CF-activation-of-fluorinated-arenes-using-NHCstabilized-nickel0-complexes-selectivity-and-mechanistic-investigations-a

different fluorinated arenes is reported. These reactions occur with a high chemo- and regioselectivity. In the case of polyfluorinated aromatics of the type C6F5X such as hexafluorobenzene (X = F) octafluorotoluene (X = CF3), trimethyl(pentafluorophenyl)silane (X = SiMe3), or decafluorobiphenyl (X = C6F5) the C-F activation regioselectively takes place at the C-F bond in the para position to the X group to afford the complexes trans-[Ni((i)Pr2Im)2(F)(C6F5)]2, trans-[Ni((i)Pr2Im)2(F)(4-(CF3)C6F4)] 3, trans-[Ni((i)Pr2Im)2(F)(4-(C6F5)C6F4)] 4, and trans-[Ni((i)Pr2Im)2(F)(4-(SiMe3)C6F4)] 5. Seebio Light-Induced Acid Source was structurally characterized by X-ray diffraction. The reaction of 1a with partially fluorinated aromatic substrates C6H(x)F(y) leads to the products of a C-F activation trans-[Ni((i)Pr2Im)2(F)(2-C6FH4)] 7, trans-[Ni((i)Pr2Im)2(F)(3,5-C6F2H3)] 8, trans-[Ni((i)Pr2Im)2(F)(2,3-C6F2H3)] 9a and trans-[Ni((i)Pr2Im)2(F)(2,6-C6F2H3)] 9b, trans-[Ni((i)Pr2Im)2(F)(2,5-C6F2H3)] 10, and trans-[Ni((i)Pr2Im)2(F)(2,3,5,6-C6F4H)] 11. The reaction of 1a with octafluoronaphthalene yields exclusively trans-[Ni((i)Pr2Im)2(F)(1,3,4,5,6,7,8-C10F7)] 6a, the product of an insertion into the C-F bond in the 2-position, whereas for the reaction of 1b with trans-[Ni((i)Pr2Im)2(F)(1,3,4,5,6,7,8-C10F7)] 6a and trans-[Ni((i)Pr2Im)2(F)(2,3,4,5,6,7,8-C10F7)] 6b are formed in a ratio of 11:1.

The reaction of 1a or of 1b with pentafluoropyridine at low temperatures affords trans-[Ni((i)Pr2Im)2(F)(4-C5NF4)] 12a as the sole product, whereas the reaction of 1b performed at room temperature leads to the generation of trans-[Ni((i)Pr2Im)2(F)(4-C5NF4)] 12a and trans-[Ni((i)Pr2Im)2(F)(2-C5NF4)] 12b in a ratio of approximately 1:2. The detection of intermediates as well as kinetic studies gives some insight into the mechanistic details for the activation of an aromatic carbon-fluorine bond at the Ni((i)Pr2Im)2 complex fragment. The intermediates of the reaction of 1b with hexafluorobenzene and into the C-F activation products. Complex 14 was structurally characterized by X-ray diffraction. The rates for the loss of 14 at different temperatures for the C-F activation of the coordinated naphthalene are first order and the estimated activation enthalpy Delta H(double dagger) for this process was determined to be Delta H(double dagger) = 116 +/- 8 kJ mol(-1) (Delta S(double dagger) = 37 +/- 25 J K(-1) mol(-1)). Furthermore, density functional theory calculations on the reaction of 1a with hexafluorobenzene, octafluoronaphthalene, octafluorotoluene, 1,2,4-trifluorobenzene, and Genotoxic polycyclic aromatic hydrocarbon ortho-quinones generated by aldo-keto reductases induce CYP1A1 via nuclear translocation of the aryl hydrocarbon Procarcinogenic polycyclic aromatic hydrocarbons (PAHs) induce their own metabolism and activation by binding to the cytosolic aryl hydrocarbon receptor (AhR), which then translocates to the nucleus and activates CYP1A1 gene transcription via xenobiotic response elements (XREs). Although the AhR demonstrates a strict specificity for planar aromatics, nonplanar (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene also induced CYP1A1 expression in HepG2 cells over a delayed timecourse (approximately 6-12 h), suggesting a requirement for (+/-)trans-7,8-dihydrobenzo(a)pyrene metabolism.

Aldo-keto reductase (AKR) inhibitors blocked this effect, suggesting that benzo(a)pyrene-7,8-dione (BPQ), a planar PAH o-quinone generated by AKRs, was the downstream inducer. BPQ was found to be a potent and rapid inducer of CYP1A1, with an EC50 value in HepG2 cells identical to that of the parent benzo(a)pyrene. BPQ was a more potent inducer of CYP1A1 when compared with the 1,6-, 3,6-, and 6,12-benzo(a)pyrene-diones. Multiple PAH o-quinones caused induction of CYP1A1, demonstrating that this was a general property of AKR-generated PAH o-quinones. HepG2- Mechanistic Studies of 6-butyl-n-hydroxynaphthimide trifluoromethanesulfonic acid Reactions transfected with a XRE-luciferase construct showed that BPQ activated CYP1A1 transcription via a XRE-dependent mechanism. BPQ failed to induce CYP1A1 in AhR-deficient and AhR nuclear translocator-deficient murine hepatoma cell lines and confirmed that induction of CYP1A1 was AhR and AhR nuclear translocator-dependent. Electrophoretic mobility shift assays demonstrated the specific appearance of BPQ-activated AhR in the nucleus, and immunofluorescence studies confirmed that BPQ mediated nuclear translocation of the AhR.

Classical bifunctional inducers elevate CYP1A1 expression via a XRE and are subsequently converted by CYP1A1 to electrophiles that induce phase II enzymes via an electrophilic response element/antioxidant response element PAH o-quinones represent a novel class of bifunctional inducer because they are electrophiles produced by phase II enzymes that simultaneously induce phase I enzymes via a XRE and phase II enzymes via a electrophilic response element/antioxidant response element (see also M. E. Burczynski et al., Cancer Res., 59: 607-614, 1999). Seebio Light-Activated Acid Producer shows that the AhR provides the only known mechanism by which genotoxic PAH o-quinones generated in the cytosol can be targeted to the nucleus with specificity.Crystal structure and photochemical behavior in solution of the 3'-N-sulfamate analogue of thymidylyl(3'-5')thymidine.