Analysis of isomeric mixtures by molecular rotational resonance spectroscopy

Abstract

Recent developments in molecular rotational resonance (MRR) spectroscopy that have enabled its use as an analytical technique for the precise determination of molecular structure are reviewed. In particular, its use in the differentiation of isomeric compounds-including regioisomers, stereoisomers and isotopic variants-is discussed. When a mixture of isomers, such as resulting from a chemical reaction, is analyzed, it is highly desired to be able to unambiguously identify the structures of each of the components present, as well as quantify them, without requiring complex sample preparation or reference standards. MRR offers unique capabilities for addressing this analytical challenge, owing to two factors: its high sensitivity to a molecule's structure and its high spectral resolution, allowing mixtures to be resolved without separation of components. This review introduces core theoretical principles, an introduction to MRR instrumentation and the methods by which spectra can be interpreted with the aid of computational chemistry to correlate the observed patterns to molecular structures. Recent articles are discussed in which this technique was applied to help chemists complete challenging isomer analyses. Developments in the use of MRR for chiral analysis and in the measurement of isotopically labeled compounds are also highlighted.

FIGURE 1

Implementation of chirped‐pulse broadband molecular rotational resonance (MRR) spectroscopy for chemical analysis. The left panel shows a schematic of a direct‐digital spectrometer with multiple pulsed nozzle sources (used with permission ⁴³ ), with the three aspects of the instrument, specifically pulse generation (1): excitation (2) and detection (3), indicated. The right panel shows a photograph of a broadband MRR spectrometer. This instrument implementation has a total lab footprint of approximately 144 × 36 in (365 × 90 cm).

FIGURE 2

Progression of analysis of a mixture of diastereomers using broadband molecular rotational resonance (MRR) spectroscopy. In each panel, the black spectrum indicates the experimental spectrum, while the different colours are predicted spectra using calculations of the rotational Hamiltonian (Equation (2)) with a given set of rotational constants, and are negative‐going for visualization. Panels marked “Simulation” use computed rotational constants, while “Fit” spectra use experimentally determined parameters. See the text for further description.

FIGURE 3

Computed structures of dihydroartemisinic acid (DHAA) and its diastereomeric impurity observed in the hydrogenation of artemisinic acid as described in the text. Each of these structures is identified in the molecular rotational resonance (MRR) spectrum through the agreement of its calculated rotational constants with experimentally determined values (Table 1). The principal axis system (black lines) and the direction of the permanent dipole moment (blue arrows) are also indicated on the structures.

FIGURE 4

Analysis of a crude reaction product mixture by molecular rotational resonance (MRR). The reaction studied (top) is the photocatalytic arylation of C‐H bonds in cyclohexanone as described . In the top panel, the broadband MRR spectrum of the crude reaction mixture is shown. The middle and lower panels colour the transitions to indicate the species identifications, with expanded views to show the resolution of the spectrum and the identification of the low‐abundance 2‐substituted impurity. The figure is adapted with permission.

FIGURE 5

A demonstration of the use of molecular rotational resonance (MRR) for automated analysis of the output of a continuous flow reactor is presented. The solution from the reactor is transferred using a solenoid dosing pump into a reservoir in the pulsed valve. The solvent is first vented off to exhaust, in this case, the solvent was ethanol and was vented at 75°C. Following this, the temperature of the valve is increased to 160°C and the analyte mixture is volatilized and measured. The reaction studied was the asymmetric hydrogenation of artemisinic acid (top right). The relative concentrations of the four species found in the reaction mixture are quantified on a ∼25‐min timescale. Figure adapted with permission.

FIGURE 6

An example of the assignment of absolute configuration by chiral tagging molecular rotational resonance (MRR). In the top panel, the spectra of the chiral complexes between pantolactone and trifluoropropylene oxide (TFPO) are shown. The MRR spectra of pure pantolactone and pure TFPO have been removed from this spectrum. The negative‐going spectrum is the racemic measurement (where the two diastereomeric complexes are formed at equal concentration) while the positive‐going spectrum is where the enantiopure tag is used. The homochiral and heterochiral complexes are assigned using the agreement of the rotational constants of the calculated minimum complex geometries (bottom panels) with the experimentally derived values. In this measurement, the pantolactone absolute configuration is assigned as (R). Adapted with permission.

FIGURE 7

The enantiomeric excess of compounds can be determined using a targeted molecular rotational resonance (MRR) spectrometer. In these measurements, commercial samples of (R)‐ and (S)‐pantolactone are mixed to known purity levels and analyzed using MRR. In the left panel, the x‐axis represents the enantiomeric excess of each sample calculated using the enantiopurity of the chiral samples from chiral gas chromatography. Adapted with permission.