Theoretical Study of Chiral Carboxylic Acids. Structural and Energetic Aspects of Crystalline and Liquid States

Lattice energy calculations by semiempirical and quantum mechanical methods have been carried out on 17 crystals of phenoxypropionic acids (PPAs), including 5 pairs of racemic and homochiral partners. Racemic crystals always consist of centrosymmetric cyclic hydrogen-bonded dimers, while homochiral crystals invariably include chain (“catemer”) motifs of O–H···O hydrogen bonds, except for one case having a pseudo-2-fold axis dimer with two molecules in the asymmetric unit. Energy differences between homochiral and racemic crystals are small, without a consistent trend of higher stability of either state. Partitioned molecule–molecule energy calculations show that hydrogen bonds compete with diffuse dispersive factors or local electrostatic interactions. Monte Carlo methods with empirical atom–atom potentials were also applied to simulate the structural and energetic equilibrium properties of some racemic and homochiral liquids. The latter are very nearly isoenergetic, apparently irrespective of molecular size, shape, and chemical constitution, and do not display significant differences in internal structure with respect to type, number, or persistency of hydrogen-bonded pairs. However, major changes in molecular conformation are predicted for PPAs upon crystallization. On the basis of these results, the roles of thermodynamics and kinetics are discussed in the context of understanding spontaneous resolution

Facts and Factors in the Formation and Stability of Binary Crystals

Despite significant ongoing experimental and computational efforts, factors involved in the choice between homomolecular and heteromolecular recognition remain elusive. Here, a large-database study of cohesive energy and intermolecular noncovalent interactions (NCI) in cocrystals from the Cambridge Structural Database has been undertaken. Centrosymmetric space groups (especially <i>P</i>1̅) are largely more frequent than unary crystals, while the frequency of chiral space groups is halved. Overall close-packing is observed, but the relative sizes of the two coformers can vary widely. 86% of extant cocrystals are hydrogen-bonded, all of which include bonding between the two coformers. Carbonyl oxygens and aromatic nitrogens are the most consistent acceptors, while the donor activity decreases according to COOH > NH ≫ R–OH series, so that COOH···N (aromatic) is the favorite H-bond. π···π stacking is another recurring interaction. The lattice energy of the binary crystal is nearly always more stabilizing than the sum of the lattice energies of pure coformers. When sublattices are considered, the AB one is mostly more stabilizing than the AA + BB sum; moreover, in most cases the A–B heteropair also ranks first in energy. Finally, it has been demonstrated that cocrystallization mainly involves the evolution to stronger hydrogen bonds than those found in the coformer crystals, implying that heterorecognition provides a thermodynamic drive to cocrystal formation. Existing cocrystals are a collection of successful attempts at cocrystallization, and conversely their common properties may provide valid suggestions along the path to success

Revealing Electron Delocalization through the Source Function

The source function (SF) introduced in late 90s by Bader and Gatti quantifies the <i>influence</i> of each atom in a system in determining the amount of electron density at a given point, regardless of the atom’s remote or close location with respect to the point. The SF may thus be attractive for studying directly in the real space somewhat elusive molecular properties, such as “electron conjugation” and “aromaticity”, that lack rigorous definitions as they are not directly associated to quantum-mechanical observables. In this work, the results of a preliminary test aimed at understanding whether the SF descriptor is capable to reveal electron delocalization effects are corroborated by further examination of the previously investigated benzene, 1,3-cyclohexadiene, and cyclohexene series and by extending the analysis to some benchmark organic systems with different unsaturated bond patterns. The SF can actually reveal, order, and quantify π-electron delocalization effects for formal double, single conjugated, and allylic bonds, in terms of the influence of distant atoms on the electron density at given bond critical points. In polycyclic aromatic hydrocarbons, the SF neatly reveals the mutual influence of the benzenoid subunits. In naphthalene it provides a rationale for the changes observed in the local aromatic character of one ring when the other is partially hydrogenated. The SF analysis describes instead biphenyl as made up by two weakly interacting benzene rings, only slightly perturbed by the combination of mutual steric and electronic effects. Eventually, a new SF-based indicator of local aromaticity is introduced, which shows excellent correlation with the aromatic index developed by Matta and Hernández-Trujillo, based on the delocalization indices. At variance with this latter and other commonly employed quantum-mechanical (local) aromaticity descriptors, the SF-based indicator does not require the knowledge of the pair density, nor the system wave function, being therefore promising for applications to experimentally derived charge density distributions

Intermolecular Recognition of the Antimalarial Drug Chloroquine: A Quantum Theory of Atoms in Molecules–Density Functional Theory Investigation of the Hydrated Dihydrogen Phosphate Salt from the 103 K X‑ray Structure

The relevant noncovalent interaction patterns responsible for intermolecular recognition of the antiplasmodial chloroquine (CQ) in its bioactive diprotonated form, CQH₂²⁺, are investigated. Chloroquine dihydrogen phosphate hydrated salt (<i>P</i>2₁/<i>c</i>) was crystallized by gel diffusion. A high-resolution single-crystal X-ray diffraction experiment was performed at 103(2) K, and a density functional theory model for the in-crystal electron density was derived, allowing the estimation of the interaction energies in relevant molecular pairs. H₂PO₄^– ions form infinite chains parallel to the monoclinic axis, setting up strong NH···O charge-assisted hydrogen bonds (CAHBs) with CQH₂²⁺. Couples of facing protonated quinoline rings are packed in a π···π stacked arrangement, whose contribution to the interaction energy is very low in the crystal and completely overwhelmed by Coulomb repulsion between positive aromatic rings. This questions the ability of CQ in setting up similar stacking interactions with the positively charged Fe-protoporphyrin moiety of the heme substrate in solution. When the heme/CQ adduct incorporates a Fe–N coordinative bond, stronger π···π interactions are instead established due to the lacking of net electrostatic repulsions. Yet, CAHBs among the protonated tertiary amine of CQ and the propionate group of heme still provide the leading stabilizing effect. Implications on possible modifications/improvements of the CQ pharmacophore are discussed

Atomistic Explanation for Interlayer Charge Transfer in Metal–Semiconductor Nanocomposites: The Case of Silver and Anatase

A concerted theoretical and experimental investigation of the silver/anatase hybrid nanocomposite, a very promising material for advanced sensing applications, is presented. We measure its exceptional electrochemical virtues in terms of current densities and reproducibility, providing their explanation at the atomic-scale level and demonstrating how and why silver acts as a positive electrode. Using periodic plane-wave DFT calculations, we estimate the overall amount of electron transfer toward the semiconductor side of the interface at equilibrium. Suitably designed (photo)­electrochemical experiments strictly agree, both qualitatively and quantitatively, with the theoretical charge transfer estimates. The unique permanent charge separation occurring in the device is possible because of the favorable synergy of Ag and TiO₂, which exploits in a favorable band alignment, while the electron–hole recombination rate and carrier mobility decrease when electrons cross the metal–semiconductor interface. Finally, the hybrid material is proven to be extremely robust against aging, showing complete regeneration, even after 1 year

Design and synthesis of constrained bicyclic molecules as candidate inhibitors of influenza A neuraminidase

<div><p>The rise of drug-resistant influenza A virus strains motivates the development of new antiviral drugs, with different structural motifs and substitution. Recently, we explored the use of a bicyclic (bicyclo[3.1.0]hexane) analogue of sialic acid that was designed to mimic the conformation adopted during enzymatic cleavage within the neuraminidase (NA; sialidase) active site. Given that our first series of compounds were at least four orders of magnitude less active than available drugs, we hypothesized that the new carbon skeleton did not elicit the same interactions as the cyclohexene frameworks used previously. Herein, we tried to address this critical point with the aid of molecular modeling and we proposed new structures with different functionalization, such as the introduction of free ammonium and guanidinium groups and ether side chains other than the 3-pentyl side chain, the characteristic side chain in Oseltamivir. A highly simplified synthetic route was developed, starting from the cyclopropanation of cyclopentenone and followed by an aziridination and further functionalization of the five-member ring. This allowed the efficient preparation of a small library of new bicyclic ligands that were characterized by enzyme inhibition assays against influenza A neuraminidases N1, its H274Y mutant, and N2. The results show that none of the new structural variants synthesized, including those containing guanidinium groups rather than free ammonium ions, displayed activity against influenza A neuraminidases at concentrations less than 2 mM. We conclude that the choice and positioning of functional groups on the bicyclo[3.1.0]hexyl system still need to be properly tuned for producing complementary interactions within the catalytic site.</p></div

Asymmetric Modular Synthesis of a Semirigid Dipeptide Mimetic by Cascade Cycloaddition/Ring Rearrangement and Borohydride Reduction

A new semirigid dipeptide mimetic was prepared on multigram scale, in good yield, and in a stereocontrolled way, starting from commercially available and unexpensive reagents, i.e.,<i> N</i>-benzylpiperidone, tosyl azide, and proline methyl ester. The optimized multicomponent process consisted of a cascade click cycloaddition and a ring rearrangement reaction, followed by a reductive step. Theoretical calculations were performed to elucidate the reaction mechanism and support the stereochemical outcome of the reduction. Finally, the new scaffold was used for the preparation of model peptidomimetics, whose β turn conformation was confirmed by dynamic NMR experiments

Synthesis of the key aziridine intermediate 12 and aziridine opening reaction.

<p>Synthesis of the key aziridine intermediate 12 and aziridine opening reaction.</p

Induced fit docking of ligand 4a (R = 4-phenylbenzyl) with N1 neuraminidase (source: pdb 2HU0).

<p>Induced fit docking of ligand 4a (R = 4-phenylbenzyl) with N1 neuraminidase (source: pdb 2HU0).</p

Control experiments with known NAIs.

<p><i>K</i>_i was determined for N1 wild-type andH274Y (both from virus A/Anhui/1/2005 H5N1) and N2 (A/Chicken/HongKong/G9/1997 H9N2).</p