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Theoretical study on acidities of (S)-proline amide derivatives in DMSO and its implications for organocatalysis.

Authors
  • Huang, Xiong-Yi1
  • Wang, Hua-Jing
  • Shi, Jing
  • 1 Department of Chemistry, University of Science and Technology of China, Hefei, 230026, China. , (China)
Type
Published Article
Journal
The Journal of Physical Chemistry A
Publisher
American Chemical Society
Publication Date
Jan 21, 2010
Volume
114
Issue
2
Pages
1068–1081
Identifiers
DOI: 10.1021/jp909043a
PMID: 20030369
Source
Medline
License
Unknown

Abstract

The acidities (pK(a) values) of proline amide derivatives are of great importance for understanding the catalytic activity of proline-based organocatalysts. The development of new catalysts could also benefit from the systematic study of the pK(a) values of these compounds. However, only a few pK(a) values of the proline-based organocatalysts are currently available due to the difficulty in experimentally measurements. In this work, we set out to study the pK(a) values of various proline amide derivatives with theoretical calculations. Different theoretical methods were evaluated and the combined method, B3PW91/6-311++G(3df,2p)//B3LYP/6-31+G(d)//HF//CPCM/UA0, was found to be the best one in reproducing the pK(a) values of structurally unrelated amides and amide derivatives in DMSO. The MAD and RMSE of the newly developed theoretical model equal to 0.98 and 1.3 pK units, respectively. The method also enabled the systematically study on various structural effects on pK(a) values of proline amide derivatives, such as the ZE-isomerization, remote substitution, and alpha-substitution effects, for the first time. The pK(a) values of a series of chiral amides were also studied in this work. Finally, we applied the theoretical method to predict a large number of proline-based organocatalysts and established an extensive acidity scale of the compounds.

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