Vojislava Pophristic

Hyperconjugation not steric repulsion leads to the staggered structure of ethane

Many molecules can rotate internally around one or more of their bonds so that during a full 360° rotation, they will change between unstable and relatively stable conformations. Ethane is the textbook example of a molecule exhibiting such behaviour: as one of its two methyl (CH3) groups rotates once around the central carbon–carbon bond, the molecule will alternate three times between an unstable eclipsed conformation and the preferred staggered conformation. This structural preference is usually attributed to steric effects; that is, while ethane rotates towards an eclipsed structure, the electrons in C–H bonds on the different C atoms are drawing closer to each other and therefore experience increased repulsion, introducing a rotation barrier that destabilizes the eclipsed structure. Stabilization of the staggered structure through rotation-induced weakening of the central C–C bond and hyperconjugation has been considered to be involved, but evaluation of the contributions of these effects to ethanes internal rotation barrier and conformational preference remains difficult. Here we report a series of ethane structure optimizations, where successive removal of different interactions indicates that ethanes staggered conformation is the result of preferential stabilization through hyperconjugation. Removal of hyperconjugation interactions yields the eclipsed structure as the preferred conformation, whereas repulsive forces, either present or absent, have no influence on the preference for a staggered conformation.

Flexing analysis of ethane internal rotation energetics

A flexing analysis of the ethane barrier energy in terms of structural (ΔEstruct), steric exchange (ΔEsteric), and hyperconjugative charge-transfer (ΔEdeloc) energy contributions has been carried out using natural bond orbitals. No evidence is found for the view that the ethane staggered equilibrium geometry or the C–C bond expansion that accompanies rotation results from steric exchange repulsion interactions. The analysis shows that ΔEstruct and ΔEdeloc have very different stereoelectronic dependencies, but that the ΔEsteric and ΔEdeloc dependencies are antagonistic. All of their contributions are strongly affected by the C–C bond expansion, with the result that the barrier mechanism cannot be understood without taking into account their different relaxation dependencies. Neglect of C–C expansion leaves the charge-transfer interactions paramount by subduing the steric and structural contributions. These interactions are found to be an important determinant for the expansion. The strong expansion depende...

Intramolecular Hydrogen Bonding in ortho-Substituted Arylamide Oligomers: A Computational and Experimental Study of ortho-Fluoro- and ortho-Chloro-N-methylbenzamides

As a part of our systematic study of foldamer structural elements, we analyze and quantify the conformational behavior of two model compounds based on a frequently used class of aromatic oligoamide building blocks. Combining computational and NMR approaches, we investigate ortho-fluoro- and ortho-chloro-N-methylbenzamide. Our results indicate that the -F substituent in an ortho position can be used to fine-tune the rigidity of the oligomer backbone. It provides a measurably attenuated but still considerably strong hydrogen bond (H-bond) to the peptide group proton when compared to the -OCH3 substituent in the same position. On the other hand, the ortho-Cl substituent does not impose significant restrictions on the flexibility of the backbone. Its effect on the final shape of an oligomer is likely governed by its size rather than by noncovalent intramolecular interactions. Furthermore, the effect of solvent on the conformational preferences of these building blocks has been quantified. The number of intramolecularly H-bonded conformations decreases significantly when going from nonprotic to protic environments. This study will facilitate rational design of novel arylamide foldamers.

Where does the dimethyl ether internal rotation barrier come from

Abstract The energetic consequences of skeletal relaxation and natural bond orbital and symmetry decomposition of the barrier energy for dimethyl ether internal rotation is analysed. The largest contribution to the barrier energy is found to involve increased p character in the oxygen σ long-pair on going to the barrier top. Opening of the COC angle, occurring because of increased Pauli exchange repulsion between in-plane CH methyl orbitals is responsible for the p character increase. However, the Pauli repulsion does not contribute importantly to the barrier energy. π-interaction effects are found to give important, but not dominant barrier energy contributions.

Hydrogen Bonding in ortho-Substituted Arylamides: The Influence of Protic Solvents

We combine molecular modeling and NMR methods to better understand intramolecular hydrogen bonding (H-bonding) in a frequently used arylamide foldamer building block, ortho-methoxy-N-methylbenzamide. Our results show that solvents have a profound influence on the cumulative number and stabilizing effects of intramolecular H-bonds, and thus conformational preferences, of foldamers based on this compound. While intramolecular H-bonds are conserved in aprotic environments, they are significantly disrupted in protic solvents. Furthermore, these solvent effects can be accurately quantified using the computational approach presented here. The results could have significant implications in foldamer design, particularly for applications in aqueous environments.

An ab initio molecular orbital study of intramolecular hydrogen bonding in ortho-substituted arylamides: Implications for the parameterization of molecular mechanics force fields

The aromatic oligoamide (arylamide) foldamer class, characterized by the repetitive aromatic‐amide pattern, is one of the most intensively studied foldamer families. In this article, the potential energy profiles with regard to torsional motions around the two types of aromatic‐amide bonds (CaCp and CaN) are obtained at the B3LYP/6‐311G(d,p) level of theory. The effect of ortho substituents with different hydrogen bonding abilities (OCH3 vs. SCH3) on the torsional potential profiles is analyzed in detail. There are several findings that have implications in foldamer design. The ortho‐SCH3 substituent on the benzene ring produces a much more flexible arylamide backbone with respect to the OCH3 substituent, as it restricts the CaCp torsion to a lesser extent. Interestingly, the rigidifying effect of the ortho‐SCH3 substituent on the CaN torsion is very similar to that of the OCH3 substituent on the same linkage type. In addition, the SCH3 substituent prefers a perpendicular orientation with respect to the benzene ring to the in‐plane one. It is also found that reparameterization of the corresponding torsional parameters, sometimes specific to the ortho substituent type, in the general amber force field is necessary for an accurate description of the backbone torsions in arylamides. Six sets of partial charge/torsional parameters for each linkage (CaCp or CaN)/substituent (OCH3 or SCH3) combination are obtained based on the ab initio torsional profiles. Initial assessments of these parameters show good agreement with the ab initio results.

Computational Prediction and Rationalization, and Experimental Validation of Handedness Induction in Helical Aromatic Oligoamide Foldamers

Metadynamics simulations were used to describe the conformational energy landscapes of several helically folded aromatic quinoline carboxamide oligomers bearing a single chiral group at either the C or N terminus. The calculations allowed the prediction of whether a helix handedness bias occurs under the influence of the chiral group and gave insight into the interactions (sterics, electrostatics, hydrogen bonds) responsible for a particular helix sense preference. In the case of camphanyl-based and morpholine-based chiral groups, experimental data confirming the validity of the calculations were already available. New chiral groups with a proline residue were also investigated and were predicted to induce handedness. This prediction was verified experimentally through the synthesis of proline-containing monomers, their incorporation into an oligoamide sequence by solid phase synthesis and the investigation of handedness induction by NMR spectroscopy and circular dichroism.

Ab Initio Calculations of Intramolecular Parameters for a Class of Arylamide Polymers

Using DFT methods, we have determined intramolecular parameters for an important class of arylamide polymers displaying antimicrobial and anticoagulant inhibitory properties. A strong link has been established between these functions and the conformation that the polymers adopt in solution and at lipid bilayer interfaces. Thus, it is imperative for molecular dynamics simulations designed to probe the conformational behavior of these systems to accurately describe the torsional degrees of freedom. Standard force fields were shown to be deficient in this respect. Therefore, we have computed the relevant torsional energy profiles using a series of constrained geometry optimizations. We have also determined electrostatic parameters using our results in combination with standard RESP charge optimization. Force constants for bond and angle potentials were calculated by iteratively matching quantum and classical normal modes via a Monte Carlo scheme. The resulting new set of parameters accurately described the conformation and dynamical behavior of the arylamide polymers.

Acetone n-radical cation conformational preference and torsional barrier

The ab initio architecture and torsional barrier for acetone n-radical cation are obtained. The 923 cm−1 MP4/6-311+G(3df,2p) barrier is calculated to be 30% higher than for neutral acetone. This increase is largely attributed to correlation effects and less importantly to increased hyperconjugative stabilization of the equilibrium cation conformer. Ionization is predicted to cause opening of the central CCC angle by 7° and cause the methyl groups to lose the C3v symmetry that they possess in neutral acetone. The torsional coordinate for the infrared active b1 (gearing) rotation is predicted to not lie purely on the torsional potential surface, but to be contaminated by puckering of the CCCO skeleton in both the neutral and cation species, thereby making the b1 infrared torsional frequencies only partially suitable for sampling the torsional potential surface.

Computational Study of the Small Zr(IV) Polynuclear Species.

Despite widespread zirconium use ranging from nuclear technology to antiperspirants, important aspects of its solvation chemistry, such as the nature of small zirconium(IV) hydroxy cluster ions in aqueous solution, are not known due to the complexity of the zirconium aqueous chemistry. Using a combination of Car-Parrinello molecular dynamics simulations and conventional quantum mechanical calculations, we have determined the structural characteristics and analyzed the aqueous solution dynamics of the two smallest zirconium(IV) cluster species possible, i.e., the dimer and trimer. Our study points to and provides detailed geometrical information for a stable structural motif for building zirconium polymers, the Zr(OH)2Zr bridging unit with 7-8 coordinated Zr ions, which, however, cannot be used to construct a stable structure for the trimer. We find that a stacked trimer, not featuring this motif, is a possible structure, though not a very stable one, shedding new light on this species, and its possible importance in the aqueous chemistry of Zr(4+) ion.