However, these diaryliodonium triflates could be accessed when using the mesityl iodide with the corresponding (hetero)arenes, albeit in a lower yield ( 3q and 3r).Īll reagents and solvents were used as received without further purification. Aryl iodides bearing strong electron-donating substituents (e.g., anisoles) or electron-rich heteroaromatic iodides (e.g., thiophene) were incompatible with the reaction conditions. These compounds are of high interest in cross-coupling and C–H arylation chemistry because they allow selective transfer of the functionalized aryl groups to the substrate. Furthermore, the use of sterically hindered mesitylene was well-tolerated, providing access to a diverse set of aryl mesityliodonium triflates ( 3f– 3p). Using different (hetero)arenes, unsymmetrical diaryliodonium salts were synthesized ( 3d, 3e). Symmetrical diaryliodonium triflates were readily produced in good to excellent yields ( 3a– 3c). Within a 2 s residence time, a diverse set of both symmetrical and unsymmetrical diaryliodonium triflates was synthesized in fair to excellent yield on a gram scale (5–10 mmol scale). With the optimized conditions in hand, we sought to demonstrate the generality of our flow protocol ( Table 1). Analogous batch experiments resulted in a lower yield (69% yield) of 3a as an inferior-quality powder precipitate. Notably, the desired di- p-tolyliodonium triflate 3a could be obtained on a gram scale (2.04 g, 89%) in excellent yield as pure and simple to handle crystals ( Figure 2). The reaction was remarkably fast and was completed within 2 s residence time. Optimal reaction conditions were obtained with 1.1 equiv of 2a and m-CPBA, and 2 equiv of TfOH and dichloroethane (DCE) as the solvent in a 100 μL microreactor. (17) The reaction between 4-iodotoluene ( 1a) and toluene ( 2a) in the presence of m-CPBA and TfOH was selected as the benchmark for our reaction optimization studies (see the Supporting Information). To avoid microreactor clogging, the mixer and reactor were submerged in an ultrasonic bath. The different reagent streams were merged in a cross-micromixer and subsequently introduced in a perfluoroalkoxy capillary reactor (PFA, 750 μm i.d., 0.1–3.0 mL). Our design consists of three individual feeds that allow separation of the hazardous reagents and control of the reaction stoichiometry by adjusting the individual flow rates. We commenced our investigations by designing a suitable continuous-flow setup ( Figure 1).
(15) Such exothermic transformations can be carried out safely in continuous-flow microreactors as the microenvironment results in an excellent heat dissipation rate. Interestingly, very high Δ H R values between −160 and −180 kJ/mol were observed, highlighting the need for a safe and reliable method to scale the reaction conditions ( Scheme 1).
The calibration of the adiabatic system was performed using the well-known neutralization reaction of sodium hydroxide with hydrochloric acid. A thermocouple was connected to the T-mixer at the end of the microreactor, which allowed us to have in-line temperature measurements.
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Assuming full conversion, we calculated the reaction enthalpy using the following equation, Δ H R = m × Cp × Δ T, where m and Cp are the mass and the heat capacity of the solvent, respectively ( Cp values of substrates were neglected, which is fair given the dilution). High vacuum was applied to the system in order to create adiabatic conditions (for more details about the setup, see the Supporting Information). Hereto, a custom-made glass tube was designed, and the cross-micromixer and microreactor were placed inside. (12) In order to rapidly determine the unknown reaction enthalpy (Δ H R) of the diaryliodonium salt synthesis, we developed an operationally simple adiabatic continuous-flow device that allowed us to calculate Δ H R values via in-line Δ T measurements (see Scheme 1c). To quantify the thermodynamic data of highly exothermic reactions, reaction calorimetry is typically used.
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