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

Abstract

Prior manual work has shown that the condensation of mesitaldehyde and pyrrole leading to tetramesitylporphyrin depends sensitively on concentration and requires cocatalysis involving BF3·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 BF3·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 BF3·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.

Synthesis of perylene-porphyrin dyads for light-harvesting studies

“…Thus, the reaction of 10 and 3-bromobenzaldehyde afforded the m-linked perylene-benzaldehyde 15 in 60% yield (Scheme 6). The mixed-aldehyde condensation of 15, mesitaldehyde, and pyrrole under BF 3 ·O(Et) 2 -ethanol cocatalysis [45] at high concentration [46] followed by oxidation with DDQ and chromatographic workup afforded the desired free base porphyrin bearing one perylene. Subsequent zinc metalation gave Dyad-4 in 17% yield (from 15).…”

“…The Sonogashira coupling of 2-bromobenzaldehyde and 2-methylbut-3-yn-2-ol afforded the o-ethynyl benzaldehyde 16 in 78% yield. The mixed-aldehyde condensation of 16, mesitaldehyde, and pyrrole was performed using BF 3 ·O(Et) 2 -ethanol cocatalysis [45] at high concentration [46] followed by DDQ oxidation (Scheme 7). The polarity of the alcohol protecting group facilitated separation of the six porphyrin products, and the nearly pure monoethynyl porphyrin was isolated following a single column chromatography procedure.…”

Extending mechanochemical porphyrin synthesis to bulkier aromatics: tetramesitylporphyrin

“…Under the first-reported conditions of the Lindsey synthesis, mesitaldehyde “failed to give good yields” of TMP [11]. Later studies of modified reaction conditions employing boron trifluoride as the acid catalyst, and small amounts of ethanol as a co-catalyst, were successful in producing TMP with yields around 30% at room temperature [13,25–26]. Optimized conditions still required reactant concentrations of 10 −2 M. Increasing or decreasing the concentration lowered the yield, as did increasing the temperature.…”

Effects of diverse acid catalysts on the reaction course in the two-step one-flask synthesis of meso-tetraphenylporphyrin

“…(1) Some aldehydes (alkyl aldehydes, aldehydes bearing nitrogen heterocycles) provide poor yields of porphyrin under TFA or BF 3 -etherate catalysis [2]. (2) Sterically hindered aldehydes such as mesitaldehyde require cocatalysis with BF 3 -etherate and an alcohol [4,5]. (3) TPP is obtained in substantially higher yield upon cocatalysis with BF 3 -etherate and a salt (e.g.…”

“…(4) Porphyrinic macrocycles such as N-confused tetraphenylporphyrin (NC-TPP) and tetraphenylsapphyrin (TPS) are formed in low yield under TFA or BF 3 -etherate catalysis [7]. (5) Acids such as methanesulfonic acid [8] and various clays [9][10][11][12][13][14][15] have been employed successfully to catalyze the two-step one-flask pyrrole + aldehyde reaction at room temperature. (6) The catalytic conditions developed for the pyrrole + aldehyde reaction often have been applied to reactions with dipyrromethanes.…”