The first HyDRA challenge for computational vibrational spectroscopy.

Vibrational spectroscopy in supersonic jet expansions is a powerful tool to assess molecular aggregates in close to ideal conditions for the benchmarking of quantum chemical approaches. The low temperatures achieved as well as the absence of environment effects allow for a direct comparison between computed and experimental spectra. This provides potential benchmarking data which can be revisited to hone different computational techniques, and it allows for the critical analysis of procedures under the setting of a blind challenge. In the latter case, the final result is unknown to modellers, providing an unbiased testing opportunity for quantum chemical models. In this work, we present the spectroscopic and computational results for the first HyDRA blind challenge. The latter deals with the prediction of water donor stretching vibrations in monohydrates of organic molecules. This edition features a test set of 10 systems. Experimental water donor OH vibrational wavenumbers for the vacuum-isolated monohydrates of formaldehyde, tetrahydrofuran, pyridine, tetrahydrothiophene, trifluoroethanol, methyl lactate, dimethylimidazolidinone, cyclooctanone, trifluoroacetophenone and 1-phenylcyclohexane-cis-1,2-diol are provided. The results of the challenge show promising predictive properties in both purely quantum mechanical approaches as well as regression and other machine learning strategies.

Setting up the HyDRA blind challenge for the microhydration of organic molecules.

The procedure leading to the first HyDRA blind challenge for the prediction of water donor stretching vibrations in monohydrates of organic molecules is described. A training set of 10 monohydrates with experimentally known and published water donor vibrations is presented and a test set of 10 monohydrates with unknown or unpublished water donor vibrational wavenumbers is described together with relevant background literature. The rules for data submissions from computational chemistry groups are outlined and the planned publication procedure after the end of the blind challenge is discussed.

A theoretical and experimental case study of the hydrogen bonding predilection of S-methylcysteine.

S-containing amino acids can lead to two types of local NH···S interactions which bridge backbone NH sites to the side chain to form either intra- or inter-residue H-bonds. The present work reports on the conformational preferences of S-methyl-L-cysteine, Cys(Me), using a variety of investigating tools, ranging from quantum chemistry simulations, gas-phase UV and IR laser spectroscopy, and solution state IR and NMR spectroscopies, on model compounds comprising one or two Cys(Me) residues. We demonstrate that in gas phase and in low polarity solution, the C- and N-capped model compound for one Cys(Me) residue adopts a preferred C5-C6γ conformation which combines an intra-residue N-H···O=C backbone interaction (C5) and an inter-residue N-H···S interaction implicating the side-chain sulfur atom (C6γ). In contrast, the dominant conformation of the C- and N-capped model compound featuring two consecutive Cys(Me) residues is a regular type I ß-turn. This structure is incompatible with concomitant C6γ interactions, which are no longer in evidence. Instead, C5γ interactions occur, that are fully consistent with the turn geometry and additionally stabilize the structure. Comparison with the thietane amino acid Attc, which exhibits a rigid cyclic side chain, pinpoints the significance of side chain flexibility for the specific conformational behavior of Cys(Me).

Supersonic jet spectroscopy of parent hemiporphycene: Structural assignment and vibrational analysis for S0 and S1 electronic states.

Hemiporphycene (HPc), a constitutional isomer of porphyrin, is studied under supersonic expansion conditions by means of laser-induced fluorescence, visible-visible hole-burning experiments, single vibronic level fluorescence techniques, and quantum chemical calculations. Only one trans form of jet-cooled HPc is observed, in contrast to solution studies that evidence a mixture of two trans tautomeric forms separated in energy by ∼1 kcal/mol. Reliable structural assignment is provided by simulating absorption and emission patterns at the density functional theory and time-dependent density functional theory levels of theory. The vibronic spectra are nicely reproduced for both electronic ground and lowest excited singlet states for the most stable trans form. In contrast to another porphyrin isomer, porphycene (Pc), no tunneling or photo-induced hydrogen transfer is detected. The lower symmetry of HPc compared with Pc and the concomitant non-equivalent positions of the inner-cavity nitrogen atoms result in a non-symmetric double minimum potential for tautomerization, larger energy barrier, and a longer tunneling distance, with the average intramolecular hydrogen bond length larger in HPc than in Pc. HPc readily forms hydrates that show red-shifted absorption relative to the bare molecule.

Molecular Recognition by a Short Partial Peptide of the Adrenergic Receptor: A Bottom-Up Approach.

Receptor-neurotransmitter molecular recognition is key for neurotransmission. Although crystal structures of the receptors are known, the mechanism for recognition is not clear. Reported here is the ultraviolet (UV) and infrared (IR) spectra of complexes between a partial peptide (SIVSF), mimicking the binding motif of a catechol ring in the adrenergic receptor, and various ligands. The UV spectra show that two isomers coexist in the complex of SIVSF with properly recognized ligands, such as protonated adrenaline (adrenalineH+ ). From IR spectra, they are assigned to catechol- and amino-bound structures. The catechol-bound structure is not observed when the ligand is replaced by nonproper molecules, such as noradrenalineH+ . The results suggest that SIVSF not only recognizes the catechol ring but can distinguish differences in the amine side chain. The method provides a new possibility for screening molecules as potential therapeutics for activating the receptor.

Does the Residues Chirality Modify the Conformation of a Cyclo-Dipeptide? Vibrational Spectroscopy of Protonated Cyclo-diphenylalanine in the Gas Phase.

The structure of a protonated diketopiperazine dipeptide, cyclo-diphenylalanine, is studied by means of infrared multiple photon dissociation spectroscopy combined with quantum chemical calculations. Protonation exclusively occurs on the oxygen site and, in the most stable conformer, results to an intramolecular OH···π interaction, accompanied by a CH···π interaction. Higher-energy conformers with free OH and NH···π interactions are observed as well, due to kinetic trapping. Optimization of the intramolecular interactions involving the aromatic ring dictates the geometry of the benzyl substituents. Changing the chirality of one of the residues has consequences on the CH···π interaction, which is of CαH···π nature for LD, while LL shows a CßH···π interaction. Higher-energy conformers also display some differences in the nature of the intramolecular interactions.

Competition between inter- and intra-molecular hydrogen bonding: An infrared spectroscopic study of jet-cooled amino-ethanol and its dimer.

The Fourier transform IR vibrational spectra of amino-ethanol (AE) and its dimer have been recorded at room temperature and under jet-cooled conditions over the far and mid infrared ranges (50-4000 cm-1) using the White-type cell and the supersonic jet of the Jet-AILES apparatus at the synchrotron facility SOLEIL. Assignment of the monomer experimental frequencies has been derived from anharmonic frequencies calculated at a hybrid CCSD(T)-F12/MP2 level. Various thermodynamical effects in the supersonic expansion conditions including molar dilution of AE and nature of carrier gas have been used to promote or not the formation of dimers. Four vibrational modes of the observed dimer have been unambiguously assigned using mode-specific scaling factors deduced from the ratio between experimental and computed frequencies for the monomer. The most stable g'Gg' monomer undergoes strong deformation upon dimerization, leading to a homochiral head to head dimer involving two strong hydrogen bonds.

Intrinsic Folding Proclivities in Cyclic ß-Peptide Building Blocks: Configuration and Heteroatom Effects Analyzed by Conformer-Selective Spectroscopy and Quantum Chemistry.

This work describes the use of conformer-selective laser spectroscopy following supersonic expansion to probe the local folding proclivities of four-membered ring cyclic ß-amino acid building blocks. Emphasis is placed on stereochemical effects as well as on the structural changes induced by the replacement of a carbon atom of the cycle by a nitrogen atom. The amide A IR spectra are obtained and interpreted with the help of quantum chemistry structure calculations. Results provide evidence that the building block with a trans-substituted cyclobutane ring has a predilection to form strong C8 hydrogen bonds. Nitrogen-atom substitution in the ring induces the formation of the hydrazino turn, with a related but distinct hydrogen-bonding network: the structure is best viewed as a bifurcated C8/C5 bond with the N heteroatom lone electron pair playing a significant acceptor role, which supports recent observations on the hydrazino turn structure in solution. Surprisingly, this study shows that the cis-substituted cyclobutane ring derivative also gives rise predominantly to a C8 hydrogen bond, although weaker than in the two former cases, a feature that is not often encountered for this building block.

Exotic Protonated Species Produced by UV-Induced Photofragmentation of a Protonated Dimer: Metastable Protonated Cinchonidine.

A metastable protonated cinchona alkaloid was produced in the gas phase by UV-induced photodissociation (UVPD) of its protonated dimer in a Paul ion trap. The infrared multiple photon dissociation (IRMPD) spectrum of the molecular ion formed by UVPD was obtained and compared to DFT calculations to characterize its structure. The protonation site obtained thereby is not accessible by classical protonation ways. The protonated monomer directly formed in the ESI source or by collision-induced dissociation (CID) of the dimer undergoes protonation at the most basic alkaloid nitrogen. In contrast, protonation occurs at the quinoline aromatic ring nitrogen in the UVPD-formed monomer.

Direct spectroscopic evidence of hyperconjugation unveils the conformational landscape of hydrazides.

The stereochemistry of hydrazides makes them especially interesting as building blocks for molecular design. An exhaustive conformational analysis of three model hydrazides was conducted in a conformer-selective approach by using a combination of high-level quantum chemistry calculations and vibrational spectroscopy in the gas phase and in solution. The NH stretch frequency was found to be highly sensitive to hyperconjugation, thus making it an efficient probe of the conformation of the neighboring nitrogen atom. This property greatly assisted the identification of the isomers observed experimentally in the conformer pool. A rationalization of the hydrazide conformational landscape is proposed, therefore paving the way for a better characterization of secondary structures in larger systems.

Chirality-dependent balance between hydrogen bonding and London dispersion in isolated (±)-1-indanol clusters.

The aggregation behavior of racemic and enantiopure 1-indanol has been studied by FTIR spectroscopy, resonant ion dip IR spectroscopy, and spontaneous Raman scattering in supersonic jets. This triple experimental approach, augmented by homology to related molecular fragments and dispersion-corrected DFT predictions, allows disentangling the complex spectroscopic signature in the OH stretch range. Evidence for chirality-sensitive aggregation via isolated OH···π bonds in competition with cooperative ···OH···OH···π patterns is collected. An accurate description of London dispersion forces provides the key to its explanation.

Mass spectrometry study and infrared spectroscopy of the complex between camphor and the two enantiomers of protonated alanine: the role of higher-energy conformers in the enantioselectivity of the dissociation rate constants.

The properties of the protonated complexes built from S camphor and R or S alanine were studied in a Paul ion trap at room temperature by collision-induced dissociation (CID) and infrared multiple-photon dissociation spectroscopy (IRMPD), as well as molecular dynamics and ab initio calculations. While the two diastereomer complexes display very similar vibrational spectra in the fingerprint region, in line with similar structures, and almost identical calculated binding energies, their collision-induced dissociation rates are different. Comparison of the IRMPD results to computed spectra shows that the SS and SR complexes both contain protonated alanine strongly hydrogen-bonded to the keto group of camphor. The floppiness of this structure around the NH⁺...O=C hydrogen bond results in a complex potential energy surface showing multiple minima. Calculating the dissociation rate constant within the frame of the transition state theory shows that the fragmentation rate larger for the heterochiral SR complex than the homochiral SS complex can be explained in terms of two almost isoenergetic low-energy conformers in the latter that are not present for the former.

Non-covalent interactions reveal the protein chain δ conformation in a flexible single-residue model.

The δ conformation is a local secondary structure in proteins that implicates a πamide N-H⋯N interaction between a backbone N atom and the NH of the following residue. Small-molecule models thereof have been limited so far to rigid proline-type compounds. We show here that in derivatives of a cyclic amino acid with a sulphur atom in the γ-position, specific side-chain/backbone N-H⋯S interactions stabilize the δ conformation sufficiently to allow it to compete with classical C5 and C7 H-bonded conformers.

Role of conformational isomerism in solvent-mediated charge transfer in chiral (S) 1,2,3,4-tetrahydro-3-isoquinoline methanol (THIQM): condensed-phase to jet-cooled spectroscopic studies.

Intramolecular charge-transfer reaction in chiral (S) 1,2,3,4-tetrahydro-3-isoquinoline methanol (THIQM) has been investigated in the condensed phase and in jet-cooled conditions by means of laser-induced fluorescence, dispersed emission, resonance-enhanced two-photon ionization, and IR-UV double resonance experiments, as well as quantum chemical calculations. In the condensed phase, THIQM only shows local emission in nonpolar and protic solvents and dual emission in aprotic polar solvents, where the solvent-polarity dependent Stokes shifted emission is ascribed to a state involving charge transfer from the nitrogen lone pair to the benzene π-cloud. Ab initio calculations reveal two low-energy conformers, which are observed in jet-cooled conditions. In the most stable conformer, THIQM(I), the CH(2)OH substituent acts as a hydrogen bond donor to the nitrogen lone pair in the equatorial position, while the second most stable conformer, THIQM(II), corresponds to the opposite NH···O hydrogen bond, with the nitrogen lone pair in the axial position. The two low-energy jet-cooled conformers of THIQM evidenced from the laser-induced fluorescence and dispersed emission spectra only show structured local emission. Complexes with usual solvents reproduce the condensed phase properties. The jet-cooled complex with aprotic polar solvent acetonitrile shows both local emission and charge transfer emission as observed in solution. The jet-cooled hydrate mainly shows local emission due to the unavailability of the nitrogen lone pair through intermolecular hydrogen bonding.

Efficient incorporation and protection of lansoprazole in cyclodextrin metal-organic frameworks.

Lansoprazole (LPZ) is an acid pump inhibitor, which readily degrades upon acidic or basic conditions and under heating. We investigated here LPZ stability upon incorporation in particles made of cyclodextrin metal-organic frameworks (CD-MOFs). LPZ loaded CD-MOFs were successfully synthesized, reaching high LPZ payloads of 23.2 ± 2.1 wt%, which correspond to a molar ratio of 1:1 between LPZ and γ-CD. The homogeneity of LPZ loaded CD-MOFs in terms of component distribution was confirmed by elemental mapping by STEM-EDX. Both CTAB, the surfactant used in the CD-MOFs synthesis, and LPZ compete for their inclusion in the CD cavities. CTAB allowed obtaining regular cubic particles of around 5 µm with 15 wt% residual CTAB amounts. When LPZ was incorporated, the residual CTAB amount was less than 0.1 wt%, suggesting a higher affinity of LPZ for the CDs than CTAB. These findings were confirmed by molecular simulations. Vibrational circular dichroism studies confirmed the LPZ incorporation inside the CDs. Solid-state NMR showed that LPZ was located in the CDs and that it remained intact even after three years storage. Remarkably, the CD-MOFs matrix protected the drug upon thermal decomposition. This study highlights the interest of CD-MOFs for the incorporation and protection of LPZ.