Non-planar Amide Group Research Articles

ChemInform Abstract: The Nonplanar Amide Group in N-Acylaziridines: Conformational Behavior and Chiroptical Properties.

ChemInform Abstract: The Nonplanar Amide Group in N-Acylaziridines: Conformational Behavior and Chiroptical Properties.

Spectroscopic properties of the nonplanar amide group: A computational study

Experimental studies suggest that amide bond may significantly deviate from planar arrangement even in linear peptides and proteins. In order to find out the extent to which such deviation may influence principal amide spectroscopic properties, we conducted a computational study of nonplanar N-methylacetamide (NMA) conformers. Vibrational absorption, Raman, and electronic spectra including optical activity were simulated with ab initio and density functional theory (DFT) methods. According to the results, small nonplanarity deviations may be detectable by nonpolarized spectroscopic techniques, albeit as subtle spectral changes. The optical activity methods, such as the vibrational circular dichroism (VCD), Raman optical activity (ROA), and electronic circular dichroism (CD, ECD), provide enhanced information about the amide nonplanarity, because planar amide is not optically active (chiral). For VCD, however, the inherently chiral contribution in most peptides and proteins most probably provides very weak signal in comparison with other contributions, such as the dipolar coupling. For the electronic CD, the nonplanarity contribution is relatively big and causes a strong CD couplet in the n-pi* absorption region accompanied by a red frequency shift. The pi-pi* CD region is relatively unaffected. The ROA spectroscopy appears most promising for the nonplanarity detection and the inherent chiral signal may dominate entire spectral parts. The amide I and III vibrational ROA bands are most challenging experimentally because of their relatively weak coupling to other peptide vibrations.

Temperature coefficient of NH chemical shifts of thioamides and amides in relation to structure

NH chemical shift temperature coefficients have been measured in a large series of N-substituted-3-piperidinethiopropionamides in which the N⋯N distances are short but of varied length, as well as in a couple of the corresponding amides and in some simpler amides and thioamides. Geometries are calculated by means of ab initio DFT methods. The N-substituted-3-piperidinethiopropionamides show in most cases strong intramolecular N–H⋯N hydrogen bonds according to IR spectra and ab initio calculations. For compounds with rather short N⋯N distances the SC–N–H moiety is non-planar. Dihedral angles as small as 160° are found. The NH chemical shift coefficients measured in non-polar solvents in all the N-substituted-3-piperidinethiopropionamides are more negative (−8 to −17 ppb/K) than in non-hydrogen bonded thioamides. For the latter in non-polar solvents like CDCl 3 and toluene the temperature coefficients are as small as −1 to −4 ppb/K. The large negative effects can be related not only to the non-planarity of the thioamide group in a way that the more pronounced the non-planarity the more negative the temperature coefficients, but also to strong hydrogen bonding and the fact that the acceptor is a nitrogen. For similar amides with non-planar amide groups and nitrogen acceptor large negative temperature coefficients are likewise seen. In polar solvents like DMF the effects in simple thioamides are uniform and close to −6 ppb/K, whereas in the more complex compound like 4p( t) the temperature coefficient is close to 0. An essential feature of measuring temperature coefficients of compounds without strong intramolecular hydrogen bonds in non-polar solvents and at low temperatures is to keep the concentration low enough to avoid dimerisation.

NMR chemical shielding surface ofN-Acetyl-N?-Methylalaninamide: A density functional study

The five energetically lowest minima on the potential energy surface of N-acetyl-N′-methylalaninamide were optimized at the Becke3LYP/DZd level of theory to compare these density functional theory results with the literature findings at restricted Hartree-Fock/3-21G. While the relative energies are very similar, the amide moiety is predicted to be much more flexible at Becke3LYP/DZd. As a consequence, the three minima that favor a nonplanar amide group differ by up to 14° in their ϕ and ψ values between the two levels. To compare the change in the density functional NMR chemical shifts with respect to ϕ and ψ with experimental results, Becke3LYP/DZd was employed to optimize a structure for N-acetyl-N′-methylalaninamide at each 30° interval on the (ϕ, ψ) surface in the regions that correspond to the α helix and the β-pleated sheet and at each 60° interval elsewhere. The corresponding NMR chemical shielding surface was computed with the density functional program deMon. The resultant NMR chemical shielding surfaces for N and Cβ are in good agreement with the experiment, while the change in the NMR chemical shielding of C′ and Cα cannot be described only in terms of ϕ and ψ. The chemical shifts for those atoms also depend on the nonplanarity of the amide moiety. We evaluated this dependence for N-methylacetamide as a model system. Estimates of the parameters derived from N-methyl-acetamide allowed the NMR-shielding surfaces of C′ and Cα to be corrected for the nonplanar nitrogen influence. Although the effect is less pronounced with lower level theoretical geometries, due to the smaller degree of pyramidalization of the amide nitrogen, the (ϕ, ψ) NMR chemical shielding surfaces will need to be corrected. The agreement with the experiment was much better for the corrected surface of C′ when the nitrogen in the α helix had a nonplanar environment. © 1997 by John Wiley & Sons, Inc.

Stereochemistry and chiroptical properties of 1,3-dialkylaziridinones (α-lactams). Chiral rules for the nonplanar amide chromophore

Structural features, configurational stability, and chiroptical properties of the nonplanar amide group in α-lactams were investigated by means of ab initio (6-31 + G*) molecular orbital calculations on (1R)-aziridinone 1, (1R)-1-methylaziridinone 2, (1R,3R)-3-methylaziridinone 3, (1R,3R)-1,3-dimethylaziridinone 4a, its cis diastereomer (1S,3R)-1,3-dimethylaziridinone 4b, and (1R,3R)-3-tert-butyl-1-methylaziridinone 5, and by experimental CD spectra of 1-tert-butyl- and 1-(1′-adamantyl)-substituted 3(R)-3-tert-butylaziridinones 6 and 7. The nitrogen inversion barriers of 4a and 4b are 2.8 and 1.6 kcal mol−1, respectively. The lowest excited singlet state of all of the aziridinones is a valence state (the nO–πCO* transition); the second is a Rydberg state (the nN–3s transition). The signs of the first and second Cotton effects in the CD spectra of the compounds 6 and 7 coincide with the calculated ones for 1 and 2 and the trans isomers 3, 4a, and 5. According to the calculated and experimental data for aziridinones 1–7 as well as to the well-known data for other nonplanar amides, the sign of the first Cotton effects is determined by the intrinsic chirality of the nonplanar amide chromophore and obeys a spiral rule. For cases where the chromophore has the conformation around the N—C(O) bond, which is close to the antiperiplanar, a reverse octant rule is proposed.

The nonplanar amide group in N-acylaziridines: conformational behavior and chiroptical properties

Chiroptical properties in the intrinsically dissymmetric amide chromophore of N-acylaziridines are investigated experimentally and by ab initio molecular orbital calculations

Conformers of trans-N-methylacetamide: Ab initio study of geometries and vibrational spectra

Energies and geometries have been obtained, at the 4-31G* level, for the four stable conformers of trans-N-methylacetamide that result from conformational isomerism of the CH3 groups. Ab initio force fields were obtained for these four structures, and the force constants were scaled to experimental matrix-isolated frequencies. The results show that the conformers should be spectroscopically distinguishable, and in fact the observed bands can be satisfactorily assigned on this basis without invoking a non-planar amide group. Conformational isomerism may also be partly responsible for the unusual breadth of the amide V band.

(1S,7S)-7-Methyl-6,9-diazatricyclo[6,3,0,01,6]tridecane-5,10-dione, a tricyclic spirodilactam containing non-planar amide groups: Synthesis, NMR, crystal structure, absolute configuration, electronic and vibrational circular dichroism

The title spirocyclic dilactam (1S,7S)-7-methyl-6,9-diazatricyclo[6,3,0,01,6]tridecan-5,10-dione (I), a molecule designed to contain non-planar amide groups, has been synthesized from an optically active precursor of known absolute configuration. The relative and absolute configuration have been determined by X-ray diffraction. The conformation of the compound has been investigated by X-ray, 1H and 13C NMR, electronic and vibrational circular dichroism. The compound possesses moderately non-planar amide groups in the two rings of nonequal geometry. The electronic CD is dominated by inherent chirality of the amide chromophores. The dilactams I and II ((1S,6S)-6-methyl-5,8-diazatricyclo[6,3,0,01,5]undecan-4,9-dione – having five-membered rings) exhibit monosignate amide I VCD and strong VCD bands in the mid-ir region.

Conformation of diastereoisomeric cyclo(neopentylglycyl-prolyls): NMR, X-ray, and CD studies

Conformation of diastereoisomeric cyclo(L-neopentylglycyl-L-prolyl) (IV) and cyclo(D-neopentylglycyl-L-prolyl) (VIII) in solution was studied by 1H and 13C NMR spectroscopy. Both compounds have approximately the same conformation of the bicyclic moiety in which the 2,5-piperazinedione ring exists in the boat form with pseudoaxial proline H(α) atom, and the proline ring is in the C(γ)-exo conformation. Rotation of the neopentyl side chain is markedly hindered. In the trans-derivative VIII the side chain occupies a pseudoaxial position with staggered rotamer about the C(α)-C(β) bond, the tert-butyl group pointing from the ring in the direction of the nitrogen atom. The preferred rotamer of the cis-isomer markedly deviates from this staggered conformation in the exo-direction relative to the piperazine ring. X-Ray diffraction analysis shows that crystal conformation of the trans-isomer VIII is very similar to that in solution. According to CD measurements, steric interactions of the acyclic side chain with the dioxopiperazine ring lead to twisted boat conformations of this ring with non-planar amide groups. From comparison with other proline-containing cyclodipeptides it follows that the effect of these interactions depends on the side chain structure. The neopentyl side chain flattens the boat conformation and reduces the deviation of the amide groups from planarity.

ChemInform Abstract: Nonplanar Amide Groups as Ligands.

AbstractWhen the trans‐Os(IV) complexes (I) are treated with a strong π‐acid ligand, CO or tBu‐ NC, a phosphine ligand is replaced and the resulting complexes are the cis‐α diastereomers (II).

Nonplanar amide groups as ligands

Os (η 4 -HBA-B)(PPh 3 )(CO) cristallise dans le systeme monoclinique, groupe d'espace P2 1 /c et sa structure est affinee jusqu'a R=0,059, Os (η 4 -CHBA-DCB)(PPh 3 ) (t-BuNC) cristallise dans Pbca avec R=0,063

Structure of 4-azatricyclo[4.3.1.13,8]undecan-5-one (homoazaadamantanone)

C10H15NO, M r = 165.24, monoclinic, P2Jn, a=17.219(1), b=6.4465(5), c=16.064(2)A, fl = 95.95 (1) °, V= 1773.5 (3) A 3, z= 8, Dm= 1.23 (1), D x = 1.24 (1) g cm -3, ,~,(Cu K~t) = 1.5418 A, /z=5.91cm -1, F(000)=720, T=295K. Final R = 0.0474 for 1936 unique observed reflections. In the unit cell, there are two symmetrically independent molecules. The amide group of the first conformational type molecule shows pyramidal arrangement of bonds at N, but this group of the second molecule is almost planar. Each conformational type forms a cyclic dimer by means of inter-amide hydrogen bonds. Introduction. The structure of the title compound (I) was determined as part of a series of studies on the potential occurrence of non-planar amide groups in amides and peptides (Ealick & van der Helm, 1977; Blfiha et al., 1978; Blfiha & Malofi, 1980; Kfilal, Bib.ha & Langer, 1984). This lactam is one of the model compounds in which the cis-amide group is embedded in a rigid tri- cyclic skeleton. Determination of properties characteris- tic for a non-planar amide group, e.g. dependence of chiroptical parameters on the extent and character of deviation from planarity, could be the starting point for finding other similar deviations in flexible amides (peptides) in solution (Blfiha & Malofi, 1980).

Non-planar conformations of methylacetamide: Solvent effect and chiroptical properties

Molecular geometries of the cisoid and transoid forms of N-methylacetamide were optimized by semiempirical methods PCILO, MNDO and MINDO/3. The first two methods afford conformations with the non-planar amide group characterized by a slightly twisted pyramid of bonds on the nitrogen atom. The positions of energy minima are distinctly shifted if the effect of solvent simulated by a continuum model is considered. Optical rotatory strengths computed for non-planar conformations exhibit quantitative agreement with previous calculations and with actual CD spectra of rigid model lactams as well.

Conformation of 3-acetamido-3,6-dideoxyhexopyranosides: Circular dichroism study

CD spectra of 15 stereoisomeric methyl 3-acetamido-3,6-dideoxyhexopyranosides were measured in methanol, 2,2,2-trifluoroethanol and acetonitrile. The data have been applied for estimation of probable conformations. The factor determining signs of the observed Cotton effects seems to be the spatial orientation of the acetamido group with respect to the pyranose ring. The possible role of a non-planar amide group is also discussed.

Synthesis and chiroptical properties of (-)-(1R)-3-azatricyclo[5,4,0,04,9]undecan-2-one - A lactam with non-planar cis-amide group

The title compound (-)-II was prepared starting from (-)-(2S)-endo-bicyclo[2,2,2]oct-5-ene-2-carboxylic acid ((-)-III). Parameters of the dichroic bands obtained in solvents of various polarity indicate the presence of a non-planar amide group in (-)-II. This amide group is of an opposite chirality and deviates less from planarity than the amide group in (-)-(3S)-4-azatricyclo[4,4,0,03,8]decan-5-one (I). Comparison of the calculated ORD curves with the experimental ones shows that molecular chirality of the σ-skeleton does not participate directly in the dichroic absorption of the amide group.

The non-planar amide group

Crystal structures of medium-ring lactams and their crystalline hydrochlorides furnish detailed information on the nature of the out-of-plane distortions of the amide group. Caprylolactam has a non-planar transoid amide group in the crystal but exists in solution as an equilibrium mixture of at least two conformations, one with a nearly planar cis-amide group, one with a non-planar transoid-amide group. The corresponding hydrochloride salt is protonated on oxygen and contains a nearly planar cis-amide group. For non-planar amide groups it is found that out-of-plane bending at nitrogen is about as important as pure twisting, the contribution from out-of-plane bending at the carbonyl carbon being smaller. These results, together with rough data on the energy differences between the lactam conformations, can be used to test various potential functions that have been proposed. It is concluded that although the equilibrium conformation of the amide group may be planar or close to it, out-of-plane deformation can be made at a very modest energy cost. In the construction of models of polypeptide chains or in fitting such models to electron-density maps of protein crystals, the strictly planar peptide unit thus incorporates restrictions that may be rather easily relaxed in the actual molecule.