Summary: The synthesis of C1‐symmetric zirconocene complexes bearing the 2,5‐dimethyl‐7H‐cyclopenta[1,2‐b:4,3‐b′]dithiophene ligand (S2‐3) linked to substituted cyclopentadienes is described. Different syntheses of S2‐3, the common intermediate for the preparation of these complexes, are discussed. Many of these complexes have been found to be highly active in propylene polymerization, to require very low amounts of methylalumoxane to be activated, and to produce poly(propylene)s of low isotacticity and melting points. 13C NMR analysis shows that the poly(propylene)s are fully regioregular and that the stereoerrors are randomly distributed, as shown by the enantiomorphic‐site triad test E ≈ 1. The experimental pentad distribution was fitted using a two‐site model with different probability parameters for each site. The probability of chain back‐skip was also taken into account. The molecular weight and crystallinity of the poly(propylene)s are dependent upon the type of substituents on the cyclopentadienyl ring, and the correlation between mmmm content and melting point of the PP confirms the random distribution of stereoerrors.Correlation between % mmmm pentad and melting point.magnified imageCorrelation between % mmmm pentad and melting point.

Cyclopenta[b]indole-based ansa-zirconocenes were prepared and studied as catalysts for propylene polymerization. Substituted 2-methyl-4-R-1,4-dihydrocyclopenta[b]indoles (R = Ph, 7a; R = o-Tol, 7b; R = Me, 7c) were synthesized and converted into the racemic forms of the corresponding ansa-zirconocenes Me2Si(2-Me-4-R-cyclopenta[b]indolyl)2ZrCl2 (R = Ph, 10a; R = o-Tol, 10b; R = Me, 10c). The structure of 10a was determined by X-ray analysis. The effectiveness in polymerization catalysis of the metallocenes compared to benchmark metallocenes rac-Me2Si(2-Me-4-Ph-Ind)2ZrCl2 (11) and rac-Me2Si(2-Me-4,5-BzInd)2ZrCl2 (12) was investigated in liquid propylene at 70 °C. Both 10a and 10b with MAO cocatalyst afforded highly isospecific (mmmm 95.9, 95.6%, respectively) and highly regisospecific polypropylene (0.17, 0.34% imbedded regioerrors), which exhibited a high melting point (T m2 = 154.2, 156.3 °C). The polymer properties were intermediate between those of 11 and 12, with the molecular weight, stereospecificity, and melting point increasing in the order 12 < 10a,b < 11. Although activities 1−2 orders of magnitude lower than for 11 and 12 were found at high MAO/Zr ratios, at low cocatalyst levels activities were similar. 10a,b were also successfully activated with alternative aluminoxanes based on branched alkylaluminums (e.g. Al(CH2CHMePh)3, obtained from α-methylstyrene), with measured activities up to 16.6 TON/((g of Zr) h) (10a/AKO). Surprisingly, no consistent effect on polymer properties of varying either the 4-aryl substituent of the cyclopenta[b]indole group or the cocatalyst was found.

1. Some glycidyl ethers (GE) have been shown to be direct mutagens in short-term in vitro tests and consequently GE are considered to be potentially mutagenic in vivo. However, GE may be metabolically inactivated in the body by two different enzymatic routes: conjugation of the epoxide moiety with the endogenous tripeptide glutathione (GSH) catalysed by glutathione S-transferase (GST) or hydrolysis of the epoxide moiety catalysed by epoxide hydrolase (EH). 2. The metabolic inactivation of five different GE, the diglycidyl ethers of bisphenol A (BADGE), 4,4'-dihydroxy-3,3',5,5'-tetramethylbiphenyl (Epikote YX4000) and 1,6-hexanediol (HDDGE) and the GE of 1-dodecanol (C12GE) and o-cresol (o-CGE), has been studied in subcellular fractions of human, C3H mouse and F344 rat liver and lung. 3. All GE were chemically very stable and resistant to aqueous hydrolysis, but were rapidly hydrolysed by EH in cytosolic and microsomal fractions of liver and lung. The aromatic GE were very good substrates for EH. In general, microsomal EH is more efficient than cytosolic EH in hydrolysis of GE, and human microsomes are more efficient than rodent microsomes. 4. The more water-soluble GE, o-CGE and HDDGE, were good substrates for GST whereas the more lipophilic GE, YX4000 and C12GE, were poor substrates for GST. In general, rodents are more efficient in GSH conjugation of GE than humans. 5. In general, the epoxide groups of YX4000 are the most and those of HDDGE the least efficiently inactivated of the five GE under study. For the other three GE no general trend was observed: the relative efficiency of inactivation varied with organ and species. 6. The large variation in metabolism observed with five representative GE indicate that GE have variable individual properties and should not be considered as a single, homogenous class of compounds.

Bronchiolo-alveolar tumors were observed in mice exposed chronically to 160 ppm styrene, whereas no tumors were seen in rats up to concentrations of 1000 ppm. Clara cells, which are predominant in the bronchiolo-alveolar region in mouse lungs but less numerous in rat and human lung, contain various cytochrome P450s, which may oxidize styrene to the rodent carcinogen styrene-7,8-oxide (SO) and other reactive metabolites. Reactive metabolites may form specific DNA adducts and induce the tumors observed in mice. To determine DNA adducts in specific tissues and cell types, rats and mice were exposed to 160 ppm [ring-U-(14)C]styrene by nose-only inhalation for 6 h in a recirculating exposure system. Liver and lungs were isolated 0 and 42 h after exposure. Fractions enriched in Type II cells and Clara cells were isolated from rat and mouse lung, respectively. DNA adduct profiles differed quantitatively and qualitatively in liver, total lung, and enriched lung cell fractions. At 0 and 42 h after exposure, the two isomeric N:7-guanine adducts of SO (measured together, HPEG) were present in liver at 3.0 +/- 0.2 and 1.9 +/- 0.3 (rat) and 1.2 +/- 0.2 and 3.2 +/- 0.5 (mouse) per 10(8) bases. Several other, unidentified adducts were present at two to three times higher concentrations in mouse, but not in rat liver. In both rat and mouse lung, HPEG was the major adduct at approximately 1 per 10(8) bases at 0 h, and these levels halved at 42 h. In both rat Type II and non-Type II cells, HPEG was the major adduct and was about three times higher in Type II cells than in total lung. For mice, DNA adduct levels in Clara cells and non-Clara cells were similar to total lung. The hepatic covalent binding index (CBI) at 0 and 42 h was 0.19 +/- 0.06 and 0.14 +/- 0.03 (rat) and 0. 25 +/- 0.11 and 0.44 +/- 0.23 (mouse), respectively. The pulmonary CBIs, based on tissues combined for 0 and 42 h, were 0.17 +/- 0.04 (rat) and 0.24 +/- 0.04 (mouse). Compared with CBIs for other genotoxicants, these values indicate that styrene has only very weak adduct-forming potency. The overall results of this study indicate that DNA adduct formation does not play an important role in styrene tumorigenicity in chronically exposed mice.

The disposition of styrene was studied in a group of 12 Sprague Dawley rats and two groups of 30 CD1 mice exposed separately to 160 ppm [ring-U-(14)C]styrene of high specific radioactivity of 1.92 TBq x mol(-1) (52 Ci x mol(-1)) for 6 h. A nose-only exposure system was successfully adapted to (1) recirculate a portion of the flow to limit the amount of (14)C-styrene required, and (2) avoid any polymerization of the compound. The mean uptake of styrene in rats was 113 +/- 7 micromol x kg(-1) x h(-1) and stable over time. The mean uptake in mice was higher, 189 +/- 53 and 183 +/- 76 micromol x kg(-1) x h(-1), for the first and second mouse inhalation experiment, but decreased steadily over time. Some of the mice, but none of the rats, showed signs of overt toxicity. The overall excretion of styrene and its metabolites was quantitatively similar in rats and mice. Urinary excretion was the primary route of excretion while fecal excretion accounted for only a very small part of the radioactivity. There was, however, a significant difference between mice and rats in the exhalation of (14)CO(2), which must have resulted from opening and subsequent breakdown of the aromatic ring. In mice the exhalation of (14)CO(2) accounted for 6.4 +/- 1.0 and 8. 0 +/- 0.5% of the styrene retained during the first and second mouse inhalation experiment. In rats, exhalation of (14)CO(2) accounted for only 2.0 +/- 0.7% of the retained styrene. Together with the results from the quantitative whole-body autoradiography (showing significantly higher binding in mouse lung and nasal passages compared to rat) the larger production of (14)CO(2) might be indicative of the formation of reactive ring-opened metabolites in the mouse lung, which, in turn, might be related to the observed development of bronchioalveolar tumors and nasal effects in mice exposed to styrene.