Chiral sensing for liquid analysis – Synergies between Quantum Cascade Lasers and Vibrational Circular Dichroism

Abstract

Both chiral small molecules and protein derived pharmaceuticals like monoclonal antibodies have been the focus of increased development in the last years, resulting in an increased need for analytics.1,2 For both categories, their therapeutic effect is intrinsically linked to their structure and indeed their chirality. It is therefore desirable to monitor and control these parameters, the enantiomeric excess for small molecules and the secondary and tertiary structure for proteins, over the production cycle of a drug. Vibrational circular dichroism (VCD) can be used in this regard, as it expands the inherent structure elucidation capabilities of mid-infrared (MIR) spectroscopy by adding chiral sensitivity as additional dimension. Unfortunately, the application of VCD is limited by several factors. The high absorbance of some solvents, like water during protein analytics, restricts the pathlength and therefore the achievable intensity, resulting in high limits of detection. Additionally, this drawback is compounded by VCD being characterized by very low intensity (~10-5 compared to classical absorbance), necessitating long acquisition times (hours) to achieve acceptable noise levels. We now present a dedicated VCD setup, utilizing a quantum cascade laser (QCL), as a viable solution to the discussed challenges. With the high brilliance of the QCL longer pathlengths, resulting in stronger signals, are possible. Our implementation of balanced detection for VCD measurements achieves a considerable reduction of laser noise, providing further advantages. We employed these advances for high time resolution studies of small molecules at a time scale of 3 minutes per measurement and low concentration measurements of the amide I band of proteins in water at 18 minutes of spectral acquisition.