Noncovalent interactions are particularly intriguing when they involve chiral molecules, because the interactions change in a subtle way upon replacing one of the partners by its mirror image. The resulting phenomena involving chirality recognition are relevant in the biosphere, in organic synthesis, and in polymer design. They may be classified according to the permanent or transient chirality of the interacting partners, leading to chirality discrimination, chirality induction, and chirality synchronization processes. For small molecules, high-level quantum chemical calculations for such processes are feasible. To provide reliable connections between theory and experiment, such phenomena are best studied in vacuum isolation at low temperature, using rotational, vibrational, electronic, and photoionization spectroscopy. We review these techniques and the results which have become available in recent years, with special emphasis on dimers of permanently chiral molecules and on the influence of conformational flexibility. Analogies between the microscopic mechanisms and macroscopic phenomena and between intra- and intermolecular cases are drawn.

The NCI (Non-Covalent Interactions) method, a recently-developed theoretical strategy to visualize weak non-covalent interactions from the topological analysis of the electron density and of its reduced gradient, is applied in the present paper to document intra- and inter-molecular interactions in flexible molecules and systems of biological interest in combination with IR spectroscopy. We first describe the conditions of application of the NCI method to the specific case of intramolecular interactions. Then we apply it to a series of stable conformations of isolated molecules as an interpretative technique to decipher the different physical interactions at play in these systems. Examples are chosen among neutral molecular systems exhibiting a large diversity of interactions, for which an extensive spectroscopic characterization under gas-phase isolation conditions has been obtained using state-of-the-art conformer-specific experimental techniques. The interactions presently documented range from weak intra-molecular H-bonds in simple amino-alcohols, to more complex patterns, with interactions of various strengths in model peptides, as well as in chiral bimolecular systems, where invaluable hints for the understanding of chiral recognition are revealed. We also provide a detailed technical appendix, which discusses the choices of cut-offs as well as the applicability of the NCI analysis to specific constrained systems, where local effects require attention. Finally, the NCI technique provides IR spectroscopists with an elegant visualization of the interactions that potentially impact their vibrational probes, namely the OH and NH stretching motions. This contribution illustrates the power and the conditions of use of the NCI technique, with the aim of providing an easy tool for all chemists, experimentalists and theoreticians, for the visualization and characterization of the interactions shaping complex molecular systems.

Isomer formation in dimeric complexes of a chiral naphthalene derivative (2-naphthyl-1-ethanol) with nonchiral or chiral primary and secondary alcohols (n-propanol, 2-methyl-1-butanol, 2-butanol, 2-pentanol) has been studied by hole-burning spectroscopy. Besides the spectroscopic discrimination between the homochiral and heterochiral complexes, previously observed in the fluorescence excitation spectra, ground-state depletion experiments have shown that each diastereoisomer is cooled in the jet in several isomeric forms. To get information on the structures of the complexes and on the influence of the solvent conformations of these structures, semiempirical calculations that rely on the exchange perturbation method have been performed. It has been shown that the most stable complexes involve a H-bond between the chromophore acting as the donor and the solvent and that they involve anti and gauche conformations of the solvent. The binding energy of the complexes results from a subtle balance between electrostatic and dispersive forces: the complexes involving the gauche and anti conformers of the solvent differ from each other by the amount of dispersion energy relative to the total interaction energy. The increase in the dispersive forces calculated for the complexes with the anti conformers has been related to a larger red shift of the absorption spectrum and is suggested to play a role in the observed chiral discrimination.

The influence of methyl and methoxy substitution in the para position of the phenolic OH functional group on the intramolecular proton-transfer properties of electronically excited salicylic acid (ESIPT) has been investigated both in solution and in the isolated gas-phase conditions provided by supersonic cooling. The dual fluorescence observed for 5-methylsalicylic acid (5-MeSA) in alkane solutions has been attributed for its blue part to the excited tautomer resulting from the intramolecular proton-transfer process and for its UV component to the dimer. A single fluorescence emission peaking at 400 nm is observed in alkane solutions of 5-methoxysalicylic acid (5-MeOSA). In the presence of proton acceptors such as diethyl ether, the 5-MeSA solution emits only in the blue region while 5-MeOSA exhibits two fluorescence bands at 400 and 475 nm. This behavior shows that the ESIPT process is promoted by complexation with proton-accepting molecules. In the supersonic expansion, the excitation and dispersed emission spectra of 5-MeSA are very similar to those previously observed for unsubstituted salicylic acid and show that the ESIPT mechanism takes place without barrier, in agreement with the model of a distorted potential surface in the excited state. In contrast, the 5-MeOSA excitation and dispersed fluorescence spectra present a mirror-image relationship that indicates that the molecule keeps a similar geometry in the ground and excited state. In this case the ESIPT reaction is prevented. Complexation with diethyl ether and acetone does not give rise to a dual fluorescence as in solutions but results in a broad emission extending toward the visible. This result may be explained by a modification of the excited potential energy surface along the tautomerization coordinate without introducing an energy barrier in the proton-transfer reaction.

Chiral recognition has been studied in neutral or ionic weakly bound complexes isolated in the gas phase by combining laser spectroscopy and quantum chemical calculations. Neutral complexes of the two enantiomers of lactic ester derivatives with chiral chromophores have been formed in a supersonic expansion. Their structure has been elucidated by means of IR-UV double resonance spectroscopy in the 3 μm region. In both systems described here, the main interaction ensuring the cohesion of the complex is a strong hydrogen bond between the chromophore and methyl-lactate. However, an additional hydrogen bond of much weaker strength plays a discriminative role between the two enantiomers. For example, the 1:1 heterochiral complex between R-(+)-2-naphthyl-ethanol and S-(+) methyl-lactate is observed, in contrast with the 1:1 homochiral complex which lacks this additional hydrogen bond. On the other hand, the same kind of insertion structures is formed for the complex between S-(±)-cis-1-amino-indan-2-ol and the two enantiomers of methyl-lactate, but an additional addition complex is formed for R-methyl-lactate only. This selectivity rests on the formation of a weak CHπ interaction which is not possible for the other enantiomer. The protonated dimers of Cinchona alkaloids, namely quinine, quinidine, cinchonine and cinchonidine, have been isolated in an ion trap and studied by IRMPD spectroscopy in the region of the ν(OH) and ν(NH) stretch modes. The protonation site is located on the alkaloid nitrogen which acts as a strong hydrogen bond donor in all the dimers studied. While the nature of the intermolecular hydrogen bond is similar in the homochiral and heterochiral complexes, the heterochiral complex displays an additional weak CHO hydrogen bond located on its neutral part, which results in slightly different spectroscopic fingerprints in the ν(OH) stretch region. This first spectroscopic evidence of chiral recognition in protonated dimers opens the way to the study of the complexes of Cinchona alkaloids involved in enantioselective catalysis. These examples show how secondary hydrogen bonds controlled by stereochemical factors govern molecular recognition processes.

The methyl ester of mandelic acid is investigated by a wide range of techniques to unravel its aggregation pattern and the influence of relative chirality of the aggregating monomers. Matrix isolation confirms that a single monomer conformation prevails. The electronic spectrum of the dimers is strongly affected by the relative monomer chirality. Vibrational effects are more subtle and can be explained in terms of the most stable homo-and heteroconfigurational dimer structures, when compared to results of MP2 and DFT-D computations. Selective IR/UV double resonance techniques and wide-band FTIR spectroscopy provide largely consistent spectroscopic fingerprints of the chirality discrimination phenomena. The dominant homochiral dimer has two intermolecular O-HÁ Á ÁOQC hydrogen bonds whereas the more strongly bound heterochiral dimer involves only one such hydrogen bond. This is a consequence of the competition between dispersion and intramolecular or intermolecular hydrogen bonding. Aromatic interactions also play a role in trimers and larger clusters, favoring homochiral ring arrangements. Analogies and differences to the well-investigated methyl lactate system are highlighted. Bulk phases show a competition between different hydrogen bond patterns. The enantiopure, racemic, and 3 : 1 crystals involve infinite hydrogen-bonded chains with different arrangements of the aromatic groups. They exhibit significantly different volatility, the enantiopure compound being more volatile than the racemic crystal. The accumulated experimental and quantum-chemical evidence turns methyl mandelate into a model system for the role of competition between dispersion forces and hydrogen bond interactions in chirality discrimination.

No abstract

Intermolecular hydrogen bonding competes with an intramolecular hydrogen bond when methanol binds to an alpha-hydroxyester. Disruption of the intramolecular OH...O=C contact in favour of a cooperative OH...OH...O=C sequence is evidenced by FTIR spectroscopy for the addition of methanol to the esters methyl glycolate, methyl lactate and methyl alpha-hydroxyisobutyrate in seeded supersonic jet expansions. Comparison of the OH stretching modes with quantum-chemical harmonic frequency calculations and 18O labelling of methanol unambiguously prove the insertion of methanol into the intramolecular hydrogen bond. This is in marked contrast to UV/IR hole burning studies of the homologous system methyl lactate: (+/-)-2-naphthyl-1-ethanol, where only addition complexes were found and the intramolecular hydrogen bond was conserved. This switch in hydrogen bond pattern from aliphatic to aromatic heterodimers is thought to reflect not only a kinetic propensity but also a thermodynamic preference for addition complexes when dispersion forces become more important in aromatic systems.