A radical approach to efficient amine synthesis

Unexpected intermediate discovered in radical nitrene transfer reactions

20 April 2015

In a concerted research effort with several European research groups, chemists of the Van 't Hoff Institute for Molecular Sciences (HIMS) have found experimental evidence for the existence of a unique type of reactive intermediate in a new amine synthesis pathway. Their findings on these ‘nitrene radicals’ have recently been published by the Journal of the American Chemical Society. The results may pave the way for cleaner and more efficient production of amines with great industrial relevance.

Chemically, amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent. As a class of compounds amines have a huge number of applications, for instance in dyes, plastics, coatings, personal care products and drugs.

When it comes to synthesizing amines, the smaller the number of steps and the cheaper the catalysts, the better. One of the possible synthetic 'short-cuts' for amine synthesis is the direct insertion of a nitrogen containing functional group into a carbon-hydrogen bond. These so-called ‘nitrene’ transfer reactions, catalyzed by cobalt(II) porphyins, have recently acquired great interest because of their sustainable merits. The use of azides as nitrene-transfer reagents results only in harmless dinitrogen gas as a side-product. Furthermore with cobalt the catalyst uses an abundant first-row transition metal instead of rare and expensive metals such as palladium or platinum.

Experimental evidence

Prof Bas de Bruin, professor Bio-inspired sustainable catalysis

Bas de Bruin, professor of bio-inspired sustainable catalysis. Photo by Jeroen Oerlemans.

It has long remained unclear how the cobalt(II) porphyin catalysts act precisely. Previous computational studies performed in the group of Bas de Bruin (HIMS, UvA) suggested that formation of nitrenes (neutral R-N moieties) at cobalt(II) can lead to electron transfer from the metal to the nitrene moiety, thus producing reactive cobalt(III) coordinated ‘nitrene radicals’ (R-N-). However, no direct experimental evidence for formation of such ‘nitrene radicals’ was demonstrated thus far.

The group now reports on a detailed spectroscopic study in which these nitrene radicals are experimentally detected and spectroscopically characterized using a variety of experimental techniques (mass spectrometry, EPR, UV-vis, IR, VCD and XAS spectroscopy). This was quite an effort since the intermediates need to be handled with care. Their generation is susceptible to presence of moisture and oxygen and it turned out to be quite a challenge to preclude the presence of even very small amounts of impurities.

Unexpected species

The study provides for the first time unequivocal, direct experimental proof for the involvement of discrete ‘nitrene radicals’ in catalytic nitrene transfer reactions. Two important key-intermediates could be characterized, of which one was a remarkable bis-nitrene radical species. This was an unexpected and exiting result since the earlier theoretical studies had not hinted at all towards such an intermediate.

key-intermediates relevant in catalytic nitrene transfer reactions

The nature of the two intermediates depends on the nitrene precursor. With organic azides (2) the ‘mono-nitrene’ species 3 were obtained, containing a single ‘nitrene radical’ moiety. When using more oxidizing iminoiodanes (4) as the nitrene precursor, the very unusual triple-radical species 5 is formed.

The identification of the intermediates greatly aids in the understanding of the reaction mechanism of the used catalyst, and to develop more efficient catalysts in the future. The exceptional species containing discrete nitrogen centered substrate radicals speak to the imagination of the researchers who are now trying to develop completely new catalytic radical-type reactions based on their findings.

International collaboration

Monalisa Goswami

HIMS PhD student Monalisa Goswami, first author of the JACS publication.

Only through the collaborative effort of several researchers, experts in their own fields, could the nature of the remarkable intermediate species be properly characterized. 

HIMS PhD student Monalisa Goswami took great effort to bring together all these scientists, thereby taking advantage of the European COST network ECOSTBio. The work was performed in close collaboration between six groups spread over three countries:

  • Bas de Bruin (HIMS, UvA);
  • Peter Zhang (University of South Florida);
  • Kallol Ray (Humboldt University Berlin);
  • Edward Reijersen & Serena DeBeer (Max Planck Institute for Chemical Energy Conversion, Mülheim a/d Ruhr);
  • Ivana Ivanović-Burmazović (University of Erlangen);
  • Sander Woutersen & Wybren Jan Buma (HIMS, UvA).

Monalisa Goswami's PdD research is funded through the Vici grant awarded to Bas de Bruin by the Netherlands Organisation for Scientific Research NWO in 2012.

Publication

Monalisa Goswami, Volodymyr Lyaskovskyy, Sérgio R. Domingos, Wybren Jan Buma, Sander Woutersen, Oliver Troeppner, Ivana Ivanović-Burmazović, Hongjian Lu, Xin Cui, X. Peter Zhang, Edward J. Reijerse, Serena DeBeer, Matti M. van Schooneveld, Florian Pfaff, Kallol Ray, and Bas de Bruin: Characterization of Porphyrin-Co(III)-‘Nitrene Radical’ Species Relevant in Catalytic Nitrene Transfer Reactions, J. Am. Chem. Soc. 2015, Publication date (web): April 6, 2015. DOI: 10.1021/jacs.5b01197

Published by  HIMS