The kinetic behavior of dimethyl-, diphenyl-, and dimesitylsilylene in hexanes solution in the presence of methanol (MeOH), tert-butanol (t-BuOH), and the respective O-deuterated isotopomers has been studied, with the goal of elucidating a detailed mechanism for the formal O-H insertion reaction of transient silylenes with alcohols in solution. The data are in all cases consistent with a mechanism involving the intermediacy of the corresponding silylene-alcohol Lewis acid-base complexes, which have been detected directly for each of the SiMe 2 -ROL and SiPh 2 -ROL (L = H or D) systems that were studied. Complexation proceeds effectively irreversibly (K eq g 2 Â 10 5 M -1 ) and at close to the diffusion-controlled rate in these cases. In contrast, the kinetic and spectroscopic behavior observed for SiMes 2 in the presence of these alcohols indicates the SiMes 2 -ROL complexes are involved as steady-state intermediates, formed reversibly and 10-100 times more slowly than is the case with SiMe 2 and SiPh 2 . Product formation from the silylene-alcohol complexes is shown to proceed via catalytic proton transfer by a second molecule of alcohol, the rate of which exceeds that of unimolecular intracomplex H-migration in all cases, even at submillimolar alcohol concentrations. The catalytic rate constants range from 10 9 to 10 10 M -1 s -1 for the SiMe 2 -ROH and SiPh 2 -ROH complexes, sufficiently fast that the isotope effect ranges from ca. 2.5 to close to unity for all but the SiPh 2 -t-BuOL complex, where it is remarkably large (k HH /k DD =10.8 ( 2.4). The value is consistent with a mechanism for catalysis involving double proton transfer within a cyclic five-membered transition state. The isotope effects on the ratio of the rate constants for catalytic proton transfer and dissociation of the SiMes 2 -MeOH and SiMes 2 -t-BuOH complexes suggest that a different mechanism for catalytic proton transfer is involved in the case of the sterically hindered diarylsilylene.

Direct irradiation of 1,1-diphenyl-, 1,1-bis[4-(trifluoromethyl)phenyl]-, and 1,1-bis[3,5-bis(trifluoromethyl)phenyl]germacyclobutanes (2, 4, and 5, respectively) in methanolic C6D12 solution affords products consistent with the competing formation of the corresponding 1,1-diarylgermenes and diarylgermylenes, along with ethylene and cyclopropane. The relative yields of the two Ge-containing primary products (germene:germylene) vary with the extent of CF3 substitution on the aryl rings, decreasing in the order 2 > 4 > 5. As was reported previously for 2, laser flash photolysis of 4 and 5 in hexane, acetonitrile, or tetrahydrofuran solution allows the detection of the corresponding transient 1,1-diarylgermenes (6 and 7, respectively), which have been identified on the basis of their UV/vis spectra (λmax ∼325 nm) and quenching studies with MeOH, tert-butyl alcohol (t-BuOH), acetic acid (AcOH), n-butylamine (n-BuNH2), and acetone. In carefully dried hexane solution, weak transient absorptions assignable to the corresponding germylenes and their respective (digermene) dimers are also observed; in the case of 5, these assignments have been confirmed by the results of steady-state and laser photolysis experiments with 1,1-bis[3,5-bis(trifluoromethyl)phenyl]-2,3-dimethyl-1-germacyclopent-3-ene (14c), which affords the germylene exclusively, in substantially higher quantum yield. The reactivities of the germenes toward each of the various substrates studied vary modestly with aryl substituent, increasing in the order acetone < t-BuOH < MeOH ≈ n-BuNH2 < AcOH. The rate constants increase with increasing trifluoromethyl substitution in the cases of alcohol and acetone addition but decrease correspondingly in the case of AcOH addition. Substrate acidity thus plays a much more dominant role in the reactions of the GeC bond with nucleophilic reagents than is the case with the homologous silene derivatives, whose reaction kinetics are controlled primarily by substrate nucleophilicity.

Insulin glargine is a long-acting analogue of human insulin that has been used to manage hyperglycemia in patients with diabetes mellitus (DM) for nearly 20 years. Insulin glargine has a relatively constant concentration-time profile that mimics basal levels of insulin and allows for once-daily administration. MYL-1501D is a biosimilar insulin glargine designed to offer greater access of insulin glargine to patients, with comparable efficacy and safety to the marketed reference product. We conducted a comprehensive panel of studies based on a formal analysis of critical quality attributes to characterize the structural and functional properties of MYL-1501D and reference insulin glargine products available in the United States and European Union. MYL-1501D was comprehensively shown to have high similarity to the reference products in terms of protein structure, metabolic activity (both in vitro cell-based assays and in vivo rabbit bioassays), and in vitro cell-based assays for mitogenic activity. The structural analyses demonstrated that the primary protein sequence was identical, and secondary and tertiary structures are similar between the proposed biosimilar and the reference products. Insulin receptor binding affinity and phosphorylation studies also established analytical similarity. MYL-1501D demonstrated high similarity in different metabolic assays of glucose uptake, adipogenesis activity, and inhibition of stimulated lipolysis. Rabbit bioassay studies showed MYL-1501D and EU-approved insulin glargine are highly similar to US-licensed insulin glargine. These product quality studies show high similarity between MYL-1501D and licensed or approved insulin glargine products and suggest the potential of MYL-1501D as an alternative cost-effective treatment option for patients and clinicians.