Thioureas are an important scaffold in organocatalysis because of their ability to form hydrogen bonds that activate substrates and fix them in a defined position, which allows a given reaction to occur. Structures that enhance the acidity of the thiourea are usually used to increase the hydrogen-bonding properties, such as 3,5-bis(trifluoromethyl)phenyl and boronate ureas. Herein, we report the synthesis of bifunctional thioureas with a chiral moiety that include either a trifluoromethyl or methyl group. Their catalytic performance in representative Michael addition reactions was used in an effort to compare the electronic effects of the fluorination at the methyl group. The observed differences concerning yields and ee values cannot be attributed solely to the different steric environments; theoretical results indicate distinct interactions within the corresponding transition states. The calculated transition states show that the fluorinated catalysts have stronger N-H···O and C-H···F hydrogen bonds, while the nonfluorinated systems have C-H···π contacts. These results have shown that a variety of hydrogen-bonding interactions are important in determining the yield and selectivity of thiourea organocatalysis. These details can be further exploited in catalyst design.
The asymmetric ring opening of azlactones via dynamic kinetic resolution (DKR) is investigated by contrasting thioureas incorporating 1-arylethyl substituents against their more acidic trifluoromethylated analogs. All the catalysts under study outperform Takemoto’s thiourea because of the inclusion of an additional chiral center. However, the difference in yield and selectivity between the fluorinated and non-fluorinated catalysts is minimal. We explain this observation by analysis of calculated transition states. Our findings show that the hydrogen bond (HB) between the NH linked to the 1-arylethyl and the negatively charged oxygen in the benzyloxy ion is the longest in the HB network, whereas the HB between the ammonium group and the same oxygen atom is the shortest. Thus, the substituents and the HB donor ability of this chiral fragment attached to the thiourea are not important in the reaction.
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