Conformational analysis. Part 34. An NMR investigation of the conformational equilibrium and intramolecular hydrogen bonding in nipecotic acid derivatives

Abstract

The ¹H NMR spectra of nipecotic acid (piperidine-3-carboxylic acid), ethyl nipecotate, nipecotamide and some of their N-methyl derivatives are reported and analysed. At −80 °C the interconversion between the two chair conformations is so slow that the spectra of the two conformers can be resolved and the conformer populations and free energy differences obtained. The proton couplings found for the individual conformers were used together with the measured couplings at room temperature to obtain the conformer free energy differences for these compounds in a variety of solvents.

The intramolecular hydrogen bonding interaction between the side chain and the ring nitrogen atom in the axial conformation may be obtained from the conformer energy differences. For nipecotic acid in D₂O ΔG_A − E = 0.41 kcal mol⁻¹. From these data the hydrogen bond energy between the CO₂⁻ and NH₂⁺ groups in the nipecotic acid zwitterion is obtained as ca. 1.7 kcal mol⁻¹ in the axial conformer even in the protic solvents methanol and water. The corresponding interactions in the cation and anion are much less (ca. 1 kcal mol⁻¹) and also do not show a large solvent effect.

In contrast the H-bond interaction between the neutral species is very solvent dependent. In nipecotamide the CONH₂⋯N hydrogen bond energy is >2 kcal mol⁻¹ in nonpolar solvents, in which the axial conformer is the major form (ΔG_A − E = −0.46 kcal mol⁻¹), but decreases to almost zero in aqueous solution in which the equatorial conformer predominates (ΔG_A − E = 1.4 kcal mol⁻¹). The CO⋯HN hydrogen bond is less affected by the solvent varying from ca. 1.8 kcal mol⁻¹ in nonpolar solvents to 1.0 kcal mol⁻¹ in D₂O in N,N-diethylnipecotamide and from 0.9 to 0.6 kcal mol⁻¹ in ethyl nipecotate.

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