One‐Pot Multimolecular Macrocyclization for the Expedient Synthesis of Macrocyclic Aromatic Pentamers by a Chain Growth Mechanism

Abstract

POCl(3)-mediated one-pot macrocyclization allows the highly selective formation of five-residue macrocycles that are rigidified by internally placed intramolecular hydrogen bonds. Mechanistic investigation by using tailored competition experiments and kinetic simulation provides a comprehensive model, supporting a chain-growth mechanism underlying the one-pot formation of aromatic pentamers, whereby the successive addition of a bifunctional monomer unit onto either another monomer or the growing oligomeric backbone is faster than other types of bimolecular condensations involving oligomers longer than monomers. DFT calculations at the B3LYP/6-31G* level reveal the five-residue pentamer to be the most stable with respect to alternative four-, six-, and seven-residue macrocycles. These novel mechanistic insights may become useful in analyzing other macrocyclization, oligomerization, and ploymerization reactions.

Polypyridine‐Based Helical Amide Foldamer Channels: Rapid Transport of Water and Protons with High Ion Rejection

“…Earlier on, we also showed that two equivalents of POCl 3 allow highly efficient one‐pot synthesis of fully hydrogen‐bonded near‐planar macrocyclic amide pentamers at room temperature, and distorted hexamers or heptamers at high temperature . Encouraged by these findings, we tested polymerization efficacy of POCl 3 at different temperatures.…”

Macrocyclic pentamers functionalised around their periphery as potential building blocks

“…24,25 These were prepared by the laborious stepwise chain growth method originally reported for the methoxy pentamers 13,33 before development of the one-pot method. [14][15][16] To date, the one-pot method has not been applied to the uoropentamers. A one-pot synthesis for the uoropentamer 3 was achieved beginning with 2-uoro-3nitrobenzoic acid (13), Pd/C-catalysed hydrogenation to 3amino-2-uorobenzoic acid 14, 34 and cyclised under the same conditions applied for the methoxy pentamers, using POCl 3 and Et 3 N in dry acetonitrile (Scheme 2).…”

“…A one-pot synthesis for the uoropentamer 3 was achieved beginning with 2-uoro-3nitrobenzoic acid (13), Pd/C-catalysed hydrogenation to 3amino-2-uorobenzoic acid 14, 34 and cyclised under the same conditions applied for the methoxy pentamers, using POCl 3 and Et 3 N in dry acetonitrile (Scheme 2). [14][15][16] The crude product was puried by sequential washing with dichloromethane, DMF and methanol to give pure 3 as a white powder, albeit in a low yield (4.0%). Washing with DMF was necessary to remove other oligomeric by-products but this step also resulted in some loss of the desired product.…”

“…They comprise 5 aryl or pyridone groups connected by two-atom linkers. Zeng et al have reported ve-fold symmetric macrocyclic aromatic pentamers [13][14][15][16] and macrocyclic pyridone pentamers 17 which contain aryl-amide links; the former have OMe, OEt or F groups in the interior positions while the pyridone pentamers have hydrogen-bonded carbonyls. Campestarenes have imine linkages and an internal hydrogen-bonded network of amine NH and OH groups.…”

Shape-persistent H-bonded macrocyclic aromatic pentamers

“…22 Mechanistic studies by kinetic simulations of experimental data suggested the POCl 3 -mediated pentamerization to take place through a chain growth mechanism where the addition of monomer into the growing backbones is faster than other competing bimolecular reactions between two monomers or two higher oligomers (Fig. 24) 86 while the corresponding macrocyclization reactions producing strained hexamer 17 and highly strained heptamers 18 likely proceed in a bimolecular fashion involving two higher oligomers. 80 Consistent with the proposed chain-growth mechanism, our continued exploration demonstrated that POCl 3 can selectively produce hybrid macrocyclic pentamers consisting of mixed building blocks that bear different exterior side chains (Fig.…”