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Dehydroamino acids are non-coded amino acids that offer unique conformational properties. Dehydrophenylalanine (DeltaPhe) is most commonly used to modify bioactive peptides to constrain the topography of the phenyl ring in the side chain, which commonly serves as a pharmacophore. The Ramachandran maps (in the gas phase and in CHCl(3) mimicking environments) of DeltaPhe analogues with methyl groups at the beta position of the side chain as well as at the C-terminal amide were calculated using the B3LYP/6-31 + G** method. Unexpectedly, beta-methylation alone results in an increase of conformational freedom of the affected DeltaPhe residue. However, further modification by introducing an additional methyl group at C-terminal methyl amide results in a steric crowding that fixes the torsion angle psi of all conformers to the value 123 degrees , regardless of the Z or E position of the phenyl ring. The number of conformers is reduced and the accessible conformational space of the residues is very limited. In particular, (Z)-Delta(betaMe)Phe with the tertiary C-terminal amide can be classified as the amino acid derivative that has a single conformational state as it seems to adopt only the beta conformation.

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A series of three homologous dimethyldiamides Ac-DeltaAla-NMe2, Ac-L-Ala-NMe2 and Ac-DL-Ala-NMe2 has been synthesized and the structures of these amides determined from single-crystal X-ray diffraction data. To learn more about the conformational preferences of compounds studied, the fully relaxed (phi-psi) conformational energy maps in vacuo (AM1) of Ac-DeltaAla-NMe2 and Ac-L-Ala-NMe2 were obtained, and the calculated minima reoptimized with the DFT/B3LYP/6-31G** method. The crystal-state results have been compared with the literature data. Ac-DeltaAla-NMe2 and other alpha,beta-dehydroamino acid dimethyldiamides, Ac-DeltaXaa-NMe2 adopt the conservative conformation of the torsion angles phi, psi = approximately -45 degrees, approximately 130 degrees, which are located in the high-energy region (region H) of Ramachandran diagram. Ac-L-Ala-NMe2 and Ac-DL-Ala-NMe2, as well as other saturated amino acid dimethylamides Ac-L/DL-Xaa-NMe2, present common peptide structures, and no conformational preferences are observed. Molecular packing of the amides analysed reveals two general hydrogen-bonded motifs. Dehydro and DL-species are paired into centrosymmetric dimers, and L-compounds form catemers. However, Ac-DeltaAla-NMe2 and Ac-DL-Ala-NMe2 constitute exceptions: their molecules also link into catemers.

The FTIR spectra were analysed in the region of the nu(s)(N-H), AI(C=O) and nu(s)(Calpha=Cbeta) bands for a series of Ac-DeltaXaa-NMe2, where DeltaXaa = DeltaAla, (Z)-DeltaAbu, (Z)-DeltaLeu, (Z)-DeltaPhe and DeltaVal, to determine a predominant solution conformation of these alpha,beta-dehydropeptide-related molecules. Measurements were taken in CCl4, DCM and MeCN solutions. In the same way, spectra of saturated analogues Ac-Xaa-NMe2, where Xaa = Ala, Abu, Leu, Phe and Val, were investigated. To help interpret the spectroscopic results, conformational maps were calculated by the B3LYP/6-31+G** method. Also, the relative energies of all conformers of the dehydro compounds in vacuo as well as in the studied solvents in addition to the theoretical IR frequencies of these conformers were calculated. For comparison, molecules of two saturated analogues, Ac-L-Ala-NMe2 and Ac-L-Phe-NMe2, were calculated in a similar way. Both unsaturated and saturated compounds, which have an aliphatic side chain, occur in CCl4 and DCM mainly as a mixture of extended conformers with the C5 H-bond and open conformers. As solvent polarity increases, participation of the open conformers also increases, and in MeCN, the model amides are almost exclusively in the open form, except Ac-DeltaAla-NMe2, which shows a small amount of the H-bonded conformer. Ac-DeltaAla-NMe2 and Ac-DeltaAbu-NMe2 have stronger C5 hydrogen bonds than those of their saturated counterparts. As the calculations indicate, the open conformation of the unsaturated amides is conformer H/F with phi, psi -44 +/- 5 degrees, 127 +/- 4 degrees. This is the second lowest in energy conformer in vacuo and in CCl4 and the lowest one in more polar solvents. The open conformation of Ac-L-Ala-NMe2 constitutes conformer C with phi, psi -101.5 degrees, 112.7 degrees. For Ac-DeltaAla-NMe2 and Ac-DeltaAbu-NMe2, FTIR also reveals the presence of a third conformer. Calculations indicate that is the semiextended conformer D with the N1-H1...N2 hydrogen bond/contact. In all solvents, Ac-L-Phe-NMe2 and Ac-(Z)-DeltaPhe-NMe2 show only the extended E and the open H/F, respectively. In both there is an amide/pi(Ph) interaction.

The Fourier transform infrared spectra are analyzed in the regions of vs(N‐H), amide I, amide II and vs(Cα=Cβ) bands for a series of Ac‐ΔXaa‐NHMe, where ΔXaa =ΔAla, (Z)‐ΔAbu, (Z)‐ΔLeu, (Z)‐ΔPhe and AVal, to determine the predominant solution conformation of these α, β‐dehydropeptide‐related molecules and the electron distribution perturbation in their amide bonds. The measurements were performed in dichloromethane (DCM). To confirm and rationalize the assignments, the spectra of the respective series of saturated Ac‐Xaa‐NHMe, recorded in DCM, and the spectra of these two series of unsaturated and saturated compounds, recorded in acetonitrile, were examined. To help interpret the spectroscopic results, the equilibrium geometrical parameters for some selected amides were used. These were optimized with ab initio methods in the 6‐31G** basis set. Each of the dehydroamides studied adopted a C5 structure, which in Ac‐ΔAla‐NHMe is fully extended and accompanied by the strong C5 hydrogen bond. Interaction with the Cα=Cβ bond lessened the amidic resonance within each of the flanking amide groups. The N‐terminal C=O bond was noticeably shorter, both amide bonds were longer than the corresponding bonds in the saturated entities and the N‐terminal amide system was distorted. Ac‐ΔAla‐NHMe constituted an exception. Its C‐terminal amide bond was shorter than the standard one and both amide systems were prototypically planar.

: The Fourier transform infrared spectra of Ac‐(E)‐ΔAbu‐NHMe were analyzed to determine the predominant solution conformation (s) of this (E)‐α,β‐dehydropeptide‐related compound and the electron density perturbation in its amide groups. The measurements were performed in dichloromethane and acetonitrile in the region of mode vs (N–H), amide I, amide II and vs (Cα= Cβ). The equilibrium geometrical parameters, calculated by a method based on the density functional theory with the B3LYP functional and the 6–31G* basis set, were used to support spectroscopic interpretation and gain some deeper insight into the molecule. The experimental and theoretical data were compared with those of three previously described molecules: isomeric Ac‐(Z)‐ΔAbu‐NHMe, Ac‐ΔAla‐NHMe, which is deprived of any β‐substituent, and saturated species Ac‐Abu‐NHMe. The titled compound assumes two conformational states in equilibrium in the DCM solution. One conformer is extended almost fully and like Ac‐ΔAla‐NHMe is C5 hydrogen‐bonded. The other adopts a warped C5 structure similar to that of Ac‐(Z)‐ΔAbu‐NHMe. The C5 hydrogen bond, unlike the H‐bond in Ac‐ΔAla‐NHMe, is disrupted by acetonitrile. The resonance within the N‐terminal amide groups in either of the (E)‐ΔAbu conformers is not as well developed as the resonance in Ac‐Abu‐NHMe. However, these N‐terminal groups, compared with the other unsaturated compounds, constitute better resonance systems in each conformationally related couple: the C5 hydrogen‐bonded Ac‐(E)‐ΔAbu‐NHMe/Ac‐ΔAla‐NHMe and the warped C5 Ac‐(E)‐ΔAbu‐NHMe/Ac‐(Z)‐ΔAbu‐NHMe. The resonance within the C‐terminal groups of the latter couple apparently is similar, but less developed than the resonance in Ac‐Abu‐NHMe. The electron distribution within the C‐terminal group of the hydrogen‐bonded C5 (E)‐ΔAbu conformer apparently is determined mainly by the electron influx from the Cα= Cβ double bond.

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