Relative Reactivities of Activated Carboxylic Acids in Amide-Forming Reactions Employed for the Synthesis of Tetraphenylporphyrin Libraries

Combinatorial synthesis has established itself as a tool for the preparation of libraries of structurally related compounds in an efficient manner.1 The most efficient way of synthesizing a combinatorial library would, of course, involve a single reaction, in which a mixture of all required building blocks reacts to produce the desired products. This approach has proven impractical for several reasons. One is the challenges associated with performing a work-up and purification of the product mixture produced in a massively combinatorial one-pot synthesis. Another, perhaps more fundamental reason is the unequal reactivities of building blocks, which leads to non-statistically distributed product mixtures, unless the stability of the products is identical (reaction performed under thermodynamic control) or the reactivities of the building blocks employed are equal (reaction performed under kinetic control). As a result, most combinatorial syntheses are performed on solid supports2,3 and in a format in which no more than one building block reacts with its substrate(s) in any given reaction mixture. This research note reports on a modest exercise in the realm of competitive, mixed condensation reactions leading to combinatorial libraries in a one-pot procedure.