Catalytic Reductive Aminolysis of Reducing Sugars: Elucidation of Reaction Mechanism

Michiel Pelckmans, Tzvetan Mihaylov, William Faveere, Jeroen Poissonnier, Frederik Van Waes, Kristof Moonen, Guy B. Marin, Joris W. Thybaut, Kristine Pierloot, Bert F. Sels

Index: 10.1021/acscatal.8b00619

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Abstract

A catalytic reductive aminolysis of reducing monosaccharides into short ethylene diamines (or C2 diamines) was recently communicated by our group (Pelckmans et al. Angew. Chem. Int. Ed. 2017, 56, 14540–14544). Here, a general mechanism for this novel reaction is proposed based on the results of a combined experimental and theoretical study. The mechanism involves hemiaminal formation and subsequent dehydration to produce a zwitterionic iminium intermediate, which undergoes fast C–C cleavage as a result of intramolecular deprotonation, followed by hydrogenation of the formed unsaturated amine intermediate. The role of the amine in facilitating the C–C scission is explained in detail and supported by DFT calculations. Different catalysts, carbohydrate substrates, and reaction conditions were tested to validate the proposed reaction mechanism. Reductive aminolysis of sugars is preferably carried out in the presence of a passivated silica(-alumina) supported Ni catalyst and an alkyl amine using 75–85 bar H2 at 125–130 °C. The water content in the reaction mixture should be kept below 33 wt % to favor dehydration equilibria in the mechanism, while the amine-to-glucose molar ratio should be kept high, preferably larger than 6, to favor the amination equilibria. The reaction rate experiences a strong solvent dependency. For instance, the presence of MeOH enhances the rate of C2 diamine formation, as compared to the use of tetrahydrofuran (THF). DFT calculations show that presence of MeOH beneficially affects both the kinetics of the nucleophilic amine attack and the C–C bond scission. These selective rate enhancements result in a 2- to 3-fold increase of the C2 diamine yield. Among a series of aminating agents, reductive aminolysis with N-methylethanolamine (MEOA) shows a 92 C% yield to the corresponding C2 diamine (BHEDMEDA). The high yield is explained by the formation of a heterocyclic oxazolidine intermediate. Since its formation occurs H2 free, a two-step one-pot production protocol, decoupling C–C scission and hydrogenation, is proposed to achieve highest C2 diamine yield.