Electrochemical C−H Functionalization of (Hetero)Arenes—Optimized by DoE

Abstract

A novel approach towards the activation of different arenes and purines including caffeine and theophylline is presented. The simple, safe and scalable electrochemical synthesis of 1,1,1,3,3,3‐hexafluoroisopropanol (HFIP) aryl ethers was conducted using an easy electrolysis setup with boron‐doped diamond (BDD) electrodes. Good yields up to 59 % were achieved. Triethylamine was used as a base as it forms a highly conductive media with HFIP, making additional supporting electrolytes superfluous. The synthesis was optimized using Design of Experiment (DoE) techniques giving a detailed insight to the significance of the reaction parameters. The mechanism was investigated by cyclic voltammetry (CV). Subsequent transition metal‐catalyzed as well as metal‐free functionalization led to interesting motifs in excellent yields up to 94 %.

Electrosynthetic Screening and Modern Optimization Strategies for Electrosynthesis of Highly Value‐added Products

“…The application of factorial designs in this case also revealed the stirring rate as a crucial factor for the reactions outcome. [14,35] Furthermore, our group used a DoE supported optimization for the electrochemical oxidation of sodium iodide to periodate at a BDD anode. [36] Previous methods of producing periodate are based on the use of lead dioxide anodes, but they are known to slowly decompose into solution during oxidation.…”

“…They used a combinatorial approach, utilizing existing experimental data and calculated descriptor values. For each solvent molecule they determined the score on each solvent scale, ending up with a [14,15,17,19] 774 × 100 matrix. By PCA treatment of the latter they found the first five principal components (PC) to account for 75 % of the total variance.…”

“…Besides that, the impact of sometimes considered minor factors like the stirring rate or inter electrode distance might be surprisingly big in some cases due to the electrolysis' nature as an interfacial reaction. [12][13][14] The resulting complexity creates the desire for systematic optimization strategies that are capable of handling these mostly non-linear systems we are confronting. When a One Variable at a Time approach is insufficient, a common step forward is using Design of Experiments (DoE) techniques that include building a regression model, thus giving detailed information about the system under investigation.…”

“…When a One Variable at a Time approach is insufficient, a common step forward is using Design of Experiments (DoE) techniques that include building a regression model, thus giving detailed information about the system under investigation. [14][15][16][17][18][19] If multiple combinations of substrates are to be considered, including measured and calculated molecular parameters can be very achieving but requires the use of more sophisticated approaches like predictive modeling methods (e. g. Multivariate Linear Regression or Principal Component Analysis) and machine learning. [20][21][22] The mentioned methods require balanced experimental data to produce good performing models.…”

Electrosynthesis 2.0 in 1,1,1,3,3,3‐Hexafluoroisopropanol/Amine Mixtures

“…A selective, scalable, and sustainable electrochemical synthesis of HFIP aryl ethers was thus developed. [60] Of particular interest is the electrochemical modification of bioactive purine derivatives, such as theophylline (45) and caffeine (48) derivatives (Scheme 13). Anilides (46,50) as well as naphthalene (47 and 49) could be converted successfully in yields up to 59 %.…”