Alkylation of Substituted Benzoic Acids in a Continuous Flow Microfluidic Microreactor: Kinetics and Linear Free Energy Relationships

Alkylation of para-substituted benzoic acids by iodomethane using an organic superbase, 1,8-bis-(tetramethylguanidino)naphthalene (TMGN) in DMF was chosen as a model reaction to test the quality of the control of experimental parameters in a continuous flow microfluidic reactor as it is expected to follow a perfect second order kinetics with a large dynamics by varying the substituents. These conditions may be directly used for the synthesis of natural product esters. Because TMGN reacts slowly with iodomethane, the three different mixing strategies between substrate, base and alkylating reagent were compared. The rate constants were determined for the reaction with a set of alkylating agents and in different solvents. In order to test the quality of the obtained data, temperature effect and free energy relationships, which are expected to follow predictable laws, were investigated. The kinetics vary over 6 orders of magnitude and follows a perfect Arrhenius law, allowing the determination of the energies, enthalpies, and entropies of activation. Finally, we established a Hammett linear relationship for a series of 16 substituted benzoic acids, leading to a reaction constant rho of -0.65 for this reaction. The quality of the obtained kinetics allowed us to discuss the outliers. All kinetics were obtained with less than 0.5 mmol of substrate.