Werner Hug

Absolute configuration of chirally deuterated neopentane

The relationship between macroscopic chirality and chirality on the molecular level was unequivocally established in 1951 through anomalous X-ray scattering. Although this technique became the definitive method for determining the absolute configuration of a molecule, one important limitation of the approach is that the molecule must contain ‘heavy’ atoms (for example, bromine). The direct determination of absolute configurations for a wider range of molecules has recently become possible by measuring a molecule’s vibrational optical activity. Here we show that instrumental advances in Raman optical activity, combined with quantum chemical computations, make it possible to determine the absolute configuration of (R)-[2H1, 2H2, 2H3]-neopentane. This saturated hydrocarbon represents the archetype of all molecules that are chiral as a result of a dissymmetric mass distribution. It is chemically inert and cannot be derivatized to yield molecules that would reveal the absolute configuration of the parent compound. Diastereomeric interactions with other molecules, optical rotation, and electronic circular dichroism are, in contrast to the well-known case of bromochlorofluoromethane, not expected to be measurable. Vibronic effects in the vacuum ultraviolet circular dichroism might reveal that the molecule is chiral, but the presence of nine rotamers would make it extremely difficult to interpret the spectra, because the spatial arrangement of the rotamers’ nuclei resembles that of enantiomers. The unequivocal spectroscopic determination of the absolute configuration of (R)-[2H1, 2H2, 2H3]-neopentane therefore presented a major challenge, one that was at the very limit of what is possible.

A novel high-throughput Raman spectrometer for polarization difference measurements

A Raman backscattering instrument which, for the first time, takes full advantage of the enormous etendue of modern holographic transmission grating spectrographs in single sample measurements is described. Developed primarily as the basic design of a new generation of Raman optical activity spectrometers, it inherently has the capability also to measure precisely and rapidly the degree of circularity of scattered light, and thus reversal coefficients. Its novel dual-channel design allows the simultaneous measurement of right and left circular scattered light and drastically reduces sensitivity to particulate matter and thermal Schlieren in the sample. As examples the rapid and precise measurement of the degree of circularity of optically inactive substances and of the vibrational Raman optical activity of D-carnitine·HCl is presented. Copyright

Raman Optical Activity of a Purelyσ-Bonded Helical Chromophore: (−)-(M)-σ-[4]Helicene

The recent synthesis of enantiomerically pure (−)-(M)-σ-[4]helicene has provided an archetype helical model system for vibrational optical activity, comparable to what π-helicenes represent in the field of electronic optical activity. We present the first measurements and the first calculations of the Raman optical activity (ROA) of this interesting molecule. Observed and calculated ROA is large throughout the vibrational spectrum, in agreement with expectations, and spectacular effects, with Δ values close to 0.5%, occur in the 900-cm−1 region. Agreement between the experimental spectrum and the theoretical one, calculated with density-functional theory for the vibrational part and Hartree-Fock linear response theory for the molecular electronic tensors, is excellent, clearly the best that has been achieved to date in the field. This allows us to place confidence in the results of an analysis of Raman and ROA scattering generation in the molecule, obtained by a newly developed graphical procedure for extracting this kind of information from ab initio calculations. One finds that relative contributions made by carbon and hydrogen atoms can be comparable in size, but can also vary considerably, even between closely lying vibrations, and that, for most vibrations, the generation of ROA difference intensity is distributed rather differently than that of Raman intensity over the shape of the molecule. The sign of the ROA is, for the set of vibrations in the 900-cm−1 region, which we analyze in detail, determined by coupling terms between the two halves of the molecule, while Raman intensity is primarily generated within the two fragments, with coupling terms between them only adding to or substracting from it.

Total Synthesis of Junionone, a Natural Monoterpenoid from Juniperus communis L., and Determination of the Absolute Configuration of the Naturally Occurring Enantiomer by ROA Spectroscopy

Recently, we reported a novel access to 2,2‐diethyl‐3‐[(E/Z)‐prop‐1‐en‐1‐yl]cyclobutanone by an intramolecular nucleophilic substitution with allylic rearrangement (SNi′) of (E)‐6‐chloro‐3,3‐diethylhept‐4‐en‐2‐one. The ring closure reaction was found to proceed with selective syn‐displacement of the leaving group. This method was now applied to the total synthesis of junionone, an olfactorily interesting cyclobutane monoterpenoid isolated from Juniperus communis, L. SNi′ Ring closure of the ketone enolate of (E)‐3,3‐dimethyl‐5‐[(2R,3R)‐3‐methyloxiran‐2‐yl]pent‐4‐en‐2‐one (R,R)‐(E)‐4′ proceeded only after the epoxide moiety had been activated by Lewis acid and led to the junionone precursors (3R)‐ and (3S)‐3‐[(1E,3R)‐3‐hydroxybut‐1‐en‐1‐yl]‐2,2‐dimethylcyclobutanone (S/R,R)‐(E)‐3. The ratio of syn‐ and anti‐conformers in the transitory molecular arrangement was found to depend on the nature of the Lewis acid. The absolute configuration of both the synthetic as well as the natural junionone, isolated from juniper berry oil, was determined by Raman Optical Activity (ROA) spectroscopy. Our experiments led to a novel synthetic route to both (+)‐ and (−)‐junionone, the first determination of the absolute configuration of natural junionone, and to the development of a practical ROA procedure for measuring milligram quantities of volatile liquids.

Efficient calculation of ROA tensors with analytical gradients and fragmentation.

We present the results of calculations of Raman optical activity spectra of sizable systems from optical tensors of the fragments, the tensors calculated by an analytic approach at the time-dependent Hartree-Fock level of theory. The analytic approach permits large basis sets which, together with the limited geometrical extent of the fragments, obviates the need for the use of London-type orbitals. The implementation of the analytical gradient approach is formulated in the atomic orbital basis by using the elements of the density matrix as variational parameters. This makes the approach directly applicable to linear scaling methods. We do not solve the response equations for the geometrical distortions of the nuclei but determine instead the second-order perturbed densities with respect to the electromagnetic field perturbations. The number of perturbed density matrices that needs to be determined is thus independent of the number of nuclei, making the approach applicable to fragments with many nuclei and with good quality basis sets. Compared to numerical differentiation schemes, the analytical approach is about 10 times faster even for moderately sized molecules.

Vibrational Raman optical activity of biological molecules

Advances in Raman optical activity (ROA) instrumentation based on the employment of a backscattering geometry together with a cooled CCD detector have now enhanced the sensitivity to the level necessary to provide vibrational ROA spectra of biological molecules in aqueous solution. Preliminary results on peptides and proteins show features originating in coupled Ca-H and N-H deformations of the peptide backbone which appear to be sensitive to the secondary conformation. Also carbohydrates show many features that appear to be characteristic of the central aspects of carbohydrate architecture with effects from the glycosidic link in di- and oligosaccharides particularly prominent. 1.

Raman Optical Activity, Spectrometers

Advances in instrumentation over the past decade have led to decisive progress in the routine measurement of Raman optical activity. The optical creation of a virtual enantiomer, in conjunction with scrambling of components of linear polarization in the exciting and scattered light without degrading its circular content, has solved the problem of deterministic offsets. Spectrographs based on planar holographic grating technology and light collection optics capable of filling their large etendue (the amount of light that an optical system is capable of collecting), combined with multichannel detection with backthinned CCDs, have reduced the shot noise problem to an extent where the possible use of transform spectroscopy, providing Jacquinot throughput and Fellget multiplexing gain simultaneously, is unlikely to provide an improvement for visible light. Flicker noise has been reduced in collinear scattering by the simultaneous detection of right and left circularly polarized light. Problems remain due to spontaneous Raman scatterings low dynamic range and due to fluorescence for excitation at visible wavelengths.

The evaluation of ω parameters in contracted density product calculations

General formulas for the rotational averages of two electron integrals with arbitrary combinations of spherical tensors in standard, Cartesian, and equivalent form are presented. The way in which the ω parameters of CDP type calculations can be obtained from rotational averages is discussed, and it is shown from numerical results that the interpretation of the ω parameters as space averages is compatible up to d orbitals with the CDP invariance requirements.