Investigating The Connectivity Between Atoms In Chiral Molecules

When the mirror image of the structure of a molecule cannot be superimposed on its parent structure, these two molecules with non-superimposable chemical structures are called enantiomers and the corresponding compounds fall under the category of chiral compounds. The enantiomers have opposite handedness, loosely categorized as left handed and right handed. Even though the enantiomers with non-superimposable mirror image structures have the same chemical composition, their chemical properties can be drastically different.

Human life owes much of its existence to chirality because the life-controlling proteins in the human body are made of chiral amino acids, all with one particular handedness. Because of this specificity of handedness in our human body, it is necessary to have the proper handedness for a chiral drug compound to function beneficially, when ingested. Therefore, it is of utmost importance to properly characterize, and document, the handedness of chiral compounds used for treating the human illnesses. In this characterization process, establishing the correct chemical structure of chiral molecules is the first step.

If an error occurs in this first step, all subsequent analyses would lose relevance. Continuous ongoing developments in scientific methods are providing sophisticated methods for verifying the chemical structures of chiral compounds.

Among the latest methods are Raman optical activity (ROA) and vibrational circular dichroism (VCD), which along with two other methods, electronic circular dichroism (ECD) and optical rotatory dispersion (ORD), are categorized as the branches of chiroptical spectroscopy. In this paper, we propose a new application of chiroptical spectroscopy.

ROA and VCD methods have come into existence in the early 1970s and since then blossomed into practically useful methods for establishing the handedness of chiral compounds. These methods depend on the fact a molecule with a particular handedness will interact differently with left handed and right handed light waves, also referred to as left circularly polarized (LCP) light and right circularly polarized (RCP) light waves.

ROA and VCD spectroscopies derive their usefulness from the differences in the interaction of LCP and RCP light waves with the vibrational transitions of a chiral molecule, and these differences depend on the chemical structure of that molecule.

ROA and VCD spectroscopies have recently been used to establish the absolute configurations (ACs), for the first time, of chiral molecules, isoflurane, bromochlorofluoromethane, and neopentane-d6. They were also used to confirm the known ACs of several chiral molecules. In all reported applications of chiroptical spectroscopy, the connectivities between the atoms of the studied chiral molecule were known.

If the connectivities between the atoms in a given chiral molecule are not known with certainty, then can chiroptical spectroscopic methods distinguish between the correct and incorrect atomic connectivities? To answer this question, several chiral compounds whose chemical structures have been mis-assigned in the literature, and later corrected, were subjected to chiroptical spectroscopic investigations.

Using spectral similarity overlap criteria, it was found that ROA and VCD spectroscopies, when applied carefully, can discriminate between the correct and incorrect atomic connectivities in chiral molecular structures. This observation is the basis for a new approach for identifying the incorrect chemical structures of chiral compounds.

This study, “To Avoid Chasing Incorrect Chemical Structures of Chiral Compounds: Raman Optical Activity and Vibrational Circular Dichroism Spectroscopies” was recently published (ChemPhysChem 2017, 18, 2459–2465). For more detailed information please see “Chiroptical Spectroscopy: Fundamentals and Applications”, Prasad L. Polavarapu, Taylor & Francis (2017).

About The Author

Prasad Polavarapu

My current research focuses in two directions. In one direction, three dimensional molecular structures of chiral molecules, in the solution or vapor phase, are determined using chiroptical spectroscopic methods. This direction also involves developing new instrumental techniques and the use of quantum theoretical techniques. In the second direction, the secondary structures of biological molecules are determined.

The specific areas of interest include:

  1. Vibrational circular dichroism (VCD), which measures the differential absorption of left versus right circularly polarized infrared radiation
  2. Vibrational Raman optical activity (VROA), which measures the corresponding difference in vibrational Raman scattering
  3. Optical rotatory dispersion (ORD), which measures the rotation of plane polarized light as a function of wavelength
  4. Electronic circular dichroism (ECD), which measures the differential absorption of left versus right circularly polarized visible radiation

The first quantum mechanical predictions of VROA [J. Phys. Chem., 94, 8106-8112 (1990)] and of optical rotation [Mol. Phys. 91, 551-554 (1997)] carried out in this laboratory led to remarkable progress in these areas.

The research in my lab uses the experimental measurements in the above mentioned areas, and combines them with either corresponding quantum mechanical predictions or spectra-structure correlations (in the case of biological molecules) to establish the structures of chiral organic molecules and biological molecules in the solution phase.

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