Quantification of the Electrophilicities of Diazoalkanes: Kinetics and Mechanism of Azo Couplings with Enamines and Sulfonium Ylides

Kinetics and mechanism of the reactions of methyl diazoacetate, dimethyl diazomalonate, 4-nitrophenyldiazomethane, and diphenyldiazomethane with sulfonium ylides and enamines were investigated by UV-Vis and NMR spectroscopy. Ordinary alkenes undergo 1,3-dipolar cycloadditions with these diazo compounds. In contrast, sulfonium ylides and enamines attack at the terminal nitrogen of the diazo alkanes to give zwitterions, which undergo various subsequent reactions. As only one new bond is formed in the rate-determining step of these reactions, the correlation lg k₂(20 °C)=s_N(N+E) could be used to determine the one-bond electrophilicities E of the diazo compounds from the measured second-order rate constants and the known reactivity indices N and s_N of the sulfonium ylides and enamines. The resulting electrophilicity parameters (−21<E<−18), which are 11–14 orders of magnitude smaller than that of the benzenediazonium ion, are used to define the scope of one-bond nucleophiles which may react with these diazoalkanes.     

Eine neue Methode zur jodometrischen Bestimmung der Rhodanund Schwefelwasserstoffs?ure

Ohne Zusammenfassung     

Modelling carbocationic polymerizations: Kinetics of the reactions of carbocations with alkenes

Reactions of carbocations with olefins and related π-nucleophiles follow second order kinetics, first order with respect to carbocation and first order with respect to olefin. The rate constants are equal for paired and non-paired ions and independent of the nature of the negative counter-ions. Rate constants k < 10⁷-10⁸ L mol⁻¹ s⁻¹ can be calculated by lg k(20 °C) = s (N+E), where E represents the strengths of the electrophiles, while nucleophiles are characterized by the slope parameter s and the nucleophilicity parameter N. These parameters can be used for selecting initiators for carbocationic polymerizations and for designing copolymers.     

Alkyl chloride-boron trichloride initiated polymerizations of isobutylene: Detailed analysis of the initial propagation steps

Living oligomerizations of isobutylene initiated either by cumyl chloride, the [1:1]-adduct of cumyl chloride to isobutylene ( P ), the [1:2]-adduct of cumyl chloride to isobutylene ( P2 ), diisobutylene hydrochloride ( P1 '), or triisobutylene hydrochloride ( P2 ') have been studied in presence of BCl₃ and benzyltriethylammonium tetrachloroborate. In contrast to common opinion, the gross propagation rates of the various telechelics depended significantly on the degree of polymerization with k_rel = 0.07, 1.8, 2.3, 1.3, 1.1, 1.0, 1.0 for Ph-C(CH₃)₂-[CH₂-C(CH₃)₂]_n-Cl with n = 1, 2, 3, 4, 5, 6, 7, respectively. These results are compared with the initiation efficiencies of (CH₃)₃C-(CH₂-C(CH₃)₂]_n-Cl (K_rel = 0.3 and 0.8 for n = 1 and 2, respectively). The consequences for the synthesis of telechelics with very narrow molecular weight distribution are discussed.     

trans‐Di­chlorotetrakis(4‐methyl­pyridine)­silicon bis­(triiodide) chloro­form solvate

At 173 K, the dication of the title compound, C₂₄H₂₈Cl₂N₄Si²⁺·2I₃^?·CHCl₃, is located on a crystallographic fourfold rotation axis. The chloro ligands occupy axial positions and the four 4‐methyl­pyridine ligands lie in the equatorial plane. The almost linear I₃^? ion is located on a crystallographic mirror plane and displays two significantly different I—I bond lengths. Furthermore, chloro­form mol­ecules, which are disordered about a centre of inversion, fill the remaining gaps in the crystal structure.     

Albumin-targeting of an oxaliplatin-releasing platinum(iv) prodrug results in pronounced anticancer activity due to endocytotic drug uptake in vivo

Oxaliplatin is a very potent platinum(ii) drug which is frequently used in poly-chemotherapy schemes against advanced colorectal cancer. However, its benefit is limited by severe adverse effects as well as resistance development. Based on their higher tolerability, platinum(iv) prodrugs came into focus of interest. However, comparable to their platinum(ii) counterparts they lack tumor specificity and are frequently prematurely activated in the blood circulation. With the aim to exploit the enhanced albumin consumption and accumulation in the malignant tissue, we have recently developed a new albumin-targeted prodrug, which supposed to release oxaliplatin in a highly tumor-specific manner. In more detail, we designed a platinum(iv) complex containing two maleimide moieties in the axial position (KP2156), which allows selective binding to the cysteine 34. In the present study, diverse cell biological and analytical tools such as laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS), isotope labeling, and nano-scale secondary ion mass spectrometry (NanoSIMS) were employed to better understand the in vivo distribution and activation process of KP2156 (in comparison to free oxaliplatin and a non-albumin-binding succinimide analogue). KP2156 forms very stable albumin adducts in the bloodstream resulting in a superior pharmacological profile, such as distinctly prolonged terminal excretion half-life and enhanced effective platinum dose (measured by ICP-MS). The albumin-bound drug is accumulating in the malignant tissue, where it enters the cancer cells via clathrin- and caveolin-dependent endocytosis, and is activated by reduction to release oxaliplatin. This results in profound, long-lasting anticancer activity of KP2156 against CT26 colon cancer tumors in vivo based on cell cycle arrest and apoptotic cell death. Summarizing, albumin-binding of platinum(iv) complexes potently enhances the efficacy of oxaliplatin therapy and should be further developed towards clinical phase I trials.

Albumin-targeting of a maleimide-containing oxaliplatin-releasing platinum(iv) prodrug results in tumor-specific drug delivery and activity as shown by LA-ICP-MS, isotope-labeling and NanoSIMS in cell culture and in vivo.