No abstract

On the basis of the strategy of promoting thermostability of α-diimine nickel catalyst by ligand backbone framework, a series of α-diimine nickel(II) complexes with bulky camphyl or diaryl-substituted backbones, [2,6-(R2)2C6H3−NC(R1)−C(R1)N−2,6-(R2)2C6H3]NiBr2 (1a, R1 = Ph, R2 = CH3; 2a, R1 = 4-methylphenyl, R2 = CH3; 3a, R1 = 4-fluorophenyl, R2 = CH3; 4a, R1 = camphyl, R2 = CH3; 4b, R1 = camphyl, R2 = i-Pr), were synthesized and used as catalyst precursors for ethylene polymerization. Crystallographic analysis revealed that the bulky camphyl backbone has a valid steric-effect on the nickel center by blocking the axial site for the metal center and suppressing the potential rotation of the CAr−N bond. Ethylene polymerizations catalyzed by these nickel α-diimine complexes activated by MAO were systematically investigated and the influences of the substituted backbones as well as reaction temperature on the catalytic activity, molecular weight and branching structure of the polymers were evaluated. It was found that the catalysts containing a camphyl backbone have excellent thermal stability and polymer structure control for ethylene polymerizations. Even at 80 °C, the 4b/MAO system still kept high activity and relatively stable kinetics and produced high molecular weight polyethylene. Moreover, the branching degrees and branched chain distribution of the polyethylenes obtained by the complex could also be controlled by tuning the reaction temperature.

Development of thermally stable nickel-based catalysts is highly desirable for industrial gas-phase olefin polymerizations. On the basis of the strategy of promoting the thermostability of nickel catalyst by the ligand backbone, we herein reported novel dibenzobarrelene-derived α-diimine nickel precatalysts for ethylene polymerization. Increasing the steric bulk on the ligand backbone was expected to inhibit the N-aryl rotation of the α-diimine ligands by the repulsive interactions, thus enhancing thermal stability (100 °C) and living fashion a temperatures up to 80 °C. Bulk ligand backbone also improved tolerance of nickel catalyst toward polar groups, and the α-diimine nickel catalyst containing a 2,6-t Bu-dibenzobarrelene backbone catalyzed living copolymerization of ethylene and methyl 10-undecenoate.

Conformational dynamics plays an important role in enzyme catalysis, allosteric regulation of protein functions and assembly of macromolecular complexes. Despite these well-established roles, such information has yet to be exploited for drug design. Here we show by nuclear magnetic resonance spectroscopy that inhibitors of LpxC—an essential enzyme of the lipid A biosynthetic pathway in Gram-negative bacteria and a validated novel antibiotic target—access alternative, minor population states in solution in addition to the ligand conformation observed in crystal structures. These conformations collectively delineate an inhibitor envelope that is invisible to crystallography, but is dynamically accessible by small molecules in solution. Drug design exploiting such a hidden inhibitor envelope has led to the development of potent antibiotics with inhibition constants in the single-digit picomolar range. The principle of the cryptic inhibitor envelope approach may be broadly applicable to other lead optimization campaigns to yield improved therapeutics.