Regression and principal component analyses of internal coordinates for the carboxamide and carboxylate groups. Diversity of amide bonding in primary carboxamides, oligopeptides, and lactams

Abstract

A new model of electronic structure of the carboxamide and carboxylate bonds is proposed to account for the diversity of the patterns of stmctural variation displayed by such bonds in the crystal structures. The geometries of the amide and carboxylate ester fragments retrieved from the Cambridge Crystallographic Data Centre database were examined by means of the regression and principal component analyses. Correlations of the C-----O and C--O/C--N bond distances and correlations of the bond distances with the out-of-plane distortions are consistent with the predictions of Pauling's resonance model only in the more extensively substituted esters, secondary amides, and common ring lactams. Surprisingly, in the unsubstituted methyl esters and primary amides, correlations between the bond distances are positive (e.g., both C--N and C----O increase or decrease). Furthermore, for themajority of the less substituted amides and lactams, an increase in pyramidalization at the nitrogen is associated with the shortening of the C--N bond instead of the expected lengthening. Consequently, factor analyses of the r(C=O), r(C--N), 10N I coordinates for the 42 subclasses of amides and lactams reveal three patterns of coupling of structural parameters; these patterns appear to be related to the major types of the amide substitution. A hypothesis explaining this diversity is based on the assumption that structural variation observed in each of the narrowly defined subclasses of amides maps out initial stages of rehybridization accompanying internal rotation; that is, the amide bonds in the crystal structures deform along the rehybridization/rotation path. It is proposed that the positions of the minimum and the saddle point along this path depend on the alkyl substitution of the bond and the size of the embedding ring.KEY WORDS: Amides; esters; resonance; X-ray, crystallography; structure correlations. distances in such molecules are similar to the ones found in simple aldehydes and ketones. Recently, an explanation of this fact has been proposed by Wiberg and Laidig, who carded out an extensive computational study of the internal rotation in amides [3]. By analyzing the geometry, force constants, electron populations, and effective charges, these authors have shown that the C=O bond of formamide is relatively unaffected by rotation for two reasons. First, this bond is highly polarized even in the rotated saddle-point structures, and the carbonyl O appears very nearly saturated with electron density, so increasing its electronic population does not 85

Inductive and Resonance Effects of Substituents on π-Face Selection

“…The urethane N lp can be expected to be more effective than the amide N lp in back-donation into σ* C - H (extended hyperconjugation), while the opposite should be true for homoconjugation . The urethane ligand promotes, therefore, the syn approach, Scheme , and the amide ligand promotes the anti approach, Scheme .…”

Protein folding, misfolding and aggregation: The importance of two-electron stabilizing interactions

“…It follows that the peptide bonds which are good N lp donors and poor H-bond acceptors should stabilize the φ i = ‒90°±30° fold while the peptide bonds which are poor N lp donors and good H-bond acceptors should stabilize the φ i = −150°±30° fold. To refine this picture we take into account computational and experimental evidence of wide variation in electronic configuration of the amide bonds in carboxamides, lactams, oligopeptides and proteins [ 7 , 32 , 60 – 63 ]. According to this evidence, one can describe bonding of peptide linkages in terms of varying contributions of the five resonance structures I-V, see Fig 1C .…”

“…(1) The structure I contributes to the configuration of the least-polarized bonds which display positive r C = O vs. r C-N correlations [ 32 ], are relatively poor acceptors of H-bonds, form largely ionic backbone-backbone H-bonds [ 64 , 65 ], and are good π/resonance N lp donors; it is compatible with the PP II helix where backbone-backbone H-bonding is absent as well as the φ i = 180°±30°/ψ i = 180°±30° fold cf. Fig 1B(d) which is stabilized by the extended N lp hyperconjugation [ 21 ].…”

“…(4) The structures IV and V contribute to the configuration of the highly- and most-polarized bonds which display negative r C = O vs. r C-N correlations [ 32 ], are good acceptors and donors of H-bonds and form largely covalent H-bonds (including the backbone-backbone C = O⋯H−C bonding [ 66 , 67 ]), but are poor π donors in the hyperconjugative interactions of N. Thus, the highly-polarized backbone segments will stabilize the φ i = ‒150°±30°/ψ i = 150°±30° fold i.e. the C 5 strands which readily assemble into β-sheets as reported in Fig 2 .…”

“…The relationship between the electronic configuration of the peptide amide bonds and the torsional potential of the protein backbone was first considered in the context of modelling the relay of chiral information via the π-conjugated systems [ 16 ]. Subsequently, a theory was proposed linking the secondary structure propensities of the Ala congeners (the Ala* amino acids) to the inductive and resonance effects of the side chains and the stereoelectronic effects [ 28 – 31 ]; the sense and relative importance of these effects was assumed to depend on the location of the peptide amide bonds along the amide rehybridization/polarization path [ 32 ]. To explore the theory’s implications, a quantum-mechanical investigation of the single-site substitutions Ala→Lac (Lac≡L-lactic acid) was carried out [ 33 ].…”