Cyclopropylcarbinyl → Homoallyl-Type Ring Opening of Ketyl Radical Anions. Structure/Reactivity Relationships and the Contribution of Solvent/Counterion Reorganization to the Intrinsic Barrier

Following a protocol developed by Mathivanan, Johnston, and Wayner (J. Phys. Chem. 1995, 99, 8190−8195), the radical anions of several cyclopropyl- and oxiranyl-containing carbonyl compounds were generated in an effort to measure the rate constants for their ring opening (ko) by laser flash photolysis. The results of these experiments are compared to those obtained from earlier electrochemical studies, and the combined data set is used to rationalize the kinetics of radical anion ring opening in a general context by using Savéant\u27s theory pertaining to stepwise dissociative electron transfer (Acc. Chem. Res. 1993, 26, 455−461). Compared to cyclopropylcarbinyl → homoallyl rearrangements of neutral free radicals, at comparable driving force, the radical anion ring openings are slightly slower. The small difference in rate is attributed to the contribution of an additional, approximately 2 kcal/mol, solvent reorganization component for the radical anion rearrangements. The solvent reorganization energy for ring opening of these radical anions is believed to be small because the negative charge does not move appreciably in the progression reactant → transition state → product

Electron Transfer Initiated Formation of Covalently Bound Organic Layers on Silicon Surfaces

An electron transfer initiated organic modification of silicon surfaces, using a donor/acceptor pair of ferrocene (Fc) and <i>N</i>-bromosuccinimide (NBS) (or <i>N</i>-bromophthalimide (NBP)), is reported for the first time. This modification method is efficient and does not require the use of heat or irradiation. Multilayer structures are formed on the surfaces through radical reactions, similar to the reduction of aryl diazonium salts. The modified surfaces were characterized by infrared reflection–absorption spectroscopy (IRRAS), X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM). IRRAS spectra clearly indicate a strong carbonyl stretch and the presence of a ferrocene moiety for each of the modified surfaces. XPS data show the presence of all elements from the donor/acceptor pair and provide strong evidence that the samples can be further modified by nucleophilic substitution. AFM imaging indicates the formation of dense layers that can be scratched away to reveal depth information on approximately 2 nm and the underlying terraces of the silicon substrate. A mechanism is proposed where radical abstraction of a surface hydrogen takes place leading to the formation of a covalently bound imidyl group, which is followed by the formation of polymeric structures through radical chain reactions

Is Clozapine-induced Weight Gain Dose-dependent? Results From a Prospective Cohort Study.

Antipsychotic-induced metabolic adverse effects are risk factors for cardiometabolic comorbidities. Whether dose lowering could mitigate such effects remains unclear. The present study aims to investigate the associations between clozapine doses and modifications of weight, blood pressure, blood glucose, and lipid levels. Linear mixed-effects models of weight changes over 1 year and of variations of other metabolic parameters over 4 months were applied to a prospective cohort of 115 patients. Age- and sex-stratified analyses of weight changes were also performed. Each 100 mg dose increment of clozapine was associated on average with a +0.48% weight increase (P = .004) over 1 year of treatment. Weight increase was greater for treatment duration ≤3 vs &gt;3 months (+0.84% and +0.47% per month, respectively, P &lt; .001), with a significant association with the dose for durations &gt;3 months (+0.54%, P = .004) and a trend for durations ≤3 months (+0.33%, P = .075). Dose increments of 100 mg were also associated with weight increases of +0.71% among adults (P = .001), +1.91% among the elderly (P &lt; .001) and +1.32% among men (P &lt; .001) with no associations among women (P = .62). Among young adults, weight change was positively associated with doses ≤300 mg/day (+2.19% per 100 mg, P = .001), whereas no association was found with doses &gt;300 mg/day (P = .60). No significant effect of clozapine dose on other metabolic parameters was found. This study reports a modest effect of clozapine dose increases on weight gain over 1 year with differences among age categories and sexes and no dose effect on other metabolic parameters over 4 months

Synthesis, structure, and biological activity of ferrocenyl carbohydrate conjugates.

Seven ferrocenyl carbohydrate conjugates were synthesized. Coupling reactions of monosaccharide derivatives with ferrocene carbonyl chloride produced {6-N-(methyl 2,3,4-tri-O-acetyl-6-amino-6-deoxy-alpha-D-glucopyranoside)}-1-ferrocene carboxamide (3), {1-O-(2,3,4,6-tetra-O-benzyl-D-glucopyranose)}-1-ferrocene carboxylate (4), and {6-O-(1,2,3,4-tetra-O-acetyl-beta-D-glucopyranose)}-1-ferrocene carboxylate (5). Similarly, 1,1'-bis(carbonyl chloride)ferrocene was coupled with the appropriate sugars to produce the disubstituted analogues bis{6-N-(methyl 2,3,4-tri-O-acetyl-6-amino-6-deoxy-alpha-D-glucopyranoside)}-1,1'-ferrocene carboxamide (8), bis{1-O-(2,3,4,6-tetra-O-benzyl-D-glucopyranose)}-1,1'-ferrocene carboxylate (9), and bis{6-O-(1,2,3,4-tetra-O-acetyl-beta-D-glucopyranose)}-1,1'-ferrocene carboxylate (10). {6-N-(Methyl-6-amino-6-deoxy-alpha-D-glucopyranoside)}-1-ferrocene carboxamide monohydrate (12) was synthesized via amide coupling of an activated ferrocenyl ester with the corresponding carbohydrate. All compounds were characterized by elemental analysis, 1H NMR spectroscopy, and mass spectrometry. X-ray crystallography confirmed the solid-state structure of three ferrocenyl carbohydrate conjugates: 2-N-(1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-D-glucopyranose)-1-ferrocene carboxamide (1), 1-S-(2,3,4,6-tetra-O-acetyl-1-deoxy-1-thio-D-glucopyranose)-1-ferrocene carboxylate (2), and 12. The above compounds, along with bis{2-N-(1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-D-glucopyranose)}-1,1'-ferrocene carboxamide (6), bis{1-S-(2,3,4,6-tetra-O-acetyl-1-deoxy-1-thio-D-glucopyranose)}-1,1'-ferrocene carboxylate (7), and 2-N-(2-amino-2-deoxy-D-glucopyranose)-1-ferrocene carboxamide (11) were examined for cytotoxicity in cell lines (L1210 and HTB-129) and for antimalarial activity in Plasmodium falciparum strains (D10, 3D7, and K1, a chloroquine-resistant strain). In general, the compounds were nontoxic in the human cell line tested (HTB-129), and compounds 4, 7, and 9 showed moderate antimalarial activity in one or more of the P. falciparum strains