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Non-covalent interactions between aromatic molecules and water are fundamental in many chemical and biological processes, and their accurate description is essential to understand molecular relative configurations. Here we present the rotational spectroscopy study of the water complexes of the polycyclic aromatic hydrocarbon 1,4-naphthoquinone (1,4-NQ). In 1,4-NQ-(H2O)1,2, water molecules bind through O-H···O and C-H···O hydrogen bonds and are located on the plane of 1,4-NQ. For 1,4-NQ-(H2O)3, in-plane and above-plane water configurations are observed exhibiting O-H···O, C-H···O, and lone pair···π-hole interactions. The observation of different water arrangements for 1,4-NQ-(H2O)3 allows benchmarking theoretical methods and shows that they have great difficulty in predicting energy orderings due to the strong competition of C-H···O binding with πand π-hole interactions. This study provides important insight into water interactions with aromatic systems and the challenges in their modeling.

Producción Científica, Self-aggregation of sevoflurane, an inhalable, fluorinated anesthetic, provides a challenge for current state-of-the-art high-resolution techniques due to its large mass and the variety of possible hydrogen bonds between monomers. Here we present the observation of sevoflurane trimer by chirped-pulse Fourier transform microwave spectroscopy, identified through the interplay of experimental and computational methods. The trimer (>600 Da), one of the largest molecular aggregates observed through rotational spectroscopy, does not resemble the binding (C–H···O) motif of the already characterized sevoflurane dimer, instead adapting a new binding configuration created predominantly from 17 CH···F hydrogen bonds that resembles a nanomicellar arrangement. The observation of such a heavy aggregate highlights the potential of rotational spectroscopy to study larger biochemical systems in the limit of spectroscopic congestion but also showcases the challenges ahead as the mass of the system increases., NSF Major Research Instrumentation program (grant CHE0960074), Ministerio de Ciencia, Innovación y Universidades - Fondo Europeo de Desarrollo Regional (grant PGC2018-098561-B-C22)

The absolute configuration of a molecule can be established by analysis of molecular rotational spectra of the analyte complexed with a small chiral molecule of known configuration. This approach of converting the analyte enantiomers, with identical rotational spectra, into diastereomers that can be distinguished spectroscopically is analogous to chiral derivatization in nuclear magnetic resonance (NMR) spectroscopy. For the rotational chiral tag method, the derivatization uses noncovalent interactions to install the new chiral center and avoids complications due to possible racemization of the analyte when covalent chemistry is used. The practical success of this method rests on the ability to attribute assigned rotational spectra to specific geometries of the diastereomeric homochiral and heterochiral tag complexes formed in the pulsed jet expansion that is used to introduce samples into the microwave spectrometer. The assignment of a molecular structure to an experimental rotational spectrum uses quantum chemistry equilibrium geometries to provide theoretical estimates of the spectrum parameters that characterize the rotational spectrum. This work reports the results of a high-sensitivity rotational spectroscopy study of the complexes formed between (3)-butyn-2-ol and verbenone. The rotational spectra of four homochiral and four heterochiral complexes are assigned. In addition, the 14 distinct, singly-substituted

A copper-catalyzed alkene transfer hydrodeuteration reaction that selectively incorporates one hydrogen and one deuterium atom across an aryl alkene is described. The transfer hydrodeuteration protocol is selective across a variety of internal and terminal alkenes and is also demonstrated on an alkene-containing complex natural product analog. Beyond using 1H, 2H, and 13C NMR analysis to measure reaction selectivity, six transfer hydrodeuteration products were analyzed by molecular rotational resonance (MRR) spectroscopy. The application of MRR spectroscopy to the analysis of isotopic impurities in deuteration chemistry is further explored through a measurement methodology that is compatible with high-throughput sample analysis. In the first step, the MRR spectroscopy signatures of all isotopic variants accessible in the reaction chemistry are analyzed using a broadband chirped-pulse Fourier transform microwave spectrometer. With the signatures in hand, measurement scripts are created to quantitatively analyze the sample composition using a commercial cavity enhanced MRR spectrometer. The sample consumption is below 10 mg with analysis times on the order of 10 min using this instrument-both representing order-of-magnitude reduction compared to broadband MRR spectroscopy. To date, these measurements represent the most precise spectroscopic determination of selectivity in a transfer hydrodeuteration reaction and confirm that product regioselectivity ratios of >140:1 are achievable under this mild protocol.

Fundamental to the synthesis of enantioenriched chiral molecules is the ability to assign absolute configuration at each stereogenic center, and to determine the enantiomeric excess for each compound. While determination of enantiomeric excess and absolute configuration is often considered routine in many facets of asymmetric synthesis, the same determinations for enantioisotopomers remains a formidable challenge. Here, we report the first highly enantioselective metal-catalyzed synthesis of enantioisotopomers that are chiral by virtue of deuterium substitution along with the first general spectroscopic technique for assignment of the absolute configuration and quantitative determination of the enantiomeric excess of isotopically chiral molecules. Chiral tag rotational spectroscopy uses noncovalent chiral derivatization, which eliminates the possibility of racemization during derivatization, to perform the chiral analysis without the need of reference samples of the enantioisotopomer.

The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine1. Beyond their widespread use in spectroscopy, mass spectrometry and mechanistic and pharmacokinetic studies, there has been considerable interest in incorporating deuterium into drug molecules1. Deutetrabenazine, a deuterated drug that is promising for the treatment of Huntington's disease2, was recently approved by the United States' Food and Drug Administration. The deuterium kinetic isotope effect, which compares the rate of a chemical reaction for a compound with that for its deuterated counterpart, can be substantial1,3,4. The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and the distribution of metabolites for a compound5, improving the efficacy and safety of a drug. The pharmacokinetics of a deuterated compound depends on the location(s) of deuterium. Although methods are available for deuterium incorporation at both early and late stages of the synthesis of a drug6,7, these processes are often unselective and the stereoisotopic purity can be difficult to measure7,8. Here we describe the preparation of stereoselectively deuterated building blocks for pharmaceutical research. As a proof of concept, we demonstrate a four-step conversion of benzene to cyclohexene with varying degrees of deuterium incorporation, via binding to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions on the cyclohexene ring can be controlled precisely. In total, 52 unique stereoisotopomers of cyclohexene are available, in the form of ten different isotopologues. This concept can be extended to prepare discrete stereoisotopomers of functionalized cyclohexenes. Such systematic methods for the preparation of pharmacologically active compounds as discrete stereoisotopomers could improve the pharmacological and toxicological properties of drugs and provide mechanistic information related to their distribution and metabolism in the body.

Direct analyses of crude reaction mixtures have been carried out using molecular rotational resonance (MRR) spectroscopy. Two examples are presented, a demonstration application in photocatalytic CH-arylation as well as generation of an intermediate in a natural product synthesis. In both cases, the reaction can proceed at more than one site, leading to a mixture of regioisomers that can be challenging to distinguish. MRR structural parameters were calculated for the low lying conformers for the desired compounds, and then compared to the experimental spectra of the crude mixtures to confirm the presence of these species. Next, quantitation was performed by comparing experimentally measured line intensities with simulations based on computed values for the magnitude and direction of the molecular dipole moment of each species. This identification and quantification was performed without sample purification and without isolated standards of the compounds of interest. The values obtained for MRR quantitation were in good agreement with the chromatographic values. Finally, previously unknown impurities were discovered within the photocatalytic CH-arylation work. This paper demonstrates the utility of MRR as a reaction characterization tool to simplify analytical workflows.

A molecular rotational resonance spectroscopy method for measuring the enantiomeric excess of pantolactone, an intermediate in the synthesis of panthenol and pantothenic acid, is presented. The enantiomers are distinguished via complexation with a small chiral tag molecule, which produces diastereomeric complexes in the pulsed jet expansion used to inject the sample into the spectrometer. These complexes have distinct moments of inertia, so their spectra are resolved by MRR spectroscopy. Quantitative enantiomeric excess (EE) measurements are made by taking the ratio of normalized complex signal levels when a chiral tag sample of high, known EE is used, while the absolute configuration of the sample can be determined from electronic structure calculations of the complex geometries. These measurements can be performed without the need for reference samples with known enantiopurity. Two instruments were used in the analysis. A broadband, chirped-pulse spectrometer is used to perform structural characterization of the complexes. The broadband spectrometer is also used to determine the EE; however, this approach requires relatively long measurement times. A targeted MRR spectrometer is also used to demonstrate EE analysis with approximately 15-min sample-to-sample cycle time. The quantitative accuracy of the method is demonstrated by comparison with chiral gas chromatography and through the measurement of a series of reference samples prepared from mixtures of (R)-pantolactone and (S)-pantolactone samples of known EE.

Enhancement of the σ-hole on the halogen atom of aryl halides due to perfluorination of the ring is demonstrated by use of the Extended Townes-Dailey (ETD) model coupled to a Natural Atomic Orbital Bond analysis on two perfluorinated aryl halides (C6F5Cl and C6F5Br) and their hydrogenated counterparts. The ETD analysis, which quantifies the halogen p-orbitals populations, relies on the nuclear quadrupole coupling constants which in this work are accurately determined experimentally from the rotational spectra. The rotational spectra investigated by Fourier-Transform microwave spectroscopy performed in supersonic expansion are reported for the parent species of C6F5Cl and C6F5Br and their 13C, 37Cl or 81Br substituted isotopologues observed in natural abundance. The experimentally determined rotational constants combined with theoretical data at the MP2/aug-cc-pVTZ level provide precise structural information from which an elongation of the ring along its symmetry axis due to perfluorination is proved.

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., We thank MINECO (CTQ2017-89150-R), Basque Government (IT1162-19 and PIBA 2018-11), the UPV/EHU (PPG17/10, GIU18/207), CSIC (2018FR0036, LINKA20249), University of Bologna (RFO), Fondazione CARISBO (2018/0353) and NSF (CHE-1903871 and CHE-2018427) for the financial support. C.C thanks MINECO for a Juan de la Cierva contract., L.E. was supported by Marie Curie fellowship PIOF-GA-2012-328405.

The microwave spectrum of 1-isocyano-1-silacyclopent-3-ene has been obtained from broad-band chirped-pulse Fourier transform microwave spectroscopy. The rotational constants (RCs) for the standard abundant isotopic species are A = 3328.4182(23), B = 1017.69404(53), and C = 1012.33297(58) MHz. The symmetric quartic centrifugal distortion constants, using the I

We demonstrate the application of molecular rotational resonance (MRR) spectroscopy to quantify regioisomeric, dehalogenated, and enantiomeric impurities in two raw materials used in the synthesis of a HIV integrase inhibitor, cabotegravir. Characterization of these raw material impurities is important due to their ability to introduce structurally similar impurities into the final drug product. MRR, due to its high resolution and selectivity to small changes in molecular structure, can perform these measurements rapidly and without the need for developing a chromatographic separation method. For 2,4-difluorobenzylamine, four impurities were quantified (benzylamine, 2-fluorobenzylamine, 4-fluorobenzylamine, and 2,6-difluorobenzylamine), while for (S)-alaninol (2-amino-1-propanol), its enantiomer, (R)-alaninol, was measured using a chiral tagging method. For both samples, the resonance frequencies of each compound of interest were first determined using a broadband spectrometer before evaluating analytical performance metrics on a faster targeted spectrometer. For the fluorobenzylamines, quantitative performance was demonstrated over the range 0.05–5 % (v/v) for each impurity, while for alaninol, measurements were performed over the range of 70–99 % enantiomeric excess. This study suggests that MRR can be useful for validating the purity of pharmaceutical raw materials.

Direct analyses of crude reaction mixtures have been carried out using molecular rotational resonance (MRR) spectroscopy, allowing identification and quantification of major and minor components without sample purification or reference standards., Direct analyses of crude reaction mixtures have been carried out using molecular rotational resonance (MRR) spectroscopy. Two examples are presented, a demonstration application in photocatalytic CH-arylation as well as generation of an intermediate in a natural product synthesis. In both cases, the reaction can proceed at more than one site, leading to a mixture of regioisomers that can be challenging to distinguish. MRR structural parameters were calculated for the low lying conformers for the desired compounds, and then compared to the experimental spectra of the crude mixtures to confirm the presence of these species. Next, quantitation was performed by comparing experimentally measured line intensities with simulations based on computed values for the magnitude and direction of the molecular dipole moment of each species. This identification and quantification was performed without sample purification and without isolated standards of the compounds of interest. The values obtained for MRR quantitation were in good agreement with the chromatographic values. Finally, previously unknown impurities were discovered within the photocatalytic CH-arylation work. This paper demonstrates the utility of MRR as a reaction characterization tool to simplify analytical workflows.

1,4‐Naphthoquinone (1,4‐NQ) is an important product of naphthalene oxidation, and it appears as a motif in many biologically active compounds. We have investigated the structure of 1,4‐NQ using chirped‐pulse Fourier transform microwave spectroscopy and quantum chemistry calculations. The rotational spectra of the parent species, and its 13C and 18O isotopologues were observed in natural abundance, and their spectroscopic parameters were obtained. This allowed the determination of the substitution r s, mass‐weighted r m and semi‐experimental r e SE structures of 1,4‐NQ. The obtained structural parameters show that the quinone moiety mainly changes the structure of the benzene ring where it is inserted, modifying the C−C bonds to having predominantly single or double bond character. Furthermore, the molecular electrostatic surface potential reveals that the quinone ring becomes electron deficient while the benzene ring remains a nucleophile. The most electrophilic areas are the hydrogens attached to the double bond in the quinone ring. Knowledge of the nucleophilic and electrophilic areas in 1,4‐NQ will help understanding its behaviour interacting with other molecules and guide modifications to tune its properties., The structure of 1,4‐naphthoquinone has been investigated by rotational spectroscopy in combination with quantum‐chemistry calculations. The determined structural parameters show that 1,4‐naphthoquinone behaves as a combination of benzene and para‐benzoquinone units. The quinone moiety changes the structure of the benzene ring in which it is inserted and makes it electron deficient.

Multiple minor isotopologues of ArHCl have been observed in natural abundance using two CP-FTMW spectrometers. These include the first known microwave observation of 38 Ar isotopologues in natural abundance. The parameters derived from fits of the spectrum have been utilized in calculating multiple molecular parameters for the system which are shown to be the best determined to date. From these new spectrum, it is shown that there is a mass-dependency of the derived effective Ar Cl bond distance and the large amplitude averaging angle of HCl is relatively invariant to mass substitution at 41.5°.

The rich potential energy surface of the water undecamer (H2O)11 was explored with a basin hopping algorithm using a TIP4P potential and other methods followed by extensive ab initio MP2 minimizations and CCSD(T) corrections. This protocol yielded 17, 66, and 125 distinct isomers within 0.5, 1.0, and 2.0 kcal mol–1 of the complete basis set CCSD(T) global minimum, respectively. These isomers were categorized into 15 different families based on their oxygen framework and hydrogen bonding topology. Determination of the global minimum proved challenging because of the presence of many nearly isoenergetic isomers. The predicted global minimum varied among ab initio methods, density functionals, and model potentials, and it was sensitive to the choice of energy extrapolation schemes, higher-order CCSD(T) corrections, and inclusion of zero-point vibrational energy. The presence of a large number of nearly degenerate structures and the isomerization between them has manifested itself in the anomalous broadening of the heat capacity curve of the undecamer in simulations around the melting region.

As the first step of a two-part chiral tagging experiment, the spectrum and subsequent isotopologue analysis on the heavy atoms of (1S)-(-)-Verbenone is presented. The spectrum has been recorded up to 69 GHz on three spectrometers, one CP-FTMW spectrometer from the University of Virginia functional from 2 to 8 GHz, a CP-FTMW spectrometer operational in the 6–18 GHz range located at the Missouri University of Science and Technology, and a Stark-modulated spectrometer operational from 48 to 72 GHz. 1250 transitions have been assigned to the parent and isotopologues for the predominantly b -type spectrum. Rotational constants and quartic centrifugal distortion constants have been determined for the parent species while for the 11 isotopologues only rotational constants have been determined. A Kraitchman analysis has been performed and the resulting coordinates are reported. The experimental heavy-atom structure has been compared to previously studied bicyclic terpenes and the computational structure and is found to be in excellent agreement with both, showing reliability of the theoretical approaches needed for the future chiral tagging work.

Reported here are CP-FTMW experiments on N-ethylformamide (NEF), previously studied by pure rotational spectroscopy in the gas phase by Hirota and co-workers (2005). Two conformers of the monomer (trans sc and cis ac), the trans-trans sc dimer, and several NEF-water complexes have been detected. (Only trans sc was observed in the earlier experiments.) Of these species, the trans-trans sc dimer is the most interesting since its three-dimensional structure bears a striking resemblance to β-turns in folded peptides. The well-known anti-parallel β-sheet structures would be expected to have near-zero dipole moments and are therefore discriminated against by the CP-FTMW method.

A molecular rotational resonance (MRR) spectrometer designed to monitor the product composition of an asymmetric continuous flow reaction online is presented. The MRR technique is highly sensitive to small changes in molecular structure and, as such, is capable of rapidly quantifying isomers as well as other impurities in a complex mixture, without chromatographic separation or chemometrics. The spectrometer in this study operates by automatically drawing a portion of the reaction solution into a reservoir, volatizing it by heating, and measuring the highly resolved MRR spectra of each of the components of interest in order to determine their relative quantity in the mixture. The reaction under study was the hydrogenation of artemisinic acid, an intermediate step in the semisynthesis of the antimalarial drug artemisinin. Four analytes were characterized in each measurement: the starting material, the product, a diastereomer of the product, and an overreduction byproduct that was not directly quantifiable by either HPLC or NMR methods. The MRR instrument has a measurement cycle time of approximately 17 min for this analysis and can run for several hours without any user interaction.

Context. Organic ring compounds play a key role in terrestrial biochemistry, and they were also most likely pivotal ingredients in Earth’s prebiotic chemistry. The five-membered ring imidazole, c-C3N2H4, is a substructure of fundamental biological molecules such as the purine nucleobases and the amino acid histidine. An unsuccessful search for imidazole in a sample of cold-core clouds and massive star-forming regions was performed almost 40 years ago. At that time, the spectroscopic knowledge of this species was scarce: the existing laboratory study was limited to the centimetre-wave region, and the precision of the rest frequencies in the millimetre regime was not adequate. Aims. The goal of the present work is to perform a comprehensive investigation of the rotational spectrum of imidazole in its ground vibrational state from the microwave region to the 1 mm wavelength regime. Methods. The rotational spectrum of imidazole was recorded in selected frequency regions from 2 to 295 GHz. These intervals were covered using various broadband spectrometers developed at DESY (Hamburg) and at the University of Virginia. High-level ab initio calculations were performed to obtain reliable estimates of the quartic and sextic centrifugal distortion constants. We used the EMoCA imaging spectral line survey to search for imidazole towards the hot molecular core Sgr B2(N2). Results. About 700 rotational transitions spanning a J interval from 0 to 59 and Kc interval from 0 to 30 were analysed using the Watson S-reduced Hamiltonian. These new data allowed the determination of a much extended set of spectroscopic parameters for imidazole in its vibrational ground state. The improved spectral data allow us to set an upper limit to the column density of imidazole in Sgr B2(N2). Its non-detection implies that it is at least 3400 times less abundant than ethyl cyanide in this source. Conclusions. With the new set of spectroscopic constants, it has been possible to compute reliable rest frequencies at millimetre wavelengths. We suggest a search for imidazole towards TMC-1, where the aromatic molecule benzonitrile was recently detected.

Journal of molecular spectroscopy 378, 111452 (2021). doi:10.1016/j.jms.2021.111452, We report our analysis of the pure rotational spectra of low-lying vibrationally excited states and heavy-atom rare isotopologues of imidazole. To facilitate searches for imidazole in the interstellar medium, we previously described the analysis of the rotational spectrum of the imidazole main isotopologue across the 2–295 GHz range, and we extend this analysis here. Structure optimisation and anharmonic frequency calculations were performed to aid the spectral analysis. Three vibrationally excited states of imidazole were assigned in our room-temperature spectra, with energies up to approximately 670 cm$^{−1}$ above the vibronic ground state. The vibrational states could act as temperature probes in warmer star-forming regions. The $^{13}$C and $^{15}$N heavy-atom isotopologues were assigned, which allowed for the structure of imidazole in the gas phase to be determined. Structural comparisons are drawn between the related heterocyclic molecules hydantoin and imidazolidine. An experimental gas-phase structure of the former is also determined in this work. The potential detection of the isotopologues could help deduce formation pathways towards imidazole and other nitrogen-containing cyclic compounds in interstellar space., Published by Academic Press, Orlando, Fla.