Aryl Oxalate Derivatives as Convenient Precursors for Generation of Aryloxyl Radicals

The use of aryloxy oxalyl chlorides (AOCs), aryloxy oxalyl tert-butyl peroxides (AOBs), and diaryl oxalates (DAOs) for unimolecular generation of phenoxyl-based radicals under solution and rigid matrix conditions is described. AOCs are usable for photochemical generation of phenoxyl radicals, but are only conveniently stable as precursors when 2,6-di-tert-butylated derivatives are used. AOBs may be used as thermal precursors to aryloxyl radicals, since they typically decompose within 2-3 h at 60-85 degrees C to give phenols. (1)H-NMR solution kinetic studies find that DeltaH() = 31 kcal/mol, and DeltaS() = +3.4 cal/mol-K for decomposition of phenoxyoxalyl tert-butyl peroxide, consistent with substantial concertedness in peroxide bond cleavage. AOBs and the more stable DAOs are also convenient photochemical phenoxyl radical precursors. AOBs yield phenoxyl radicals more readily by photolysis than do corresponding DAOs, but the DAOs have fewer side reactions that can quench the product phenoxyl radicals.     

Nitroxide radicals as probes for exploring the binding properties of the cucurbit[7]uril host

EPR spectroscopy was used for the first time to explore the binding properties of cucurbit[7]uril (CB7), a representative member of the cucurbituril family. Evidence for the formation of a complex between nitroxide radicals and the host system in an aqueous solution was provided by large changes in the nitrogen hyperfine splitting, attributed to the different polar environments experienced by the included radical. In the presence of alkali cations, the EPR spectra of benzyl tert-butyl nitroxide were characterised by new signals attributed to the radical hosted in the CB7 cavity in which one metal cation is in close contact with the nitroxidic oxygen. The formation of the coordination complex results in a substantial increase in the electron spin density on the nitrogen in inverse order with respect to the size of the cation owing to increased localisation of negative charge on the oxygen atom from bonding to the alkali cation. The EPR spectra showed selective line-broadening effects as a result of metal exchange between bulk water and the coordination complex. Analysis of the EPR linewidth variations allowed us to measure the corresponding kinetic rate constants for the first time. NMR spectroscopy showed that this behaviour is not peculiar to nitroxides but is also exhibited by the related carbonyl compounds. These data allowed us to quantify the template effect and to reach the conclusion that, in the presence of a guest having a coordinating lone pair, the formation of ternary metal-guest-CB complexes must be taken into account when discussing the complexation behaviour of cucurbituril derivatives in the presence of salts.     

EPR studies on electron transfer reactions between O-benzoyl-N-alkylhydroxylamines and perfluoroacyl peroxides. Generation of n- and sec-alkyl perfluoroacyl nitroxides and sec- and tert-alkyl perfluoroalkyl nitroxides

Both EPR studies and product analysis have disclosed that the oxidation of O-benzoyl-N-alkylhydroxylamines (1, 4, 7) by perfluoroacyl peroxides (2) is an electron transfer-initiated process. Depending on the nature of the alkyl groups in the substrates, the caged radical pair CP₁ (RN OCOPh, R_fCOO) may react through different radical pathways resulting in different nitroxides along with the neutral products. With primary, benzyl and secondary alkyl groups, a 1,2-acyl shift becomes the predominant pathway resulting in acyl nitroxides (3, 5). With tert-alkyl groups such as tert-butyl, tert-alkyl perfluoroalkyl nitroxides (8) are formed via β-scission of both RN*OCOPh and R_fCOO*. A general mechanistic pathway is proposed for the titled reactions generating the quite useful fluorinated nitroxides.     

Synthesis of an extremely crowded naphthalene via a stable norbornadienone.

Computational studies at the HF/3-21G and B3LYP/6-31G(d) levels suggest that 5,6,8-tri(tert-butyl)-1,2,3,4-tetraphenylnaphthalene (2) is perhaps the most crowded naphthalene derivative that will show normal stability; more highly congested naphthalenes will prefer to exist as the corresponding Dewar isomers. Initial attempts to prepare 2 by reacting 3,4,5,6-tetraphenylbenzyne with 2,3,5-tri(tert-butyl)cyclopentadienone at 83 degrees C gave instead a stable norbornadienone, 1,2,4-tri(tert-butyl)-5,6,7,8-tetraphenyl-9-oxo-1,4-dihydro-1,4-methanonaphthalene (3), which was characterized by X-ray crystallography. The experimental and calculated (HF/3-21G) activation energies (E(a)) for the decarbonylation of 3 were quite high: 39 and 46 kcal/mol, respectively, a manifestation of the substantially increased strain in the transition state as the tert-butyl groups are forced together. The naphthalene 2 was obtained in good yield by heating 3 in refluxing toluene, and its X-ray structure showed exceptional distortions from a normal naphthalene geometry. However, 2 is not completely stable, and it decomposes upon prolonged heating in xylenes.     

The palladium-catalysed copper-free Sonogashira coupling of isoindoline nitroxides: a convenient route to robust profluorescent carbon-carbon frameworks

A series of novel acetylene-substituted isoindoline nitroxides were synthesised via palladium-catalysed copper-free Sonogashira coupling. These results demonstrate that the Sonogashira reaction is suitable for the generation of a wide range of aryl nitroxides of expanded structural variety. The novel aryl-iodide containing nitroxide, 5-iodo-1,1,3,3-tetramethylisoindolin-2-yloxyl, 3, was a key intermediate for this coupling, giving acetylene-substituted isoindoline nitroxides in high yield. Subsequent reaction of the deprotected ethynyl nitroxide 12 with iodinated polyaromatics furnished novel aromatic nitroxides with extended-conjugation. Such nitroxides have been described as profluorescent, as their quantum yields are significantly lower than those of the corresponding diamagnetic derivatives. The quantum yields of the naphthyl- and phenanthryl-acetylene isoindoline nitroxides (13 and 14) were found to be 200-fold and 65-fold less than the non-radical methoxyamine derivatives (23 and 24). Ethyne- and butadiyne-linked nitroxide dimers could also be synthesised by this cross coupling methodology.     

Controlled radical polymerization of styrene in the presence of nitronyl nitroxides

Bulk radical polymerization of styrene in the presence of nitronyl nitroxides (2-(4-substituted phenyl)-4,4,5,5-tetramethyl-4,5-dihydroimidazolyl-1-oxyl 3-oxide) was studied. All nitronyl nitroxides, like other nitroxyl radicals such as 2,2,6,6-tetramethylpiperidine 1-oxyl radical (TEMPO), act as reversible radical scavengers. The efficiency of controlling the polymerization is affected by the substituent at the 4′-position. The efficiency increases with electron donating strength of 4′-substituents, at least at the beginning of the reaction. However, the thermal stability of nitronyl nitroxides decreases in the same order. Thus, TEMPO is more suitable than nitronyl nitroxides for controlled/“living” radical polymerization of styrene.     

The effect of the secondary structure on dissociation of peptide radical cations: fragmentation of angiotensin III and its analogues

Fragmentation of protonated RVYIHPF and RVYIHPF-OMe and the corresponding radical cations was studied using time- and collision energy-resolved surface-induced dissociation (SID) in a Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR MS) specially equipped to perform SID experiments. Peptide radical cations were produced by gas-phase fragmentation of Co (III)(salen)-peptide complexes. Both the energetics and the mechanisms of dissociation of even-electron and odd-electron angiotensin III ions are quite different. Protonated molecules are much more stable toward fragmentation than the corresponding radical cations. RRKM modeling of the experimental data suggests that this stability is largely attributed to differences in threshold energies for dissociation, while activation entropies are very similar. Detailed analysis of the experimental data obtained for radical cations demonstrated the presence of two distinct structures separated by a high free-energy barrier. The two families of structures were ascribed to the canonical and zwitterionic forms of the radical cations produced in our experiments.     

Novel acyclic nitroxides for nitroxide‐mediated polymerization: Kinetic,electron paramagnetic resonance spectroscopic,X‐ray diffraction,and molecular modeling investigations

This work describes the synthesis of new hydrophobic acyclic nitroxides [derived from 2,2,5‐trimethyl‐4‐phenyl‐3‐azahexane‐3‐nitroxide (TIPNO)] designed to be employed in radical miniemulsion polymerization. We present the synthetic strategies employed to obtain these different nitroxides and the determination of certain important parameters, such as the dissociation rate constant, the combination rate constant, and the decomposition rate constant, of the corresponding alkoxyamines. All these new nitroxides give good control of the bulk radical polymerization of styrene in comparison with the parent TIPNO. The molecular structure of some nitroxides presented herein has been elucidated by single‐crystal X‐ray diffraction, and their structural determination helps us to understand better the influence of the nitroxide structure on the activation energy. A molecular modeling study has also been conducted on these new nitroxides, and a good linear correlation between the activation energy and the CNC bond angle for a series of nitroxides with the same type of leaving radical has been found. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 1926–1940, 2006     

Design and use of β-phosphorus nitroxides and alkoxyamines in controlled/“living” free radical polymerizations

Persistent nitroxides and their corresponding alkoxyamines are important regulators of living radical polymerization. Here we describe the synthesis of β-phosphorus nitroxides bearing a β-hydrogen, that present very interesting properties for the control of the radical polymerization of styrenes, acrylates and other monomers. A large series of alkoxyamines derived from these nitroxides was prepared, and Electron Spin Resonance (ESR) was used to determine both the temperature (T_c) and the rate constant (k_d) for their homolysis. For the whole series of alkoxyamines (27 compounds), a very good linear correlation was found between T_c and logk_d. Satisfactory linear correlations were found between T_c and calculated (PM3 method) Bond Dissociation Energy (BDE) of the NO-C bond, for series of alkoxyamines with the same type of leaving radical. The characteristics of free radical polymerization of styrene carried out in the presence of these new nitroxides and alkoxyamines will be discussed.     

Polyaromatic Profluorescent Nitroxide Probes with Enhanced Photostability

Novel profluorescent mono‐ and bis‐isoindoline nitroxides linked to napthalimide and perylene diimide structural cores are described. These nitroxide‐fluorophore probes display strongly suppressed fluorescence in comparison to their corresponding non‐radical diamagnetic methoxyamine derivatives. The perylene‐based probe possessing two isoindoline systems tethered through ethynyl linkages was shown to be the most photostable in solution, demonstrating significantly enhanced longevity over the 9,10‐bis(phenylethynyl)anthracene fluorophore used in previous profluorescent nitroxide probes.     

Electron ionization-induced loss of a methyl radical from 1-cyclopropyl-4-substituted-1,2,3,6 tetrahydropyridine derivatives

The electron ionization mass spectra of 1-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridine derivatives are characterized by a base peak corresponding to [M-15]⁺. Evidence is presented to support a fragmentation process involving an initial cyclopropyl ring opening of the parent cyclopropylaminyl radical cation followed by intramolecular transfer of a hydrogen atom from the ring carbon atoms α to nitrogen to the primary carbon-centered radical and finally a fragmentation step proceeding by loss of a methyl radical and formation of a stable N-ethenyldihydropyridinium ion, the [M-15]⁺ fragment.     

Molecular design of a new class of spin-labeled ribonucleosides with N-tert-butylaminoxyl radicals

We designed a new type of spin-labeled nucleosides with an N-tert-butylaminoxyl radical which is introduced to the nucleobase directly. Purine and pyrimidine ribonucleosides containing the aminoxyl radical such as 1a-d, 2, 3, and 4 were synthesized to investigate the stability and behavior of the N-tert-butylaminoxyl radical on a nucleobase. Lithiation of tri-O-silylated 6-chloropurine ribonucleoside (5) followed by reaction with 2-methyl-2-nitrosopropane (MNP) gave the key compound 6a, which was further converted to 6b-d. Oxidation of the obtained 6a-d and their triols (7a-d) with Ag(2)O led to formation of the corresponding stable spin-labeled nucleosides (8a-d and 1a-d), which were confirmed by EPR spectroscopy. Similarly, the precursors of spin-labeled pyrimidines (13, 20, and 23) were synthesized by site-selective lithiation of tri-O-protected pyrimidine derivatives (9, 18, and 21) followed by the reaction with MNP and deprotection. An EPR study showed that the aminoxyl radicals (2, 3, and 4) were stable and that their hyperfine structures were dependent on the position of the radical. Electron densities of pyrimidine also affected hyperfine structures.     

Parallel kinetic resolution of tert-butyl (RS)-3-alkyl-cyclopentene-1-carboxylates for the asymmetric synthesis of 3-alkyl-cispentacin derivatives

The double mutual kinetic resolution of tert-butyl (RS)-3-benzyl-cyclopentene-1-carboxylate with a 50 : 50 mixture of lithium (RS)-N-benzyl-N-alpha-methylbenzylamide and lithium (RS)-N-3,4-dimethoxybenzyl-N-alpha-methylbenzylamide gives, after protonation with 2,6-di-tert-butylphenol, a 50 : 50 mixture of the readily separable N-benzyl-(1SR,2RS,3RS,alphaRS)- and N-3,4-dimethoxybenzyl-(1SR,2RS,3RS,alphaRS)-beta-amino esters in >98% de in each case. This product distribution indicates that these amides react at very similar rates and with no mutual interference to furnish readily separable products, and are thus ideal for parallel kinetic resolution. The efficient parallel kinetic resolution (E > 65) of a range of tert-butyl (RS)-3-alkyl-cyclopentene-1-carboxylates with a pseudoenantiomeric mixture of homochiral lithium (S)-N-benzyl-N-alpha-methylbenzylamide and lithium (R)-N-3,4-dimethoxybenzyl-N-alpha-methylbenzylamide gives, after separation and N-deprotection, a range of carboxylate protected 3-alkyl-cispentacin derivatives in >98% de and >95% ee.     

The vibrational group frequency of the N-O* stretching band of nitroxide stable free radicals

The group frequency of the N-O radical stretching vibration has received scant attention in the literature. The few existing treatments of the vibrational spectroscopy of nitroxides are incomplete at best and potentially misleading to workers in the field. To close this gap in the available knowledge, the existing literature on the vibrational spectra of nitroxide stable free radicals is critically reviewed with particular reference to the wavenumber position of the N-O stretching vibration, nu(N-O). Poor evidentiary bases for the assignment nu(N-O) were found in many instances. Ab initio Density Field Theory calculations using a model chemistry of UB3LYP at the 6-311++G(d,p) level were performed to obtain a theoretical band position of nu(N-O) for comparison with the published data. Large discrepancies between the theoretical and experimental values were found for the radical 3-carbamoyl-2,2,5,5-tetramethyl-3-pyrrolin-1-yloxyl, which currently sets the lower limit of the accepted wavenumber range of nu(N-O), as well as for the nitronyl and iminyl nitroxides. The wavenumber position of nu(N-O) was found to occur in the range 1450-1420cm(-1) for 5-membered cyclic nitroxides and 1395-1340cm(-1) for 6-membered cyclic and acyclic nitroxides. In nitronyl nitroxides, the symmetric stretching vibration occurs in the region 1470cm(-1), but coupling to other modes makes specific band assignments problematic for the nitronyl nitroxide group.     

Reactions of Substituted Boryl Radicals with Nitroalkanes. EPR, Kinetic, and Product Studies

The radical-initiated reaction of amine-boranes and phosphine-boranes, LBH(3) (L = R(3)N, R(3)P) with aliphatic nitro compounds has been investigated in order to explore the possibility of reducing tertiary nitroalkanes to the corresponding hydrocarbons. In all the examined cases boroxy nitroxides, RN(O(*))OBLH(2), resulting from the addition of ligated boryl radicals, LBH(2)(*), to an oxygen atom of the nitro group were detected and characterized by EPR spectroscopy. This reaction occurs at room temperature with a rate constant of 1.5 x 10(7) M(-)(1) s(-)(1) for LBH(2)(*) = Me(3)NBH(2)(*) and RNO(2) = Me(3)CNO(2). The boroxy nitroxides from tertiary nitroalkanes decay by a fragmentation reaction occurring with cleavage of the nitrogen-oxygen bond, rather than of the carbon-nitrogen bond as would be required for the reduction to the corresponding alkane to take place. The Arrhenius parameters for this fragmentation have been determined in few cases.     

A highly stereoselective, modular route to (E)-vinylsulfones and to (Z)- and (E)-alkenes

A recently discovered radical fragmentation of 2-fluoro-6-pyridinoxy derivatives allows a new highly stereoselective and convergent route to (E)-vinylsulfones from allylic alcohols. Reductive desulfonylation or nickel-catalyzed couplings furnish di- and trisubstituted (E)- and (Z)-alkenes.     

Kinetic stabilization of the o-quinoidal 3,4-benzotropone system

Kinetic stabilization of the o-quinoidal 3,4-benzotropone system was investigated. The parent 3,4-benzotropone undergoes rapid [pi8 + pi10] dimerization in fluid solution even at -78 degree C while triptycene-fused derivative having a tert-butyl group at the C6 position of the tropone moiety was found to be stable indefinitely under similar conditions. The relative importance of the triptycene moiety and the tert-butyl group in for the kinetic stabilization was evaluated.     

Kinetics of pseudoliving free-radical copolymerization of styrene and methyl methacrylate by the reversible addition fragmentation chain-transfer mechanism

The kinetics of copolymerization of styrene with methyl methacrylate in the presence of tert-butyl dithiobenzoate as a reversible addition fragmentation chain-transfer agent has been studied. Formation of radical intermediates has been investigated. In a wide range of monomer mixture compositions, the kinetic features of pseudoliving radical copolymerization of this monomer pair in the presence of both a low-molecular-mass reversible addition fragmentation chain-transfer (RAFT) agent and a polymer RAFT agent being formed are close to the corresponding features of the homopolymerization of styrene.     

Comparative study of the response of membrane electrodes based on calix[6]arene and calix[8]arene derivatives to organic ammonium ions.

p-tert-Butylcalix[8]arene-octaacetic acid octaethyl ester and calix[8]arene-octaacetic acid octaethyl ester well recognized 2-phenylethylamine and phenylalanine methyl ester compared with the corresponding calix[6]arene derivatives. Moreover, the calix[8]arene derivatives, especially one having tert-butyl groups, gave better selectivity against biologically active amines having a complicated structure, such as norephedrine. We considered the interaction between calixarenes and organic ammonium ions from the viewpoint of molecular symmetries.     

Joint theoretical experimental investigation of the electron spin resonance spectra of nitroxyl radicals: application to intermediates in in situ nitroxide mediated polymerization (in situ NMP) of vinyl monomers

Density functional theory (DFT) calculations have been performed to address the structure of nitroxide intermediates in controlled radical polymerization. In a preliminary step, the reliability of different theoretical methods has been substantiated by comparing calculated hyperfine coupling constants (HFCCs) to experimental data for a set of linear and cyclic alkylnitroxyl radicals. Considering this tested approach, the nature of different nitroxides has been predicted or confirmed for (a) the reaction of C-phenyl- N- tert-butylnitrone and AIBN, (b) N- tert-butyl-alpha-isopropylnitrone and benzoyl peroxide, (c) tert-butyl methacrylate polymerization in the presence of sodium nitrite as mediator, and (d) for the reaction of a nitroso compound with AIBN. Values of HFCC experimentally determined have been confirmed by DFT calculations.