy in a cold ion trap to derive a detailed description of the protonated homodimers of (1R,2S)-cis- and (1R,2R)-trans-1-amino-2-indanol (c-AI2H+, t-AI2H+). Although the protonated monomers (c-AIH+, t-AIH+) only differ by the chirality of one carbon atom, their conformations are clearly distinct. c-AIH+ has an intramolecular NH+O hydrogen bond (H-bond), while t-AIH+ lacks such an interaction. This has crucial consequences on the geometry and stability of the corresponding c-AI2H+ and t-AI2H+ dimers. While there is a competition between intra- and intermolecular H-bonds in c-AI2H+, the formation of t-AI2H+ does not require deformation of the monomers. This difference results in higher binding energies of t-AI2H+ compared to c-AI2H+. To optimize the H-bond network, the two dimers do not necessarily involve the corresponding most stable monomers. c-AI2H+ and t-AI2H+ differ in their UV photodissociation mass spectra and in their electronic spectra, which suggests different geometries also in the excited state.

Vibrational circular dichroism of a 2,5-diketopiperazine (DKP) peptide: Evidence for dimer formation in cyclo LL or LD diphenylalanine in the solid state.

The diastereomer diketopiperazine (DKP) peptides built on phenylalanine, namely, cyclo diphenylalanine LPhe-LPhe and LPhe-DPhe, were studied in the solid phase by vibrational circular dichroism (VCD) coupled to quantum chemical calculations. The unit structure of cyclo LPhe-LPhe in KBr pellets is a dimer bridged by two strong NH…O hydrogen bonds. The intense bisignate signature in the CO stretch region is interpreted in terms of two contributions arising from the free COs of the dimer and the antisymmetrical combination of the bound COs. In contrast, cyclo LPhe-DPhe shows no VCD signal in relation to its symmetric nature.

Photofragmentation mechanisms in protonated chiral cinchona alkaloids.

The photo-stability of protonated cinchona alkaloids is studied in the gas phase by a multi-technique approach. A multi-coincidence technique is used to demonstrate that the dissociation is a direct process. Two dissociation channels are observed. They result from the C8-C9 cleavage, accompanied or not by hydrogen migration. The branching ratio between the two photo-fragments is different for the two pseudo-enantiomers quinine and quinidine. Mass spectrometry experiments coupling UV photo-dissociation of the reactants and structural characterization of the ionic photo-products by Infra-Red Multiple Photo-Dissociation (IRMPD) spectroscopy provide unambiguous information on their structure. In addition, quantum chemical calculations allow proposing a reactive scheme and discussing it in terms of the ground-state geometry of the reactant.