N-formyl-stabilizing quasi-catalytic species afford rapid and selective solvent-free amination of biomass-derived feedstocks

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Feb 13, 2019
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Initial thinking

We (Z.F., R.S., H.L.) submitted a joint proposal between Nanjing Agricultural University (China) and Tohoku University (Japan) for biomass upgrading to allow a two-year postdoctoral study (H.L.) at Tohoku University. In preparing the proposal, we wrote a review on biomass valorization (Bifunctional solid catalytic materials, https://doi.org/10.1016/j.pecs.2016.04.004) and published a book on bifunctional catalysts (Production of Biofuels and Chemicals with Bifunctional Catalysts, www.springer.com/gp/book/9789811051364.  In those surveys, we concluded that amination of biomass-derived feedstocks would be a good research topic, but it would require us to develop highly-sophisticated catalytic reaction systems, handle hydrogen or ammonia, and make careful optimization of reaction conditions for a given feedstock.  For example, amination of biomass-derived platform chemicals that contain more than one functional group (e.g. furanic aldehydes such as furfural) are not readily synthesized with either classical or non-catalytic methods, because the furan ring is easily opened to form random amino species.  Thus, a new approach was needed that ultimately lead to our discovery of some very important chemistry. 

Unexpected Results

Our research groups study the fast hydrolysis of biomass and materials production by rapid heating and mixing of starting materials typically under flow conditions.  We imagined that if we could rapidly heat up starting materials to reaction conditions, then it might be possible to improve the selectivity of aminations.  On a small-scale, microwave heating is attractive for rapid heating of starting materials (furfural, ammonium formate, formamide, formic acid) and fortunately, there was a microwave reaction specialist in our group (M.W.) who had a suitable experimental rig to test the idea.  Even with rapid heating, we expected that we would have to design some sort of new robust bifunctional catalysts to selectively aminate furfural.  However, when the microwave heating experiments (H.L., M.W.) and analyses (H.G., Y.H.) were made, highly unexpected results were revealed.  Remarkably, experiments using rapid heating rates with formic acid and formamide in different ratios gave selective aminations that were controllable (Fig. 1) for reaction times on the order of minutes without a heterogeneous catalyst!

Figure 1.
Figure 1. Selective amination of platform chemicals using rapid-heating and formamide with formic acid to generate N-formyl species. R1 and R2 can contain functional groups.  Primary, secondary or tertiary amines are obtained by treatment of the respective amide with methanol.

Here, formic acid acts not only as an H-donor, but also as an acid catalyst for the generation of the N-formyl species that lead to C-N bond activation and stabilization of aminated intermediates. 

Mechanism

Figure 2 (top) shows the amination of furfural with the protocol and the N-formyl-stabilizing catalytic species.  The gem-diamine, FDFAM, is rapidly produced in detectable amounts from in situ formed N-formyl imine or carbinolamine intermediates.  To study the mechanism theoretically, we added two collaborators (Y.S., E.J.M.H.) from Eindhoven University of Technology (TU/e) who performed DFT calculations (Fig. 2, bottom).    The FDFAM intermediate is highly-stable and could be identified in both microwave and oil bath heating experiments.

Figure 2.
Figure 2. Amination of furfural (FUR) to 1 using formamide (AM) with formic acid (FA) showing (top) N-formyl stabilizing quasi-catalytic species and (bottom) DFT calculation showing pathway with lower energy intermediate gem-diamine, FDFAM.

Spectacular Scope

The protocol is broadly applicable to both biomass-derived carboxides and to the synthesis of N-formyl imides for producing combination compounds, polymer-free monomers or heterocyclic compounds from aldehydes, ketones, carboxylic acids, or their mixtures as shown by reactions (S1) - (S6) (Fig. 3). 

Figure 3.
Figure 3. Extension of protocol to other substrates showing the broadness of the scope (S1-S6).

New Avenues

The protocol is adaptable to flow chemistry studies and has great potential for scale-up.  Further, the use of heterogeneous catalysis may possibly be used to enhance aspects of the present work or to develop new protocols.

Summing Up

All in all, it has been a wonderful journey, both in the research, in the collaboration with highly-talented international members and in working with the Nature staff, editors and reviewers, who helped us passionately to realize the potential of the chemistry.  See https://rdcu.be/bma7w and supporting materials for full reviewer comments and author replies.

For details, please refer to our paper at: https://www.nature.com/articles/s41467-019-08577-4.

Go to the profile of Richard Smith

Richard Smith

Professor, Tohoku University

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