The Absolute Configuration of Bromochlorofluoromethane

Abstract

Bromochlorofluoromethane is the simplest chiral molecule that is used as an example to illustrate chirality or asymmetric carbon atoms, yet its absolute configuration remains uncertain. The synthesis of bromochlorofluoromethane in a pure form was achieved by Berry and Sturtevant in 1942. [1] They determined its boiling point, melting point, and refractive dispersion, but the individual enantiomers were not resolved. Despite the unavailability of enantiomers and their optical rotation values, Brewster hypothesized that (S)-bromochlor-ofluoromethane would have positive optical rotation, assuming that the polarizabilities decrease in the order Br > Cl > H > F. [2] Hargreaves and Modarai were able to resolve the enantiomers of 1-bromo-1-chloro-1-fluoroacetone and convert them into the corresponding bromochlorofluoromethane enantiomers. [3] They reported the specific rotations to be þ 0.20 and À0.13. In 1973 Applequist predicted, using an atom±dipole interaction model and assuming the polarizabilities to be in the order, Br > Cl > F > H, that (S)-bromochlorofluoromethane would have positive optical rotation. [4] However, the different polarizability orders chosen by Brewster and Applequist would yield opposite conclusions. [5] Collet and co-workers achieved optical resolution of bromochlorofluoromethane by enantioselective inclusion in cryptophan C. [6] Using the NMR resonance signals of (þ) and (À) enantiomers encapsulated in cryptophan, they estimated the enantiomeric excess and maximum rotation values at five different wavelengths. In a different approach, Wilen et al. also resolved the enantiomers of bromochlorofluoromethane using brucine [5] and addressed the ambiguity remaining in the absolute configuration of bromochlorofluoromethane; Brewster and Applequist had arrived at the same assignment but using mutually conflicting polarizability trends. Wilen et al. concluded that ™experimental determination of the absolute configuration of bromochlorofluoromethane is a challenge∫. [5] Using a quantum-mechanical static method, the specific rotation of (R)-bromochlorofluoromethane at the sodium D line was predicted (without the Lorentz factor) to be À6. [7,8] Comparison of this value with the experimental value of À1.78 reported by Collet et al. for enantiopure (À)-bromochlorofluoromethane, and based on the comparison of experimental and ab initio predicted Raman optical-activity (ROA) spectra, it was concluded that the absolute configuration of bromochlorofluoromethane is (S)-(þ) and (R)-(À). [7] Previous conclusions [7] on the absolute configuration were based on quantum-mechanical calculations of both ROA and specific rotation, carried out at the Hartree±Fock (HF) level using smaller basis sets. Since then, evidence has been collected [9] to indicate that the HF level calculations, because of lack of electron correlation, are not quantitatively accurate. DFT, [10] which includes electron correlation using density functionals, has now been widely accepted as the preferred approach for predicting molecular properties a...

Vibrational optical activity

“…Although the first tranche of such calculations of ROA spectra did not reach high levels of accuracy, they nonetheless proved valuable. For example, the absolute configuration of the archetypal chiral molecule CHFClBr, which had resisted assignment for over 100 years, was reliably determined from a comparison of the experimental and ab initio theoretical ROA spectra [73,74]. Analogous VCD studies of this molecule are less favourable because the frequencies of many of the fundamental normal modes of vibration are too low to be experimentally accessible, whereas all are accessible in the ROA spectrum.…”

Raman Optical Activity and Raman Spectra of Amphetamine Species—Quantum Chemical Model Calculations and Experiments

“…The theory of ROA has already been fully established, a few years after the phenomenon was reported [18], but a quantum-chemical calculation was first realized almost 20 years later [19], and the method became even more reliable once the development of the method for calculating frequency dependent polarizabilities [20] was found. Although ROA quantum-chemical calculations are still representing a challenge, the absolute configurations of CHFClBr [21,22] and deuterated neopentane have already been achieved [23].…”

An experimental and theoretical study of the valence shell photoelectron spectrum of bromochlorofluoromethane

“…Bromochlorofluoromethane is one of the simplest chiral molecules possessing an asymmetric carbon atom and, as such, its geometric and electronic structure have attracted considerable interest [1][2][3][4][5][6]. Although the molecule contains two relatively heavy atoms, its size is sufficiently small for its physical properties to be calculated reliably using advanced theoretical and computational approaches.…”