Calix[3]Pyrrole and Related Macrocycles: Synthesis and Properties

Abstract

Calix[4]pyrrole is a porphyrinogen-like macrocycle in which four pyrrole units are linked by four sp3-hybridized carbon atoms at the α-positions. While such tetrapyrrolic macrocycles are readily synthesized by acid-catalyzed condensation reactions of pyrrole monomer and carbonyl compound, analogous macrocycles composed of three pyrrole units are always not observed. Calix[3]pyrrole is a ring-contracted analogue of calix[4]pyrrole, and has been missing in porphyrin-related chemistry. In this presentation, the first synthesis of calix[3]pyrrole and its furan-embedded analogues is reported, and their unique reactivity derived from their macrocyclic ring strain will be discussed.Synthesis of calix[3]pyrrole started with a linear trimer of 3,3-dimethylpentane-2,5-dione. Intramolecular cyclization of the linear hexaketone was accomplished in 5 steps to give a cyclic hexaketone precursor. Paal–Knorr type pyrrole formation reaction of cyclic hexaketone gave calix[3]pyrrole in 41% yield (Scheme 1). Using similar strategies, analogous calix[3]-type macrocycles, namely, calix[1]furan[2]pyrrole, calix[2]furan[1]pyrrole, and calix[3]furan, were successfully synthesized. Single crystal X-ray diffraction analysis of calix[3]pyrrole revealed its strained structure, and the theoretical calculations showed the strain energy of calix[3]pyrrole is 22.1 kcal/mol per unit higher than that of calix[4]pyrrole. Such strain energy tends to decrease as the number of pyrrole unit decreased.Calix[3]pyrrole exhibited unique reactivity derived from macrocyclic ring strain under acidic (Rothemund–Lindsey) conditions that are frequently used for porphyrin synthesis. When calix[3]pyrrole was dissolved in 10 mM solution of trifluoroacetic acid in dichloromethane, calix[6]pyrrole was quantitatively formed within 30 seconds (Scheme 1). Similar strain-induced ring expansion was observed for calix[1]furan[2]pyrrole, but full conversion took approximately 5 minutes. On the other hand, calix[2]furan[1]pyrrole and calix[3]furan did not show ring expansion. Detailed mechanistic analysis revealed that protonation at a pyrrole unit in calix[3]pyrrole triggers irreversible ring-cleavage to give a linear tripyrrane moiety which undergoes cyclodimerization under acidic conditions.The strain-induced ring expansion reaction of calix[3]pyrrole solved a long-standing question in porphyrin-related chemistry. Tripyrrolic macrocycles such as calix[3]pyrrole are, even formed, not isolable from pyrrole condensation reaction using acid, because the strain-induced conversion to calix[6]pyrrole is too fast. Besides, this reaction provided a novel approach to ring-expanded calix-type macrocycles. Figure 1