SUMMARY Activation of AMP-activated protein kinase (AMPK) is thought to convey many of the beneficial effects of exercise via its inhibitory effect on acetyl-CoA carboxylase 2 (ACC2) and promotion of fatty acid oxidation. Hence, AMPK and ACC have become major drug targets for weight loss and improved insulin action. However, it remains unclear if or how activation of the fatty acid oxidation pathway without a concomitant increase in energy expenditure could be beneficial. In this study we have used either pharmacological (administration of the AMPK agonist 5′ aminoimidazole-4-carboxamide-riboside (AICAR)) or genetic means (mutation of the ACC2 gene in mice) to manipulate fatty acid oxidation to determine if this is sufficient to promote leanness. Both of these strategies increased whole body fatty acid oxidation without altering energy expenditure or adiposity. We conclude that negative energy balance is a pre-requisite for weight reduction and increased fatty acid oxidation per se has little, if any, effect to reduce adiposity.

Gas-phase photoelectron spectroscopy and density functional theory have been used to investigate the interactions between the sulfur -orbitals of arene dithiolates and high-valent transition metals as minimum molecular models of the active site features of pyranopterin Mo͞W enzymes. The compounds (Tp*)MoO(bdt) (compound 1), Cp 2Mo(bdt) (compound 2), and Cp 2Ti(bdt) (compound 3) [where Tp* is hydrotris(3,5-dimethyl-1-pyrazolyl)borate, bdt is 1,2-benzenedithiolate, and Cp is 5 -cyclopentadienyl] provide access to three different electronic configurations of the metal, formally d 1 , d 2 , and d 0 , respectively. The gas-phase photoelectron spectra show that ionizations from occupied metal and sulfur based valence orbitals are more clearly observed in compounds 2 and 3 than in compound 1. The observed ionization energies and characters compare very well with those calculated by density functional theory. A ''dithiolate-folding-effect'' involving an interaction of the metal in-plane and sulfur-orbitals is proposed to be a factor in the electron transfer reactions that regenerate the active sites of molybdenum and tungsten enzymes. C oordination by the sulfur atoms of one or two ene-1,2-dithiolate (dithiolene) ligands of the novel substituted pyranopterin-dithiolate (''molybdopterin''; ref. 1) is a common structural feature of mononuclear molybdenum-containing enzymes (2-4). These enzymes catalyze a wide range of oxidation͞reduction reactions in carbon, sulfur, and nitrogen metabolism. Fig. 1 shows the structure of the active site of sulfite oxidase, a representative example (5, 6) of the coordination of the pyranopterin-dithiolate (hereafter abbreviated S 2 pdt; ref. 7). These structural results raise fundamental questions about the role of the S 2 pdt coordination in the overall catalytic cycle of molybdenum enzymes (8). The unusual ability of ene-1,2-dithiolate ligands to stabilize metals in multiple oxidation states has been recognized since the compounds were first investigated (9). Proposed roles for the S 2 pdt ligand include functioning as an electron transfer conduit from the metal to other prosthetic groups (10) and as a modulator of the oxidation͞reduction potential of the metal site (10). During catalysis, the metal center is proposed to pass through the M(VI͞V͞IV) oxidation states, i.e., the Mo d electron count changes from d 0 to d 1 to d 2 . Thus, studies of discrete metal dithiolate complexes encompassing these and related electron configurations may provide insight concerning metal thiolate bonding and reactivity in enzymes.Previous structural studies of model molybdenum complexes of the type (Tp*)MoE(1,2-dithiolate) [where E is O or NO, Tp* is hydrotris(3,5-dimethyl-1-pyrazolyl)borate, and the 1,2-dithiolates are bdt (1,2-benzenedithiolate), bdtCl 2 (3,6-dichlorobenzenedithiolate), and qdt (2,3-quinoxalinedithiolate)] have shown that the fold angle of the dithiolate metallacycle along the S⅐⅐⅐S vector (Fig. 2) varies in a way that depends on the occupation of a d orbital that is in the equatorial pl...

Schiff base ligands (L1: sulfated and L2: selenated) having a ferrocene core synthesized by reacting ferrocene-carboxaldehyde with 2-(phenylthio/seleno)ethylamine on treatment with NaPdCl in the presence of NaOAc give cyclopalladated complexes [Pd(L1/L2-H)Cl] (1/2). Complex 1 of a sulfated Schiff base L1, on reacting with one equivalent of triphenylphosphine gives complex [Pd(L1-H)PPhCl] (3), formed due to cleavage of a Pd-S bond. With 2 such a reaction does not occur, as a Pd-Se bond being stronger than that of its sulfur analogue does not get cleaved. L1, L2 and their complexes 1-3 were authenticated with HR-MS, H,C{H} and Se{H} NMR spectroscopy. The single crystal structures of 1-3 were determined with X-ray diffraction. Palladium in all three complexes has nearly a square planar geometry. The Pd-S, Pd-Se and Pd-P bond distances are 2.4249(12), 2.5058(14) and 2.2445(17) Å respectively. The catalytic activity of complexes 1-3 was explored for O-arylation of phenol and Suzuki-Miyaura coupling (SMC) of phenylboronic acid with aryl bromides and chlorides. The optimum reaction time for SMC of ArBr is 3 h whereas for ArCl it is 6 h. The TON values of O-arylation catalyzed with complexes 1-3 are up to ∼170 (TOF, 28 h) and SMC ∼9300 (TOF, 3100 h) for the reaction time of the order of 3 and 6 h respectively. The catalytic process is somewhat more efficient with 2 (Pd bonded with a selenoether group), than 3, followed by 1.

The reactions of 4-bromo-1-(2-chloroethyl)-1H-pyrazole prepared from 4-bromopyrazole with the in situ generated PhSNa, PhSeNa, Na(2)S and Na(2)Se have resulted in thio/selenoether ligands L1-L4 respectively. The complexes [PdL1/L2Cl(2)](1-2) and [PdL3/L4Cl]BF(4) (3-4) of these ligands have been synthesized by reacting them with [PdCl(2)(CH(3)CN)(2)] in CH(3)CN at 70 °C. The L1-L4 and their complexes (1-4) have been characterized with spectroscopic techniques viz.(1)H, (13)C{(1)H} and (77)Se{(1)H} NMR, IR and HR-MS. Single crystal structures of 1-4 determined by X-ray diffraction reveal nearly square planar geometry around Pd in each case. Thermally stable, moisture/air insensitive complexes 1-4 have been found to be efficient pre-catalysts for Suzuki-Miyaura coupling reactions (yield up to 96% in 2 h). Nano-particles (NPs) (size ~3-19 nm) were formed in the beginning of these reactions. They are composed of Pd and S or Se with more % of Pd. These NPs also catalyze Suzuki coupling and appear to play an important role in catalysis. Single source one pot synthesis of Pd(4)Se and PdSe NPs (size ranges ~8-26 nm), capped with trioctylphosphine (TOP), has been developed by thermolysis of 2 and 4 at 200-250 °C in TOP. HR-TEM, SEM, SEM-EDX and powder XRD have been used to authenticate these nano-particles. The NPs of PdP(2) are formed when attempts were made to prepare nano-sized phases of palladium-sulfide by thermolysis of 1 and 3 in TOP.

Three new N-alkyl-N′-(2-ethyl-1-selenophenyl)imidazolium salts, L1−L3 (differing in the chain length of alkyl substituent of N), which are precursors to (Se, C NHC ) ligands and their N-heterocyclic carbene (NHC) complexes [Pd(L-HX)Cl 2 ] (1−3) [L = L1−L3, X = I/Br], have been synthesized and characterized by multinuclear NMR and HR-MS. For the synthesis of Pd complexes 1−3 from appropriate imidazolium salts (L1−L3), the route of the silver carbene transfer reaction has been adopted. Single-crystal structures of 1 and 2 have been established with X-ray diffraction. Thermally stable, moisture-and airinsensitive complexes 1−3 have been found to be efficient catalysts for Suzuki− Miyaura coupling reactions (yield up to 96% in 2 h at 80 °C). Nanoparticles (NPs) (size of 80−85% particles ∼2−5 nm) formed in the beginning of these reactions (i.e., when the temperature of the reaction mixture reaches 80 °C) appear to be important for catalytic coupling, probably as dispensers of Pd(0), and contain Pd and Se. The Pd:Se is nearly 3:2, 4:5, and 1:1 in NPs formed from 1, 2, and 3, respectively. The catalytic activity of 3, having the longest alkyl chain containing (Se C NHC ) ligand among the three complexes, has been found to be higher relative to those of 1 and 2. The length of the alkyl chain present in the complex molecule probably controls the catalytic activity by influencing the dispersion of NPs (containing Pd and Se) generated in situ during the catalytic process. The two-phase test has indicated a homogeneous nature of catalytic process, which probably occurs via leaching of Pd(0) from these NPs. This is first example where Pd−Se NPs catalyze Suzuki coupling largely via a homogeneous process, which is probably combined with oxidative addition to Pd(0) at the surface. The effect of alkyl chain length on catalytic efficiency may be useful in designing ligands/Pd complexes that efficiently catalyze Suzuki−Miyaura coupling.

The Pd17Se15 nanoparticles, synthesized for the first time from a single source precursor [Pd(L)Cl2] {L = 1,3-bis(phenylselenyl)propan-2-ol} and grafted onto graphene oxide, show high catalytic activity in C-O coupling between aryl/heteroaryl chlorides/bromides and phenol at room temperature (Pd loading 1 mol%; yield up to 94%).

PdP2 and Pd4S nanoparticles (NPs) (size: ∼2-6 and 9-15 nm respectively) have been prepared for the first time from a single source precursor complex [Pd(L)Cl2] (1) by its one pot thermolysis at 200 °C in TOP and OA/ODE (1 : 1) respectively. These NPs were stirred with graphene oxide (GO) at room temperature to prepare NP composites, GO-PdP2 and GO-Pd4S. The GO-PdP2 NPs have been synthesized for the first time. The thioether ligand L prepared by reaction of 1,3-dibromo-2-propanol with the in situ generated PhSNa reacts with [PdCl2(CH3CN)2] in CH3CN at 70 °C resulting in 1. The L and 1 have been characterized by (1)H and (13)C{(1)H} NMR and HR-MS. The single crystal structure of 1 determined by X-ray diffraction reveals nearly square planar geometry around the Pd metal centre. The catalytic activities of two palladium nano-phases having phosphorus and sulphur respectively as a co-constituent for Suzuki-Miyaura coupling have been found to be exceptionally different, as PdP2 nanoparticles (NPs) grafted on graphene oxide (GO-PdP2) are significantly more efficient than Pd4S NPs grafted on GO. Without grafting PdP2 and Pd4S both have low efficiency. This is the first report comparing the influence of P and S on the catalytic activity of Pd NPs. TEM, SEM-EDX and powder-XRD have been used to authenticate all NPs. The GO-PdP2 NPs have been found to be efficient catalysts for Suzuki-Miyaura coupling reactions (yield up to 96% in 30 min) at room temperature to 80 °C. Their recyclability has been found up to 6 cycles. In contrast, GO-Pd4S NPs are little active in comparison with GO-PdP2 NPs. The size of NPs and their distribution on GO appear to be key factors affecting the catalytic efficiency of the composite NPs. Leaching of Pd from GO-PdP2 NPs contributes significantly to the catalysis as evidenced by the three phase test, hot-filtration and recycling experiments. The catalysis is almost homogeneous.

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