High-Yielding Flow Synthesis of a Macrocyclic Molecular Hinge

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.

Enabling Technology for Supramolecular Chemistry

“… Examples of supramolecular species and precursors and self-assembly processes that have been examined or enhanced using enabling technology for process control ( Puigmartí-Luis et al, 2010 ; Numata et al, 2015a ; Rubio-Martinez et al, 2016b ; Gong et al, 2016 ; Thorne et al, 2019 ; Puigmarti-Luis et al, 2021 , This figure contains an image of Figure 2a from Thorne et al that has been used to make this composite figure under the terms of a Creative Commons Attribution 4.0 International License https://creativecommons.org/licenses/by/4.0/ ), screening ( Greenaway et al, 2018 ), optimisation ( Jones et al, 2021 , The flow diagram and crystal structures in the optimization panel have been reused from Figure 2 and 11 from https://pubs.acs.org/doi/abs/10.1021/jacs.1c02891 respectively with permission from the ACS. Further permission related to the material excerpted should be redirected to the ACS), and scale up ( Briggs et al, 2015 ; Rubio-Martinez et al, 2016a ).…”

“…Intermediates can be isolated from the reaction stream and separately analysed to provide a better understanding of the reaction pathway and general self-assembly processes ( Sagmeister et al, 2021 ). For example, recently Jones et al (2021) exploited this to optimise the synthesis of a macrocyclic molecular hinge using a semi-continuous method informed by at-line analysis. Here, the fast heat transport possible in flow enabled a rapid temperature change mid-synthesis, leading to a threefold increase in yield and simultaneous reduction in reaction times.…”

“…Recently, flow chemistry has been used to optimize the yield, selectivity, and limited scale-up, of both macrocyclic ( Bogdan and James, 2010 ; Bogdan and James, 2011 ; Bedard et al, 2013 ; Bédard et al, 2015 ; Lucke et al, 2016 ; Morin et al, 2019 ; Jones et al, 2021 ; Seemann et al, 2021 ) and cage ( Briggs et al, 2015 ; Kitchin et al, 2015 ) supramolecular structures. For example, Bédard et al synthesized medicinally relevant ( Marsault and Peterson, 2011 ) macrocyclic lipids under continuous flow, with yields of up to 97% in short reaction times ( Bedard et al, 2013 ).…”

Quid Pro Flow

“…By moving the analytical probe or having multiple analysis points, reaction kinetics or pathway can be elucidated, given that flow path length = time under continuous conditions . As analytical chemistry offers increasingly rapid and sensitive measurements, more techniques are being incorporated into flow processes: LC, GC, , MS, , particle sizing, IR, , optical methods, and NMR , are more established, but more recently PXRD, , optical emission spectroscopy, SAXS/WAXS, − 3D microscopy, magnetometry, and even single crystal XRD have been reported as inline or online methods. In each case, the method must be optimized for the desired analyte, concentration, and sensitivity required …”

“…Another area of potentially rapid development is the breadth of chemistries that are performed in flow. Traditionally focused on organic synthesis and small molecules, there are now increasing reports of more complex systems being synthesized in flow including supramolecular ,,, and macromolecular materials. ,,− The opportunities that flow offers for enhanced safety and process control also particularly benefit situations where the reagents or transient species are hazardous (e.g., diazonium salts, organometallics, hydrogenation, and fluorination). ,− …”