Commonly used by chemists as ligands for catalysts, cyclic imino ethers can also be polymerized to make materials that could help transport drugs into cells. Bart Verbraeken had been trying, unsuccessfully, to polymerize a seven-membered cyclic imino ether when he suspected that something was amiss.
The analogous five- and six-membered compounds polymerized readily, and in Verbraeken’s experience working with the molecules at Ghent University, they had a sweet and pungent odor. Yet the compound he was working with, which he prepared using a reported procedure, didn’t smell like anything at all.
Following the scent, or rather the lack of one, Verbraeken, now working at the engineering company Parker Hannifin Benelux, along with his Ghent colleagues discovered that the nearly half-dozen papers reporting the synthesis and characterization of seven-membered cyclic imino ethers were wrong: Chemists had made a different type of molecule and misassigned it as the seven-membered compound (J. Am. Chem. Soc. 2018, DOI: 10.1021/jacs.8b10918).
The cyclic imino ether sleuths, led by Ghent University’s Richard Hoogenboom, developed a simple, albeit modest-yielding, synthesis to prepare cyclic imino ethers on a multigram scale and confirmed their structures with crystal X-ray diffraction. The chemists were unable to polymerize the seven-membered molecules, and calculated that their rate of reaction was 60 times as slow as that of the six-membered rings and 540 times as slow as that of the five-membered rings.
The team determined that the compounds reported in the literature were actually N-acylated pyrrolidines, which cannot undergo ring-opening polymerization, explaining their lack of reactivity. The confusion over their identity probably arose from a misreading of the nuclear magnetic spectroscopy (NMR) data. The spectra of the aryl amide compounds display the same number of hydrogen peaks as those of the seven-membered cyclic imino ethers. But Hoogenboom’s team noticed that the peak pattern in the previous spectra didn’t match that of the five- and six-membered compounds, while the data from their compounds did. The previous syntheses followed procedures similar to those for making the five- and six-membered compounds. For some unknown reason, these procedures didn’t yield the seven-membered variety, instead making N-acylated pyrrolidines.
Ian D. Jenkins, a synthetic chemist at Griffith University, coauthored a 2008 paper that reported the synthesis of cyclic imino ethers, including the misassigned seven-membered compounds (Org. & Biomol. Chem. 2008, DOI: 10.1039/b818310d). Jenkins congratulates the team on correcting the literature and says he’s not sure how they missed it. “I think we never considered that the structure might not be correct in the case of the seven-membered ring when the five- and six- membered ring cyclizations were straightforward.”
Looking back, he says the broad NMR signals, which suggests rotation around an amide bond, should have tipped them off that the structure wasn’t right. “The most interesting, and perhaps concerning, aspect is that none of the reviewers, possibly 12 reviewers of the 6 papers reporting the syntheses of seven-membered cyclic imino ethers, questioned that this structure might not be correct,” Jenkins says.
Wesley Moran, an organic chemist at the University of Huddersfield, reported a misassigned seven-membered cyclic imino ether in 2015 (Org. Lett. 2015, DOI: 10.1021/acs.orglett.5b00333). His group had developed a cyclization reaction for unsaturated amides and had formed what they thought was a seven-membered cyclic imino ether in low yield. They didn’t question the compound’s identity because the NMR data matched the literature values, he says, adding that the compound was a liquid so they wouldn’t have been able to obtain a crystal structure.
Although he says he’s disappointed that he and his colleagues didn’t catch their error, Moran says that the pyrrolidine product may actually be a more interesting finding. It would open an avenue for his cyclization chemistry to access pyrrolidinols. He says those compounds could be more useful as synthetic building blocks than the cyclic imino ethers and plans to pursue this reactivity in his lab.
This story was updated on Dec. 27, 2018, to correct Bart Verbraeken's current affiliation. He currently works at Parker Hannifin Benelux and not at the University of California, Santa Barbara, where he was a visiting researcher.