Absolute optical chiral analysis using cavity-enhanced polarimetry

Bougas et al., Sci. Adv. 8, eabm3749 (2022) 3 June 2022 SCIE N C E A D V A NCES | RESEA R CH A RT ICL E 1 of 10 C HE M ICAL PH YSICS Absolute optical chiral analysis using cavity-enhanced polarimetry Lykourgos Bougas1*, Joseph Byron2, Dmitry Budker1,3,4, Jonathan Williams2,5 Chiral analysis is central for scientific advancement in the fields of chemistry, biology, and medicine. It is also indispensable in the development and quality control of chiral compounds in the chemical and pharmaceutical industries. Here, we present the concept of absolute optical chiral analysis, as enabled by cavity-enhanced pola- rimetry, which allows for accurate unambiguous enantiomeric characterization and enantiomeric excess determi- nation of chiral compounds within complex mixtures at trace levels, without the need for calibration, even in the gas phase. Our approach and technology enable the absolute postchromatographic chiral analysis of complex gaseous mixtures, the rapid quality control of complex mixtures containing chiral volatile compounds, and the online in situ observation of chiral volatile emissions from a plant under stress. INTRODUCTION Chiral analysis—enantiomeric characterization and enantiomeric excess (e.e.) determination—is a challenging task as the chemical and physical properties of enantiomers are identical, so enantiomers can only be distinguished through their interaction with another chiral object (1). For this reason, analytical techniques such as optical polarimetry, mass spectrometry (MS), and nuclear magnetic resonance (NMR) rely on the chirality of light or of a molecular environment (as in the case of chiral chromatography). These tech- niques, however, require extensive calibrations for accurate analysis and typically fail to reliably detect chiral compounds at trace levels within complex mixtures. Modern chirality-sensitive optical tech- niques such as photoionization (2–4), femtosecond (5), microwave (6), and superchiral light–based (7, 8) spectroscopies offer specific advantages, including sensitivities sufficient for gas-phase sensing or the detection of protein monolayers. However, such techniques cannot currently operate within complex environments such as chiral sensing in ambient air. Most crucially, the overall inability of all aforementioned techniques to allow for accurate real-time measurements without the need for calibration prevents in situ real-time study of important chemical, biological, and medical dynamical processes, such as the response of biological organisms to sickness (9) or stress (10). Molecular optical activity measurements remain the best option to address these limitations. Optical rotary dispersion (ORD) and circular dichroism (CD), in particular, remain the most widely used techniques for measuring chirality (1). However, molecular chiropti- cal signals are intrinsically weak (~10−5 to 10−3 rad) and often masked by dominant backgrounds. As a result, the application of chiral analysis by ORD and CD measurements has remained limited to the detection of high-concentration samples, particularly liquids. Recently, a polarimetric technique for enhanced ORD and CD measurements was developed, dubbed as cavity-enhanced chiral polarimetry (CCP) (11–14). CCP uses a ring (four-mirror) optical cavity in a bowtie configuration, where the light always passes through the chiral sample from the same direction, to enhance the chiroptical signals (ORD and CD) by the large number of cavity passes (optimally >104; Fig. 1 and fig. S1). Crucially, the placement of an intracavity Faraday rotator, in relation to the symmetry of natural optical activity and the available counterpropagating modes of propagation within the cavity, enables crucial signal-reversal operations that allow for absolute polarimetric measurements not requiring sample removal for a null-sample measurement or instru- ment calibration (13–15). To date, however, all CCP experiments have us