High-Yielding Flow Synthesis of a Macrocyclic Molecular Hinge

Jones, Christopher D.; Kershaw Cook, Laurence J.; Marquez-Gamez, David; Luzyanin, Konstantin V.; Steed, Jonathan W.; Slater, Anna G.

Abstract

Many molecular machines are built from modular components with well-defined motile capabilities, such as axles and wheels. Hinges are particularly useful, as they provide the minimum flexibility needed for a simple and pronounced conformational change. Compounds with multiple stable conformers are common, but molecular hinges almost exclusively operate via dihedral rotations rather than truly hinge-like clamping mechanisms. An ideal molecular hinge would better reproduce the behavior of hinged devices, such as gates and tweezers, while remaining soluble, scalable, and synthetically versatile. Herein, we describe two isomeric macrocycles with clamp-like open and closed geometries, which crystallize as separate polymorphs but interconvert freely in solution. 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. Using mechanistic information from NMR kinetic studies and at-line mass spectrometry, we developed a semicontinuous flow synthesis with maximum conversions of 85–93% and over 80% selectivity for a single isomer. The macrocycles feature voids that are sterically protected from guests, including reactive species such as fluoride ions, and could therefore serve as chemically inert hinges for adaptive supramolecular receptors and flexible porous materials.

Citation

Jones, C. D., Kershaw Cook, L. J., Marquez-Gamez, D., Luzyanin, K. V., Steed, J. W., & Slater, A. G. (2021). High-Yielding Flow Synthesis of a Macrocyclic Molecular Hinge. Journal of the American Chemical Society, 143(19), 7553-7565. https://doi.org/10.1021/jacs.1c02891

• Journal Article Type: Article
• Acceptance Date: Apr 20, 2021
• Online Publication Date: May 7, 2021
• Publication Date: May 19, 2021
• Deposit Date: Oct 27, 2021
• Publicly Available Date: Dec 16, 2021
• Journal: Journal of the American Chemical Society
• Print ISSN: 0002-7863
• Electronic ISSN: 1520-5126
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 143
• Issue: 19
• Pages: 7553-7565
• DOI: https://doi.org/10.1021/jacs.1c02891
• Public URL: https://durham-repository.worktribe.com/output/1232964