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This week’s issue of the scientific journal ChemPhysChem features a cover illustration highlighting work by researchers from the Van ’t Hoff Institute for Molecular Sciences (HIMS). They improved the sensitivity of one of the most important spectroscopic methods for determining chiral molecular structure. The ‘molecular astronaut’ in the illustration reveals a remarkable detail.

Cover ChemPhysChem Molecular Photonics VCD research
Cover of ChemPhysChem Volume 16, Issue 16 (16 Nov 2015). Artwork by Nuno Baptista.

The cover artwork accompanies a so-called Concept article in which ChemPhysChem puts novel and eye-catching research in the spotlight. First author is Sérgio Domingos, who recently graduated under the supervision of Molecular Photonics professors Wybren Jan Buma and Sander Woutersen.

Spatial variations

In the article the Amsterdam chemists present an innovative, highly effective method to determine the spatial structure of chiral molecules. Such molecules exist in two forms that are mirror images of each other, similar to our two hands being mirror images. Because of this analogy the two forms are referred to as left- and right-handed molecular enantiomers.

This particular property of chirality is essential for the chemical and biological activity of these molecules. The ability to determine the 'handedness' of chiral molecules therefore is crucial in establishing how molecular structure and activity are related. This is key, for example, for the development of novel drugs.

Unfortunately the determination of chiral structure is quite difficult, even more so when the molecules are in solution which is almost always the case. Under these conditions the left- and right-handed forms of chiral molecules are only distinguishable by the fact that they have slightly different absorptions of left- and right-circularly polarized light.

Cover ChemPhysChem Molecular Photonics VCD research DETAIL
A subtle reference on the back of the ‘molecular astronaut’ makes clear that for this kind of research the UvA is the place to be! Artwork by Nuno Baptista.

The technique of Vibrational Circular Dichroism (VCD) makes use of this effect, but the measured absorption differences are very small. Recording VCD spectra therefore usually takes a lot of time, with measurement times of one to two days not being uncommon.

Signal amplification

The Amsterdam scientists have now discovered how to amplify these weak signals by a factor of a hundred to a thousand. They present relatively simple chemical steps which enable fast and unambiguous chiral structure determination. Moreover, their approach allows them to zoom in on smaller parts of large chiral molecules and bring these ‘into the spotlight’ (as illustrated in the ChemPhysChem cover illustration). In this way it is possible to determine the detailed structure at that particular location, and to study how this structure changes under the influence of external factors such as pH and temperature, or when a drug molecule binds to the molecular system.

Theoretical analysis

The improvement finds its origin in a thorough theoretical analysis of what ultimately determines VCD signal intensities. Such an analysis predicts that the sensitivity of the method should increase dramatically if ‘vibronic coupling’ comes into play. That is when the motion of the nuclei in the molecule and that of the electrons become strongly coupled. In other words, with carefully chosen chemical modifications it is possible to let oscillating atoms in the molecule influence the electronic distribution in the molecule and thereby contribute to the difference in absorption. The result is a stunning amplification of the differential absorption.


S. R. Domingos, F. Hartl, W. J. Buma, S. Woutersen: Elucidating the Structure of Chiral Molecules by using Amplified Vibrational Circular Dichroism: From Theory to Experimental Realization ChemPhysChem 2015, 16, 3363 DOI: 10.1002/cphc.201500551