Polyazamacrocycles are some of the strongest and most versatile ligands, with just one example, cyclen, being coordinated to every metal from lithium to plutonium. Richman and Atkins’s transformatively high-yielding cyclization of polyazamacrocycles including cyclen, reported in 1974, has long been attributed to the Thorpe-Ingold effect; the steric repulsion of the bulky toluenesulfonyl protecting groups in Richman-Atkins cyclization is thought to restrict internal rotation in the macrocyclic precursors, diethylene triamine and diethanolamine. This would result in curved conformations which differ little from the conformation of the cyclic product. Surprisingly, in the 45 year history of Richman-Atkins cyclization there has been no experimental evidence of the Thorpe-Ingold effect, which the present work demonstrates. The solid-state and solution-state conformations of toluenesulfonyl(diethylene triamine) and toluenesulfonyl(diethanolamine) derivatives have been studied via X-ray diffraction and NOESY. Multiple crystal structure overlays of protected precursors with the protected macrocycle show high conformational correlation via low root-mean-square deviations. Present work also, and more surprisingly, achieved Richman-Atkins cyclization with exceedingly small groups (formyl, methyl, hydrogen) on the center nitrogen of the diethylene triamine precursor. These results seem contradictory to the Thorpe-Ingold effect, in that the sterics on the central nitrogen are apparently not responsible for the curvature required for cyclization. Potential energy surfaces show that sulfonamide and sulfonate moieties adopt a gauche conformation about the ethane “arms” of the diethylene triamine and diethanolamine cyclization precursors. These gauche conformations are lower in energy than the anti conformations, similar to the so-called fluorine gauche effect. The effects of hyperconjugation and electrostatic polarization contributing to the observed gauche effect are weighed. Sulfonamide protecting groups provide steric bulk to Richman-Atkins precursors but also require extremely acidic deprotection conditions that have greatly hindered functionalization of azamacrocycle scaffolds. Hopefully, an understanding of the electronic effects contributing to Richman-Atkins cyclization as presented herein will allow a wider variety of protecting groups, or even pre-functionalization, to be used to enable more facile synthesis of polyazamacrocycle ligands.

Thorpe-Ingold effect versus electronic effects in Richman-Atkins cyclization

ACS Fall 2020 Virtual Meeting

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