Anion Binding Affinity: Acidity versus Conformational Effects.

Area of Science:

• Computational Chemistry
• Supramolecular Chemistry
• Organic Chemistry

Background:

• Anion receptors are crucial in various chemical processes.
• Understanding the conformational preferences of anion receptors is key to optimizing their function.
• Previous assumptions about the dominant conformation of certain anion receptors may be inaccurate.

Purpose of the Study:

• To investigate the gas- and solution-phase conformational equilibria of substituted (thio)ureas, (thio)squaramides, and croconamides.
• To determine the predominant conformers of these anion receptors using high-level quantum chemical calculations.
• To correlate conformational preferences with observed binding affinities and acidity.

Main Methods:

• High-level quantum chemical calculations were employed to model conformational energies.
• Gas-phase and solvent-phase calculations were performed to simulate different environments.
• Experimental Nuclear Magnetic Resonance (NMR) Nuclear Overhauser Effect (NOE) measurements were used for validation.

Main Results:

• Gas-phase calculations indicate that the syn-syn conformer is often the thermodynamic minimum, contrary to the commonly assumed anti-anti conformer.
• Solvent polarity influences conformational stability, favoring the anti-anti conformer in more polar solvents.
• Croconamides consistently favor the syn-syn conformation, even in solution.
• Observed chloride binding affinities for thioureas and croconamides are lower than predicted by pKa values, potentially due to conformational reorganization requirements.

Conclusions:

• The conformational equilibrium of anion receptors significantly impacts their binding properties.
• The syn-syn conformer is frequently the dominant form, challenging prior assumptions.
• Conformational flexibility must be considered in the rational design of novel anion receptors and organocatalysts.