Strained Cyclophane Macrocycles: Impact of Progressive Ring Size Reduction on Synthesis and Structure

TLDR

The study reports synthesis, crystal structures, and strain energies for 11‑ to 14‑membered cyclophane macrocycles, highlighting how ring‑size reduction and added constraints increase strain and distort typical geometries. Macrocyclization was performed by copper‑catalyzed azide–alkyne cycloaddition in flow at high temperature, and the macrocycle/dimer ratio was explained by the macrocycle’s strain energy. The strained cyclophanes enable unique spatial orientations of functional groups unavailable in unstrained analogs, and the most strained 11‑membered system—first to contain a 1,4‑disubstituted 1,2,3‑triazole—demonstrates the upper limit of strain achievable with this synthesis.

Abstract

The synthesis, X-ray crystal structures, and calculated strain energies are reported for a homologous series of 11- to 14-membered drug-like cyclophane macrocycles, representing an unusual region of chemical space that can be difficult to access synthetically. The ratio of macrocycle to dimer, generated via a copper catalyzed azide–alkyne cycloaddition macrocyclization in flow at elevated temperature, could be rationalized in terms of the strain energy in the macrocyclic product. The progressive increase in strain resulting from reduction in macrocycle ring size, or the introduction of additional conformational constraints, results in marked deviations from typical geometries. These strained cyclophane macrocyclic systems provide access to spatial orientations of functionality that would not be readily available in unstrained or acyclic analogs. The most strained system prepared represents the first report of an 11-membered cyclophane containing a 1,4-disubstituted 1,2,3-triazole ring and establishes a limit to the ring strain that can be generated using this macrocycle synthesis methodology.