Over 50% of currently marketed pharmaceutical drugs contain one or more optically active pharmaceutical ingredients. Two-thirds of prescription drugs are chiral, with the majority of new chiral drugs being single enantiomers. Enantioselective synthesis, also called asymmetric catalysis, is an important method used to control stereoselectivity in their production. The advantage of the asymmetric catalysis, is that each molecule of chiral catalyst, by virtue of being continually regenerated, can yield many molecules of chiral product. This type of catalyst has significant potential advantages over older procedures which can yield only up to 50% of the desired enantiomer. For this reason, it is important to understand the molecular interactions of these catalytic reactions to design and optimize them. In 1979, Koga and coworkers reported that (+)-menthoxyaluminium dichloride, a chiral Lewis acid catalyst, worked effectively to form stereoselective products but did not offer an explanation for how this stereoselectivity was achieved. In an attempt to develop a model for stereoselectivity, Corey and coworkers employed the formyl hydrogen bond, but it did not fully explain Koga’s results. We hypothesize that an α-hydrogen bond, a novel catalytic element, is another important stereochemical control factor in this catalytic reaction. When these two control elements, the formyl bond and the α-hydrogen bond, are employed together, a more complete rationale for Koga's results can be achieved. To test our hypothesis experimentally, we modeled BF3 with N,N-dimethylformamide, N,N-dimethylacetamide and N,N-dimethylacrylamide computationally using M062X/jul-cc-pvDz. Simultaneously, we started growing single crystals of these same three complexes for X-ray diffraction. Our goal is to find reinforcing evidence for these two intramolecular complex interactions. Results confirm that the computational model is consistent with the X-ray structure of BF3-DMF because the formyl hydrogen bond length in our prediction (2.2 Å) is similar to the crystallographic length (2.3 Å). In addition, our computational prediction of the α-hydrogen bond length in BF3-DMA is 2.2 Å which supports our hypothesis, especially because the energy difference between BF3-DMF and BF3-DMA is 0.4 kcal/mol which means that both types of hydrogen bonds compete with each other in the complexes studied.

Evidence for formyl and α-hydrogen bonding in asymmetric organic reactions from single crystal X-ray diffraction and density functional theory

253rd National Meeting (2017)

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