Anion binding versus intramolecular hydrogen bonding in neutral macrocyclic amides

Area of Science:

• Supramolecular Chemistry
• Organic Chemistry

Background:

• Amide groups are key hydrogen-bond donors in anion receptors.
• Structure-affinity relationships of amide-based macrocyclic receptors are not well-studied.

Purpose of the Study:

• Synthesize and investigate macrocyclic tetraamides based on isophthalic acid.
• Determine structure-affinity relationships for anion binding.
• Understand the impact of intramolecular hydrogen bonding on receptor conformation and binding.

Main Methods:

• Synthesis of macrocyclic tetraamides (5-8).
• (1)H NMR titrations in DMSO.
• Theoretical and experimental structural studies.
• X-ray crystallography of anion complexes.

Main Results:

• Anion affinity decreases with increasing macrocycle size.
• Isophthalic acid-based macrocycles exhibit lower potency than pyridine congeners.
• Intramolecular hydrogen bonds between isophthalic bis-amide fragments close the macrocyclic cavity.
• Anion binding induces a conformational switch to an all-syn conformation.
• Aromatic CH groups contribute to anion binding.

Conclusions:

• The self-complementary nature of isophthalic bis-amide fragments limits anion binding by pre-forming intramolecular hydrogen bonds.
• Despite poor preorganization, specific macrocycles show improved binding compared to analogues.
• Crystal structures confirm inclusive complex formation and highlight the role of aromatic CH interactions.