Wednesday, 30 November 2022 to Thursday, 1 December 2022

Flow synthesis of a macrocyclic molecular hinge

Wed30  Nov12:05pm(30 mins)
Dr Anna Slater


The synthesis of molecular materials and supramolecular systems is challenging – in part because their formation and self-assembly is strongly influenced by reaction environment. We use three approaches to control supramolecular synthesis and/or self-assembly: 1) tuning the building blocks;1 2) varying the interaction strength between building blocks,2 and 3) controlling the reaction environment.3,4
This talk will focus on approach 3, illustrating this via the semi-continuous formation of a macrocyclic molecular hinge. Molecular hinges provide a pronounced conformational change, but almost exclusively operate via dihedral rotations rather than truly hinge-like clamping mechanisms. We describe two isomeric macrocycles with clamp-like open and closed geometries, which crystallize as separate polymorphs but interconvert freely in solution.4 An unusual one-pot addition cyclization reaction was used to produce the macrocycles on a multigram scale from inexpensive reagents, without supramolecular templating or high-dilution conditions.
By performing the synthesis in a flow reactor with two heated coils, we were able to ensure optimal temperature for each step and automate reagent additions at fixed time points. Use of a dynamic back-pressure regulator (BPR) allowed the reaction temperature to be safely increased above solvent boiling point. Furthermore, a switching valve enabled automatic LC-MS analysis of the reaction mixture, providing insight into the reaction mechanism via detection of intermediates. This approach tripled the yield and optimized the selectivity at > 80% for a single isomer. This study showcases our ability to rapidly optimize reactions in flow using real-time data, and suggests some exciting ways forward to exploit flow technology in the field of supramolecular synthesis.5 The talk will finish by exploring how automation could further transform our approach to discovery in supramolecular chemistry.
[1] V. Abet† and F. T. Szczypiński† et al., Angew. Chem. Int. Ed., 2020, 59, 38, 16755-16763
[2] A. G. Slater et al., Nat. Chem., 2017, 9, 17-25.
[3] M. E. Briggs† and A. G. Slater† et al., Chem. Commun., 2015, 51, 17390-17393.
[4] C. D. Jones et al., J. Am. Chem. Soc. 2021, 143, 19, 7553–7565.
[5] K. Ollerton, R. L. Greenaway and A. G. Slater, Frontiers in Chem., 2021, 9:774987

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