bond rotation
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A novel series of naphthalene derivatives were designed and synthesized based on the strategy focusing on the restriction of the flexible bond rotation of OX2R selective agonist YNT-185 (1) and their agonist activities against orexin receptors were evaluated. The 1,7-naphthalene derivatives showed superior agonist activity than 2,7-naphthalene derivatives, suggesting that the bent form of 1 would be favorable for the agonist activity. The conformational analysis of 1,7-naphthalene derivatives indicated that the twisting of the amide unit out from the naphthalene plane is important for the enhancement of activity. The introduction of a methyl group on the 2-position of 1,7-naphthalene ring effectively increased the activity, which led to the discovery of the potent OX2R agonist 28c (EC50 = 9.21 nM for OX2R, 148 nM for OX1R). The structure-activity relationship results were well supported by a comparison of the docking simulation results of the most potent derivative 28c with an active state of agonist-bound OX2R cryo-EM SPA structure. These results suggested important information for understanding the active conformation and orientation of pharmacophores in the orexin receptor agonists, which is expected as a chemotherapeutic agent for the treatment of narcolepsy.

Typical photowitches interconvert between two different states by simple isomerization reactions, which represents a fundamental limit for applications. To expand the switching capacity usually different photoswitches have to be linked together leading to strong increase in molecular weight, diminished switching function, and less precision and selectivity of switching events. Herein we present an approach for solving this essential problem with a different photoswitching concept. A basic molecular switch architecture provides precision photoswitching between eight different states via controlled rotations around three adjacent covalent bonds. All eight states can be populated one after another in an eight-step cycle by alternating between photochemical Hula-Twist isomerizations and thermal single bond rotations. By simply changing solvent and temperature the same switch can also undergo a different cycle instead interconverting just five isomers in a selective sequence. This behavior is enabled through the discovery of an unprecedented photoreaction, a one photon dual single bond rotation.

Regularly dressing of CBN honing wheel is an effective way to keep its sharpness and correct geometry during honing process. This study aims to understand the fracture mechanism of single CBN grain in the dressing process of honing wheel. The honing wheel dressing process was simplified into the dressing process of grinding wheel, and the bond-based Peridynamic method considering bond rotation effect was developed to investigate the progressive fracture evolution, stress characteristics, and fracture modes of CBN grains in this process. It was found that fracture evolution of CBN grains mainly underwent four stages: elastic deformation, damage initiation, crack formation, and macro fracture. In addition, the fracture initiation and propagation were mainly determined by the tensile and shear stress, where the former led to mode I fractures and the latter led to mode II fractures. The propagation of mode I fractures was stable while the propagation of mode II fracture was unstable. The results show that the Peridynamic approach has great potential to predict the fracture mechanism of CBN grain in the dressing process of honing and grinding wheels.

The de novo computational design of proteins with predefined three-dimensional structure is becoming much more routine due to advancements both in force fields and algorithms. However, creating designs with functions beyond folding is more challenging. In that regard, the recent design of small beta barrel proteins that activate the fluorescence of an exogenous small molecule chromophore (DFHBI) is noteworthy. These proteins, termed mini Fluorescence Activating Proteins (mFAPs), have been shown increase the brightness of the chromophore more than 100-fold upon binding to the designed ligand pocket. The design process created a large library of variants with different brightness levels but gave no rational explanation for why one variant was brighter than another. Here we use quantum mechanics and molecular dynamics simulations to investigate how molecular flexibility in the ground and excited states influences brightness. We show that the ability of the protein to resist dihedral angle rotation of the chromophore is critical for predicting brightness. Our simulations suggest that the mFAP/DFHBI complex has a rough energy landscape, requiring extensive ground-state sampling to achieve converged predictions of excited-state kinetics. While computationally demanding, this roughness suggests that mFAP protein function can be enhanced by reshaping the energy landscape towards states that better resist DFHBI bond rotation.

The experimentally motivated question of the acetylene bromoboration mechanism was addressed in order to suggest possible radical isomerization pathways for the syn-adduct. Addition–elimination mechanisms starting with a bromine radical attack at the “bromine end” or the “boron end” of the C=C bond were considered. Dispersion-corrected DFT and MP2 methods with the SMD solvation model were employed using three all-electron bases as well as the ECP28MWB ansatz. The rate-determining, elimination step had a higher activation energy (12 kcal mol−1) in case of the “bromine end” attack due to intermediate stabilization at both the MP2 and DFT levels. In case of the “boron end” attack, two modes of C–C bond rotation were followed and striking differences in MP2 vs. DFT potential energy surfaces were observed. Employing MP2, addition was followed by either a 180° rotation through an eclipsed conformation of vicinal bromine atoms or by an opposite rotation avoiding that conformation, with 5 kcal mol−1 of elimination activation energy. Within B3LYP, the addition and rotation proceeded simultaneously, with a 9 (7) kcal mol−1 barrier for rotation involving (avoiding) eclipsed conformation of vicinal bromines. For weakly bound complexes, ZPE corrections with MP2 revealed significant artifacts when diffuse bases were included, which must be considered in the Gibbs free energy profile interpretation.

Medium-sized benzo-fused N-heterocycles – a core structure in several important pharmaceuticals – have a diverse range of interesting conformational and stereochemical properties which arise from restricted bond rotation in the...

Herein, the chemoselectivity of the multicomponent domino Knoevenagel/Diels-Alder reaction is investigated in terms of theoretical calculations. Structures of reagents, transition states, intermediates and products are optimized at the M062X/6-31+G(d,p) level of theory. The reaction mechanism involves processes of bond rotation, isomerization, asymmetric cycloaddition, acid-base and nucleophile-electrophile competitions, which are studied to deliver a clear information of the mechanism in terms of chemoselectivity considerations. Accordingly, the chemoselectivity of the reaction is controlled by the releasing acetone during the decomposition of Meldrum acid in the presence of methanol and L-proline (DG# = 61.45 kcal mol-1). Comparing calculated results (gas and solvent phase) with the experimental ones showed that utilizing these reagents are the kinetical favorite path for the chemoselective multicomponent cascade Knoevenagel/Diels-Alder reaction to produce the predominant product (>95 %). The results suggest that the creation of cis-spiro cyclohexanone is the predominant chemoselective product under kinetic control of the desired enone.

AbstractExcited-state intramolecular proton transfers (ESIPT) are one of the fastest reactions in chemistry (<100 fs) which – among other features like high photostability – makes them an important reaction class for molecular switches. ESIPTs can be coupled with double bond rotation/isomerization, so that molecules can act as “molecular cranes”, facilitating long-range proton transfer. A versatile model system is 7-hydroxy-4-methylquinoline-8-carbaldehyde (HMQCA): it features two proton-accepting sites, two stable ground-state isomers and should allow for easy derivatization. There is also experimental and theoretical reference data available, however, only for static properties, e.g. ground-state IR spectra or potential energy surface scans. In this contribution we show the results of full-dimensional surface-hopping molecular dynamics (MD) of HMQCA after photo-excitation, employing semiempirical quantum mechanics coupled to floating-occupation configuration interaction. The results support the potential of HMQCA as prototype system for directed proton transport by ESIPT.