Medium Effects on the 1,3-Dipolar Cycloaddition of Pyridazinium Dicyanomethanide with Ethyl Vinyl Ketone in Pure and Mixed Solvents from QM/MM Simulations

The 1,3-dipolar cycloaddition reaction between pyridazinium dicyanomethanide <b>1</b> and ethyl vinyl ketone (EVK) has been reported to be a concerted mechanism based on gas-phase ab initio calculations. Our current investigation of this 1,3-dipolar cycloaddition reaction in water, methanol, acetonitrile, H₂O–CH₃CN, and CH₃OH–CH₃CN mixtures using novel two-dimensional potentials of mean force (2-D PMF) calculations coupled to QM/MM simulations predicts an alternative free energy surface that supports a stepwise mechanism. The results for the kinetic effect are uniformly in close accord with experimental data and reflect a trigger point for the exponential rate rise in water–acetonitrile mixture. When methanol replaced water, the rate enhancements are more gradual, and there is no trigger point. Calculations in pure solvents and their mixtures at 25 °C and with pure water and acetonitrile at 37 °C indicate that the secondary bridging H-bonding from the first water molecules is necessary for the exponential rate enhancements, which is strong supported by the experimental results. This work provides new insight into solvent effects on 1,3-dipolar cycloaddition reaction

Computational Mechanism Study of Catalyst-Dependent Competitive 1,2-C→C, −O→C, and −N→C Migrations from β‑Methylene-β-silyloxy-β-amido-α-diazoacetate: Insight into the Origins of Chemoselectivity

Doyle et al. [J. Am. Chem. Soc. 2013, 135, 1244−1247] recently reported an efficient catalyst-controlled chemoselectivity of competitive 1,2-C→C, −O→C, and −N→C migrations from β-methylene-β-silyloxy-β-amido-α-diazoacetates using dirhodium or copper catalysts. With the aid of density functional theory calculations, the present study systematically probed the mechanism of the aforementioned reactions and the origins of the catalyst-controlled chemoselectivity. Similar to the method reported in the literature, simplified catalyst models Rh₂(O₂CH)₄ and Rh₂(<i>N</i>-methylformamide)₄ have been used in our initial calculations. However, using the Rh₂(O₂CH)₄ model could not describe the energies of all possible pathways, and high selectivity of three competitive migrations could not be achieved. In order to appropriately describe this 1,2-migration system, real catalyst models Rh₂(cap)₄, Rh₂(esp)₂, and CuPF₆ have been employed. It was found that the steric and electronic effects of ligands significantly influence the free energy barrier, which ultimately changes the chemoselectivity. In the CuPF₆ system, the electronic effects, coupled with the steric factor, give a qualitative explanation for the exclusive chemoselectivity of 1,2-N→C migration over 1,2-C→C or −O→C migration. On the other hand, the bulky ligands of dirhodium catalysts result in the significant steric hindrance around the dirhodium centers and withdrawal of the empty space around the bulky −OTBS group. By analyzing the divergence of three different migration transition states using the distortion/interaction and natural bond orbital analyses, it was found that the 1,2-N→C migration will suffer from a high free energy barrier because of the steric repulsion between the carbonyl group and the carbonyl oxygen of the pyrazolidinone ring. For 1,2-C→C and −O→C migrations, changing the ligands of dirhodium catalysts can change the electronic properties of carbenes, and that is the reason for controlling the major product by changing the dirhodium catalysts. The mechanistic proposal is supported by the calculated chemoselectivities, which are in good agreement with the experimental results

Supplemental Material - Does Long-Term Shift Work Increase the Risk of Dementia? A Systematic Review and Meta-Analysis

Supplemental Material for Does Long-Term Shift Work Increase the Risk of Dementia? A Systematic Review and Meta-Analysis by Yang Hai, Ying Xue, and Yu-hong Wang in American Journal of Alzheimer's Disease & Other Dementias®</p

Microsolvated Model for the Kinetics and Thermodynamics of Glycosidic Bond Dissociative Cleavage of Nucleoside D4G

Using the microsolvated model that involves explicit water molecules and implicit solvent in the optimization, two proposed dissociative hydrolysis mechanisms of 2′,3′-didehydro-2′,3′-dideoxyguanosine (d4G) have been first investigated by means of M06-2X­(CPCM, water)/6-31++G­(d,p) method. The glycosidic bond dissociation for the generation of the oxacarbenium ion intermediate is the rate-determining step (RDS). The subsequent nucleophilic water attack from different side of the oxacarbenium ion intermediate gives either the α-product [(2<i>S</i>,5<i>S</i>)-5-(hydroxymethyl)-2,5-dihydrofuran-2-ol] or β-product [(2<i>R</i>,5<i>S</i>)-5-(hydroxymethyl)-2,5-dihydrofuran-2-ol] and is thus referred to as α-path (inversion) and β-path (retention). Two to five explicit water molecules (<i>n</i> = 2–5) are considered in the microsolvated model, and <i>n</i> = 3 or 4 is the smallest model capable of minimizing the activation energy for α-path and β-path, respectively. Our theoretical results suggest that α-path (<i>n</i> = 3) is more kinetically favorable with lower free energy barrier (RDS) of 27.7 kcal mol^–1, in contrast to that of 30.7 kcal mol^–1 for the β-path (<i>n</i> = 4). The kinetic preference of the α-path is rationalized by NBO analysis. Whereas thte β-path is more thermodynamically favorable over the α-path, where the formation of β-product and α-product are exergonic and endergonic, respectively, providing theoretical support for the experimental observation that the β-cleavage product was the major one after sufficient reaction time. Comparisons of d4G with analogous cyclo-d4G and dG from kinetic free energy barriers and thermodynamic heterolytic dissociation energies were also carried out. Our kinetic and thermodynamic results manifest that the order of glycosidic bond stability should be d4G < cyclo-d4G < dG, which agrees well with the reported experimental stability order of d4G compounds and analogues and gives further understanding on the influence of 6-cyclopropylamino and unsaturated ribose to the glycosidic bond instability of d4G

JSDM models

The file can be read in R, including the full structure of the fitted models, BaysComm, Boral, Mistnet, HMSC, and Gjam

Observation data for modelling

The file is in a form of R data, including all data used to fit the JSDMs, that is ,the biomass of multispecies and environmental variables of water temperature, salinity and depth

Epidemics and Frequent Recombination within Species in Outbreaks of Human Enterovirus B-Associated Hand, Foot and Mouth Disease in Shandong China in 2010 and 2011

<div><p>The epidemiology and molecular characteristics of human enterovirus B (HEV-B) associated with hand, foot and mouth disease (HFMD) outbreaks in China are not well known. In the present study, we tested 201 HEV isolates from 233 clinical specimens from patients with severe HFMD during 2010–2011 in Linyi, Shandong, China. Of the 201 isolates, 189 were fully typed and 18 corresponded to HEV-B species (six serotypes CVA9, CVB1, CVB4, Echo 6, Echo 25 and Echo 30) using sensitive semi-nested polymerase chain reaction analysis of VP1 gene sequences. Phylogenetic analysis based on the VP1 region showed that eight E30SD belonged to a novel sub-genogroup D2; E25SD belonged to a novel sub-genogroup D6; E6SD belonged to sub-lineage C6 and five CVB1SD belonged to subgroup 4C; and B4SD belonged sub-lineage D2. The full viral genomes of the CVB1SD, E6SD, E25SD and E30SD isolates were sequenced. Analysis of phylogenetic and similarity plots indicated that E25SD recombined with E25-HN-2, E30FDJS03 and E4AUS250 at noncontiguous P2A–P3D regions, while E30SD, E30FDJ03, E25-HN-2 and E9 DM had shared sequences in discrete regions of P2 and P3. Both E6SD and B1SD shared sequences with E1-HN, B4/GX/10, B5-HN, and A9-Alberta in contiguous regions of most of P2 and P3. Genetic algorithm recombination detection analysis further confirmed the existence of multiple potential recombination points. In conclusion, analysis of the complete genomes of E25SD, E30SD, CVB1SD and E6SD isolated from HFMD patients revealed that they formed novel subgenogroup. Given the prevalence and recombination of these viruses in outbreaks of HFMD, persistent surveillance of HFMD-associated HEV-B pathogens is required to predict potential emerging viruses and related disease outbreaks.</p></div

Phylogeny of E6 based on 875 nucleotides of the VP1 gene generated by the neighbor-joining algorithm implemented in MEGA (version 5.0) software using the Kimura 2-parameter substitution model and 1000 bootstrap pseudo-replicates.

<p>•Strains isolated in this investigation. ♦Strains isolated from Shandong. ○Strains isolated from other provinces of China.</p

Distribution of human echovirus serotypes from hospitalized HFMD cases in Linyi, China, 2010–211.

<p>Percentage of each serotype among total isolates for each year. (a) HEV in 2010; (b) HEV in 2011. Echo, Echovirus; CAV, Coxsackievirus A; CBV, Coxsackievirus B.</p

Phylogeny of CVB1 based on 475 nucleotides of the VP1 gene generated by the neighbor-joining algorithm implemented in MEGA (version 5.0) software using the Kimura 2-parameter substitution model and 1000 bootstrap pseudo-replicates.

<p>•Strains isolated in this investigation. ♦Strains isolated from Shandong. ○Strains isolated from other provinces of China.</p