A New Rule(r) for Nitrobenzene-Based Synthesis of meso -Tetraarylporphyrins under Continuous-Flow: Design of Experiments-Guided Optimization

In this work, design of experiments (DoE) methodologies were applied to optimize the continuous-flow synthesis of various meso -aryl-substituted porphyrins. Starting from the synthesis of meso -tetraphenylporphyrin (TPP), a response surface model was established correlating yield with temperature and residence time. The study was then extended to structurally and electronically diverse aldehydes, leading to the classification of substrates into four electronic families (groups A–D), based on Mulliken charge calculations at the carbonyl carbon. For each group, optimized quadratic models were developed, enabling the prediction of specific experimental conditions for maximum yield. These predictions were validated through the synthesis of over 10 porphyrin derivatives under continuous-flow conditions. Notably, yields as high as 50% were achieved, and significant productivities were recorded. This modular approach demonstrates the power of combining DoE modeling with electronic structure calculations for scalable, efficient, and generalizable synthesis of functional porphyrins, paving the way for their broader application in catalysis, photomedicine, and materials science.