Entropy-driven population distributions in a prototypical molecule with two flexible side chains: O-(2-acetamidoethyl)-N-acetyltyramine

Abstract

Resonant two-photon ionization (R2PI), resonant ion-dip infrared (RIDIR), and UV-UV hole-burning spectroscopies have been employed to obtain conformation-specific infrared and ultraviolet spectra under supersonic expansion conditions for O-(2-acetamidoethyl)-N-acetyltyramine (OANAT), a doubly substituted aromatic in which amide-containing alkyl and alkoxy side chains are located in para positions on a phenyl ring. For comparison, three single-chain analogs were also studied: (i) N-phenethyl-acetamide (NPEA), (ii) N-(p-methoxyphenethyl-acetamide) (NMPEA), and (iii) N-(2-phenoxyethyl)-acetamide (NPOEA). Six conformations of OANAT have been resolved, with S(0)-S(1) origins ranging from 34,536 to 35,711 cm(-1), denoted A-F, respectively. RIDIR spectra show that conformers A-C each possess an intense, broadened amide NH stretch fundamental shifted below 3400 cm(-1), indicative of the presence of an interchain H bond, while conformers D-F have both amide NH stretch fundamentals in the 3480-3495 cm(-1) region, consistent with independent-chain structures with two free NH groups. NPEA has a single conformer with S(0)-S(1) origin at 37,618 cm(-1). NMPEA has three conformers, two that dominate the R2P1 spectrum, with origin transitions between 35,580 and 35,632 cm(-1). Four conformations, one dominate and three minor, of NPOEA have been resolved with origins between 35,654 and 36,423 cm(-1). To aid the making of conformational assignments, the geometries of low-lying structures of all four molecules have been optimized and the associated harmonic vibrational frequencies calculated using density functional theory (DFT) and RIMP2 methods. The S(0)-S(1) adiabatic excitation energies have been calculated using the RICC2 method and vertical excitation energies using single-point time-dependent DFT. The sensitivity of the S(0)-S(1) energy separation in OANAT and NPOEA primarily arises from different orientations of the chain attached to the phenoxy group. Using the results of the single-chain analogs, tentative assignments have been made for the observed conformers of OANAT. The RIMP2 calculations predict that interchain H-bonded conformers of OANAT are 25-30 kJ/mol more stable than the extended-chain structures. However, the free energies of the interchain H-bonded and extended structures calculated at the preexpansion temperature (450 K) differ by less than 10 kJ/mol, and the number of extended structures far outweighs the number of H-bonded conformers. This entropy-driven effect explains the presence of the independent-chain conformers in the expansion, and cautions future studies that rely solely on relative energies of conformers in considering possible assignments.

Conformations of γ‐Aminobutyric Acid (GABA): The Role of the n→π* Interaction

“…The fact that conformer gG1 is still one of those highly populated in the supersonic expansion and the concordance between relative intensities and predicted Gibbs energies can be taken as an indication that the conformational stability order could be close to the theoretical one that predicts conformer gG1 as the global minimum. These results also show the importance of using Gibbs energies instead of electronic energies to correctly predict relative population of conformers when forms with and without intramolecular interactions coexist 20…”

“…For GABA the relative population ordering strongly disagrees with the predicted MP2 relative energies: gG 1<GG1<GG3< GG 2< gG 2<aG1<gG3<ga1<aa1. This disagreement can be taken as a proof for the coexistence in GABA of conformers having intramolecular interactions (folded) with those free of them (extended) 20. The later are less rigid and would have an increase in entropy related to a higher density of accessible vibrational states.…”

Isolated Neutral Peptides

“…During this complex cooling process following vaporisation, conformational isomerisations take place until the isomerisation rates fall down below the characteristic time of the expansion, freezing de facto the populations [184]. These final populations resulting from a high temperature conformational equilibrium suggest that Gibbs energies are more suitable than enthalpy at 0 K to compare with experiment, which has been supported by various examples on small molecules [186] where the distribution is correctly predicted by a room temperature equilibrium, as well as by recent work on peptides and flexible molecules [88,107,135,187,188]. These systems existing under conformations of very different entropic behaviours, e.g.…”

Compact Folding of Isolated Four‐Residue Neutral Peptide Chains: H‐Bonding Patterns and Entropy Effects

“…The results from several groups, focused on specific systems in which conformations of very different natures could play a role in the observation, provide hints about the process that controls the final population observed in a supersonic expansion, whatever the initial vaporisation process (thermal or laser-desorption). [35,41,[45][46][47][48] This was particularly obvious in the recent example of the coexistence of extended and folded conformers of A2b in a jet, in spite of a 0 K energy difference of about 15 kJ mol À1 . [41] This energetic gap, however, disappears when one considers Gibbs free energies at a finite temperature (e.g., 300 K), because of the very different entropy of the extended and folded forms.…”