Title

Fourier transform vibrational circular dichroism: Step-scan instrumentation and biological applications

Date of Award

1998

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

Laurence A. Nafie

Second Advisor

Teresa B. Freedman

Keywords

Fourier transform, Vibrational circular dichroism, Step-scan instrumentation

Subject Categories

Analytical Chemistry | Chemistry

Abstract

In this dissertation, the instrument design and optimization of two step-scan Fourier transform vibrational circular dichroism (FT-VCD) spectrometers are described and several applications of VCD spectroscopy using this instrumentation are reported. The solution conformation and absolute configuration of a number of pharmaceutical and biological molecules are determined, and in addition, several analyses of optical purity measurements using the VCD spectroscopic method are illustrated.

The development of FT-VCD spectrometers based on a Nicolet Magna 850 FTIR for the mid-IR region and a Bruker IFS-55 FTIR for the near-IR region is described. It is demonstrated that using concentric optical elements with careful alignment, VCD spectra for single enantiomers of a chiral sample can be obtained with low levels of interfering artifacts and high signal-to-noise ratio. In the mid-IR region, the comparison of traditional sequential rapid-scan, new simultaneous rapid-scan and step-scan shows that the simultaneous rapid-scan method gives the highest quality, and sequential rapid-scan and the step-scan mode follow closely. In the step-scan method, a wide range of step speeds and lock-in-amplifier time constants can be used, and the VCD noise level is proportional to the actual data-averaging time. In the near-IR region, although VCD spectra can be collected in the rapid-scan mode, higher signal-to noise ratios are achieved for step-scan measurements by a factor of 2. It is shown that an InSb detector with very high D* only improves the signal-to-noise ratio slightly comparing to an MCT detector, and both Nicolet-based and Bruker based instruments give the same spectral quality using the same InSb detector.

FT-VCD spectra of the small pharmaceutical molecules propranolol, ibuprofen, naproxen and a series of cyclosporins and four β-turn peptides have been measured. Ab initio molecular orbital calculations were used in interpreting the spectra. Solution conformational structures of propranolol, the cyclosporins and the peptides are characterized. The positive VCD features for the S-configuration of the chiral center common to ibuprofen and naproxen are identified. It is demonstrated that optical purity can be measured with a precision of 1% ee by VCD measurements without enantiomeric separation or chemical modification of the sample.

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