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

Abstract

Unsymmetrical ditopic ligands can self‐assemble into reduced‐symmetry Pd2L4 metallo‐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 Pd2L4 cage isomers, ranking the likelihood for exclusively forming cis‐Pd2L4 assemblies. From this narrowed search space, we successfully synthesised four new, low‐symmetry, cis‐Pd2L4 cages.

Unlocking the computational design of metal–organic cages

“…An interesting approach to solving this process looks at using computational models to help design/monitor the design workflow by scoring the ''safety'' of calculation methods (based on DFT). 180 Automated approaches, like ours in stk, 95,99 and those of the Duarte, 101,143 and Hay groups 80 show progress in developing generalisable design workflows to explore MOCs. Overall, the development of low-cost cheminformatic, semiempirical and DFT approaches using large and diverse benchmark sets can provide robust and broadly applicable methods for studying MOCs with reasonable accuracy, which is crucial for highthroughput design processes.…”

“…Furthermore, stk can construct cages with arbitrary ligand placements and alignments, allowing for heteroleptic cage construction and the consideration of configurational isomers. 99 This feature is especially crucial for MOC construction because the metal complex often needs to be constructed prior to cage construction ( Fig. 5a ) with a specific stereochemistry.…”

“…Furthering our exploration of these systems, we implemented a joint computational and experimental evaluation workflow for Pd 2 L 4 MOCs formed from unsymmetrical ligands. 99 In this example, we assumed a single topology (Pd 2 L 4 ) was most likely to form based on enthalpic arguments. We targeted a low-cost, “good enough”, prediction of the self-assembly outcome to guide experimental decision making.…”

“…For example, we coupled pyWindow and a geometrical measure based on the displacement of Pd centres (termed “ Δ Pd ” in ref. 99 ) to measure the size and anisotropy of the cis -Pd 2 L 4 cages we generated from unsymmetrical ligands. 99 Also, Young et al measured the twist of Pd 2 L 4 cages during MD simulations to correlate cage flexibility to guest binding affinity.…”

“… 99 ) to measure the size and anisotropy of the cis -Pd 2 L 4 cages we generated from unsymmetrical ligands. 99 Also, Young et al measured the twist of Pd 2 L 4 cages during MD simulations to correlate cage flexibility to guest binding affinity. 143 Fig.…”