Achieving selectivity in porphyrin bromination through a DoE-driven optimization under continuous flow conditions

Abstract

The post-functionalization of porphyrins through the bromination in β position of the pyrrolic rings is a relevant transformation because the resulting bromoderivatives are useful synthons to covalently link a variety of chemical architectures to a porphyrin ring. However, single bromination of porphyrins is a challenging reaction for the abundancy of reactive β-pyrrolic positions in the aromatic macrocycle. We herein report a synthetic procedure for the efficient preparation of 2-bromo-5,10,15,20-tetraphenylporphyrin (1) under continuous flow conditions. The use of flow technology allows to reach an accurate control over critical reaction parameters such as temperature and reaction time. Furthermore, by performing the optimization process through a statistical DoE (Design of Experiment) approach, these parameters could be properly adjusted with a limited number of experiments. This process led us to a better understanding of the relevant factors that govern porphyrins monobromination and to obtain compound 1 with an unprecedent 80% yield.

New Opportunities for Organic Synthesis with Superheated Flow Chemistry

“…DoE can be multiobjective and can help in the assessment of intercorrelations between various parameters . For example, Carofiglio et al optimized a flow procedure for the selective monobromination of a porphyrin . In batch, N -bromosuccinimide (3 equiv) was added dropwise over 4 h on the substrate in refluxing chloroform.…”

“…34 For example, Carofiglio et al optimized a flow procedure for the selective monobromination of a porphyrin. 35 In batch, N-bromosuccinimide (3 equiv) was added dropwise over 4 h on the substrate in refluxing chloroform. With a 17-experiment DoE in flow, the authors accessed optimized conditions.…”

Flow Chemistry for Synthesis of 2-(C-Glycosyl)acetates from Pyranoses via Tandem Wittig and Michael Reactions

“…In addition, flow systems have inherently higher pressures over batch, controlled through use of a back-pressure regulator (BPR). These factors of flow chemistry provide numerous benefits over batch techniques, such as improved safety, greater heat transfer, improved mixing profiles, the potential for automation, and improved scalability. − The advent of commercial laboratory-scale flow reactors has also made flow chemistry more accessible to synthetic chemists and boosted growth of this field over the past two decades. − …”