Radical Cation Diels-Alder By Electrocatalyst
Authors: Imada Yasushi , Chiba Kazuhiro , Okada Yohei 
Published: February 2020

In recent years, redox reactions with single electron transfer have received significant attention from many chemists. Organo-catalysts and photo-catalysts have been growing as a promising approach to electron path-ways. The electrochemical method is also playing roles as one of the most straightforward processes. With this method, we designed intermolecular carbon-carbon bond forming reactions, in which electron is the key reagent and the catalytic amount of electricity is enough for the full conversion. For example, radical cation Diels-Alder reaction with aromatic "redox tag" is in accordance with it. In this reaction, the chain cycle is the key factor to realize the significant decrease of consumed electricity. Our success leads to the development of the environmentally friendly and extreme high productivity synthetic method to produce the compound which has useful chemical structure for natural compounds and pharmaceuticals.

Our investigation commenced with the reaction between trans-anethole (1) and isoprene (2), using electrocatalytic approach. In the reaction, it is understood well that the radical cation (3
・
+) is generated, accompanying by chain process (Fig. 1). From cyclic voltammetry investigation, it is indicated that 1 (Ep
ox = 1.07 V vs. Ag/AgCl) is anodically oxidized selectively in the presence of 2 (Ep
ox = 1.83 V vs Ag/AgCl). Based on this, we demonstrate that the aromatic radical cation, which is given by the intermolecular [4 + 2] cycloaddition between radical cation 1
・
+ and 2, gives rise to a radical cation chain cycles and completion of the reaction with the catalytic amount of electricity. Here, we envisioned that the aromatic ring of 1might work as a redox tag to accomplish an electrocatalytic Diels-Alder reaction. Hence, we carried out anodic oxidation of 1in the presence of 2 equiv. of 2 at 1.00 V vs. Ag/AgCl. Beyond our expectation, only 0.1 F/mol of electricity was sufficient to make the reaction completed in excellent yield. This result suggests that the aromatic radical cation 3
・
+ was reduced predominantly by 1, comparing the reduction at the electrodes. Furthermore, the investigation of Cyclic Voltammetry shows that the oxidation peak of Diels-Alder adduct (3) is 1.40 V vs Ag/AgCl, which is sufficiently higher than that of 1. It can explain that radical cation 3
・
+ would oxidize 1 preferably, leading to the chain propagation. Based upon the mechanistic comprehension, we confirmed the applicable range of substrates, which are dienophile and diene, in the electrocatalytic Diels-Alder reaction. It showed that the moderate range of dienes was available, but the scope of styrene structures was limited.

To obtain deeper insight into the mechanism, we conducted density functional theory (DFT) calculations. The calculation results demonstrate that the Dies-Alder reaction is proceed in stepwise mechanism.

Besides, we speculated that the combination of electrolyte and solvent had an important role in this reaction. Although we have tried to use a variety of electrolytes and solvents, we have not found better media than LiClO4 / Nitromethane which leads this reaction to the excellent yield and faraday efficiency. Considering that using tetrabutylammonium perchlorate did not work in this reaction, we assume that Li+ has the important role. With the investigation of 7Li NMR and the heat of solution, it is implied that the solvation of ions is the key factor to achieve the electrocatalytic C-C bond forming reaction.

Then, we turned out interest to how much we could improve the electro-energy efficiency. As we demonstrated above, only 0.1 F/mol, was enough to complete the reaction. However, we postulated that it still has room to be encouraged. We screened several factors; type of cell, type of electrodes, electrode’s surface area, reaction temperature, concentration of starting materials, concentration of electrolyte, etc… Surprisingly, it turned out that the concentration of substrates had the significant impact on the efficient production. Based upon the optimized condition, we have succeeded in that only 0.015 F/mol realized the full conversion. It is demonstrated by GC-MS monitoring that from 0.005 F/mol to 0.01 F/mol, the average number of chain cycle is 106.

This optimized condition has the potential of having a big impact on chemical and pharmaceutical production. Our electrochemical approach realizes the environmentally friendly and extreme high productive synthetic method; requiring only a small amount of solvent and electrolyte, high electro-energy efficiency and recyclable. Taking advantage of these points, we demonstrate that we can scale up the production of the compounds that have useful chemical structure for natural compounds and pharmaceuticals. It is noted that electro chemical approach is promising for not only green but also economical chemistry.

Figure 1