Unveiling the Neutral Forms of Glutamine

Neutral glutamine has been evaporated by laser ablation of its solid sample to seed a rare gas carrier prior to a supersonic expansion and proved by Fourier transform microwave techniques. We report on three distinct neutral conformers that show a singular non‐interacting and flexible amide sidechain in contrast with the other proteinogenic aliphatic amino acids. It could explain the essential biological role of glutamine as a nitrogen source, and its unique ability to form a variety of hydrogen bonds with peptide backbones. Common computational methods fail to predict the delicate balance of intramolecular interactions controlling the geometry of the most stable conformer. The spectroscopic data here reported can be used to benchmark novel computational methods in quantum chemistry.     

How Aromatic Fluorination Exchanges the Interaction Role of Pyridine with Carbonyl Compounds: The Formaldehyde Adduct

The rotational spectrum of the weakly bound complex pentafluoropyridine⋅⋅⋅formaldehyde has been investigated using Fourier transform microwave spectroscopy. From the analysis of the rotational parameters of the parent species and of the ¹³C and ¹⁵N isotopologues, the structural arrangement of the adduct has been unambiguously established. The full ring fluorination of pyridine has a dramatic effect on its binding properties: It alters the electron density distribution at the π-cloud of pyridine creating a π-hole and changing its electron donor-acceptor capabilities. In the complex, formaldehyde lies above the aromatic ring with one of the oxygen lone pairs, as conventionally envisaged, pointing toward its centre. This lone pair⋅⋅⋅π-hole interaction, reinforced by a weak C−H⋅⋅⋅N interaction, indicates an exchange of the electron-acceptor roles of both molecules when compared to the pyridine⋅⋅⋅formaldehyde adduct. Tunnelling doublets due to the internal rotation of formaldehyde have also been observed and analysed leading to a discussion on the competition between lone pair⋅⋅⋅π-hole and π⋅⋅⋅π stacking interactions.     

The Effect of Dispersion on the Structure of Diphenyl Ether Aggregates

Dispersion interactions can play an important role in understanding unusual binding behaviors. This is illustrated by a systematic study of the structural preferences of diphenyl ether (DPE)–alcohol aggregates, for which OH???O‐bound or OH???π‐bound isomers can be formed. The investigation was performed through a multi‐spectroscopic approach including IR/UV and microwave methods, combined with a detailed theoretical analysis. The resulting solvent‐size‐dependent trend for the structural preference turns out to be counter‐intuitive: the hydrogen‐bonded OH???O structures become more stable for larger alcohols, which are expected to be stronger dispersion energy donors and thus should prefer an OH???π arrangement. Dispersion interactions in combination with the twisting of the ether upon solvent aggregation are key for understanding this preference.     

Stacked but not Stuck: Unveiling the Role of π→π* Interactions with the Help of the Benzofuran–Formaldehyde Complex

The 1:1 benzofuran–formaldehyde complex has been chosen as model system for analyzing π→π* interactions in supramolecular organizations involving heteroaromatic rings and carbonyl groups. A joint “rotational spectroscopy–quantum chemistry” strategy unveiled the dominant role of π→π* interactions in tuning the intermolecular interactions of such adduct. The exploration of the intermolecular potential energy surface led to the identification of 14 low-energy minima, with 4 stacked isomers being more stable than those linked by hydrogen bond or lone-pair→π interactions. All energy minima are separated by loose transition states, thus suggesting an effective relaxation to the global minimum under the experimental conditions. This expectation has been confirmed by the experimental detection of only one species, which was unambiguously assigned owing to the computation of accurate spectroscopic parameters and the characterization of 11 isotopologues. The large number of isotopic species opened the way to the determination of the first semi-experimental equilibrium structure for a molecular complex of such a dimension.     

Hydrogen Bonding in the Dimer and Monohydrate of 2-Adamantanol: A Test Case for Dispersion-Corrected Density Functional Methods

Weakly-bound intermolecular clusters constitute reductionist physical models for non-covalent interactions. Here we report the observation of the monomer, the dimer and the monohydrate of 2-adamantanol, a secondary alcohol with a bulky ten-carbon aliphatic skeleton. The molecular species were generated in a supersonic jet expansion and characterized using broadband chirped-pulse microwave spectroscopy in the 2–8 GHz frequency region. Two different gauche-gauche O-H···O hydrogen-bonded isomers were observed for the dimer of 2-adamantanol, while a single isomer was observed for the monomer and the monohydrate. The experimental rotational parameters were compared with molecular orbital calculations using density functional theory (B3LYP-D3(BJ), B2PLYP-D3(BJ), CAM-B3LYP-D3(BJ), ωB97XD), additionally providing energetic and electron density characterization. The shallow potential energy surface makes the dimer an interesting case study to benchmark dispersion-corrected computational methods and conformational search procedures.     

Decoding the Structure of Non-Proteinogenic Amino Acids: The Rotational Spectrum of Jet-Cooled Laser-Ablated Thioproline

The broadband rotational spectrum of jet-cooled laser-ablated thioproline was recorded. Two conformers of this system were observed and identified with the help of DFT and ab initio computations by comparison of the observed and calculated rotational constants and ¹⁴N quadrupole coupling constants as well as the predicted energies compared to the observed relative populations. These conformers showed a mixed bent/twisted arrangement of the five-membered ring similar to that of the related compound thiazolidine with the N–H bond in axial configuration. The most stable form had the COOH group in an equatorial position on the same side of the ring as N-H. The arrangement of the C=O group close to the N-H bond led to a weak interaction between them (classified as type I) characterized by a noncovalent interaction analysis. The second form had a trans-COOH arrangement showing a type II O–H···N hydrogen bond. In thioproline, the stability of conformers of type I and type II was reversed with respect to proline. We show how the conformation of the ring depends on the function associated with the endocyclic N atom when comparing the structures of isolated thioproline with its zwitterion observed in condensed phases and with peptide forms.     

Increasing Complexity in Adamantyl Thioethers Characterized by Rotational Spectroscopy

We report on the synthesis and characterization using high-resolution rotational spectroscopy of three bulky thioethers that feature an adamantyl group connected to a sulfur atom. Detailed experimental and theoretical structures are provided and compared with the 1,1′-diadamantyl ether. In addition, we expand on previous findings concerning microsolvation of adamantyl derivatives by investigating the cluster formation between these thioethers and a water molecule. The investigation of such clusters provides valuable insights into the sulfur-centered hydrogen bonding in thioethers with increasing size and steric repulsion.     

The Hydrogen Bond and Beyond: Perspectives for Rotational Investigations of Non-Covalent Interactions

In the last decade, experiment and theory have expanded our vision of non-covalent interactions (NCIs), shifting the focus from the conventional hydrogen bond to new bridging interactions involving a variety of weak donor/acceptor partners. Whereas most experimental data originate from condensed phases, the introduction of broadband (chirped-pulse) microwave fast-passage techniques has revolutionized the field of rotational spectroscopy, offering unexplored avenues for high-resolution studies in the gas phase. We present an outlook of hot topics for rotational investigations on isolated intermolecular clusters generated in supersonic jet expansions. Rotational spectra offer very detailed structural data, easily discriminating the isomeric or isotopic composition and effectively cancelling any solvent, crystal, or matrix bias. The direct comparison with quantum mechanical predictions provides insight into the origin of the inter- and intramolecular interactions with much greater precision than any other spectroscopic technique, simultaneously serving as test-bed for fine-tuning of theoretical methods. We present recent examples of rotational investigations around three topics: oligomer formation, chiral recognition, and identification of halogen, chalcogen, pnicogen, or tetrel bonds. The selected examples illustrate the benefits of rotational spectroscopy for the structural and energetic assessment of inter-/intramolecular interactions, which may help to move from fundamental research to applications in supramolecular chemistry and crystal engineering.     

London Dispersion and Hydrogen-Bonding Interactions in Bulky Molecules: The Case of Diadamantyl Ether Complexes

Diadamantyl ether (DAE, C₂₀H₃₀O) represents a good model to study the interplay between London dispersion and hydrogen-bond interactions. By using broadband rotational spectroscopy, an accurate experimental structure of the diadamantyl ether monomer is obtained and its aggregates with water and a variety of aliphatic alcohols of increasing size are analyzed. In the monomer, C−H⋅⋅⋅H−C London dispersion attractions between the two adamantyl subunits further stabilize its structure. Water and the alcohol partners bind to diadamantyl ether through hydrogen bonding and non-covalent O_{water/alcohol}⋅⋅⋅H−C_DAE and C−H_alcohol⋅⋅⋅H−C_DAE interactions. Electrostatic contributions drive the stabilization of all the complexes, whereas London dispersion interactions become more pronounced with increasing size of the alcohol. Complexes with dominant dispersion contributions are significantly higher in energy and were not observed in the experiment. The results presented herein shed light on the first steps of microsolvation and aggregation of molecular complexes with London dispersion energy donor (DED) groups and the kind of interactions that control them.     

Rotational Spectroscopy of 2-Furoic Acid and Its Dimer: Conformational Distribution and Double Proton Tunneling

Structural and tunneling properties of the 2-furoic acid (FA) monomer and dimer were investigated using rotational spectroscopy and DFT calculations. CREST, a conformational ensemble space exploration tool, was used to identify all possible low-energy conformations of the FA monomer and dimer, followed by the DFT geometry optimization and harmonic frequency calculations. Broadband rotational spectra in the 2–6 and 8–12 GHz regions were recorded in a supersonic jet expansion. The monomeric FA was found to exist dominantly as three different conformers: I , II , and III in a jet, with I and II taking on the cis-COOH configuration while III having the trans-COOH configuration. For the FA dimer, only the I – II conformer was observed experimentally, whereas the symmetric I – I and II – II conformers were not observed because of their zero dipole moments. The analysis of the splittings in the rotational transitions of I – II allowed one to extract the tunneling splitting to be 1056.0(12) MHz. The barrier height was determined to be ∼442 cm⁻¹ using the scaled potential energy scans at several different levels of theory.     

Gas-Phase Conformational Map of the Amino Acid Isovaline

Four conformers of the non-proteinogenic α-amino acid isovaline, vaporized by laser ablation, are characterized by Fourier-transform microwave techniques in a supersonic expansion. The comparison between the experimental rotational and ¹⁴N nuclear quadrupole coupling constants and the ab initio calculated ones provides conclusive evidence for the identification of the conformers. The most stable species is stabilized by an N−H⋅⋅⋅O =C intramolecular hydrogen bond and a cis-COOH interaction, whereas the higher-energy conformers exhibit an N⋅⋅⋅H−O intramolecular hydrogen bond and trans-COOH, as in other aliphatic amino acids. The spectroscopic data herein reported can be used for the astrophysical purpose in a possible detection of isovaline in space.     

Unveiling the Noncovalent Interaction of Thiazol-2-ylidene and Its Derivatives as N-heterocyclic Carbene with Different Proton Donor Molecules

The importance of noncovalent interaction has gained attention in various domains covering drug and novel catalyst design. The present study mainly characterizes the role of hydrogen bond (H-bond) and other intermolecular interactions in different (1 : 1) complex analogues formed between the N-aryl-thiazol-2-ylidene (YR) and five proton donor (HX) molecules. The analysis of the singlet-triplet energy gap ( ) confirmed the stability of the singlet state for this class of N-aryl-thiazol-2-ylidenes than the triplet state. The interaction energy values of the YR-HX complexes follow the order: YR-NH₃<YR-HCN<YR-H₂O<YR-MeOH<YR-HF. In addition, substituting the H-atom of the N−H bond with bulky groups (−R) leads to an increase in the interaction energy of the YR-HX complexes. Hence, it was found that the replacement of N-atom in N-heterocyclic carbene (NHC) by S-atom forming N-aryl-thiazol-2-ylidene results in comparable intermolecular interactions with proton donor molecules similar to imidazole-2-ylidene (NHC). The current study enlightened the role of noncovalent interactions in carbene complexes with proton donor molecules. We hope that our work on carbene chemistry will pave the way for its application in the designing and synthesis of efficient catalysts.     

Perfluorobutyric Acid and Its Monohydrate: A Chirped Pulse and Cavity Based Fourier Transform Microwave Spectroscopic Study

Rotational spectra of perfluorobutyric acid (PFBA) and its monohydrate were studied with a broadband chirped pulse and a narrow‐band cavity based Fourier transform microwave spectrometer, and high‐level ab initio calculations. Extensive conformational searches were performed for both the acid and its monohydrate at the MP2/6‐311++G(2d,p) level of theory. Two and three conformers were predicted to exist for PFBA and its monohydrate, respectively. One set of rotational transitions was observed and assigned for each, PFBA and its monohydrate. Based on the measured broadband spectra, we confidently conclude that only one dominant conformer exists in each case. The orientation of the hydroxyl group in PFBA was determined by using isotopic analysis. Comparison of the observed transition intensities and the calculated electric dipole moment components allowed us to identify the most stable monohydrate conformation, which takes on an insertion hydrogen‐bonding topology. Comparisons to the shorter chain analogues, that is, trifluoroacetic acid, perfluoropropionic acid, and their monohydrates, are made to elucidate the general trend in their conformational preference and binding topologies.     

A Toolbox for Glutamine Use in Dissolution Dynamic Nuclear Polarization: from Enzymatic Reaction Monitoring to the Study of Cellular Metabolic Pathways and Imaging

Glutamine is under scrutiny regarding its metabolic deregulation linked to energetic reprogramming in cancer cells. Many analytical techniques have been used to better understand the impact of the metabolism of amino acids on biological processes, however only a few are suited to work with complex samples. Here, we report the use of a general dissolution dynamic nuclear polarization (D-DNP) formulation using an unexpensive radical as a multipurpose tool to study glutamine, with insights from enzymatic modelling to complex metabolic networks and fast imaging. First, hyperpolarized [5-¹³C] glutamine is used as molecular probe to study the kinetic action of two enzymes: L-asparaginase that has been used as an anti-metabolic treatment for cancer, and glutaminase. These results are also compared with those acquired with another hyperpolarized amino acid, [1,4-¹³C] asparagine. Second, we explored the use of hyperpolarized (HP) substrates to probe metabolic pathways by monitoring metabolic profiles arising from hyperpolarized glutamine in E. coli extracts. Finally, a highly concentrated sample formulation is proposed for the purpose of fast imaging applications. We think that this approach can be extended to formulate other amino acids as well as other metabolites and provide complementary insights into the analysis of metabolic networks.     

Cation-π Interactions between a Noble Metal and a Polyfunctional Aromatic Ligand: Ag+(benzylamine)

The structure of an isolated Ag⁺(benzylamine) complex is investigated by infrared multiple photon dissociation (IRMPD) spectroscopy complemented with quantum chemical calculations of candidate geometries and their vibrational spectra, aiming to ascertain the role of competing cation-N and cation-π interactions potentially offered by the polyfunctional ligand. The IRMPD spectrum has been recorded in the 800–1800 cm⁻¹ fingerprint range using the IR free electron laser beamline coupled with an FT-ICR mass spectrometer at the Centre Laser Infrarouge d'Orsay (CLIO). The resulting IRMPD pattern points toward a chelate coordination (N-Ag⁺-π) involving both the amino nitrogen atom and the aromatic π-system of the phenyl ring. The gas-phase reactivity of Ag⁺(benzylamine) with a neutral molecular ligand (L) possessing either an amino/aza functionality or an aryl group confirms N- and π-binding affinity and suggests an augmented silver coordination in the product adduct ion .     

Infrared Spectroscopy Evidence of Weak Interactions in Frustrated Lewis Pairs Formed by Tris(pentafluorophenyl)borane

Frustrated Lewis pairs (FLPs) have been widely investigated as promising catalysts due to their metal-free feature and ability to activate small molecules. Since their discovery, many works have been investigating how these Lewis pairs (intermolecular pairs) are held together in an encounter complex. This prompted several studies based on theoretical investigations, but experimental ones are limited yet. In this communication we show evidence of weak intermolecular interactions between Lewis acids and Lewis bases, distinguishing the Lewis adduct from FLPs, by probing fluorine-carbon vibrational modes using infrared spectroscopy. The main evidence is based on the band shifts occurring in FLPs due to weak hydrogen bonds between the hydrogen atoms of the Lewis base and the fluorine atoms of Lewis acid.     

The shape of leucine in the gas phase.

Two structures of neutral leucine are detected in the jet-cooled rotational spectrum of a laser-ablation molecular-beam Fourier transform microwave (LA-MB-FTMW) experiment. The comparison between the experimental rotational and (14)N nuclear quadrupole coupling constants and those calculated ab initio provides conclusive evidence for the identification of the conformers. The most stable species is stabilized by a N-H...O=C intramolecular hydrogen bond and a cis-COOH interaction, while a higher-energy conformer exhibits a N...H-O intramolecular hydrogen bond and trans-COOH, as in lower aliphatic amino acids. The isobutyl side chain adopts the same configuration in the two conformers of leucine, characterized by a trans arrangement of the C'-C(alpha)-C(beta)-C(gamma)-C(delta) chain. The differences with the preferred side chain configurations observed in valine and isoleucine are discussed.