Previously we have shown that POCl3-mediated H-bonding-directed one-pot macrocyclization allows for the highly selective preparation of five-residue macrocycles as the predominant product with low yields of hexamers and an undetectable occurrence of both tetramers and heptamers.Replacing the interiorly arrayed methyl groups with ethyl groups in these 4-7 residue macrocycles alters the relative stability order among them.Specifically,ethoxy-substituted six-residue macrocycle,rather than pentamer,turns out to be computationally the most stable,suggesting that ethoxy-containing hexamer possibly can be formed as the major product under suitable conditions.We have investigated this possibility by varying reaction temperatures and concentrations,invariably affording pentamer as the major macrocycle with strained circular hexamers and highly strained circular heptamers produced in substantial amounts.This discrepancy can be reasonably explained on the basis of bimolecular reactions between two oligomers higher than monomers via kinetic simulations.In this scenario,the acyclic pentamer is kinetically "trapped" to undergo an intramolecular cyclization to yield circular pentamer,rather than to produce acyclic hexamer.As a result,acyclic hexamer precursor is generated largely from sterically demanding bimolecular reactions between a dimer and a tetramer,or between two trimers that are kinetically slower than the pentamer-producing chain-growth reactions.We additionally found that one-pot macrocyclization proceeds to the largest extent at 40 ℃,an intriguing finding that highlights the low reactivities of acid chloride and amine groups in these H-bond-enforced acyclic oligomeric intermediates.
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