Relative Rates of Metal-Free Azide-Alkyne Cycloadditions: Tunability over 3 Orders of Magnitude.

The thermal (3 + 2) dipolar azide-alkyne cycloaddition, proceeding without copper or strained alkynes, is an underutilized ligation with potential applications in materials, bioorganic, and synthetic chemistry. Herein, we investigate the effects of alkyne substitution on the rate of this reaction, both experimentally and computationally. Electron-withdrawing groups accelerate the reaction, providing a range of relative rates from 1.0 to 2100 between the slowest and fastest alkynes studied. Unexpectedly, aryl groups conjugated to the alkyne significantly retard the reaction rate. In contrast, a sulfonyl, ester-substituted alkyne is reactive enough that it couples with an azide at room temperature in a few hours. This reactivity scale should provide a guide to those who wish to use this ligation under mild conditions.

Covalently linked plasticizers: triazole analogues of phthalate plasticizers prepared by mild copper-free "click" reactions with azide-functionalized PVC.

Copper-free azide-alkyne click chemistry is utilized to covalently modify polyvinyl chloride(PVC). Phthalate plasticizer mimics di(2-ethylhexyl)-1H-triazole-4,5 dicarboxylate (DEHT), di(nbutyl)-1H-1,2,3-triazole-4,5-dicarboxylate (DBT), and dimethyl-1H-triazole-4,5-dicarboxylate(DMT) are covalently attached to PVC. DEHT, DBT, and DMT have similar chemical structures to traditional plasticizers di(2-ethylhexyl) phthalate (DEHP), di(n-butyl) phthalate (DBP), and dimethyl phthalate (DMP), but pose no danger of leaching from the polymer matrix and forming small endocrine disrupting chemicals. The synthesis of these covalent plasticizers is expected to be scalable, providing a viable alternative to the use of phthalates, thus mitigating dangers to human health and the environment.

Urushiol detection using a profluorescent nitroxide.

A method to visually detect minute amounts of urushiol, the toxic catechol from poison oak, poison ivy, and poison sumac, has been developed utilizing the reaction of a profluorescent nitroxide with the B-n-butylcatecholboronate ester formed in situ from urushiol and B-n-butylboronic acid. The resulting N-alkoxyamine is strongly fluorescent upon illumination with a fluorescent lamp, allowing the location of the toxic urushiol contamination to be visualized. This methodology constitutes the groundwork for the future development of a spray to detect urushiol to avoid contact dermatitis, as well as to detect catecholamines for biomedical applications.

Degradation of Polyvinyl Chloride by Sequential Dehydrochlorination and Olefin Metathesis.

Polyvinyl chloride (PVC) is a problematic waste plastic with limited options for recycling or upcycling. Herein, we demonstrate preliminary results in breaking down the long carbon chains of PVC into oligomers and small organic molecules. First, treatment with a substoichiometric amount of alkali base effects elimination of HCl to form a salt and creates regions of conjugated carbon-carbon double bonds, as determined by 1 H NMR and UV-Vis spectroscopy. Olefin cross metathesis with an added partner alkene then cleaves carbon-carbon double bonds of the polymer backbone. Addition of allyl alcohol to the dehydrochlorination step introduces allyloxy groups by substitution of allylic chlorides. Subsequent metathesis of the pendant allyloxy groups provides a reactive terminal alkene to promote insertion of the metathesis catalyst onto the olefins in the all-carbon backbone. The products obtained are a mixture of PVC oligomers with greatly reduced molecular weights and a small-molecule diene corresponding to the substituents of the added alkene, as evidenced by 1 H and DOSY NMR and GPC. This mild procedure provides a proof of concept towards harvesting carbon resources from PVC waste.

Synthesis and spin trapping properties of polystyrene supported trifluoromethylated cyclic nitrones.

Polystyrene supported fluorinated cyclic nitrone spin-traps: Resin-2-HFDMPO (2-hydroxymethyl-2-methyl-5-(trifluoromethyl)-3,4-dihydro-2H-pyrrole-1-oxide) and Resin-2-PFDMPO (2-(3-hydroxypropyl)-2-methyl-5-(trifluoromethyl)-3,4-dihydro-2H-pyrrole 1-oxide) containing a trifluoromethyl pyrroline-N-oxide core were developed to detect free radicals under flow conditions. A continuous flow EPR technique was used to evaluate the spin trapping properties of these tethered nitrones. While both resins trapped radicals, polymer supported nitrone Resin-2-PFDMPO with a longer and more flexible linker showed a more information rich spectrum than Resin-2-HFDMPO.

Tracking silver delivery to bacteria using turn-on fluorescence.

Herein we present a novel silver complex [Ag(qBODIPY)(CF3SO3)] (1) that exhibits dramatic increase in fluorescence upon silver release. Complex 1 has a minimum inhibitory concentration comparable to that of silver nitrate. Confocal microscopy was used to track the delivery of silver to bacterial targets.

Novel methodology for the synthesis of N-alkoxyamines.

[reaction: see text] We report a new methodology for the synthesis of the N-alkoxyamines, which can be used as initiators in "living" free radical polymerization. Silyl radical abstraction from alkyl halides allows the synthesis of N-alkoxyamines inaccessible by other methods.

Distance-dependent Fluorescence Quenching and Binding of CdSe Quantum Dots by Functionalized Nitroxide Radicals.

Quantum dot (QD) fluorescence is effectively quenched at low concentration by nitroxides bearing amine or carboxylic acid ligands. The association constants and fluorescence quenching of CdSe QDs with these derivatized nitroxides have been examined using electron paramagnetic resonance (EPR) and fluorescence spectroscopy. The EPR spectra in the non-protic solvent toluene are extremely sensitive to intermolecular and intramolecular hydrogen bonding of the functionalized nitroxides. Fluorescence measurements show that quenching of QD luminescence is nonlinear, with a strong dependence on the distance between the radical and the QD. The quenched fluorescence is restored when the surface-bound nitroxides are converted to hydroxylamines by mild reducing agents, or trapped by carbon radicals to form alkoxyamines. EPR studies indicate that photoreduction of the nitroxide occurs in toluene solution upon photoexcitation at 365 nm. However, photolysis in benzene solution gives no photoreduction, suggesting that photoreduction in toluene is independent of the quenching mechanism. The fluorescence quenching of QDs by nitroxide binding is a reversible process.

A Proximal Bisnitroxide Initiator: Studies in Low-Temperature Nitroxide-Mediated Polymerizations.

Nitroxide-mediated "living" radical polymerization with bisalkoxyamine 2,5,5,8,8,11-hexamethyl-4,9-(1-phenylethoxy)-3,10-diphenyl-4,9-diazadodecane produces polymers of controlled length and narrow molecular weight distributions at temperatures ranging from 70 to 110 °C. Polymerizations were run successfully with styrene (St), tert-butyl acrylate (tBA), and dimethylacrylamide (DMA). EPR measurements of the homolysis of this bisalkoxyamine and monoalkoxyamine 2,2,5-trimethyl-3-(1-phenylethoxy)-4-phenyl-3-azahexane at temperatures ranging from 85 to 105 °C give rate constants for the bisalkoxyamine that are approximately twice as large as those for the monoalkoxyamine. (1)H NMR investigations of the decomposition of both alkoxyamines at 125 °C show enhanced decomposition for the bisalkoxyamine. EPR decomposition studies at 120 °C on the corresponding bis- and mononitroxides 2,5,5,8,8,11-hexamethyl-3,10-diphenyl-4,9-diazadodecane-4,9-bisnitroxide and 2,2,5-trimethyl-4-phenyl-3-azahexane-3-nitroxide also show accelerated bisnitroxide decomposition. Low-temperature EPR studies of the bisnitroxide reveal an unusually strong radical-radical interaction, suggesting enhanced stabilization of the intermediate mononitroxide formed during polymerization by interaction with the proximal N-alkoxyamine. The transient mononitroxide is postulated to be stabilized by delocalization of the unpaired electron density over five atoms.

Structural requirements for optimized delivery, inhibition of oxidative stress, and antiapoptotic activity of targeted nitroxides.

Suppression of mitochondrial production of reactive oxygen species is a promising strategy against intrinsic apoptosis typical of degenerative diseases. Stable nitroxide radicals such as 4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl (TEMPOL) and its analogs combine several important features, including recycleability, electron acceptance from respiratory complexes, superoxide dismutase mimicry, and radical scavenging. Although successful in antioxidant protection, their effective concentrations are too high for successful in vivo applications. Recently (J Am Chem Soc 127:12460, 2005), we reported that 4-amino 2,2,6,6-tetramethyl-1-piperidinyloxy, covalently conjugated to a five-residue segment of gramicidin S (GS), was integrated into mitochondria and blocked actinomycin D (ActD)-induced superoxide generation and apoptosis. Using a model of ActD-induced apoptosis in mouse embryonic cells, we screened a library of nitroxides to explore structure-activity relationships between their antioxidant/antiapoptotic properties and chemical composition and three-dimensional (3D) structure. High hydrophobicity and effective mitochondrial integration are necessary but not sufficient for high antiapoptotic/antioxidant activity of a nitroxide conjugate. By designing conformationally preorganized peptidyl nitroxide conjugates and characterizing their 3D structure experimentally (circular dichroism and NMR) and theoretically (molecular dynamics), we established that the presence of the beta-turn/beta-sheet secondary structure is essential for the desired activity. Monte Carlo simulations in model lipid membranes confirmed that the conservation of the d-Phe-Pro reverse turn in hemi-GS analogs ensures the specific positioning of the nitroxide moiety at the mitochondrial membrane interface and maximizes their protective effects. These new insights into the structure-activity relationships of nitroxide-peptide and -peptide isostere conjugates are instrumental for development of new mechanism-based therapeutically effective agents.

Radical [n + 1] annulations with sulfur dioxide.

[reaction: see text] A new methodology for [n + 1] radical annulation using sulfur dioxide as a geminal radical acceptor/donor is presented. This methodology provides a novel route to the formation of five-, six-, and seven-membered cyclic sulfones utilizing a radical chain mechanism under very mild conditions.