Supramolecular Protection of Carboxylic Acids via Hydrogen Bonding: Selectivity, Reversibility, and Design Principles

Area of Science:

• Organic Chemistry
• Supramolecular Chemistry
• Systems Chemistry

Background:

• Traditional covalent protecting groups can be inefficient and lack dynamic control.
• Selective functionalization of molecules with multiple reactive sites remains a challenge in organic synthesis.

Purpose of the Study:

• To develop a supramolecular protecting group (sPG) for selective protection of dicarboxylic acids.
• To enable preferential esterification of monocarboxylic acids in the presence of dicarboxylic acids.
• To understand and optimize the supramolecular protection strategy using computational modeling.

Main Methods:

• Development of a supramolecular protecting group based on reversible hydrogen bonding.
• Experimental validation of selective esterification under synthetically relevant conditions.
• Creation and validation of a systems chemistry model to analyze and optimize the sPG performance.

Main Results:

• Achieved high selectivity (selectivity factor s=72) for protecting dicarboxylic acids over monocarboxylic acids.
• Demonstrated efficient preferential esterification of monocarboxylic acids.
• Validated a computational model that accurately reflects experimental observations.

Conclusions:

• The supramolecular protecting group (sPG) offers an efficient and dynamic alternative to covalent protecting groups.
• Computational modeling provided key insights into selectivity-limiting factors and guided optimization.
• This strategy has broad implications for developing new synthetic tools for selective organic transformations.