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Carvacrol is an aromatic monoterpenoid found in thyme oil. Due to its implications for human health, it is important to elucidate its structure and its intramolecular interactions. We have characterised the carvacrol monomer, its complex with water, its dimer, and even its trimer in a supersonic expansion using mass-resolved laser spectroscopy techniques complemented by quantum-chemical computations. The resonance-enhanced multiphoton ionisation spectrum of the monomer features several transitions, which were assigned to the same conformer, confirmed by ion-dip infrared spectroscopy. However, a conclusive assignment of the infrared bands to one of the four conformations of carvacrol remains elusive. The experimental spectra for the monohydrated, the homodimer, and the homotrimer point to the detection of the lowest energy isomer in each case. Their structures are governed by a balance of intramolecular interactions, specifically hydrogen bonding and dispersion forces. Comparison with other similar systems demonstrates that dispersion interactions are key to the stabilisation of the aggregates, being present in all the structures. However, the hydrogen bonding is the dominant force as observed in the lowest-energy conformations.

The popular sweetener, aspartame, is an agonist of the tongue's sweet taste receptor. How water molecules affect its conformation or which aspartame atoms are more prone to interact with solvent are helpful questions to understand its activity in different environments. Here, the combination of IR-UV spectroscopic techniques with computational simulations has been successfully applied to characterize aspartame·water 0-2 clusters, showing that the addition of water molecules simplifies the conformational panorama of aspartame, favoring the formation of folded structures by interaction with the polar part of the molecule.

Noncovalent interactions involving sulfur centers play a relevant role in biological and chemical environments. Yet, detailed molecular descriptions are scarce and limited to very simple model systems. Here we explore the formation of the elusive S-H···S hydrogen bond and the competition between S-H···O and O-H···S interactions in pure and mixed dimers of the conformationally flexible molecules 2-phenylethanethiol (PET) and 2-phenylethanol (PEAL), using the isolated and size-controlled environment of a jet expansion. The structure of both PET-PET and PET-PEAL dimers was unraveled through a comprehensive methodology that combined rotationally resolved microwave spectroscopy, mass-resolved isomer-specific infrared laser spectroscopy, and quantum chemical calculations. This synergic experimental-computational approach offered unique insights into the potential energy surface, conformational equilibria, molecular structure, and intermolecular interactions of the dimers. The results show a preferential order for establishing hydrogen bonds following the sequence S-H···S < S-H···O ≲ O-H···S < O-H···O, despite the hydrogen bond only accounting for a fraction of the total interaction energy.

We employed microwave spectroscopy to investigate the 1:1 complexes of hexafluorobenzene with trimethylamine and quinuclidine, respectively. These complexes exhibit a C 3 v symmetry and are stabilized by nitrogen lone pair···π-hole interactions along the C 3 axes. The N···π-center distances were determined to be 3.110(1) and 3.040(2) Å, respectively, which are shorter than that of hexafluorobenzene-ammonia at 3.2685(3) Å. Additionally, the strength of the intermolecular interaction increases with cluster size. While it was initially expected that the electron-donating effect of alkyl groups was responsible for changing the N···π interaction, the symmetry-adapted perturbation theory analysis revealed that, from hexafluorobenzene-ammonia to both hexafluorobenzene-alkylamines, electrostatic interaction actually decreases while dispersion interaction increases and becomes dominant. Interestingly, dispersion interaction decreases while electrostatic interaction increases from C 6 F 6 -N(CH 3 ) 3 to C 6 F 6 -NC 7 H 13 . The splitting pattern of the spectra indicates hexafluorobenzene rotates freely relative to its partners along the axis of the N···π-hole interactions.

Sugars, together with amino acids and nucleobases, are the fundamental building blocks of a cell. They are involved in many fundamental processes and they especially play relevant roles as part of the immune system. The latter is connected to their ability to establish a collection of intermolecular interactions, depending on the position of their hydroxyl groups. Here we explore how the position of the OH in C4, the anomeric conformation and the nature substituent affect the interaction with phenol, which serves as a probe of the preferred site for the interaction. Using mass-resolved excitation spectroscopy and density functional calculations, we unravel the structure of the dimers and compare their conformation with those found for similar systems. The main conclusion is that the hydroxymethyl group has a very strong influence, guiding the whole aggregation process and that the position of the substituent in C4 has a stronger influence on the final structure of the dimer than the anomeric conformation.

Hydrogen bonds and stacking interactions are pivotal in biological mechanisms, although their proper characterisation within a molecular complex remains a difficult task. We used quantum mechanical calculations to characterise the complex between caffeine and phenyl-β-D-glucopyranoside, in which several functional groups of the sugar derivative compete with each other to attract caffeine. Calculations at different levels of theory (M06-2X/6-311++G(d,p) and B3LYP-ED=GD3BJ/def2TZVP) agree to predict several structures similar in stability (relative energy) but with different affinity (binding energy). These computational results were experimentally verified by laser infrared spectroscopy, through which the caffeine·phenyl-β-D-glucopyranoside complex was identified in an isolated environment, produced under supersonic expansion conditions. The experimental observations correlate with the computational results. Caffeine shows intermolecular interaction preferences that combine both hydrogen bonding and stacking interactions. This dual behaviour had already been observed with phenol, and now with phenyl-β-D-glucopyranoside, it is confirmed and maximised. In fact, the size of the complex's counterparts affects the maximisation of the intermolecular bond strength because of the conformational adaptability given by the stacking interaction. Comparison with the binding of caffeine within the orthosteric site of the A2A adenosine receptor shows that the more strongly bound caffeine·phenyl-β-D-glucopyranoside conformer mimics the interactions occurring within the receptor.

The selection of cytosine, guanine, thymine, and adenine as components of the information biopolymers was a complex process influenced by several factors. Among them, the intermolecular interactions may have played a determinant role. Thus, a deep understanding of the intermolecular interactions between nucleobases and other prebiotic molecules may help understand the first instants of chemical evolution. Following this hypothesis, we present here a combined spectroscopic and computational study of theobromine 2 -adenine and thebromine-adenine 2 trimers. While adenine is a nucleobase, theobromine was probably part of the prebiotic chemistry. The trimers were formed in jets and probed by a combination of UV and IR spectroscopic techniques. The spectra were interpreted in light of the predictions obtained using density-functional methods. The results suggest the existence of a subtle balance between formation of hydrogen bonds and π-π interactions. Thus, while theobromine 2 -adenine tends to form complex in stacked structures, theobromine-adenine 2 prefers formation of planar structures, maximizing the interaction by hydrogen bonds. The small energy difference between planar and stacked structures highlights the importance of accurately modeling the dispersion forces in the functionals to produce reliable predictions.

Peptides containing variations of the β-amyloid hydrophobic core and five-membered sulfamidates derived from β-amino acid α-methylisoserine have been synthesized and fully characterized in the gas phase, solid state and in aqueous solution by a combination of experimental and computational techniques. The cyclic sulfamidate group effectively locks the secondary structure at the N-terminus of such hybrid peptides imposing a conformational restriction and stabilizing non-extended structures. This conformational bias, which is maintained in the gas phase, solid state and aqueous solution, is shown to be resistant to structure templating through assays of in vitro β-amyloid aggregation, acting as β-sheet breaker peptides with moderate activity., (© 2022 Wiley-VCH GmbH.)

Gas-phase spectroscopic studies of alcohol clusters offer accurate information on the influence of non-covalent interactions on molecular recognition, and are of paramount importance to model supramolecular and biological chemical processes. Here, we examine the role of the aliphatic side chain in the self-aggregation of aromatic alcohols, using a multi-methodological gas-phase approach which combines microwave spectroscopy and mass-resolved electronic and vibrational laser spectroscopy. Spectroscopic and electronic structure computations were carried out for the dimer, trimer and tetramer of 2-phenylethanol, extending previous investigations on smaller aromatic alcohols. While the conformational flexibility of the ethyl group anticipates a variety of torsional isomers, the intra- and inter-molecular interactions restrict molecular conformations and favour particularly stable isomers. The conformational landscape of the clusters is very shallow and multiple competing isomers were rotationally and/or vibrationally detected, including three dimer species, two trimers and two tetramers. Cluster growth is associated with a tendency to form cyclic hydrogen bond structures.

Herein, we have investigated the structure of phenyl formate⋅⋅⋅water (PhOF⋅⋅⋅H 2 O) dimer and various non-covalent interactions present there using gas-phase laser spectroscopy and microwave spectroscopy combined with quantum chemistry calculations. Two conformers of PhOF⋅⋅⋅H 2 O (C1 and T1), built on the two cis/trans conformers of the bare molecule, have been observed in the experiment. In cis-PhOF, there is an n CO → π A r * interaction between the lone-pair orbital of the carbonyl oxygen atom and the π* orbital of the phenyl ring, which persists in the monohydrated C1 conformer of PhOF⋅⋅⋅H 2 O according to the NBO and NCI analyses. On the other hand, this interaction is absent in the trans-PhOF conformer as the C=O group is away from the phenyl ring. The C1 conformer is primarily stabilized by an interplay between O-H⋅⋅⋅O=C hydrogen bond and O-H⋅⋅⋅π interactions, while the stability of the T1 conformer is primarily governed by the O-H⋅⋅⋅O=C hydrogen bond. The most important finding of the present work is that the conformational preference of the PhOF monomer is retained in its monohydrated complex., (© 2022 Wiley-VCH GmbH.)

One of the most fascinating questions in chemistry is why nature chose CGAT as the alphabet of life. Very likely, such selection was the result of multiple factors and a long period of refinement. Here, we explore how the intermolecular interactions influenced such process, by characterizing the formation of dimers between adenine, theobromine and 4-aminopyrimidine. Using a combination of mass-resolved excitation spectroscopy and DFT calculations, we determined the structure of adenine-theobromine and 4-aminopyrimidine-theobromine dimers. The binding energy of these dimers is very close to the canonical adenine-thymine nucleobases. Likewise, the dimers are able to adopt Watson-Crick conformations. These findings seem to indicate that there were many options available to build the first versions of the informational polymers, which also had to compete with other molecules, such as 4-aminopyrimidine, which does not have a valid attaching point for a saccharide. For some reason, nature did not select the most strongly-bonded partners or if it did, such proto-bases were later replaced by the nowadays canonical CGAT., (© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The role of non-covalent interactions (NCIs) has broadened with the inclusion of new types of interactions and a plethora of weak donor/acceptor partners. This work illustrates the potential of chirped-pulse Fourier transform microwave technique, which has revolutionized the field of rotational spectroscopy. In particular, it has been exploited to reveal the role of NCIs' in the molecular self-aggregation of difluoromethane where a pentamer, two hexamers and a heptamer were detected. The development of a new automated assignment program and a sophisticated computational screening protocol was essential for identifying the homoclusters in conditions of spectral congestion. The major role of dispersion forces leads to less directional interactions and more distorted structures than those found in polar clusters, although a detailed analysis demonstrates that the dominant interaction energy is the pairwise interaction. The tetramer cluster is identified as a structural unit in larger clusters, representing the maximum expression of bond between dimers., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

When hydrogen is completely replaced by fluorine, arenes become prone to forming a lone pairπ-hole non-covalent bond with ligands presenting electron rich regions. Such a species is ammonia, which confirms this behavior engaging its lone pair as the electron donor counterpart in the 1 : 1 adducts with hexafluorobenzene and pentafluoropyridine. In this work, the geometrical parameters of the interaction have been unambiguously identified through the detection, by means of Fourier transform microwave spectroscopy, of the rotational spectra of both normal species and their 15NH3 isotopologues. An accurate analysis of the experimental data, including internal dynamics effects, endorsed by quantum chemical calculations, both with topological analysis and energy decomposition method, extended to the hydrogenated arenes and their water complexes, proved the ability of ammonia to create a stronger and more flexible lone pairπ-hole interaction than water. Interestingly, the higher binding energies of the ammonia lone pairπ-hole interactions correspond to larger intermolecular distances.

The cyclohexanol homodimer acts as a delicate test model of the role of dispersion forces in intermolecular association. Whereas phenol produces a single dimer, the suppression of π interactions and the larger conformational flexibility in cyclohexanol results in multiple isomerism, with six competing dimers of the free molecule being observed in a supersonic jet expansion. Rotational spectroscopy reveals accurate structural data, specifically the formation of homo- and heterochiral diastereoisomers and the presence of both equatorial and axial forms in the dimers. Four dispersion-corrected density-functional molecular orbital calculations were tested against the experiment, with B3LYP-D3(BJ) offering good structural reproducibility with an Alrich's triple-ζ basis set. However, the prediction of the dimer energetics is largely model-dependent, thus offering a testbed for the validation of dispersion-corrected computational models., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Understanding the molecular basis of the appearance of life on Earth is an exciting research field. Many factors may have influenced the election of the molecules used by living beings and evolution may have modified those original compounds. In an attempt to understand the role played by intermolecular interactions in the election of CGAT as the alphabet of life, we present here a thorough experimental and computational study on the interaction of theobromine with water. Theobromine is a xanthine derivative, structurally related to the nucleobases, and also present in many living beings. The experimental results demonstrate that the most stable isomer of theobromine-water was formed and detected in supersonic expansions. This isomer very well resembles the structure of the dimers between nucleobases and water, offering similar values of binding energy. A comparison between the results obtained for theobromine-water with those reported in the literature for monohydrates of nucleobases is also offered.

We explore the influence of the relative position of the methyl substituent on the photophysics of theophylline and theobromine, two molecules that are structurally related to the DNA bases. Using a combination of spectroscopic techniques and quantum mechanical calculations, we show that moving the methyl group from N1 in theophylline to N7 in theobromine causes significant differences in their excited state properties, i.e., it produces pyramidalization of N7 in the excited state of the latter. Paradoxically, this modification seems to have little effect on the structural properties of the cation and the ionization process. It is suggested that similar effects may exist in the excited state properties of DNA bases.

Direct spectroscopic evidence of a reaction occurring between acrolein and water and involving the exchange of an oxygen atom has been obtained by characterizing the non-covalently bound water complexes and their isotopic forms, via rotational spectroscopy. The experimental geometries of the binary and ternary water complexes have been determined, and other stationary points on the reaction path have been characterized using ab initio quantum chemical methods at the MP2/6-311++G(d,p) level. These results can enhance the understanding of the water-mediated atmospherically important reactions involving acrolein.

Intermolecular interactions are difficult to model, especially in systems formed by multiple interactions. Such is the case of caffeine-phenol. Structural data has been extracted by using mass-resolved excitation spectroscopy and double resonance techniques. Then the predictions of seven different computational methods have been explored to discover structural and energetic discrepancies between them that may even result in different assignments of the system. The results presented herein highlight the difficulty of constructing functionals to model systems with several competing interactions, and raise awareness of problems with assignments of complex systems with limited experimental information that rely exclusively on energetic data., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The tumor-associated carbohydrate Tn antigens include two variants, αGalNAc- O-Thr and αGalNAc- O-Ser. In solution, they exhibit dissimilar shapes and dynamics and bind differently to the same protein receptor. Here, we demonstrate experimentally and theoretically that their conformational preferences in the gas phase are highly similar, revealing the essential role of water. We propose that water molecules prompt the rotation around the glycosidic linkage in the threonine derivative, shielding its hydrophobic methyl group and allowing an optimal solvation of the polar region of the antigen. The unusual arrangement of αGalNAc- O-Thr features a water molecule bound into a "pocket" between the sugar and the threonine. This mechanism is supported by trapping, for the first time, such localized water in the crystal structures of an antibody bound to two glycopeptides that comprise fluorinated Tn antigens in their structure. According to several reported X-ray structures, installing oxygenated amino acids in specific regions of the receptor capable of displacing the bridging water molecule to the bulk-solvent may facilitate the molecular recognition of the Tn antigen with threonine. Overall, our data also explain how water fine-tunes the 3D structure features of similar molecules, which in turn are behind their distinct biological activities.

This work deals with the controlled nucleation of aniline from the isolated molecule until formation of a moderately large aggregate: aniline nonamer. The structure of the cluster at each step of the nucleation was unravelled combining mass-resolved IR spectroscopy and computational chemistry, demonstrating that aggregation is primarily guided by formation of extensive N-H⋅⋅⋅N hydrogen-bond networks that give the aggregates a sort of branched backbone, in clear competition with multiple N-H/C-H⋅⋅⋅π and π⋅⋅⋅π interactions. The result is the co-existence of close nucleation paths connecting relational aggregates. The delicate balance of molecular forces makes the aniline clusters a challenge for molecular orbital calculations and an ideal system to refine the present nucleation models. Noticeably, spectroscopic signatures characteristic of the condensed phase are apparent in the nanometer-size aggregates formed in this work., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We explored the molecular basis of tyrosine as the docking amino acid for the first glucose molecule during the synthesis of glycogen. The IR spectra show that the aromatic ring acts as bait to keep the position where the next glucose unit has to bind clear, by luring non-desirable molecules towards the aromatic ring. Only, α-/β-glucose shows particular affinity for the O3H and O4H moieties.

Folding processes play a crucial role in the development of function in biomacromolecules. Recreating this feature on synthetic systems would not only allow understanding and reproducing biological functions but also developing new functions. This has inspired the development of conformationally ordered synthetic oligomers known as foldamers. Herein, a new family of foldamers, consisting of an increasing number of anthracene units that adopt a folded sigmoidal conformation by a combination of intramolecular hydrogen bonds and aromatic interactions, is reported. Such folding process opens up an efficient through-space charge transport channel across the interacting anthracene moieties. In fact, single-molecule conductance measurements carried out on this series of foldamers, using the scanning tunnelling microscopy-based break-junction technique, reveal exceptionally high conductance values in the order of 10 -1 G 0 and a low length decay constant of 0.02 Å -1 that exceed the values observed in molecular junctions that make use of through-space charge transport pathways.

Sugars are small carbohydrates which play numerous roles in living organisms such as storage of energy or as structural components. Modifications of specific sites within the glycan chain can modulate a carbohydrate's overall biological function as it happens with nucleic acids and proteins. Hence, identifying discrete carbohydrate modifications and understanding their biological effects is essential. A study of such processes requires of a deep knowledge of the interaction mechanism at the molecular level. Here, we use a combination of laser spectroscopy in jets and quantum mechanical calculations to characterize the interaction between phenyl-β-d-glucopyranoside and N-methylacetamide as a model to understand the interaction between a sugar and a peptide bond. The most stable structure of the molecular aggregate shows that the main interaction between the peptide fragment and the sugar proceeds via a C[double bond, length as m-dash]OH-O2 hydrogen bond. A second conformer was also found, in which the peptide establishes a C[double bond, length as m-dash]OH-O6 hydrogen bond with the hydroxymethyl substituent of the sugar unit. All the conformers present an additional interaction point with the aromatic ring. This particular preference of the peptide for the hydroxyl close to the aromatic ring could explain why glycogenin uses tyrosine in order to convert glucose into glycogen by exposing the O4H hydroxyl group for the other glucoses for the polymerization to take place.

The four bases of DNA constitute what is known as the "alphabet of life". Their combination of proton-donor and acceptor groups and aromatic rings allows them to form stacking structures and at the same time establish hydrogen bonds with their counterparts, resulting in the formation of the well-known double-helix structure of DNA. Here we explore the aggregation preferences of cytosine in supersonic expansions, using a combination of laser spectroscopic techniques and computations. The data obtained from the experiments carried out in the cold and isolated environment of the expansion allowed us to establish which are the leading interactions behind aggregation of cytosine molecules. The results obtained demonstrated that ribbon-like structures held together by hydrogen bonds are the preferred conformations in the small clusters, but once the tetramer was reached, the stacking structures became enthalpically more stable. Stacking is further favoured when cytosine is replaced by its 1'-methylated version, as demonstrated by quantum-mechanical calculations performed using the same level that reproduced the experimental results obtained for cytosine aggregates. A discussion on the biological implications that such observations may have is also offered.

Carbohydrates are, together with amino acids, DNA bases, and lipids, the building blocks of living beings. They play a central role in basic functions such as immunity and signaling, which are governed by noncovalent interactions between sugar units and other biomolecules. To get insights into such interactions between monosaccharide units, we used a combination of mass-resolved laser spectroscopy in supersonic expansions and molecular structure calculations. The results obtained clearly demonstrate that the small stability difference between the α/β anomers of glucopyranose derivatives is reversed and amplified during molecular aggregation, making the complexes of the β-anomers significantly more stable. The amplification mechanism seems to be formation of extensive hydrogen-bond networks extending through the two interacting molecules. The same mechanism must be at play in the interactions of biological and synthetic receptors with glycans, which exhibit, in general, a higher affinity for a specific anomer, usually the beta anomer.

Sugars are fundamental building blocks for living organisms and their interaction with proteins plays a central role in fundamental biological processes, such as energy storage and production, post-transductional modifications or immune response. Understanding those processes require deep knowledge of the forces that drive the interactions at the molecular level. Here we explore the interactions between α/β-methyl-d-glucopyranose and β-phenyl-d-glucopyranose with phenol, and the chromophore of tyrosine, using a combination of mass-resolved laser electronic spectroscopy in supersonic expansions and quantum mechanical calculations. The structures of the complexes detected in the jet are stabilized by a subtle equilibrium between several types of weak interactions, among which the dispersion forces may tilt the balance. In particular, the small structural changes introduced by the orientation of the anomeric substituent are amplified by the interaction with phenol. Consequently, the number of conformational isomers detected experimentally is different for each system and they present also differences in the preferred solvation site. Furthermore, inclusion of entropic terms for the calculated structures is advisable to understand the energetic reasons for the detection of a small set of experimental conformational isomers.

The interaction of the general anesthetic propofol with an individual residue of threonine in the membrane receptors has been modeled in the gas phase by examining the adduct of propofol with the isopropanol side-chain. We determined the structural preferences of the cluster using a combination of mass-resolved laser spectroscopy and quantum mechanical calculations. The first electronic transition of propofol-isopropanol was recorded with vibrational resolution using resonant two-photon ionization (R2PI) and ion dip IR spectroscopy. The spectra obtained were compared with density-functional calculations (DFT) using the M06-2X functional in order to obtain the cluster's structure. Three isomers have been detected. The results suggest that propofol acts as a Brønsted acid, donating a proton to the isopropanol molecule in a conformation that resembles that of propofol-water, but displaced towards the aromatic ring, due to the interaction with the aliphatic side of isopropanol. The higher affinity of propofol for isopropanol compared to water may correlate with the biological role of propofol at the protein binding site. On the other hand, propofol shows a similar affinity for isopropanol and phenol, which could explain the mobility that propofol experiences inside the GABAA cavity.

Objectives: Although vesicoureteral reflux (VUR) is a very frequent pathology in the pediatric age and represents an important part of the activity of pediatricians, pediatric urologists, nephrologists, and radiologists, yet there is controversy about its global management both in diagnosis and treatment. The objective of this paper is to perform an update in the use of different imaging techniques in the diagnosis and followup of VUR and to propose a work up protocol., Methods: We describe the imaging techniques: VCUG, ultrasound, intravenous urography, bladder-ultrasound, DMSA, MRI, and their role in the evaluation and followup of VUR. We performed a bibliographic review about the topic and present the experience of our working group on VUR., Results: The bibliographic review shows a clear evolution of the concepts of VUR and also the management algorithms. The concepts of congenital renal lesion without urinary tract infection (UTI) or acquired lesion after UTI are clearly differentiated in the most recent reviews. Reflux is passing from being the center of the problem to a secondary phenomenon in relation to UTI, and this is leading to a change of diagnostic strategy, less and less invasive., Conclusions: VCUG has been to date the first and indisputable technique for the management of VUR, mainly in the diagnostic phase, but technological advances in the area of ultrasound (ultrasound contrasts, harmonic image, etc.) have converted ultrasound in the first imaging technique for the management of VUR in pediatric age. On the other hand, work-up algorithms have changed due to the great impact prenatal diagnosis is having in the management of urinary tract anomalies.