Carbonyl-carbonyl (CO⋯CO) interactions are emerging noncovalent interactions found in many small molecules, polyesters, peptides and proteins. However, little is known about the effect of the relative orientation of the two carbonyl groups on the nature of these interactions. Herein, we first show that simple homodimers of acetone and formaldehyde can serve as models to understand the effect of relative orientations of the two carbonyl groups on the nature of CO⋯CO interactions. Further, from a comprehensive statistical analysis of molecules having inter- or intramolecular CO⋯CO interactions, we show that the molecules can be broadly categorized into six different structural motifs (I-VI). The analysis of pyramidality of the acceptor carbon atoms in these motifs and natural bond orbital (NBO) analysis suggest that the relative orientation of the two interacting carbonyl groups determines whether the orbital interaction between the two carbonyl groups would be n → π∗ or π → π∗ or a combination of both. © 2019 The Royal Society of Chemistry.

Sahariah B.

Sarma B.K.

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Shiv Nadar University

Chemical Science

n → π* has emerged as an important noncovalent interaction that can affect the conformations of both small- A nd macromolecules including peptides and proteins. Carbonyl-carbonyl (CO⋯CO) n → π* interactions involving CO groups are well studied. Recent studies have shown that the CO⋯CO n → π* interactions are the most abundant secondary interactions in proteins with a frequency of 33 interactions per 100 residues and, among the various secondary interactions, n → π* interactions are expected to provide the highest enthalpic contributions to the conformational stability of globular proteins. However, n → π* interactions are relatively weak and provide an average stabilization of about 0.25 kcal mol-1 per interaction in proteins. The strongest n → π* interaction could be as strong as a moderate hydrogen bond. Therefore, it is challenging to detect and quantify these weak interactions, especially in solution in the presence of perturbation from other intermolecular interactions. Accordingly, spectroscopic investigations that can provide direct evidence of n → π* interaction are limited, and the majority of papers published in this area have relied on X-ray crystallography and/or theoretical calculations to establish the presence of this interaction. The aim of this perspective is to discuss the studies where a spectroscopic signature in support of n → π* interaction was observed. As the "n → π* interaction"is a relatively new terminology, there remains the possibility of there being earlier studies where spectroscopic evidence for n → π* interactions was obtained but it was not discussed in light of the n → π* terminology. We noticed several such studies and, as can be expected, these studies were often overlooked in the discussion of n → π* interactions in the recent literature. In this perspective, we have also discussed these studies and provided computational support for the presence of n → π* interaction. © 2020 the Owner Societies.

Physical Chemistry Chemical Physics

Spectroscopic evidence of n → π∗ interactions involving carbonyl groups

In recent years, some X-ray structural and computational evidence has emerged for noncovalent carbon bonding (C-bond). However, evidence of C-bonds in solution is limited. Herein, from the conformational analyses of strategically designedN-methyl-N,N'-diacylhydrazines, we for the first time show that C-bonds can be modulated to control the conformational preferences of small molecules in solution. We show that unusual N(amide)?C-X noncovalent carbon bonding interactions stabilize thetrans-cis(t-c) amide bond rotamers ofN-methyl-N,N'-diacylhydrazines over the expectedtrans-trans(t-t) rotamers. © The Royal Society of Chemistry 2020.

Chemical Communications

Conformational control ofN-methyl-N,N'-diacylhydrazines by noncovalent carbon bonding in solution

We report the solid-phase synthesis of N,N′-di(acylamino)-2,5-diketopiperazine, an acylhydrazide-based conformationally rigid 2,5-DKP scaffold having exocyclic N-N bonds. We also show that different combinations of acylhydrazides, carbazates, semicarbazides, amino acids, and primary amines can be used to synthesize a highly diverse collection of hybrid DKP molecules via the solid-phase submonomer synthesis route. Finally, we show incorporation of a methyl substituent in one of the carbon atoms of the DKP ring to generate chiral daa- and hybrid-DKPs without compromising the synthetic efficiency. Copyright © 2020 American Chemical Society.

Journal of Organic Chemistry

Solid-Phase Synthesis of Hybrid 2,5-Diketopiperazines Using Acylhydrazide, Carbazate, Semicarbazide, Amino Acid, and Primary Amine Submonomers

The incorporation of the recently discovered reciprocal n → π∗ interactions in 2,5-diketopiperazines (DKPs) is reported to design a novel N,N′-di(acylamino)-2,5-diketopiperazine (daa-DKP) scaffold. The design, synthesis, and structural features of daa-DKPs and the effect of reciprocal n → π∗ interactions in their structural rigidity is discussed. Copyright © 2018 American Chemical Society.

Organic Letters

N, N′-Di(acylamino)-2,5-diketopiperazines: Strategic Incorporation of Reciprocal n → π∗ Interactions in a Druglike Scaffold

Carbonyl-carbonyl n→πinteractions where a lone pair (n) of the oxygen atom of a carbonyl group is delocalized over the πorbital of a nearby carbonyl group have attracted a lot of attention in recent years due to their ability to affect the 3D structure of small molecules, polyesters, peptides, and proteins. In this paper, we report the discovery of a "reciprocal" carbonyl-carbonyl interaction with substantial back and forth n→πand π→πelectron delocalization between neighboring carbonyl groups. We have carried out experimental studies, analyses of crystallographic databases and theoretical calculations to show the presence of this interaction in both small molecules and proteins. In proteins, these interactions are primarily found in polyproline II (PPII) helices. As PPII are the most abundant secondary structures in unfolded proteins, we propose that these local interactions may have implications in protein folding. © 2017 The Author(s).