Bidentate substrate binding in Brønsted acid catalysis: structural space, hydrogen bonding and dimerization

Area of Science:

• Asymmetric organocatalysis
• Stereoselective synthesis
• Catalysis

Background:

• BINOL derived chiral phosphoric acids (CPAs) are effective organocatalysts for asymmetric synthesis.
• Bidentate binding via two hydrogen bonds is often assumed to achieve high stereoselectivity.
• Experimental insights into CPA-substrate organization and stereoinduction origins are limited.

Purpose of the Study:

• To elucidate the structural space and hydrogen bonding in CPA/imine complexes.
• To experimentally validate the proposed bidentate binding motif.
• To determine the origin of stereoselectivity in CPA-catalyzed reactions.

Main Methods:

• Low-temperature Nuclear Magnetic Resonance (NMR) studies on 19 CPA/imine combinations.
• Computational studies, including molecular dynamics simulations.
• Detection of *trans*-hydrogen bond scalar couplings and NOESY experiments.

Main Results:

• Experimentally validated CPA-substrate hydrogen bonding via *trans*-hydrogen bond scalar couplings.
• Observed preference for [CPA/imine]₂ dimer formation, contrary to the bidentate binding hypothesis.
• Identified specific CPA/imine monomer structures through fine-tuning interactions, revealing stereodetermining elements.

Conclusions:

• The prevalent interaction between CPAs and imines is dimerization, not the assumed bidentate binding.
• Well-defined monomeric CPA/imine complexes can be obtained by controlling steric and noncovalent interactions.
• The study pinpoints the catalyst's 3,3'-substituents and substrate shielding as key factors for stereoselectivity.