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Cation radicals formed via gas-phase electron transfer to multiply protonated polypeptides have been found to react with molecular oxygen. Such cation radicals are of interest within the context of electron transfer dissociation, a phenomenon with high utility for the characterization of peptide and protein primary structures. Most of the cation radicals show the attachment of O(2) under room temperature storage conditions in an electrodynamic ion trap. At higher temperatures and under conditions of collisional activation, the oxygen adduct species lose O(2), HO(*), or HO(2)(*), depending upon the identity of the side chain at the radical site. The fragments containing the C-terminus, the so-called z-ions, which are predominantly radical species, engage in reactions with molecular oxygen. This allows for the facile distinction between z-ions and their complementary even-electron c-ion counterparts. Such a capability has utility in protein identification and characterization via mass spectrometry. Intact electron transfer products also show oxygen attachment. Subsequent activation of such adducts show dissociation behavior very similar to that noted for z-ion adducts. These observations indicate that ion/radical reactions can be used to probe the locations of radical sites in the undissociated electron transfer products as well as distinguish between c- and z-type ions.

The ring-opening reactions of the radical cations of hexamethyl Dewar benzene (1) and Dewar benzene have been studied using density functional theory (DFT) and complete active-space self-consistent field (CASSCF) calculations. Compound 1 is known to undergo photoinitiated ring opening by a radical cation chain mechanism, termed "quantum amplified isomerization" (QAI), which is due to the high quantum yield. Why QAI is efficient for 1 but not other reactions is explained computationally. Two radical cation minima of 1 and transition states located near avoided crossings are identified. The state crossings are characterized by conical intersections corresponding to degeneracy between doublet surfaces. Ring opening occurs by formation of the radical cation followed by a decrease in the flap dihedral angle. A rate-limiting Cs transition state leads to a second stable radical cation with an elongated transannular C-C bond and an increased flap dihedral. This structure proceeds through a conrotatory-like pathway of Cs symmetry to give the benzene radical cation. The role of electron transfer was investigated by evaluating oxidation of various systems using adiabatic ionization energies and electron affinities calculated from neutral and cation geometries. Electron-transfer theory was applied to 1 to investigate the limiting effects of back-electron transfer as it is related to the unusual stability of the two radical cations. Expected changes in optical properties between reactants and products of Dewar benzene compounds and other systems known to undergo QAI were characterized by computing frequency-dependent indices of refraction from isotropic polarizabilities. In particular, the reaction of 1 shows greater contrast in index of refraction than that of the Dewar benzene parent system.

The reaction mechanism for the disproportionation of the toxic superoxide radical to molecular oxygen and hydrogen peroxide by the nickel-dependent superoxide dismutase (NiSOD) has been studied using the B3LYP hybrid DFT method. Based on the recent X-ray structures of the enzyme in the resting oxidized Ni(III) and X-ray-reduced Ni(II) states, the model investigated includes the backbone spacer of six residues (sequence numbers 1-6) as a structural framework. The side chains of residues His1, Cys2, and Cys6, which are essential for nickel binding and catalysis, were modeled explicitly. The catalytic cycle consists of two half-reactions, each initiated by the successive substrate approach to the metal center. The two protons necessary for the dismutation are postulated to be delivered concertedly with the superoxide radical anions. The first (reductive) phase involves Ni(III) reduction to Ni(II), and the second (oxidative) phase involves the metal reoxidation back to its resting state. The Cys2 thiolate sulfur serves as a transient protonation site in the interim between the two half-reactions, allowing for the dioxygen and hydrogen peroxide molecules to be released in the reductive and oxidative phases, respectively. The His1 side chain nitrogen and backbone amides of the active site channel are shown to be less favorable transient proton locations, as compared to the Cys2 sulfur. Comparisons are made to the Cu- and Zn-dependent SOD, studied previously using similar models.

Electronic and structural factors controlling the competition between 5-exo-dig and 6-endo-dig cyclizations of sp2-radicals were analyzed using a combination of available experimental data and computation. Although the stereoelectronically favored 5-exo pathways usually has the lower activation energy, formation of a new aromatic ring not only makes the 6-endo process favorable thermodynamically in conjugated systems but also lowers its activation barrier to the extent where the 5-exo/6-endo selectivity is controlled by subtle factors such as the different sensitivity of the two pathways to strain effects in polycyclic systems. In particular, the stronger sensitivity of the 5-exo pathway to strain leads to a crossover in selectivity. The 6-endo cyclization is kinetically favored in smaller (and strained) cycles, whereas the 5-exo cyclization has lower barriers in the larger rings.

For small cyclic peptides, one electron capture by the [M + 2H](2+) ion generates numerous fragments corresponding to amino acid losses, side-chain losses, and losses of some low molecular weight species such as H(2)O, CH(3)(*), C(3)H(6), and (*)CONH(2). As predicted, the side-chain cleavages are amplified relative to linear peptides of similar size, but the amino acid losses were unexpected because they require that one electron capture cause more than one backbone cleavage, a phenomenon which necessitates further refinement or reinterpretation of current ECD mechanisms. A modified mechanism is postulated in which nonergodic electron capture fragmentation generates an alpha-carbon radical species that then propagates along the protein backbone. This radical migration initiates multiple free radical rearrangements, which cause both multiple backbone cleavages and additional side-chain cleavages.

A unified synthesis of several quinone sesquiterpenes is described herein. Essential to this strategy is a novel radical addition reaction that permits the attachment of a fully substituted bicyclic core 16 to a variably substituted quinone 10. The addition product 15 can be further functionalized, giving access to natural products with a high degree of oxygenation at the quinone unit. The quinone addition reaction is characterized by excellent chemoselectivity, taking place only at conjugated and unsubstituted double bonds, and regioselectivity, being strongly influenced by the resonance effect of heteroatoms located on the quinone ring. These features were successfully applied to the synthesis of avarol (1), avarone (2), methoxyavarones (4, 5), ilimaquinone (6), and smenospongidine (7), thereby demonstating the synthetic value of this new method.

Cyclopropylcarbinyl --> homoallyl and related rearrangements of radical ions (a) are frequently used as mechanistic "probes" to detect the occurrence of single electron transfer in chemical and biochemical processes, (b) provide the basis for mechanism-based drug design, and (c) are important tools in organic synthesis. Unfortunately, these rearrangements are poorly understood, especially with respect to the effect of substrate structure on reactivity. Frequently, researchers assume that the same factors which govern the reactivity of neutral free radicals also pertain to radical ions. The results reported herein demonstrate that in some cases structure-reactivity trends in radical ion rearrangements are very different from neutral radicals. For radical ions, delocalizations of both charge and spin are important factors governing their reactivity.

We present a general linear-response method for including nonequilibrium solvation effects (solvent friction effects) in variational transition state theory with multidimensional tunneling (VTST/MT) for calculating reaction rate constants in solution. The generalized Langevin approach is used to include a collective solvent coordinate into VTST/MT, and a general prescription is suggested for coupling this collective solvent coordinate to the solute, which is treated in its full dimensionality. The new formalism is illustrated by application to the aqueous free radical reaction H + CH3OH → H2 + CH2OH at 298 K. This reaction is treated with a linear mixing of Hartree−Fock theory and Austin Model 1 with specific reaction parameters (HF||AM1-SRP). The results with nonequilibrium solvation (NES) are compared to those obtained earlier with the separable equilibrium solvation (SES) and the equilibrium solvation path (ESP) approximations. We focus on the speedup due to solvation and on the kinetic isotope effects...

2,2-Dichloro- or 2,2-dibromovinylcyclopropane was condensed with electron-deficient alkenes in a phenylthio radical catalyzed process to afford 4-substituted and 4,5-disubstituted-1,1 -dihalo-3-vinylcyclopentane derivatives in good yield and with good-to-excellent diastereoselectivity for the 3,4-cis isomer. Neither electron-rich nor β-oubstituted alkenes led to good yields of cyclopentane products. The diastereoselectivity and reactivity profiles of these transformations are satisfactorily rationalized by application of existing transition-state models of radical reactions

The readily synthesis enediynes 12a-j posssessing a tethered olefin radical acceptor can participate in a tandem enediyne-radical cyclization to yield dihydrobenzindene derivatives 14a-j. In the present study, the scope of thin reaction was expanded to include a wide variety of olefin acceptors. Substitution at both ends of olefin leads to the formation of two diastereomers 14b and 14c in a 3.5:1 ratio when R 3 is Me and R 2 is CO 2 Me. The structures of the dihydrobenzindene products 14b and 14c were confirmed by generating a radical from 25 by a tributyltin hydride reaction which undergoes radical cyclization; thin radical in similar to the enediyne-generated radical, which also cyclizes

Reactions between solvated electrons and substrates yielding fast-cleaving anion radicals or giving rise to concerted bond cleavage occur during the mixing of the two reactants. They are described by a model allowing the quantitative prediction of product distribution in which the initial and successive chemical steps take place in a thin reaction layer located within the diffusion layer where the two reactants mix. The essential cause of the observed leaving-group effects resides in the decrease of the amount of electrons in the reaction layer as the initiating reaction becomes faster and faster. In the case of S RN 1 substitutions, an additional factor is the parallel acceleration of the electron transfer between the substituted anion radical and the substrate

The core of tetrodotoxin is a densely functionalized carbocycle for which an annulated pyranose can be envisaged as a retron. The carbocyclic ring is constructed upon a rigid 1,6-anhydro template which permits the early introduction of the key angular nitrogen, and concomitantly positions a trap for reaction with a carbon-centered radical generated chemospecifically at C6. The carbocyclic entity is elaborated in this process leading to a caged system with the capability for generating all of the stereogenic centers. A novel procedure using tert-butylhyponitrite is described for C6 dehydrogenation pursuant to the intramolecular radical cyclization. © 1993, American Chemical Society. All rights reserved.

Single-crystal X-ray analysis of four alkenes that undergo stereoselective radical addition reactions are reported. The facial selectivity of radical additions to these alkenes is understood based upon their solid-state conformations. Alkenes which have a conformation placing a group at a position in space sterically protecting one the faces from addition undergo radical addition with diastereofacial selectivity. The structures of the alkenes are analyzed by the polar coordinates of groups relative to the alkenes center undergoing addition

Thermolysis of the coenzyme B 12 model complex, 1, leads to an equilibrium between 1 and the benzyl migration product 2, but for to even a few percent of the usual radical-recombination product bibenzyl, eq 1. Further investigation of this intermolecular reaction between freely diffusing radicals has revealed a selectivity of ca. 10 5 to 1 (i.e., 99.999%) for 1 and 2 in comparison to bibenzyl (0.001%)

A facile but low-field synthesis of [n]staffanes (the oligomers of [1.1.1]propellane n=1-5) functionalized on one or both ends is described,and their properties are summarized. The substituents are -COOCH 3 ,-n-C 4 H 9 ,-C 6 H 5 ,-Br,-I and -SCOCH 3 , and their conversion to others,such as -COOH, -COCH 3 and -SH,is demonstrated. it is proposed that these rod-shaped molecules will be useful in the development of a molecular-size civil engeneering construction set analogous to children's toy construction sets

Sunlamp irradiation of 1-substituted 5-iodo-1-pentynes, 5 equiv of phenyl isocyanide, and 1.5 equiv of hexamethylditin in tert-butylbenzene (0.01-0.025 M) at 150 o C produces 9-substituted 2,3-dihydro-1H-cyclopenta [b] quinolines in 36-70% yields. A mechanistic proposal for this first example of a 4+1 radical annulation includes the following: (1) radical addition to an isonitrile, (2) cyclization of the resulting imidoyl radical to the alkyne, (3) addition of the so-formed vinyl radical to the aromatic ring, and (4) rearomatization. When substituted isonitriles (p-F p-OMe, m-F) are employed, the major unrearranged products are accompanied by 7-30% or rearranged products. Independent generation of a proposed intermediate suggests that the rearranged products arise by initial closure of the vinyl radical to form a five-membered ring, followed by C-N bond cleavage and recyclization

Hydrogen atoms are generated by mercury photosensitization in an unexceptional apparatus that makes them readily available for organic chemistry on a preparatively useful scale at 1 atm of pressure and temperatures from 0-150°C. The H atoms add to CH 2 =CH-CH 2 X to give the intermediate radical CH 3 -(•CH)-CH 2 X, which dimerizes to give CH 3 CH(CH 2 X)-CH(CH 2 X)CH 3 . The saturated substrates CH 3 CH 2 CH 2 X undergo H abstraction to give CH 3 CH 2 (•CH)X as intermediates and CH 3 CH 2 CH(X)-CH(X)CH 2 CH 3 as final products. The reaction shows a tolerance for different functional groups, X, which may be an alkyl or fluoroalkyl chain or contain vinyl, epoxy, ester, ketone, nitrile, and silyl groups. Radical disproportionation products are also formed but are easily separated. H atoms attack the weakest C-H bonds of the substrates with high selectivity. In our earliest direct mercury photosensitization, Hg* often failed to attack the substrate C-H bonds to give dimers; the presence of H 2 strongly suppresses direct Hg* chemistry

The two alkenes studied were both amides of 2,5-dimethylpyrrolidine, available as either the R,R or S,S enantiomer from D- or L-alanine. Our alkene studied was the unsymmetrical monoamide derived from 4-oxo-2-pentenoic acid (1), while the other substrate examined was the diamide of fumaric acid, 2. Hexyl, cyclohexyl, and tert-butyl radical addition to the amide of 4-oxo-2-pentenoic acid (1) gave approximately equal amounts of addition at the carbonyl and amide ends of the alkene. This approach provides the highest reported stereoselectivity for radical addition to an acyclic chiral alkene. Furthermore, a rationale for the diastereoselectivity is presented that suggests that the amide selectivity in steric in origin and will be general

We describe a new tandem radical cyclization strategy for the construction of the congested angular triquinane portion of the naturally occurring tetraquinane crinipellin A. The preparation and cyclization of three 5,5-disubstituted-1,4-dimethyl-1,3-cyclopentadienes are detailed. This cyclization strategy results in a 1,4-functionalization of the cyclopentadiene nucleus, mediated by an allylic radical cyclization. Each tandem cyclization produces two diastereomeric triquinanes in a rationof 5:1. The minor diastereomer possesses the correct relative stereochemistry for the D-ring isopropyl group of crinipellin A. A tandem cationic cyclization, paralleling the radical cyclizations, is also described

A variety of medium-sized thionolactones have been prepared and condensed with nucleophiles giving alkylated thioacetals upon quenching with methyl iodide. Reductive desulfurization using triphenyltin hydride under radical conditions afforded the corresponding cyclic ethers rapidly and efficiently and, in most cases, with complete stereocontrol. This methodology has been proven through the construction of model systems of rings B and D of brevetoxin A (1) and a synthesis of (±)-lauthisan

Synthese de tetrafluoro-3,3,4,4 cyclobutene-1 (ou hexafluoro-3,3,4,4,5,5 cyclopentene-1 ou octafluoro cyclohexene-1) de phosphonique-1,2 acide et de difluoro-1,2 ethylenediphosphonique-1,2 acide a partir de la reaction de [bromo diethoxyphosphoryl fluoro] methyl sulfinate avec HO°. Le difluoro-1,2 ethylenediphosphonique-1,2 acide reagit avec de la poudre de zinc et donne le complexe [Zn(H 2 O) 6 ] + [O(HO)P(O)CF=CFP(O)(OH)O] 2− qui est etudie par diffraction RX

Irradiation of RMn(CO) 5 (R=η 1 -C 5 Cl 5 ,η 1 -C 6 H 5 CH 2 ) in alkane glasses at 95 K leads to CO loss as the only detectable photoprocess: the ring-slipped (η 3 -C 5 Cl 5 )Mn(CO) 4 and (η 5 -C 5 Cl 5 )Mn(CO) 3 or (η 3 -C 6 H 5 CH 2 )Mn(CO) 4 are formed, respectively. The identities of the η 3 intermediates from (η 1 -C 5 Cl 5 )Mn(CO) 5 and (η 1 -C 6 H 5 CH 2 )Mn(CO) 5 have been established by spectroscopic means and by chemical-trapping experiments

Anodic oxidation of the important half-sandwich compound CoCp(CO)2, 1, has been studied under gentle electrolyte conditions, e.g., chlorinated hydrocarbons with weakly coordinating anion (WCA) supporting electrolyte anions. The 17-electron cation 1+ produced at E(1/2)(1) = 0.37 V vs FeCp2(0/+) undergoes a surprising reaction with neutral 1 to form the dimer radical cation [Co2Cp2(CO)4] +, 2+, which has a metal-metal bond unsupported by bridging ligands. The dimer radical is oxidized at a slightly more positive potential (E(1/2) = 0.47 V) to the corresponding dication 2(2+). Observation of the oxidation of 2+ is without precedent in confirming a radical-substrate (R-S) dimerization process by direct voltammetric detection of the R-S intermediate, K(eq) = 3 x 10(4) M(-1) for [2+]/[1][1+]. The R-S mechanism and the reaction products have been characterized by voltammetry, electrolysis, fiber-optic IR spectroscopy, and ESR measurements. DFT calculations indicate that removal of an electron from 1 results in rehybridization in 1+, thereby opening the metal center for interaction with the neutral compound 1, which has a relatively basic metal center. The LUMO of the dimer dication 2(2+) is metal-metal antibonding, and its half-occupancy in 2+ results in lengthening of the Co-Co bond from 2.64 A to 3.14 A. Inclusion of solvent in the (COSMO) calculations shows that solvation effects are necessary to account for the fact that E(1/2)(2) > E(1/2)(1). These results show the importance of medium effects in probing the fundamental redox chemistry of half-sandwich metal complexes.

Conventional metal-catalyzed organic radical reactions and living radical polymerizations (LRP) performed in nonpolar solvents, including atom-transfer radical polymerization (ATRP), proceed by an inner-sphere electron-transfer mechanism. One catalytic system frequently used in these polymerizations is based on Cu(I)X species and N-containing ligands. Here, it is reported that polar solvents such as H(2)O, alcohols, dipolar aprotic solvents, ethylene and propylene carbonate, and ionic liquids instantaneously disproportionate Cu(I)X into Cu(0) and Cu(II)X(2) species in the presence of a diversity of N-containing ligands. This disproportionation facilitates an ultrafast LRP in which the free radicals are generated by the nascent and extremely reactive Cu(0) atomic species, while their deactivation is mediated by the nascent Cu(II)X(2) species. Both steps proceed by a low activation energy outer-sphere single-electron-transfer (SET) mechanism. The resulting SET-LRP process is activated by a catalytic amount of the electron-donor Cu(0), Cu(2)Se, Cu(2)Te, Cu(2)S, or Cu(2)O species, not by Cu(I)X. This process provides, at room temperature and below, an ultrafast synthesis of ultrahigh molecular weight polymers from functional monomers containing electron-withdrawing groups such as acrylates, methacrylates, and vinyl chloride, initiated with alkyl halides, sulfonyl halides, and N-halides.

The radical cation of Dewar benzene, 1*+, has been generated and observed by optical spectroscopy in cryogenic matrices. 1*+ distinguishes itself by a charge resonance band at 600 nm, very similar in shape and position to that observed for the related radical cation of norbornadiene. This coincidence indicates that in ground-state 1*+ the odd electron is also located in a pi-MO. The energy of the charge resonance transition, which is very sensitive to the dihedral angle between the four-membered rings in 1*+, is predicted consistently too low by TD-DFT and CASPT2. Probably this angle is too large in the B3LYP and CASSCF geometries. As 1*+ can be observed at 77 K, it must be separated by a barrier of at least 7-8 kcal/mol from its very exothermic decay to the radical cation of benzene, 2*+. An analysis shows that the ring-opening of 1*+ is a multistep process involving two avoided crossings between potential surfaces of different symmetry and electronic nature. Owing to the orbital symmetry-forbidden nature of the process, the energy of 1*+ starts by increasing steeply on stretching the central C-C bond, but then the system undergoes a crossing to a 2A1 surface which leads adiabatically to an excited state of 2*+. Therefore, another avoided crossing must be transited before the molecule can decay on the ground-state surface of 2*+. The rearrangement of 1*+ to 2*+ is an example of a "pseudodiabatic" thermal reaction that transits between potential surfaces representing very different electronic structures.

A detailed study of the regioselectivity of 1,2-oxygen migration was conducted using the unsymmetrically substituted singlet 2,2-dialkoxy-1,3-diarylcyclopentane-1,3-diyls 5. The alkoxy group selectively migrates to the electron-donating p-methoxyphenyl-substituted carbon. The regioselective migration of oxygen clearly indicates a hyperconjugative resonance structure, that is, zwitterionic characteristics, in singlet 2,2-dialkoxy-1,3-diyls. This represents the first attempt to experimentally probe the contribution of hyperconjugation to stabilizing the singlet state.

The combination of the air-stable RuIII complex [Cp*RuCl2(PPh3)] with AIBN can be used to catalyze the atom transfer radical addition reactions of polychlorinated compounds and of sulfonyl chlorides to olefins with unprecedented turnover numbers of up to 44 000.

Multicenter covalent pi-bonding between pi-conjugated radicals has been recently recognized as a novel and important bonding interaction. The Cope rearrangement of cyclo-biphenalenyl 9 is studied by exploring its potential energy surface with density functional theory (DFT), and it is found that pi-bonding plays a critical role in the rearrangement process. Affected by this, the rearrangement of 9 takes place by a stepwise mechanism through an unusual pi-intermediate 10, of C2h symmetry, which can be characterized as a 2 x 13pi + 2 x 2pi system. The pi-intermediate has a long inter-phenalenyl distance of R approximately 2.8 angstroms, which is shorter than the sum of the van der Waals radii displaying multicenter covalent pi-bonding between the two phenalenyl units. The energy of the pi-intermediate 10 is higher than that of the sigma-bonded reactant 9 by approximately 2 kcal/mol according to the employed spin-restricted DFT. NMR chemical shift calculations support the sigma-bonded 9 as the global minimum. The calculated activation barrier of approximately 6 kcal/mol for the Cope rearrangement is consistent with the stepwise mechanism. A covalent pi-bonding effect in the pi-intermediate 10 is demonstrated indirectly by the shortening of inter-naphthalene distance of the dianion and dication of the cyclophane 14 compared to that of its neutral counterpart. The unusual pi-bonded structure with a long inter-phenalenyl distance becomes the most stable structure for the ethano-bridged derivative 13, which should have observable paramagnetism according to the calculated paramagnetic susceptibility.

Taking advantage of a radical-based methodology, mild and chemoselective phosphination reactions of organic halide and alkyl imidazole-1-carbothioates have been developed. The mild reaction conditions allow labile functional groups to survive during the reaction.

We describe a novel procedure for the straightforward synthesis of seven-membered carbocycles via free-radical chemistry, based on titanocene(III)-catalyzed 7-endo-dig and 7-endo-trig cyclizations. This procedure has proved to be useful for the chemical preparation of terpenoids with different skeletons containing cycloheptane rings, including the first total syntheses of dauca-4(11),8-diene (2), barekoxide (3), authentic laukarlaol (81), and a valparane diterpenoid (72), as well as a substantially improved synthesis of karahanaenone (1). We also provide theoretical and experimental evidence in support of a plausible mechanism, which may rationalize the preference for the unusual 7-endo cyclization mode shown by radicals with substitution patterns characteristic of the linalyl, nerolidyl, and geranyl linalyl systems. In light of these chemical findings, we discuss the potential involvement of radical cyclizations in the biosynthesis of some terpenoids containing seven-membered carbocycles.

Kinetics and thermodynamics of 5-endo-dig radical cyclizations were studied using a combination of DFT computations and Marcus theory. When the reactant is stabilized by conjugation of the radical center with the bridge pi-system, the cyclization starts with reorientation of the radical orbital needed to reach the in-plane acetylene pi-orbital in the bond-forming step. This reorientation leads to loss of the above conjugative stabilization, increases the activation energy, and renders such cyclizations less exothermic. As a result, even when the radical needed for the 5-endo cyclization is formed efficiently, it undergoes either H-abstraction or equilibration with an isomeric radical. Only when the bridging moiety is saturated or when intramolecular constraints prevent the overlap of the bridge pi-orbital and the radical center, 5-endo cyclizations may be able to proceed with moderate efficiency under conditions when H-abstraction is slow. The main remaining caveat in designing such geometrically constrained 5-endo-dig cyclizations is their sensitivity to strain effects, especially when polycyclic systems are formed. The strain effects can be counterbalanced by increasing the stabilization of the product (e.g., by introducing heteroatoms into the bridging moiety). Electronic effects of such substitutions can be manifested in various ways, ranging from aromatic stabilization to a hyperconjugative beta-Si effect. The 4-exo-dig cyclization is kinetically competitive with the 5-endo-dig process but less favorable thermodynamically. As a result, by proper design of reaction conditions, 5-endo-dig radical cyclizations should be experimentally feasible.

The long held notion that hexenyl radicals bearing large substituents on the radical carbon cyclize to give 1,2-trans-substituted cyclopentanes is experimentally disproved by study of the radical cyclization of an assortment of simple and complex substrates coupled with careful product analysis and rigorous assignment of configurations. X-ray studies and syntheses of authentic samples establish that the published assignments for cis- and trans-1-tert-butyl-2-methylcyclopentane must be reversed. The original assignment based on catalytic hydrogenation of 1-tert-butyl-2-methylenecyclopentane was compromised by migration of the double bond prior to hydrogenation. The cyclization of 1-tert-butylhexenyl radical is moderately cis selective, and the selectivity is increased by geminal substitution on carbon 3. This selectivity trend is general and extends to relatively complex substrates. It has allowed Ihara to reduce the complexity of an important class of round trip radical cyclizations to make linear triquinanes to the point where two tricyclic products-cis-syn-cis and cis-anti-cis-account for about 80% of the products. However, the further increase in selectivity that was proposed by lowering the temperature is shown to be an artifact of the analysis methods and is not correct. This work solidifies "1,2-cis selectivity" in cyclizations of 1-subsituted hexenyl radicals as one of the most general stereochemical trends in radical cyclizations.

(-)-Siccanin (1), a natural product possessing significant antifungal properties, was synthesized enantioselectively via a biomimetic route. This synthetic route features two sequential radical cyclizations: a Ti(III)-mediated radical cyclization of epoxyolefin 48 to construct the B-ring, and a Suarez reaction to establish the tetrahyrofuran ring. Chiral chroman moiety of siccanin was prepared based on our recent development of the Pd-catalyzed asymmetric allylic alkylation (AAA) of phenol trisubstituted allyl carbonates. Several other members of the siccanin family were also synthesized including siccanochromenes A (2), B (3), E (6), F (7), and the methyl ether of siccanochromene C (55). These studies may shed light on the biosynthesis of this novel family of compounds.

Piperidine and pyrrolidine nitroxides, such as 2,2,6,6-tetramethylpiperidinoxyl (TPO) and 3-carbamoylproxyl (3-CP), respectively, are cell-permeable stable radicals, which effectively protect cells, tissues, isolated organs, and laboratory animals from radical-induced damage. The kinetics and mechanism of their reactions with .OH, superoxide, and carbon-centered radicals have been extensively studied, but not with .NO2, although the latter is a key intermediate in cellular nitrosative stress. In this research, .NO2 was generated by pulse radiolysis, and its reactions with TPO, 4-OH-TPO, 4-oxo-TPO, and 3-CP were studied by fast kinetic spectroscopy, either directly or by using ferrocyanide or 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate), which effectively scavenge the product of this reaction, the oxoammonium cation. The rate constants for the reactions of .NO2 with these nitroxides were determined to be (7-8) x 10(8) M(-)(1) s(-)(1), independent of the pH over the range 3.9-10.2. These are among the highest rate constants measured for .NO2 and are close to that of the reaction of .NO2 with .NO, that is, 1.1 x 10(9) M(-1) s(-1). The hydroxylamines TPO-H and 4-OH-TPO-H are less reactive toward .NO2, and an upper limit for the rate constant for these reactions was estimated to be 1 x 10(5) M(-1) s(-1). The kinetics results demonstrate that the reaction of nitroxides with .NO2 proceeds via an inner-sphere electron-transfer mechanism to form the respective oxoammonium cation, which is reduced back to the nitroxide through the oxidation of nitrite to .NO2. Hence, the nitroxide slows down the decomposition of .NO2 into nitrite and nitrate and could serve as a reservoir of .NO2 unless the respective oxoammonium is rapidly scavenged by other reductant. This mechanism can contribute toward the protective effect of nitroxides against reactive nitrogen-derived species, although the oxoammonium cations themselves might oxidize essential cellular targets if they are not scavenged by common biological reductants, such as thiols.

The unexpected reaction of tetrakis[di-tert-butyl(methyl)silyl]disilagermirenes (1a and 1b) with GeCl2.dioxane results in the quantitative formation of trans-1,2-dichloro-1,2,3,4-tetrakis[di-tert-butyl(methyl)silyl]-3Delta-1,2,3,4-disiladigermetene, 2, representing the first cyclotetrametallene containing two different heavier group 14 elements and the first digermene incorporated in a four-membered ring. trans-1,2-Dichloro-1,2,3,4-tetrakis[di-tert-butyl(methyl)silyl]-3Delta-1,2,3,4-disilagermastannetene (8), with a Ge=Sn double bond, was also prepared by the reaction of 1 with SnCl2.dioxane. The crystal structure of 2 was established by X-ray crystallography, which showed a folded four-membered ring skeleton with a long Ge=Ge double bond (2.2911(4) A). The structural peculiarities of 2, as well as the possible mechanism of its formation, are also discussed.

Free-radical mediated stannylcarbonylation of azaenynes provides a general [n + 1]-type annulation approach leading to alpha-stannylmethylene lactams. The cyclization is unusual in its breadth, covering 4-exo, 5-exo, 6-exo, 7-exo, and 8-exo modes.

A novel polymer hybridization method, “polymer scrambling”, was developed on the basis of the macromolecular radical crossover reaction between the main chains of dynamic covalent polymers. The macromolecular crossover reaction was successfully monitored by GPC and NMR measurements. The present methodology is innovative for the preparation of novel polymer hybrid materials at the nanometer scale.

Phosphoric esters of secondary alcohols are ubiquitous in biological systems. However, despite the obvious interest of the corresponding difluoromethylene phosphonates as isopolar mimics, a single example of such an analogue featuring this particular substitution pattern has so far been reported in the literature, due to synthetic problems associated with their preparation. The lithium salt of diethyl difluoromethylphosphonothioate 28d provides a solution to this problem, as demonstrated by an 8-step synthesis of all five fully protected analogues of nucleoside 3'-phosphates in 9-18% overall yield, from readily available ketones. Sulfur is shown to play a crucial role in the introduction of the phosphorus-substituted difluoromethylene unit onto the furanose ring. Complete diastereoselectivity is observed in the three steps of the process requiring stereocontrol. The key conversion of the P=S bond into its oxygenated analogue is simply achieved by use of m-chloroperoxybenzoic acid. It is noteworthy that the synthesis can be carried out on large scale: a 31-g batch of compound 26b has been prepared. The deprotected nucleoside 3'-phosphate analogues can be liberated from their precursors as exemplified by the conversion of 7b, 8b, and 9b into the corresponding difluorophosphonic acids, isolated in the form of their disodium salts.

A macrodiolide antibiotic pamamycin-607 was synthesized by joining two hydroxy acid components. Three cis-2, 5-disubstituted tetrahydrofuran rings in the molecule were stereoselectively prepared by radical cyclization reactions of beta-alkoxyvinyl ketone intermediates and a beta-alkoxymethacrylate substrate. The key step of the synthesis is characterized by the predominant threo product formation in the radical cyclization reaction of a beta-alkoxymethacrylate intermediate.

The rate of coupling of alkyl radicals with the persistent aminoxyl radical 1,1,3,3-tetramethylisoindolin-N-oxyl (1) has been used as a kinetic probe to determine absolute rate coefficients for the addition of alkyl radicals to methyl acrylate. The results are discussed in terms of the role of the structure and functionalization of the attacking radical on the rates of addition, particularly as they affect steric, polar, and enthalpic factors. The aminoxyl method is assessed against other methods for determining free radical addition rate coefficients.

Polar effects are demonstrated to play an important role in controlling the reactivity of polyaromatic sigma-radicals that are structurally related to the active intermediates of the enediyne anticancer type antibiotics. This was accomplished by measuring the rate constants of hydrogen atom abstraction for novel, charged dehydroquinolines, dehydroisoquinolines, dehydrobenzenes, and dehydronaphthalenes in the gas phase by using Fourier-transform ion cyclotron resonance mass spectrometry. The reactivity trends observed for these radicals upon hydrogen atom abstraction from tetrahydrofuran and 2-methyltetrahydrofuran, simple models of deoxyribose, do not reflect differences in reaction exothermicities, radical sizes, exact location of the radical site in the ring system, or heteroatom-radical site distances. However, the reactivity trends match the trend in the calculated electron affinities of the radicals. The radicals' different electrophilicities result in variations in the reaction barrier due to different extents of polarization of the transition state. Generally, the reaction efficiencies are the greatest when the formally charged heteroatom is contained within the same ring system as the radical site. In this case, polar effects have the greatest influence on radical reactivity. Hence, insertion of a basic heteroatom (which gets protonated in biological systems) into specific locations in the polyaromatic ring system of the sigma-biradicals, which ultimately cause cleavage of DNA exposed to the enediyne antitumor drugs, should allow tuning of the reactivity of these radicals.

The authors examined the AIBN-induced radical reaction of n-octyl bromide (1) (Scheme 1) with Bu{sub 3}SnH under CO pressure in hope of trapping of carbon monoxide by octyl radical followed by hydrogen abstraction from tin hydride. When the reaction on a 0.5-mmol scale was conducted under CO pressure, using an autoclave with an inserted glass tube (5 mol % of AIBN, benzene (10 mL), 80{degree}C, 3 h), the desired aldehyde 2 was obtained together with n-octane (3), formed via simple reduction of 1. Surprisingly, this radical/CO trapping sequence proceeds even at 15 atm of CO pressure to give 2 in 38% yield (run 2). Generally, higher pressures of CO resulted in the increase of 2. These results demonstrate that the control of the relative concentrations of CO to tin hydride is an important factor to effect the CO trapping leading to aldehyde 2.

Dibutyl(trifluoromethanesulfoxy)stannane (Bu2Sn(OTf)H, 1a) was found to be very valuable for highly diastereoselective homolytic hydrostannylation of allyl and homoallyl alcohols. alpha,beta-Disubstituted allyl alcohols and alpha,gamma-disubstituted homoallyl alcohols were converted into gamma- and delta-stannylated alcohols with high 1,2-syn and 1,3-syn diastereoselectivity, respectively. The origin of the stereochemical outcomes can be rationalized by conformational fixation of the intermediary beta-stannylalkyl radical by coordination of the hydroxy group to the Lewis acidic tin center.

The reactions of stable cyclic dialkylgermylene 2 and dialkylstannylene 3 with 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) radical (2 equiv) gave the corresponding 1:2 adducts 4 and 5, respectively, which were characterized by NMR, MS, and X-ray analyses. The kinetics of the stepwise addition of two TEMPO molecules to germylene 2 revealed that the initial addition of TEMPO to 2 was 1010 times slower than the second TEMPO addition to the resulting germyl radical. The origin of the rate difference was discussed on the basis of the qualitative perturbation theory. In contrast to the reactions of 2 and 3, the reaction of dialkylsilylene 1 with TEMPO gave an interesting 1,3-dioxadisiletane derivative.