How Strong is Hydrogen Bonding to Amide Nitrogen?

Area of Science:

• Organic Chemistry
• Physical Chemistry
• Biochemistry

Background:

• Protonation of the carboxamide nitrogen is vital for in vivo and in vitro processes like isomerization and hydrolysis.
• While protonation in distorted amides is well-studied, data on undistorted amides, particularly concerning hydrogen bonding to amide nitrogen, is limited.
• Intramolecular hydrogen bonding to amide nitrogen is considered an initial stage of proton transfer, meriting further investigation of its enthalpy.

Purpose of the Study:

• To investigate the enthalpy of intramolecular hydrogen bonding involving the amide nitrogen atom in undistorted amides.
• To utilize novel "amide proton sponges" derived from peri-substituted naphthalenes as model systems for this study.

Main Methods:

• Synthesis and investigation of peri-substituted naphthalenes with a protonated dimethylamino group adjacent to the amide nitrogen.
• Utilized X-ray analysis, Nuclear Magnetic Resonance (NMR) spectroscopy, and basicity measurements.
• Performed quantum chemical calculations to analyze the hydrogen bonding interactions.

Main Results:

• Confirmed the existence of an intramolecular hydrogen bond involving the amide nitrogen atom in the synthesized model compounds.
• Characterized the hydrogen bond strength as being on the borderline between moderate and weak interactions, with enthalpies ranging from 2-7 kcal/mol.
• The "amide proton sponges" effectively modeled intramolecular hydrogen bonding in undistorted amides.

Conclusions:

• Established a model system for studying intramolecular hydrogen bonds in undistorted amides.
• Quantified the enthalpy of these borderline moderate-to-weak hydrogen bonds involving amide nitrogen.
• The findings contribute to understanding fundamental amide chemistry relevant to biological and chemical processes.