Investigation of Cocatalysis Conditions Using an Automated Microscale Multireactor Workstation: Synthesis of meso-Tetramesitylporphyrin

Prior manual work has shown that the condensation of mesitaldehyde and pyrrole leading to tetramesitylporphyrin depends sensitively on concentration and requires cocatalysis involving BF 3 ·O(Et) 2 and ethanol or other protic species. We have applied an automated microscale chemistry workstation capable of parallel or adaptive experimentation to systematically investigate these cocatalysis conditions. Examination of experimental grids spanning a 1000-fold range of the concentrations of BF 3 ·O(Et) 2 and ethanol identified the best cocatalysis conditions for various mesitaldehyde and pyrrole concentrations. As the reaction concentration increased from 10 to 200 mM, the optimal yields were achieved with a parallel increase in BF 3 ·O(Et) 2 concentration (from 3.3 to 56 mM), but the amount of ethanol remained relatively constant. Catalysis conditions were identified that afforded ∼30% yields for reactants in the range of 10−73 mM, thereby enabling the reaction to be performed at increased concentration without loss in yield. Application of a catalyst searching protocol identified ethylene glycol, 2-methoxyethanol, and methanol as effective cocatalysts from a set of 12 candidates. Collectively, these results show the utility of an automated chemistry workstation in acquiring a comprehensive set of data concerning the scope of cocatalysis in the reaction of mesitaldehyde and pyrrole.