High‐Throughput Computational Evaluation of Low Symmetry Pd2L4Cages to Aid in System Design**

Andrew Tarzia,James E M Lewis,Kim E Jelfs

doi:10.1002/ange.202106721

Abstract

AbstractUnsymmetrical ditopic ligands can self‐assemble into reduced‐symmetry Pd2L4metallo‐cages with anisotropic cavities, with implications for high specificity and affinity guest‐binding. Mixtures of cage isomers can form, however, resulting in undesirable system heterogeneity. It is paramount to be able to design components that preferentially form a single isomer. Previous data suggested that computational methods could predict with reasonable accuracy whether unsymmetrical ligands would preferentially self‐assemble into single cage isomers under constraints of geometrical mismatch. We successfully apply a collaborative computational and experimental workflow to mitigate costly trial‐and‐error synthetic approaches. Our rapid computational workflow constructs unsymmetrical ligands and their Pd2L4cage isomers, ranking the likelihood for exclusively formingcis‐Pd2L4assemblies. From this narrowed search space, we successfully synthesised four new, low‐symmetry,cis‐Pd2L4cages.

Highlights

Nature has evolved spectacular control over self-assembly processes to produce biological machinery for which high-fidelity of composition and structure is essential for effective functionality
In recent work, we found that the formation of a single Pd2L4 cage isomer from the selfassembly of unsymmetrical ditopic ligands with Pd(II) ions only occurred when there was a significant difference in the calculated energies of the possible isomers.[45]
In previous work it was found that the energy separations of the isomers of [Pd2L4]4+ cages assembled from unsymmetrical ligands, calculated using Density functional theory (DFT) methods, correlated well with experimental observations of single isomer formation.[45]

Summary

Introduction

Nature has evolved spectacular control over self-assembly processes to produce biological machinery for which high-fidelity of composition and structure is essential for effective functionality. Since first being reported over twenty years ago,[4] lantern-type Pd2L4 cages,[5,6,7] assembled from “naked” Pd(II) ions and ditopic ligands (L), have become an extensively studied class of metal-organic polyhedra (MOPs).[8,9,10,11,12] Wide-ranging applications for these cages have been investigated, including in drug delivery,[13,14,15] biomedicine,[16,17,18,19,20,21] catalysis,[22,23,24,25] and guest encapsulation/recognition.[26,27,28,29,30,31,32] To simplify the self-assembly process, most previous reports have focussed on high-symmetry systems derived from single, symmetrical ligands. It is expected that through the controlled introduction of asymmetry, cages could be designed with more intricate, anisotropic binding sites with specific shapes and functionalities.[33]

Objectives

Methods

Results

Conclusion