A1 Journal article (refereed)
Hypersensitive Inhibition of Organocatalysts by Halide Salts : Are Two Catalysts Involved in the Mannich Reaction? (2024)

Leino, T., Noutsias, D., Helttunen, K., Moilanen, J., Tarkkonen, E., Kalenius, E., Kiesilä, A., & Pihko, P. M. (2024). Hypersensitive Inhibition of Organocatalysts by Halide Salts : Are Two Catalysts Involved in the Mannich Reaction?. European Journal of Organic Chemistry, Early online. https://doi.org/10.1002/ejoc.202400321

JYU authors or editors

Leino, Teppo
Noutsias, Dimitris
Helttunen, Kaisa
Tarkkonen, Eeki
Kalenius, Elina
Kiesilä, Anniina
Pihko, Petri

Publication details

All authors or editors: Leino, Teppo; Noutsias, Dimitris; Helttunen, Kaisa; Moilanen, Jani; Tarkkonen, Eeki; Kalenius, Elina; Kiesilä, Anniina; Pihko, Petri M.

Journal or series: European Journal of Organic Chemistry

ISSN: 1434-193X

eISSN: 1099-0690

Publication year: 2024

Publication date: 08/04/2024

Volume: Early online

Publisher: Wiley-VCH Verlag

Publication country: Germany

Publication language: English

DOI: https://doi.org/10.1002/ejoc.202400321

Publication open access: Openly available

Publication channel open access: Partially open access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/97505

Abstract

Conformationally flexible tertiary amine—thiourea-urea catalysts 1 and 2 for the Mannich reaction between imines and malonate esters are efficiently inhibited by quaternary ammonium halides. NMR titrations, isothermal titration calorimetry (ITC) and NOE experiments showed that the catalysts bind chloride and bromide ions with relatively high affinities (K = 103– 105 M–1 in acetonitrile). The halide ions not only block the active site of the catalysts, but they also refold into catalytically inactive conformations upon complexation in an allosteric-like event. At substoichiometric inhibitor:catalyst ratios, the catalysts displayed hypersensitivity to the inhibitors, with overall rates that were lower than those expected from simple 1st order kinetics and 1:1 inhibitor:catalyst stoichiometry. To rationalize the observed hypersensitivity, different kinetic scenarios were examined. For catalyst 2 and the Takemoto catalyst (6), the data is consistent with 2nd order dependency on catalyst concentration, suggesting that a mechanism involving only a single catalyst in the catalytic cycle is not operative. For catalyst 1, an alternative scenario involving 1st order in catalyst and catalyst poisoning could also rationalize the hypersensitivity. Inhibition of catalysts 1 and 2 by halide salts led to significant loss of enantioselectivity, but Takemoto catalyst 6 was inhibited with essentially no change in enantioselectivity.

Keywords: catalysis; catalysts; isomerism; organic chemistry

Fields of science: