Reversal of Syn-Anti Preference for Carboxylic Acids along the Reaction Coordinate for Proton Transfer. Implications for Intramolecular Catalysis

Abstract

Carboxylate anions are more basic on the syn side because carboxylic acids are more stable with the proton syn to the carbonyl oxygen than anti. This led Gandour to propose that carboxylic anions should act as catalytic bases, as in enzymes, better on the syn side than the anti. However, numerous experimental tests have failed to reveal a strong preference. We resolve this problem by showing, on the basis of Linnett structures and MO calculations, that as a proton gradually departs from its firm syn position in the un-ionized COOH group, its preference for syn over anti diminishes rapidly, crossing over to a preference for anti before the midpoint of the reaction coordinate has been reached. Therefore in catalytic events, where the proton is partially transferred, the preference could favor either syn or anti and is small.

SynvsAntiCarboxylic Acids in Hybrid Peptides: Experimental and Theoretical Charge Density and Chemical Bonding Analysis

“…Experimental and theoretical studies in the gas phase and solution confirm that the syn lone pairs in carboxylates are more basic, although the difference in basicity of the two carboxylate lone pairs is not as large as originally proposed. , …”

“…Experimental and theoretical studies in gas phase and solution confirm that the syn lone pairs in carboxylates are more basic, although the difference in basicity of the two carboxylate lone pairs is not as large as originally proposed. 6,7 The carboxylate group, like other hydrogen-bonding acceptors, can play a role for directing molecular organisation of catalytic components along with promoting catalysis.…”

“…Experimental and theoretical studies in the gas phase and solution confirm that the syn lone pairs in carboxylates are more basic, although the difference in basicity of the two carboxylate lone pairs is not as large as originally proposed. 6,7 The carboxylate group, like other hydrogen-bonding acceptors, can play a role for directing molecular organization of catalytic components along with promoting catalysis. Although basicity and hydrogen bonding ability are two intrinsic properties of syn and anti lone pairs of oxygen atoms in carboxylates, 8−10 it has been addressed that stereoelectronic preferences for the two different roles that the carboxylate group plays (molecular organization by H-bond formation and catalytic activity governed by basicity) might not be similar.…”

Assessing the Conformational Equilibrium of Carboxylic Acid via Quantum Mechanical and Molecular Dynamics Studies on Acetic Acid

“…A recent review article discusses the competition between intramolecular and intermolecular hydrogen bonds in solution, stating that an intramolecular hydrogen bond may be disrupted in protic solution, such as water, when the increase in internal energy is offset by two or more solute–solvent intermolecular hydrogen bonds. Another study found that the carboxyl group has no strong preference, kinetically and thermodynamically, for the syn (or anti ) conformation in proton transfer catalysis . The anti state may also be important to consider when calculating solvation free energies .…”

Assessing the Conformational Equilibrium of Carboxylic Acid via QM and MD Studies on Acetic Acid

“…Another study found that the carboxyl group has no strong preference, kinetically and thermodynamically, for the syn (or anti ) conformation in proton trans-fer catalysis. 13 The anti state may also be important to consider when calculating solvation free energies. 14 Finally, the anti conformation is not insignificantly represented in structures from the Cambridge Structural Database, 15 supported by related crystallographic and theoretical charge density studies.…”