Gas-Phase 1H NMR Study of N-Ethyl-N-methyl Amides: Torsional Barrier and Conformer Equilibria Around the Peptide Bond

Abstract

The most stable conformer has the //-ethyl group syn to the carbonyl, except for X = H where it is anti to the carbonyl. Activation free energies AG*29s in kcal mol-1 (gas/solution) are 16.4 (0.1)/18.2 (0.1) for X = CF3 (in CCL,), 15.4 (0.2)/18.5 (0.2) for X = CH3 (in DMSO-t/6), and 19.6 (0.2)/21.0 (0.2) for X = H (in DMSO-i/e). Gas-phase values of AG*298 are lower the liquid-phase values by 1.4-3.1 kcal mol-1. This is consistent with previous experimental studies.

Gas-Phase Nuclear Magnetic Resonance Study of (15N)Trifluoroacetamide: Comparison of Experimental and Computed Kinetic Parameters

“…(1) Primary Amides Exhibit Medium Effects Similar to Those of Tertiary Amides . The medium dependence of the rotational barrier in amides has been examined for several tertiary amides and thioamides. − ,, ,29 Liquid barriers are dependent on solvent and concentration; high polarity and/or amide concentration favor higher amide rotational barriers. Invariably, however, rotational barriers (as measured by Δ G ⧧ 298 values) are lower in the gas phase than in the liquid phase, regardless of solvent or concentration.…”

“…Unfortunately, gas-phase dynamic NMR studies of primary amides are difficult for several reasons. First, the vapor pressure of primary amides is extremely low, usually less than that for the tertiary amides that have been more extensively studied. − Vaporization of enough amide for acquisition of gas-phase spectra is further impaired by the affinity of the amide hydrogens for the glass NMR tube. Also, whereas dimethyl amides have three equivalent protons at the exchanging sites, primary amides have only one.…”

Spectroscopic analysis of imidazolidines Part V: 1H and 13C NMR spectroscopy and conformational analysis of N-acylimidazolidines

“…Compound R NMR spectroscopic methods have been successfully used for obtaining information about the stereochemistry of amides. 5,6 In line with our previous studies related to spectral and biological properties of imidazolidines, [1][2][3][4] we prepared a series of 1-acyl-3-arylimidazolidines 11 (heterocyclic tertiary amides). Because the complete knowledge of structure, including stereochemistry, is essential for lead optimization in drugs discovery, we report herein our studies concerning the structural features of several of those compounds (1-15) ( Table 1) as studied by NMR spectroscopy.…”

“…1 In order to elucidate structure-activity correlations, the study of their conformational features, specially the substituent orientation in molecules of biological interest, has been the object of several investigations. Our laboratory has used 1 H-and 13 C-NMR spectroscopy to study the conformational characteristics of imidazolidines having different substitution patterns (alkyl or aryl groups) at 2,3 Electron delocalization originating from the contribution of structure II (Figure 1) gives partial double-bond character to the N-CO amide bond in its ground state, with rotational barriers in the 15-23 kcal/mol range, [5][6][7][8][9] causing the geometric and magnetic non-equivalence of the nitrogen substituents when R . [5][6][7][8][9] In particular, the E/Z equilibrium in heterocyclic tertiary amides and related compounds has been reviewed.…”

Gas-Phase 1H NMR Studies of Internal Rotation Activation Energies and Conformer Stabilities of Asymmetric N,N-Disubstituted Formamides and Trifluoroacetamides

“…Again, rotational barriers were observed to decrease with increasing alkyl substituent size. In 1995, Suarez and True presented the first systematic study of rotational barriers in the gas phase of asymmetrically substituted amides. Their studies of gas- and solution-phase N -ethyl- N -methylformamide, N -ethyl- N -methyltrifluoroacetamide, and N -ethyl- N -methylacetamide found that, as with the disubstituted systems, the rotational barrier decreases with increasing substituent bulk, but to a lesser extent in the trifluoroacetamides where electronegativity differences dominate.…”