Diversity, isomer composition, and design of combinatorial libraries of tetrapyrrole macrocycles

Abstract

Combinatorial libraries of substituted tetrapyrrole macrocycles, which can now be prepared via a variety of approaches, typically are rich in isomers. Terminology for describing such isomers (due to distinct patterns of peripheral substituents) is delineated in several illustrative examples. A hierarchical relationship exists of molecular formula, condensed formula(s) of substituents, set(s) of pyrrole collocates (conveying each pair of β-pyrrolic substituents), and isomers of substituted tetrapyrrole macrocycles. Isomers with identical pyrrole collocate sets can arise owing to distinct positions or orientations of the (homo- or hetero-substituted) pyrrolic units in a macrocycle. Consideration of a handful of virtual combinatorial libraries illustrates tradeoffs of library size, chemical richness, and isomeric content. As one example, octa-derivatization of a tetrapyrrole scaffold with eight reactants A–H affords 2,099,728 members (99.7% isomers, 82,251 pyrrole collocate sets, and 6,435 condensed formulas) whereas the reversible self-condensation of four pyrroles that bear the same eight entities (AB, CD, EF, GH) affords 538 members (93.5% isomers, 35 pyrrole collocate sets, and 35 condensed formulas). Derivatization affords all combinations and permutations whereas self-condensation of substituted pyrroles carries collocational restrictions. Understanding such tradeoffs and the structural origin of isomerism are important aspects in the design of tetrapyrrole combinatorial libraries.