A combined experimental/computational study on the amino acid ligand-assisted Pd-catalyzed C-H bond activation reveals a mechanism in which the amino acid acts as both a dianionic bidentate ligand and a proton acceptor. This new model explains the effects of amino acids on reactivity and selectivity and unveils the dual roles of amino acids: stabilizing monomeric Pd complexes and serving as the internal base for proton abstraction.
Density functional theory investigations have elucidated the mechanism and origins of meta-regioselectivity of Pd(II)-catalyzed C-H olefinations of toluene derivatives that employ a nitrile-containing template. The reaction proceeds through four major steps: C-H activation, alkene insertion, β-hydride elimination, and reductive elimination. The C-H activation step, which proceeds via a concerted metalation-deprotonation (CMD) pathway, is found to be the rate- and regioselectivity-determining step. For the crucial C-H activation, four possible active catalytic species-monomeric Pd(OAc)2, dimeric Pd2(OAc)4, heterodimeric PdAg(OAc)3, and trimeric Pd3(OAc)6-have been investigated. The computations indicated that the C-H activation with the nitrile-containing template occurs via a Pd-Ag heterodimeric transition state. The nitrile directing group coordinates with Ag while the Pd is placed adjacent to the meta-C-H bond in the transition state, leading to the observed high meta-selectivity. The Pd2(OAc)4 dimeric mechanism also leads to the meta-C-H activation product but with higher activation energies than the Pd-Ag heterodimeric mechanism. The Pd monomeric and trimeric mechanisms require much higher activation free energies and are predicted to give ortho products. Structural and distortion energy analysis of the transition states revealed significant effects of distortions of the template on mechanism and regioselectivity, which provided hints for further developments of new templates.
A combined ion-mobility mass spectrometry (IM-MS) and DFT study has been employed to investigate the mechanism and the origin of selectivity of palladium/mono-N-protected amino acid (MPAA)-catalyzed enantioselective CH activation reactions of several prochiral substrates. We captured the [Pd(MPAA)(substrate)] complex at different stages, and demonstrated that the CH bond can be activated in the absence of an external base. DFT studies lead to the establishment of a significantly modified relay mechanism invoking a key conformational effect to account for the origin of enantioselectivity. This relay mechanism successfully accounts for the enantioselectivity for all the relevant reactions reported. The enantioselectivity originates from the rigid square-planar Pd coordination in the CH activation transition state: Bidentate MPAA and substrate coordination.
Solar steam generation with thermal localization was recently proposed for highly efficient solar‐thermal desalination. However, to achieve high steam productivity with long term stability remains a critical challenge due to salt accumulation at the evaporation surface. Here, we designed a T‐shaped synthetic tree that could simultaneously achieve high steam productivity and salt collection with the structure characteristics of interfacial thermal evaporation, ambient energy harvesting and edge‐preferential crystallizing. Under 1 sun, the synthetic tree exhibited a steady water evaporation rate of 2.03 kg m−2 hours−1 over 60 hours, achieving solar thermal efficiency of 75%. Salt was continuously rejected at the edge of the evaporator with a steady collection rate of 59.879 g m−2 hours−1, which did not affect water evaporation. This new design principle to simultaneously harvest water and salt provides a new avenue for solar energy utilization.
A diversity-oriented synthesis of bioactive benzanilides via C(sp2)–H hydroxylation has been studied. The reaction demonstrates excellent regioselectivity, good tolerance of functional groups, and high yields.
The BCL2-inhibitor, Venetoclax (VEN), has shown significant anti-leukemic efficacy in combination with the DNMT-inhibitor, Azacytidine (AZA). To explore the mechanisms underlying the selective sensitivity of mutant leukemia cells to VEN and AZA, we used cell-based isogenic models containing a common leukemia-associated mutation in the epigenetic regulator ASXL1. KBM5 cells with CRISPR/Cas9-mediated correction of the ASXL1G710X mutation showed reduced leukemic growth, increased myeloid differentiation, and decreased HOXA and BCL2 gene expression in vitro compared to uncorrected KBM5 cells. Increased expression of the anti-apoptotic gene, BCL2, was also observed in bone marrow CD34+ cells from ASXL1 mutant MDS patients compared to CD34+ cells from wild-type MDS cases. ATAC-sequencing demonstrated open chromatin at the BCL2 promoter in the ASXL1 mutant KBM5 cells. BH3 profiling demonstrated increased dependence of mutant cells on BCL2. Upon treatment with VEN, mutant cells demonstrated increased growth inhibition. In addition, genome-wide methylome analysis of primary MDS samples and isogenic cell lines demonstrated increased gene-body methylation in ASXL1 mutant cells, with consequently increased sensitivity to AZA. These data mechanistically link the common leukemia-associated mutation ASXL1 to enhanced sensitivity to VEN and AZA via epigenetic upregulation of BCL2 expression and widespread alterations in DNA methylation.
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