Computational Insight into the Mechanism of Ruthenium(II)-Catalyzed α-Alkylation of Arylmethyl Nitriles Using Alcohols.

The ruthenium(II)-catalyzed α-alkylation reaction of arylmethyl nitriles (phenylacetonitrile) using alcohols (ethanol) in toluene has been extensively investigated by means of SMD-M06-2X/6-311G(d,p)-LANL2dz (LAnL2dz for Ru, 6-311G(d,p) for other atoms) calculations. Detailed mechanistic schemes have been proposed and discussed. The catalytically active Ru(II) complex was generated by the base-induced KCl elimination from the catalyst precursor [(PNPPh)RuHCl(CO)]. The overall Ru(II) catalytic cycle consists of three basic processes: (1) ethanol-to-aldehyde transformation catalyzed by the 16-electron unsaturated ruthenium pincer catalyst; (2) a 16-electron unsaturated ruthenium pincer catalyst catalyzed condensation reaction of arylmethyl nitrile with aldehyde, which leads to PhC(CN)=CHCH3; (3) hydrogenation of PhC(CN)=CHCH3, which leads to the formation of the α-alkylated arylmethyl nitrile product (PhCH(CH2CH3)CN). The DFT results revealed that the rate-determining barrier of the overall reaction was 23.9 kcal/mol of the H-transfer step in the third process. The reaction of PhC(CN)=CHCH3 with the dihydride Ru complex, which is generated in the ethanol-to-aldehyde transformation process, is the more preferable hydrogenation mechanism than hydrogenation of vinyl nitrile-Ru complex by H2. Using alcohol as the reactant not only fulfills the requirement of the borrowing-H strategy but also lowers the barriers of the H-migration steps.

Electroacupuncture pretreatment induces rapid tolerance to bupivacaine cardiotoxicity in rats.

BACKGROUND: Evidence suggests that electroacupuncture (EA) protects against arrhythmia and myocardial injury induced by myocardial ischaemia-reperfusion. However, to our knowledge, it remains unknown whether EA could alleviate bupivacaine-induced cardiotoxicity. Therefore, we aimed to explore the effect of EA pretreatment on bupivacaine-induced cardiac arrest and outcomes of cardiopulmonary resuscitation (CPR) in rats. METHODS: 24 adult male Sprague-Dawley rats were randomly divided into two groups: EA (n=12), and minimal acupuncture (MA) (n=12). Rats in both groups were needled at bilateral PC6, ST36, and ST40. Needles in the EA group were electrically stimulated for 60 min. ECG and invasive arterial blood pressure measurements were recorded. Two hours after EA or MA, 10 mg/kg bupivacaine was infused intravenously at a rate of 5 mg/kg/min in all rats. Rats suffering cardiac arrest were immediately subjected to CPR. At the end of the experiment, arterial blood samples were taken from surviving rats for blood gas analysis. RESULTS: The time from bupivacaine infusion until 20% prolongation of the QRS and QT interval, and the time to cardiac arrest, were notably increased among the rats pretreated with EA. Moreover, EA pretreatment significantly improved mean arterial pressure and heart rate at all monitored points after bupivacaine infusion. The proportion of animals surviving was higher in the EA group (9/12) than the MA group (3/12) at the end of experiment (p=0.039). CONCLUSIONS: Tolerance to bupivacaine-induced cardiotoxicity appeared to be increased following EA pre-treatment. The mechanism of action underlying the effects of EA on bupivacaine-induced cardiotoxicity requires further investigation.