Among the many physicochemical properties used to distinguish chiral molecules, perhaps none has had as profound and sustained an impact in the realm of chemistry as the characteristic interactions that take place with polarized light. Of special note is the dispersive (non-resonant) phenomenon of circular birefringence (CB), the manifestation of which first was reported over two centuries ago and which still is employed routinely – in the more familiar guise of specific optical rotation – to gauge the enantiomeric purity of the products emerging from asymmetric syntheses. Concerted experimental and theoretical efforts designed to probe such electronic optical activity in isolated chiral molecules will be presented, with special emphasis directed towards the marked influence that intramolecular (vibrational and conformational) dynamics and intermolecular (environmental) perturbations can exert upon the intrinsic chiroptical response. Requisite isolated-molecule measurements have been made possible by our continuing development of cavity ring-down polarimetry (CRDP), an ultrasensitive polarimetric scheme that has permitted the first quantitative analyses of optical rotatory dispersion (ORD or wavelength-resolved CB) to be performed in rarefied (gaseous) media. Various technical aspects of CRDP will be discussed to illustrate the unique capabilities and practical limitations afforded by this novel methodology. Comparison of specific rotation values acquired for a broad spectrum of rigid and flexible chiral species under complementary isolated and solvated conditions will highlight the intimate coupling that exists among electronic and nuclear degrees of freedom as well as the pronounced, yet oftentimes counterintuitive, effects incurred by subtle solute-solvent interactions. The disparate nature of optical activity extracted from different surroundings will be demonstrated, with quantum-chemical calculations serving to elucidate the structural, electronic, and environmental provenance of observed behavior. In addition to unraveling basic processes that mediate chiroptical response in condensed media, the vapor-phase ORD benchmarks resulting from these studies afford a critical assessment for computational predictions of dispersive optical activity and for their burgeoning ability to assist in the assignment of absolute stereochemical configuration.

The chiral tagging method for rotational spectroscopy uses an established approach in chiral analysis of creating a complex with an enantiopure tag so that enantiomers of the molecule of interest are converted to diastereomer complexes. Since the diastereomers have distinct structure, they give distinguishable rotational spectra. Camphor was chosen as an example for the chiral tag method because it has spectral properties that could pose challenges to the use of three wave mixing rotational spectroscopy to establish absolute configuration. Specifically, one of the dipole moment components of camphor is small making three wave mixing measurements challenging and placing high accuracy requirements on computational chemistry for calculating the dipole moment direction in the principal axis system. The chiral tag measurements of camphor used the hydrogen bond donor 3-butyn-2-ol. Quantum chemistry calculations using the B3LYP-D3BJ method and the def2TZVP basis set identified 7 low energy isomers of the chiral complex. The two lowest energy complexes of the homochiral and heterochiral complexes are observed in a measurement using racemic tag. Absolute configuration is confirmed by the use of an enantiopure tag sample. Spectra with ¹³C-sensitivity were acquired so that the carbon substitution structure of the complex could be obtained to provide a structure of camphor with correct stereochemistry. The chiral tag complex spectra can also be used to estimate the enantiomeric excess of the sample and analysis of the broadband spectrum indicates that the sample enantiopurity is higher than 99.5%. The structure of the complex is analyzed to determine the extent of geometry modification that occurs upon formation of the complex. These results show that initial isomer searches with fixed geometries will be accurate. The reduction in computation time from fixed geometry assumptions will be discussed.

Many biologically important molecules are chiral and perform their biological functions in an aqueous medium. In this study, we investigate the intermolecular interactions of methyl glycidate, a chiral epoxy ester, with water using rotational spectroscopy. We examine the competition among the three hydrogen-bond acceptor sites at methyl glycidate: the epoxy oxygen, the carbonyl oxygen, and the ester oxygen when interacting with water. We also probe how interaction with water modifies the methyl internal rotation barriers and conformational distribution of methyl glycidate. The possible large amplitude and tunnelling motions associated with water are investigated and analyzed.

Infrared and vibrational circular dichroism (VCD) spectra of methyl glycidate, a chiral epoxy ester, were measured in CCl₄ and water in the 1000 cm⁻¹ – 1800 cm⁻¹ region. The experimental VCD spectra of methyl glycidate in water and in CCl₄ show noticeable differences. In particular, there are strong VCD signatures at the water bending mode region, which can be attributed to chirality transfer from chiral methyl glycidate to water through hydrogen-bonding interactions. We applied the clusters-in-a-liquid model¹ where both implicit and explicit solute-solvent interactions are considered to simulate the experimental infrared and VCD features of methyl glycidate in CCl₄ and water. All final geometry optimizations, frequency calculations, infrared and VCD intensity calculations were performed at the B3LYP-D3BJ/6-311++G(2d,p) level of theory where D3BJ is Grimme’s empirical dispersion correction with damping factor.² We emphasize the link between the small methyl glycidate hydrates and the main long-lived species which exist in aqueous solution. 1 A. S. Perera, J. Thomas, M. R. Poopari, Y. Xu, Front. Chem. 2016, 4, 1-17. 2 S. Grimme, S. Ehrlich, L. Goerigk, J. Comp. Chem. 2011, 32, 1456-1465.

Chiral five-and-six membered ring ketones are important molecules that are found in many biological systems and can exist in many possible conformers. In this talk, experimental and computational investigation of solvent, temperature and concentration effects on the circular dichroism (CD) and optical rotation (OR) of (R)-3 -methylcyclohexanone (R3MCH), (R)-3-methylcyclopentanone (R3MCP) and carvone conformers will be discussed. CD and OR measurements of these ketones gaseous samples and in ten common solvents of wide polarity range for different concentrations and sample temperatures were recorded and related to molecular conformation. Density functional theoretical calculations were performed using Gaussian09 at B3LYP functions with aug-cc-pVDZ level of theory. Also, CD and OR spectra for the optimized geometries of the ketones dominant conformers were computed over the ultraviolet and visible region in the gas phase as well as in ten solvents of varying polarity range, and under the umbrella of the polarizable continuum model (PCM). By comparing theoretical and experimental results, few thermodynamic parameters were deduced for the individual equatorial and axial conformers of each molecule in gas phase and in solvation.

We present a simple method for control of ro-vibrational populations in polyatomic molecules in the presence of inhomogeneous electric fields [1]. Cooling and trapping of heavy polar polyatomic molecules has become one of the frontier goals in high-resolution molecular spectroscopy, especially in the context of parity violation measurement in chiral compounds [2]. A key step toward reaching this goal would be development of a robust and efficient protocol for control of populations of ro-vibrational states in polyatomic, often floppy molecules. Here we demonstrate a modification of the stark-chirped rapid-adiabatic-passage technique (SCRAP) [3], designed for achieving high levels of control of ro-vibrational populations over a selected region in space. The new method employs inhomogeneous electric fields to generate space- and time- controlled Stark-shifts of energy levels in molecules. Adiabatic passage between ro-vibrational states is enabled by the pump pulse, which raises the value of the Rabi frequency. This Stark-chirped population transfer can be used in manipulation of population differences between high-field-seeking and low-field-seeking states of molecules in the Stark decelerator [4]. Appropriate timing of voltages on electric rods located along the decelerator combined with a single pump laser renders our method as potentially more efficient than traditional Stark decelerator techniques. Simulations for NH₃ show significant improvement in effectiveness of cooling, with respect to the standard 'moving-potential' method [5]. At the same time a high phase-space acceptance of the molecular packet is maintained.

Chiral analysis of a commercial sample of (1S)-(-)-verbenone has been performed using the chiral tag approach. The chirped-pulse Fourier transform microwave spectrum of the verbenone-butynol complex is measured in the 2-8 GHz frequency range. Verbenone is placed in a nozzle reservoir heated to 333K (about 1 Torr vapor pressure). The complex is formed by using a carrier gas of neon with approximately 0.1% butynol. The expansion pressure is about 2 atm. A measurement using racemic butynol is performed to identify isomers of both diastereomer complexes. Quantum chemistry calculations using the B3LYP-D3BJ method with the def2TZVP basis set provided estimated spectroscopic constants for the homochiral and heterochiral complexes. This analysis included 8 isomers for each diastereomer. Four rotational spectra are identified for isomers of the homochiral complex and correspond to the four lowest energy isomers from the theoretical study. Three heterochiral complexes are identified and also correspond to the lowest energy isomers from theory. Subsequent measurements were made with enantiopure tag (both (R)-(+)-3-buty-2-nol and (S)-(-)-3-butyn-2-ol) to establish the absolute configuration of verbenone. The sensitivity of the measurement was sufficient to perform ¹³C-isotopologue analysis of three of the homochiral complexes and two of the heterochiral complexes. These results provide definitive structures of verbenone with correct stereochemistry. The commercial sample has relatively low enantiomeric excess with the certificate of analysis reporting an EE of 53.6%. Using the intensities of assigned transitions of the chiral tag complexes, the enantiomeric excess was determined from the broadband rotational spectrum through the ratio of the intensities of pairs of transitions. A total of 2617 pairs of transitions were analyzed. The average EE was found to be 53.6% with a standard deviation of 2%.

Over the last years, microwave three-wave mixing (M3WM) experiments have been shown to provide a sensitive way to generate and measure enantiomer-specific molecular responses. These experiments opened the door for enantiomeric excess determination in complex samples without previous separation or purification. We present here a new type of experiment, based on M3WMSandra Eibenberger, John Doyle, and David Patterson, arXiv:1608.04691 (2016) to achieve enantiomeric enrichment of a chiral sample by using microwave pulses. We will show that control over the relative phases and polarizations of pulses provides a way to selectively populate a specific quantum rotational state with an enantiomer of choice. The experimental implementation as well as the characterization of the observed enantiomer-selective responses will be presented and discussed. As a proof of concept and to showcase the applicability of our approach we will present the enantiomer enrichment of several terpenes.

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Footnotes:

Sandra Eibenberger, John Doyle, and David Patterson, arXiv:1608.04691 (2016),

Complexes of propylene oxide with 3-butyn-2-ol were observed in the molecular rotational spectra, and isotopologue analysis allowed for structural determination of the complexes. Using a gas mixture of 0.1% propylene oxide and 0.1% 3-butyn-2-ol in neon, the broadband rotational spectrum was measured in the 2-8 GHz frequency range using a chirped-pulse Fourier transform microwave spectrometer. Four isomers of each diastereomer pair, formed by a hydrogen bond between the two monomers, are identified in quantum chemistry study of the complex using B3LYP-D3BJ with the def2TZVP basis set. The initial measurement used racemic samples of both molecules in order to obtain all possible isomers of the complex in the pulsed jet expansion. A total of six distinct spectra were assigned in the racemic measurement - three for both the homochiral and heterochiral complex. Substitution structures for the most intense homochiral and heterochiral complexes were obtained. These complexes use the two lowest energy conformations of butynol despite conformational cooling of the monomer, resulting in a single identified isomer. This result shows that a wide range monomer conformational geometries need to be examined when performing searches for the lowest energy geometry. Analysis of the diastereomer spectra was used to develop a method for determining the enantiomeric excess of 3-butyn-2-ol and propylene oxide for use as a chiral tag, which could be used in subsequent measurements to determine enantiomeric excess. The sensitivity limits for enantiomeric excess determination and the linearity of the rotational spectroscopy signals as a function of sample enantiomeric excess will be presented.

We present the application of Fourier transform microwave (FTMW) spectroscopy in monitoring the chiral purity of components in a reaction mixture. This is of particular interest due to the increasing use of continuous pharmaceutical manufacturing processes, in which a number of attributes (including the chiral purity of the product) can change on short time scales. Therefore, new techniques that can accomplish this measurement rapidly are desired. The excellent specificity of FTMW spectroscopy, coupled with newly developed techniques for measuring enantiomeric excess in a mixture, have motivated this work. In collaboration with B. Frank Gupton (Virginia Commonwealth University), we are testing this application first with the synthesis of artemisinin. Artemisinin, a common drug for malaria treatment, is of high global health interest and subject to supply shortages, and therefore a strong candidate for continuous manufacturing. It also has moderately high molecular weight (282 amu) and seven chiral centers, making it a good candidate to test the capabilities of FTMW spectroscopy. Using a miniature cavity-enhanced FTMW spectrometer design,R.D. Suenram, J.U. Grabow, A.Zuban, and I.Leonov, Rev. Sci. Instrum. 70, 2127 (1999).e aim to demonstrate selective component quantification in the reaction mixture. Future work that will be needed to fully realize this application will be discussed.

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Footnotes:

R.D. Suenram, J.U. Grabow, A.Zuban, and I.Leonov, Rev. Sci. Instrum. 70, 2127 (1999).w

The measurement of the parity violating energy difference ∆_pvE between the enantiomers of chiral molecules is among the major current challenges in high resolution spectroscopy and physical-chemical stereochemistry.M. Quack , Fundamental Symmetries and Symmetry Violations from High-resolution Spectroscopy, Handbook of High Resolution Spectroscopy, M. Quack and F. Merkt eds.,John Wiley & Sons Ltd, Chichester, New York, 2001, vol. 1, ch. 18, pp. 659-722._'S. Albert, I. Bolotova, Z. Chen, C. Fábri, L. Horný, M. Quack, G. Seyfang and D. Zindel, Phys.Chem.Chem.Phys.18, 21976−21993 (2016).heoretical predictions have recently identified dithiine^b and trisulfaneC. Fábri, L. Horný and M. Quack, ChemPhysChem16, 3584−3589 (2015).s suitable candidates for such experiments. We report the first successful high−resolution analyses of the Fourier transform infrared (FTIR) spectra of trisulfane. A band centered at 861.0292 cm^-1 can be assigned unambiguously to the chiral trans conformer by means of ground state combination differences in comparison with known pure rotational spectra. M. Liedtke, K. M. T. Yamada, G. Winnewisser and J. Hahn, J.Mol.Struct.413, 265−270 (1997). second band near 864.698 cm^-1 S. Albert, I. Bolotova, Z. Chen, C. Fbri, L. Horn, M. Quack, G. Seyfang and D. Zindel, Phys.Chem.Chem.Phys.18, 21976-21993 (2016).TC. Fbri, L. Horn and M. Quack, ChemPhysChem16, 3584-3589 (2015).aM. Liedtke, K. M. T. Yamada, G. Winnewisser and J. Hahn, J.Mol.Struct.413, 265-270 (1997).A