Attractive Noncovalent Interactions versus Steric Confinement in Asymmetric Supramolecular Catalysis

TL;DR

This paper compares two supramolecular catalysts to determine how noncovalent interactions and cavity size affect reaction rates and selectivity.

Contribution

The study reveals that stronger noncovalent interactions in a larger catalyst significantly enhance reaction rates and enantioselectivity.

Findings

The larger catalyst with stronger noncovalent interactions showed a 100-fold rate acceleration in ketone reduction.

The larger catalyst achieved 84% enantioselectivity compared to 14% in the smaller catalyst.

Stabilizing noncovalent interactions, not steric confinement, were found to be the main drivers of the observed effects.

Abstract

The remarkable catalytic performance of enzymes stems
from their
ability to engage in precise noncovalent interactions (NCIs) within
a sterically confined space. Supramolecular catalysis seeks to emulate
and understand these strategies through the rational design of simple
and controlled catalyst microenvironments. While both steric confinement
and attractive interactions have been invoked as key to host activity,
their relative contribution to rate enhancement and selectivity, as
well as potential trade-offs, remains an outstanding question. Here,
we address this question by systematically comparing two metal–organic
supramolecular catalysts, which differ in the strength of their attractive
noncovalent interactions and in their cavity volume. Our findings
reveal that the catalyst with the larger cavity, and with stronger
available NCIs, exhibits both significant rate acceleration (100-fold)
and enhanced enantioselectivity (84% vs 14% ee) in a model ketone
reduction compared to its smaller analogue. Mechanistic analysis,
binding competition experiments, and computational modeling indicate
that these differences predominantly stem from stabilizing noncovalent
interactions in the larger catalyst, a result that challenges existing
steric-based models of supramolecular stereoinduction. Understanding
the governing factors of asymmetric induction and rate acceleration
in supramolecular hosts will undoubtedly inform future catalyst design.

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