Above its critical aggregation concentration the tfa salt of the peptide A 6 K self-assembles into micron long, hollow nanotubes with uniform diameters of 52 nm and crystalline order. Here we combine the use of SAXS with cryoTEM and cryo-electron tomography (cryoET, 3D cryoTEM) to study the formation process of the 2D crystalline A 6 K nanotubes. This study reveals that the formation of these tubes in fact is a crystal growth process, involving different mechanisms depending on the conditions used. Inorganic crystals have been demonstrated to form not only through ion-by-ion addition but also through non-classical mechanisms including oriented attachment. Here we show an organic crystalline material that can form through molecule-by-molecule growth as well as through oriented attachment. We discuss the mechanisms in relation to the supersaturation levels of the peptide solutions and the molecular interactions between the peptide molecules in the tubular assemblies. The proposed mechanisms are supported by semi-empirical molecular orbital calculations and time resolved dissolution experiments.
The alcoholysis of cyclic meso-anhydrides catalyzed by β-amino alcohols has been investigated with DFT quantum mechanics to determine the mechanism of this reaction. Both nucleophilic catalysis and general base catalysis pathways are explored for methanol-induced ring opening of an anhydride catalyzed by a chiral amino alcohol. The nucleophilic pathway involves a late transition state with a high energy barrier. In this mechanism, methanolysis is expected to take place following the amine-induced ring opening of the anhydride. In the base-catalyzed mechanism, methanol attack on one carbonyl group of the meso-anhydride is assisted by the β-amino alcohol; the amine functionality abstracts the methanol proton. The chiral amino alcohol also catalyzes the reaction by stabilizing the oxyanion that forms upon ring opening of the anhydride by hydrogen bonding with its alcoholic moiety. Both stepwise and concerted pathways have been studied for the general base catalysis route. Transition structures for both are found to be lower in energy than in the nucleophilic mechanism. Overall this study has shed light on the mechanism of the β-amino alcohol-catalyzed alcoholysis of cyclic meso-anhydrides, showing that the nucleophilic pathway is approximately 100 kJ mol−1 higher in energy than the general base pathway.
Remarkable progress in the area of asymmetric organocatalysis has been achieved in the last decades. Cinchona alkaloids and their derivatives have emerged as powerful organocatalysts owing to their reactivities leading to high enantioselectivities. The widespread usage of cinchona alkaloids has been attributed to their nontoxicity, ease of use, stability, cost effectiveness, recyclability, and practical utilization in industry. The presence of tunable functional groups enables cinchona alkaloids to catalyze a broad range of reactions. Excellent experimental studies have extensively contributed to this field, and highly selective reactions were catalyzed by cinchona alkaloids and their derivatives. Computational modeling has helped elucidate the mechanistic aspects of cinchona alkaloid catalyzed reactions as well as the origins of the selectivity they induce. These studies have complemented experimental work for the design of more efficient catalysts. This Account presents recent computational studies on cinchona alkaloid catalyzed organic reactions and the theoretical rationalizations behind their effectiveness and ability to induce selectivity. Valuable efforts to investigate the mechanisms of reactions catalyzed by cinchona alkaloids and the key aspects of the catalytic activity of cinchona alkaloids in reactions ranging from pharmaceutical to industrial applications are summarized. Quantum mechanics, particularly density functional theory (DFT), and molecular mechanics, including ONIOM, were used to rationalize experimental findings by providing mechanistic insights into reaction mechanisms. B3LYP with modest basis sets has been used in most of the studies; nonetheless, the energetics have been corrected with higher basis sets as well as functionals parametrized to include dispersion M05-2X, M06-2X, and M06-L and functionals with dispersion corrections. Since cinchona alkaloids catalyze reactions by forming complexes with substrates via hydrogen bonds and long-range interactions, the use of split valence triple-ζ basis sets including diffuse and polarization functions on heavy atoms and polarization functions on hydrogens are recommended. Most of the studies have used the continuum-based models to mimic the condensed phase in which organocatalysts function; in some cases, explicit solvation was shown to yield better quantitative agreement with experimental findings. The conformational behavior of cinchona alkaloids is also highlighted as it is expected to shed light on the origin of selectivity and pave the way to a comprehensive understanding of the catalytic mechanism. The ultimate goal of this Account is to provide an up-to-date overlook on cinchona alkaloid catalyzed chemistry and provide insight for future studies in both experimental and theoretical fields.
The asymmetric desymmetrization of meso‐cyclic anhydrides catalyzed by the pseudoenantiomeric pairs of cinchona alkaloids, quinine (QN) and quinidine (QD), has been subjected to a computational study employing density functional theory (DFT) to understand the origin of the experimentally observed stereoselectivity. The spatial placement of the catalyst with respect to the anhydride, which resembles a molecular tweezer, was found to be the primary reason for the stabilization of the oxyanion forming in the transition states, as well as the oxyanion intermediate observed along the reaction coordinate. The distortion–interaction model has been employed to rationalize the experimentally observed enantiomeric ratios. The assistance of solvent molecules was essential in the prediction of experimental enantioselectivities.
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