Behind the Science: Regioselective Functionalization of Fluoroarenes by Direct Ferration

Behind the Science: Regioselective Functionalization of Fluoroarenes by Direct Ferration

Author: Jonathan Faiz, Kim Meyer, Eva Hevia

Angewandte Chemie International Edition editors, Dr. Jonathan Faiz, Senior Associate Editor, and Dr. Kim Meyer, Associate Editor, talk to Professor Eva Hevia, University of Strathclyde, Glasgow, UK, about her article on regioselective functionalization of fluoroarenes by C–H and C–F bond activations.

Organofluorines are used widely in the life sciences, where the electronic nature of the fluorine atom elicits useful physicochemical properties; among them, improved bioactivity and stability, and absorption into biological tissues. Fluoroarenes, in particular, are structural components of many pharmaceuticals, imaging agents, and pesticides. However, the unstable nature of intermediates produced by traditional C–H and C–F bond activation routes (using organolithium base, for example) present a considerable obstacle to functionalization of these useful chemicals.

Eva Hevia’s team has derived an artful solution to this challenge using sodium-mediated ferration to achieve deprotonative metalation of fluoroarenes. At the heart of their strategy is a sodium tris(amido)ferrate base in which a “toothless” iron bis(amide) base is partnered with the strong base sodium hexamethyldisilazide.



Professor Hevia, in your recent Angewandte Chemie Communication you describe an unusual C–H activation route within which a bimetallic sodium ferrate base is used to access regioselectively functionalized fluoroarenes. What has led you to the area of organometallic chemistry in the first place, and then to the fascinating niche of polar organometallics and cooperative effects in organometallic transformations?

During my undergraduate years at the Universidad de Oviedo, Spain, I became fascinated with organometallic chemistry; it was an area that combined the best of both organic and inorganic worlds. Also, I think I was inspired by the enthusiasm and passion for the field of several Professors in the chemistry department, where organometallic chemistry is particularly strong. Thus, when I had to choose an area for my Ph.D. studies it was a no-brainer for me.

After my Ph.D., I carried out a postdoc with Robert Mulvey, a leading figure in polar organometallic chemistry, who has been one of the pioneers on exploiting chemical synergy within main-group bimetallic complexes. During this time I became aware of the vast potential of this area of research and was intrigued by how much is still to be understood in terms of metal-metal and metal-ligand-metal cooperativity. Now I utilize this cooperativity for improving or developing new bond-forming applications.



What is the broader impact of this paper for the scientific community?

Recent breakthroughs by our group and others have shown that pairing alkali metals with low-polarity main-group metals such as Zn, Mg, or Al, switches on special cooperative effects are obtained, generating new chemistry which cannot otherwise be accomplished by single-metal reagents on their own. This paper extends this cooperativity into a new area of earth-abundant green transition metals, specifically Fe(II).

Thus while Fe(II) amides are generally very poor bases, by combining them with a sodium amide, building a mixed Na/Fe complex (sodium ferrate), we can deprotonate molecules such as fluoroarenes—which are frustratingly challenging substrates in metallation chemistry using more conventional RLi bases—at room temperature, and regioselectively using direct cooperative Fe–H exchange. An example which highlights the synergic power of this Na/Fe bimetallic partnership is that by tuning the stoichiometry of these reactions it is also possible to activate C–F bonds in these substrates, transforming them into C–N bonds, a reactivity which is unprecedented in organoiron chemistry. Two bond activations for the price of one!



Do you have any plans for future work extending from this study? If so, could you please provide some details?

We are very excited with these initial findings which have opened up a treasure chest of future opportunities, considering how synthetically relevant Fe(II) complexes are in synthesis and catalysis. We want to understand better how Na-Fe cooperation works, as well as investigating their reactivity in C–H/C–F bond activation for a wider range of organic molecules, with special emphasis on their further functionalization in organic synthesis. Ultimately, building on the stoichiometric successes we aim to upgrade some of these processes to catalytic regimes, an area where iron complexes have been widely studied but where the potential of alkali-metal ferrates still remains untapped.



Judging from your research home page and your twitter feed (@EvaHeviaGroup), you are an advocate for representation of women in science. Do you have any advice for young women pursuing a career in chemistry?

When I started my career I never thought twice about the fact that there were not many women at a senior level. It was only when I started to climb up the academic ladder that I realized that every step I took up, the number of female colleagues decreased … My advice would be if you enjoy chemistry just go for it! It can be a rocky steep path but the rewards compensate for all the hard times.

Also, whether you are a woman or a man, I think mentoring is a key essential, and in my case I have been very lucky to have excellent mentors all the way throughout my career, who have helped and supported me and importantly sometimes they have encouraged me to put myself forward for things that I was not sure if I was ready for. My main message has to be, “Be bold and aim for the top!”



Globally, research institutes and universities are striving for gender equality. What progress would you like to see in the field of chemistry?

I would like to see chemistry becoming much more diverse, with a significant increase in the number of female scientists reaching top academic/research positions, so being a female professor is not a rarity anymore. There are a lot of gender stereotypes that need to be destroyed. Just to give you an example, not that long ago, in a conference dinner where I was a keynote speaker I was asked if I was there to accompany my husband (!!). While unacceptable and frustrating, this anecdote just reflects the gloomy reality that there are not that many chemistry female professors and female speakers at conferences, and that even in scientific environments, gender bias still exists.

To finish on a positive note, there is an increasing number of good initiatives coming forward that are tackling gender barriers. In the UK, the Athena SWAN charter (established in 2005 to advance the careers of women in science, technology, engineering, maths, and medicine) has already made an impact on how research institutes and universities support and advance women’s careers in science. It just needs accelerating!

The article they talked about



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