The Richman-Atkins synthesis transformed the accessibility of aliphatic azamacrocycle ligands 50 years ago and was almost immediately thereafter proposed to proceed via a Thorpe-Ingold (gem-disubstituent) effect. Although the Thorpe-Ingold effect is well-documented in many small systems, it has never been demonstrated in azamacrocycles. 1,4,7,10-Tetraazacyclododecane (cyclen), the prototypical azamacrocycle, is conventionally synthesized from N,N',N'-Ts3-ethylenediamine and O,N',O''-Ts3-diethanolamine using alkali carbonates. We measured the RMSD of crystal structure overlays for the central C-C-N-C-C fragment of diethylene triamines and diethanolamines relative to cyclen and 1,4,7-triazacyclononane (tacn) versus pentane crystallized in the extended conformation. The data from nearly twenty crystal structures from both our laboratory and the literature shows a four-fold lower RMSD averaging ~0.2 Å, thereby providing the first-ever proof for this proposed steric effect. Richman-Atkins macrocyclization is typically thought to require sulfonamide protecting groups on all the nitrogens to effect cyclization. Surprisingly, we also identified the central nitrogen in the diethylene triamine fragment as capable of accommodating a wide range of protecting groups (enabling facile 3:1 orthogonal substitution), including no protecting group. Since sterics could not explain these observations, we turned to the electronic gauche effect. Using gas-phase DFT calculations we demonstrate that conformationally-restricted gauche conformations are preferred due to electronic effects. We then produced a range of desymmetrized N-Ns,N'-X,N''-Ts-diethylene triamines where the central nitrogen is substituted with a range of substituents (X) from hydrogen to tri-isopropylbenzensulfonamide. The Ns and Ts substituents on the opposite ends of the diethylene triamine resulted in methylene frequencies sufficiently separated in 1H NMR spectra to enable quantitative NOESY measurement of the intramolecular distances in solution. The intermolecular methylene distances were in close agreement with predicted values from crystal structures and DFT calculations. Therefore, we also report that a hitherto unrecognized gauche effect likely explains, in part, why such electron-withdrawing sulfonamide substituents are required on most, but not all, nitrogens in Richman-Atkins azamacrocycle synthesis.

First proof of Thorpe-Ingold steric effects and surprising electronic effects in the Richman-Atkins cyclization of azamacrocycle ligands

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