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A critical assessment of possible pitfalls in absolute configuration assignment using Vibrational Circular Dichroism

Elke Debie UGent (2009)
abstract
Vibrational Circular Dichroism (VCD) is no longuer a curious novelty in the field of molecular spectroscopy as VCD spectrometers are commercially available as well as the algorithms to calculate the spectra, which are implemented in various software packages. This makes VCD routinely applicable for the determination of absolute configurations. The VCD technique is gaining interest in mainly pharmaceutical industry and the technique also has been accepted by regulatory agencies (e.g. FDA) as a proof of absolute configuration (AC). Since a misassignment can have serious consequences, it is of vital importance that all assignments are done correctly. Our experience, however, shows that assignemnt can be hindered by serious problems. First of all, VCD measurements are done in solution, while the calculations are usually performed for a single molecule in vacuum. Intermolecular interactions can cause discrepancies between experimental and theoretical spectra. Inclusion of the solvent in the calculations leads to an improved agreement with the experiments for the case of pulegone and camphor. The agreement of computed VCD spectra with experimental ones, is known to depend strongly on the extent to which all relevant conformations are included in the calculations. This means that conformational analysis, especially for large flexible molecules, has to be performed very carefully. This is illustrated using dipetidyl peptidases (DPP) inhibitors. It is also demonstrated how manipulation of the synthesis pathway may help skirt these problems. Finally, the influence of temperature on experimental VCD spectra was studied. First, it was assumed that the interpretation of the experimental spectra would be simplified at lower temperatures due to a decrease in the number of significantly populated conformations. The effect of lowering the temperature is demonstrated for borneol, 3-methylcyclohaxonon and limonene showing that, unfortunately, different effects counterbalance the expected simplification of the spectrum.
Please use this url to cite or link to this publication:
author
promoter
UGent and WA Herrebout
organization
year
type
dissertation (monograph)
subject
pages
VI, 222 + annexes pages
publisher
Ghent University. Faculty of Sciences
place of publication
Ghent, Belgium
defense location
Gent : Faculteit Wetenschappen
defense date
2009-01-16 00:00
language
English
UGent publication?
yes
classification
D1
copyright statement
I have retained and own the full copyright for this publication
id
470207
handle
http://hdl.handle.net/1854/LU-470207
alternative location
http://lib.ugent.be/fulltxt/RUG01/001/376/216/RUG01-001376216_2010_0001_AC.pdf
date created
2009-01-19 08:53:08
date last changed
2009-10-14 10:19:03
@phdthesis{470207,
  abstract     = {Vibrational Circular Dichroism (VCD) is no longuer a curious novelty in the field of molecular spectroscopy as VCD spectrometers are commercially available as well as the algorithms to calculate the spectra, which are implemented in various software packages. This makes VCD routinely applicable for the determination of absolute configurations. The VCD technique is gaining interest in mainly pharmaceutical industry and the technique also has been accepted by regulatory agencies (e.g. FDA) as a proof of absolute configuration (AC). Since a misassignment can have serious consequences, it is of vital importance that all assignments are done correctly. Our experience, however, shows that assignemnt can be hindered by serious problems.
First of all, VCD measurements are done in solution, while the calculations are usually performed for a single molecule in vacuum. Intermolecular interactions can cause discrepancies between experimental and theoretical spectra. Inclusion of the solvent in the calculations leads to an improved agreement with the experiments for the case of pulegone and camphor.
The agreement of computed VCD spectra with experimental ones, is known to depend strongly on the extent to which all relevant conformations are included in the calculations. This means that conformational analysis, especially for large flexible molecules, has to be performed very carefully. This is illustrated using dipetidyl peptidases (DPP) inhibitors. It is also demonstrated how manipulation of the synthesis pathway may help skirt these problems.
Finally, the influence of temperature on experimental VCD spectra was studied. First, it was assumed that the interpretation of the experimental spectra would be simplified at lower temperatures due to a decrease in the number of significantly populated conformations. The effect of lowering the temperature is demonstrated for borneol, 3-methylcyclohaxonon and limonene showing that, unfortunately, different effects counterbalance the expected simplification of the spectrum.},
  author       = {Debie, Elke},
  language     = {eng},
  pages        = {VI, 222 + annexes},
  publisher    = {Ghent University. Faculty of Sciences},
  school       = {Ghent University},
  title        = {A critical assessment of possible pitfalls in absolute configuration assignment using Vibrational Circular Dichroism},
  url          = {http://lib.ugent.be/fulltxt/RUG01/001/376/216/RUG01-001376216\_2010\_0001\_AC.pdf},
  year         = {2009},
}

Chicago
Debie, Elke. 2009. “A Critical Assessment of Possible Pitfalls in Absolute Configuration Assignment Using Vibrational Circular Dichroism”. Ghent, Belgium: Ghent University. Faculty of Sciences.
APA
Debie, E. (2009). A critical assessment of possible pitfalls in absolute configuration assignment using Vibrational Circular Dichroism. Ghent University. Faculty of Sciences, Ghent, Belgium.
Vancouver
1.
Debie E. A critical assessment of possible pitfalls in absolute configuration assignment using Vibrational Circular Dichroism. [Ghent, Belgium]: Ghent University. Faculty of Sciences; 2009.
MLA
Debie, Elke. “A Critical Assessment of Possible Pitfalls in Absolute Configuration Assignment Using Vibrational Circular Dichroism.” 2009 : n. pag. Print.