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Knitting: Recently Antonchick and Manna described a unique annulation that knits together three acetophenones to construct cyclopropanes. The cascade is mediated by organocopper and free radical species, and amounts to the first known [1+1+1] cyclotrimerization. It works well for ketones having electron-deficient or electron-rich substituents in their aryl rings. DTBP=di-tert-butylperoxide.

John C. Walton and Raphael C. Mordi acknowledge the financial support of EaStCHEM. Canthaxanthin is a carotenoid that lacks pro-vitamin A activity but is known to have antioxidant activity. The products of its oxidation in oxygen were found to be mainly substituted apo-carotenals and apo-carotenones. The product profile resembles that obtained in the oxidation of β-carotene, except that with canthaxanthin these products are the 4-oxo-β-apo-carotenals and 4-oxo-β-apo-carotenones. Epoxides and diepoxides were clearly identified from β-carotene oxidation but in contrast, with canthaxanthin, apart from 5,6-epoxy-canthaxanthin, which was detected at the early stage of oxidation and minor quantities of 5,6-epoxy-β-ionone and 5,6-epoxy-4-oxo-β-apo-11-carotenal, no other epoxides were detected. The identities of these products lead us to suggest that the mechanism of canthaxanthin oxidation bears significant similarity to that of β-carotene. Postprint

Heterogeneous semiconductor photoredox catalysis (SCPC), particularly with TiO2, is evolving to provide radically new synthetic applications. In this review we describe how photoactivated SCPCs can either (i) interact with a precursor that donates an electron to the semiconductor thus generating a radical cation; or (ii) interact with an acceptor precursor that picks up an electron with production of a radical anion. The radical cations of appropriate donors convert to neutral radicals usually by loss of a proton. The most efficient donors for synthetic purposes contain adjacent functional groups such that the neutral radicals are resonance stabilized. Thus, ET from allylic alkenes and enol ethers generated allyl type radicals that reacted with 1,2-diazine or imine co-reactants to yield functionalized hydrazones or benzylanilines. SCPC with tertiary amines enabled electron-deficient alkenes to be alkylated and furoquinolinones to be accessed. Primary amines on their own led to self-reactions involving C–N coupling and, with terminal diamines, cyclic amines were produced. Carboxylic acids were particularly fruitful affording C-centered radicals that alkylated alkenes and took part in tandem addition cyclizations producing chromenopyrroles; decarboxylative homo-dimerizations were also observed. Acceptors initially yielding radical anions included nitroaromatics and aromatic iodides. The latter led to hydrodehalogenations and cyclizations with suitable precursors. Reductive SCPC also enabled electron-deficient alkenes and aromatic aldehydes to be hydrogenated without the need for hydrogen gas.

Multivariate statistical techniques are applied to particulate matter (PM) and meteorological data to identify the sources responsible for evening PM spikes at Sunland Park, NM (USA). The statistical techniques applied are principal components analysis (PCA), redundancy analysis (RDA), and absolute principal components scores analysis (APCSA), and the data evaluated are 3-h average (6-9 p.m.) PM(2.5) mass and chemical composition and 1-h average PM(2.5) and PM(10) mass and environmental data collected in the winter of 2002. Although the interpretation of the data was complicated by the presence of sources which are likely changing in time (e.g. brick kilns), the multivariate analyses indicate that the evening high PM(2.5) is associated with burning-activities occurring to the south of Sunland Park, and these emissions are characterized by elevated Sb, Cl(-), and elemental carbon; approximately 68% of the PM(2.5) mass can be attributed to this source. The PM(10) evening peaks, on the other hand, are mainly caused by resuspended dust generated by vehicular movements south of the site and transported by the local terrain-induced drainage flow.

The reaction is proposed to proceed via a radical decarboxylation-addition-cyclization pathway initiated by SET from the acids to photo-excited maleimide.

Photochemical reactions employing TiO2 and carboxylic acids under dry anaerobic conditions led to several types of C–C bond-forming processes with electron-deficient alkenes. The efficiency of alkylation varied appreciably with substituents in the carboxylic acids. The reactions of aryloxyacetic acids with maleimides resulted in a cascade process in which a pyrrolochromene derivative accompanied the alkylated succinimide. The selectivity for one or other of these products could be tuned to some extent by employing the photoredox catalyst under different conditions. Aryloxyacetic acids adapted for intramolecular ring closures by inclusion of 2-alkenyl, 2-aryl, or 2-oximinyl functionality reacted rather poorly. Profiles of reactant consumption and product formation for these systems were obtained by an in situ NMR monitoring technique. An array of different catalyst forms were tested for efficiency and ease of use. The proposed mechanism, involving hole capture at the TiO2 surface by the carboxylates follow...

OA funded through the RCUK OA block grant. Selective syntheses are now available for compounds of many classes, based on C-centered radicals, exploiting a diverse range of mechanisms. The prospect for chemistry based around N- and O-centered radicals is probably more favorable because of the importance of heterocycles as biologically active materials. Heteroradical chemistry is still comparatively underdeveloped due to the need for safe and easy ways of generating them. Oxime esters appeared promising candidates to meet this need because literature reports and our EPR spectroscopic examinations showed they readily dissociated on photolysis with production of a pair of N- and O-centered radicals. It soon became apparent that a whole suite of benign oxime-containing molecules could be pressed into service. The bimodality of the oxime motif meant that by suitable choice of functionality the reactions could be directed to yield selectively products from either the N-centered radicals or from the O-centered radicals. We found that on one hand photolyses of acetophenone oxime esters of carboxylic acids yielded alicyclics. On the other hand, aromatic and heteroaromatic acyl oximes (as well as dioxime oxalates) afforded good yields of phenanthridines and related heterocycles. Easily prepared oxime oxalate amides released carbamoyl radicals, and pleasingly, β-lactams were thereby obtained. Oxime carbonates and oxime carbamates, available via our novel 1,1'-carbonyldiimidazole (CDI)-based preparations, were accessible alternatives for iminyl radicals and hence for phenanthridine preparations. In their second modes, these compounds proved their value as precursors for exotic alkoxycarbonyloxyl and carbamoyloxyl radicals. Microwave-assistance was shown to be a particularly convenient procedure with O-phenyl oxime ethers. The iminyl radicals generated from such precursors with alkene, alkyne, and aromatic acceptor substituents furnished pyrrole, quinoline, phenanthridine, benzonaphthiridine, indolopyridine, and other systems. Microwave irradiations with 2-(aminoaryl)alkanone O-phenyl oximes enabled either dihydroquinazolines or quinazolines to be obtained in very good yields. The fine quality of the EPR spectra, acquired during photolyses of all the O-carbonyl oxime types, marked this as an important complement to existing ways of obtaining such spectra in solution. Quantifications enabled SARs to be obtained for key reaction types of N- and O-centered radicals, thus putting mechanistic chemistry in this area on a much firmer footing. Surprises included the inverse gem-dimethyl effect in 5-exo-cyclizations of iminyls and the interplay of spiro- with ortho-cyclization onto aromatics. Insights into unusual 4-exo-cyclizations of carbamoyl radicals showed the process to be more viable than pent-4-enyl 4-exo-ring closure. Another surprise was the magnitude of the difference in CO2 loss rate from alkoxycarbonyloxyl radicals as compared with acyloxyl radicals. Their rapid 5-exo-cyclization was charted, as was their preferred spiro-cyclization onto aromatics. The first evidence that N-monosubstituted carbamoyloxyls had finite lifetimes was also forthcoming. It is evident that oxime derivatives have excellent credentials as reagents for radical generation and that there is ample room to extend their applications to additional radical types and for further heterocycle syntheses. There is also clear scope for the development of preparative procedures based around the alkoxyl and aminyl radicals that emerge downstream from oxime carbonate and oxime carbamate dissociations. Publisher PDF

Kaskaden-, Domino- und Tandemreaktionen, bei denen zwei oder mehr chemische Umwandlungen als Eintopfreaktionen ablaufen, werden immer popularer, da sie die Effizienz von Synthesen verbessern und die Umwelt weniger belasten. Diese Kaskaden enthalten nicht nur mechanistische Glanzstucke, sondern ermoglichen auch kompakte und elegante Synthesen komplexer Naturstoffe. Langere Kaskaden erfordern allerdings eine Vielzahl funktioneller Gruppen, die an ganz bestimmten Stellen in sorgfaltig entworfenen Startmolekulen angeordnet sein mussen. Wir geben hier einen Uberblick uber die sagenhafte Spannweite von Kaskaden unimolekularer Radikalreaktionen und stellen ein nutzliches System zur Klassifizierung solcher Kaskaden vor. Es dient zur Bewertung und zum Vergleich von Kaskadenreaktionen und hilft beim Design von Synthesen fur Polycyclen. Kaskadenreaktionen von Dienen unter doppelter Cyclisierung fuhren zu Cyclopentylcyclopentan- oder Bicyclo[3.3.0]octanderivaten. Aus Vorstufen mit einem Ring als Templat liesen sich stereokontrolliert Triquinane und viele hierzu verwandte Verbindungen synthetisieren. Unter den Kaskadenreaktionen mit Ringspaltungen sind die zu Ringerweiterungen fuhrenden die nutzlichsten, denn sie machen auch Polycyclen mit mittleren Ringen zuganglich. Die entscheidenden Designmerkmale grosartiger dreistufiger Kaskaden, mit denen Steroidgeruste teilweise oder vollstandig erhalten werden, sind linear angeordnete Radikalacceptoren mit Methylgruppen an jedem funften C-Atom in dem als Vorstufe dienenden Polyen. Die Ringspaltung ist die Umkehrung der Cyclisierung. Besonders bei symmetrischen Strukturen kann dies zu reversiblen Sequenzen fuhren und damit endlos sich wiederholende Kaskaden auslosen, die von wunderbar fluktuierenden Strukturen getragen werden. Das Arbeitsgebiet der „Programmierung“ organischer Molekule, um Produktstrukturen gezielt zu erhalten, entwickelt sich rasch. Koordinierung und Klassifizierung der noch ungeordneten Datenmengen auf diesem Gebiet sollen das Design erleichtern und somit immer mehr und auch komplexere Strukturen zuganglich machen.

Photodimerization of carboxylic acids and alkylations of alkenes with carboxylic acids are promoted by TiO2 or platinized TiO2.

Applications of microwave (MW)-assistance to radical-mediated organic preparations and procedures are reviewed. Radical additions and cyclisations onto a wide range of acceptors benefited from the technique, as did organic halide reductions by tin hydrides and numerous cascade and sequential processes. Reaction times of chain processes initiated by AIBN were, in several cases, reduced to a few minutes. Regioselectivity in radical additions and ring closures was normally maintained under MW conditions, although stereoselectivities were usually poorer. MW methods have been developed for generation of C-, N-, O-, S- and P-centred radicals. As a result of this a notable number and diversity of heterocycles have been accessed. MW-methods have opened up several new and innocuous alternatives to toxic organotin reagents. Alkoxyamines smoothly release C-centred radicals and oxime ethers provide a variety of iminyl radicals on MW heating. In addition, several types of organo-element and organometallic precursors have yielded novel C-centred and hetero-radicals. To date applications of MW-assistance to homolytic processes are comparatively limited, but it is clear the alliance of the two holds a lot of promise.

When Iris germanica , Hydrocotyle verticillata , Glyceria maxima and Juncus effusus plants were treated anoxically and subsequently returned to air, long-lived free radicals were rapidly generated in the plant tissues and were detected by EPR spectroscopy. The free radicals in I. germanica rhizomes were extracted into aqueous alkali; the EPR spectrum of the aqueous solution showed fine structure which indicated the presence of at least two oxygen-centred radicals. The EPR data, and the radical lifetimes, suggested that they were probably semiquinone radical anions. Product analysis of the alkaline extract indicated that the main components were a set of flavonoids including quercetin, irisolone, selenone and derivatives of irigenin. The main flavonoids had more reduced and/or more alkylated structures than those from I. germanica grown under normal aerobic conditions. Semiquinone radical anions can readily be generated from quercetin, and similar flavonoids with 1,2-dihydroxy-, 1,4-dihydroxy- or trihydroxy-substitution patterns, by interaction with superoxide. However, the EPR-detected radicals were probably derived from flavonoids more heavily substituted than quercetin.

Oxime carbonates (I), (III), (V) and (VII) are found to be excellent precursors for the generation of iminyl radicals under UV irradiation.

EPR spectroscopic observations and product studies showed that the trimethylsilyl group undergoes 1,2-migration from carbon to nitrogen in aminyl radicals, Me 3 SiCh 2 O . → . CH 2 NHSiMe 3 , and from carbon to oxygen in alkoxyl radicals, Me 3 SiCh 2 O . → . CH 2 OSiMe 3 .

The rearrangement of the bicyclo[1.1.1]pentan-1-ylmethyl radical (9) and the bicyclo[2.1.1]hexan-1-yl-methyl radical (10) to the corresponding methylenecycloalkylmethyl radical (11, 12) has been studied kinetically by EPR spectroscopy and, in the case of 10, by tributyltin hydride reduction. Activation energies of 7.1 ± 1.2 kcal mol–1 and 9.3 ± 0.5 kcal mol–1 have been determined for 9 and 10, respectively, while the corresponding pre-exponential factors have been determined to be 12.3 ± 1.5 and 12.0 ± 1.0, respectively. Rearrangement of 9 has an unusually low activation barrier; this has also been investigated by ab initio molecular-orbital calculations. UHF/3-21 G level of theory predicts a barrier of 7.8 kcal mol–1, in excellent agreement with that obtained experimentally, while a somewhat higher value (11.2 kcal mol–1) is predicted at the UHF/6-31 G* level. All of these data indicate that relief of ring strain is a major contributing factor to the rapid rearrangement of these radicals.

Hydrogen abstraction from thiophen-3(2H)-ones gives 3-oxothiophen-2-yl radicals which have been observed by EPR spectroscopy at temperatures below ambient. The structures, enthalpies of formation, and spin densities of these species have been investigated by semiempirical SCF MO methods. The radicals readily couple to give dimers which (except for 2-substituted 3-hydroxythiophenes) are susceptible to a second hydrogen abstraction step to give extensively delocalized dimeric radicals; EPR spectroscopy showed the 5,5′-disubstituted dimeric radicals to be significantly persistent even at higher temperatures. A mechanism for the oxidation of thiophen-3(2H)-ones by air and one-electron oxidants is proposed and justified.

Oxiranylmethyl and 3-methyl-3-oxetanylmethyl radicals were generated from the corresponding bromides and their rearrangements to allyloxyl and 2-methylprop-2-enyloxymethyl radicals respectively, were studied by kinetic EPR spectroscopy. The former radical was shown to ring open with a rate constant o⪢ 4 x 108 s−1 at 25°C. The following kinetic parameters were measured for ring opening of the latter radical: k(25°C) = 8.9 x 102 s−1, log[A/s−1] = 13.97, E/kJ mol−1 = 63.3. Comparison of this data with that of related radicals supported the proposal that the transition state for β-scission of three-membered and four-membered cycloalkylmethyl radicals has dipolar character.

A series of 4-substituted cubyl radicals was generated by bromine atom abstraction from 1-bromo-4-substituted cubanes. EPR observations showed that the cubyl radicals abstracted secondary hydrogen atoms from the ethyl groups of triethylsilane and decayed mainly by second-order combination reactions. tert-Butoxyl radicals abstracted hydrogen atoms from cubane at least 26 times more rapidly than from cyclopropane at -90 o C. Electron-withdrawing substituents on cubane greatly reduced this rate. tert-Butoxyl radicals selectively abstracted the cage hydrogens rather than primary methyl hydrogens from methylcubane

Tricyclo [3.1.1.03,6]hept-6-yl radicals were generated by bromine abstraction from 6-bromo-tricyclo[3.1.1.03,6] heptane , and observed by e.p.r. spectroscopy. In spite of their high ring strain the radicals were found not to rearrange readily but to take part in bimolecular combination reactions and to abstract hydrogen from the methylene groups of triethylsilane. Similar treatment of 6-bromomethyltricyclo[3.1.1.03,6] heptane gave tricyclo [3.1.1.03,6]hept-6- ylmethyl radicals, which rearranged so rapidly that only the product of β-scission, the 6-methylenebicyclo[3.1.1]hept-3-yl radical, was observed spectroscopically . The rate constant for β-scission of the tricyclo [3.1.1.03,6]hept-6-ylmethyl radical, estimated from e.p.r. experiments and also from reduction of 6-bromomethyltricyclo[3.1.1.03,6] heptane with tributyltin hydride, was found to be >5×109 s-1 at 298 K.

3-Methylcyclohexa-1,4-diene-3-carboxylates and 2-methyl-2,5-dihydrofuran-2-carboxylates decompose to generate free alkyl radicals which have been incorporated into chain reactions producing alkyl bromides, alkene adducts and ring-closure products.

Absolute rate constants for reactions of bicyclo[1.1.1]pent-1-yl radicals with α-methylstyrene (1.4 × 10 7 M −1 s −1 ) and 1,4-cyclohexadiene (4.6 × 10 5 M −1 s −1 ) at 25° C were measured by laser flash photolysis. This bridgehead radical is more reactive than tert -butyl which we attribute to its high s -character and the absence of steric shielding of the radical center.

3-Substituted cyclohexadienyl radical generated by hydrogen abstraction from 3-alkylcyclohexa-1,4-diene-3-carboxylic acids readily fragment to produce alkyl radicals and benzoic acid; suitably functionalised alkyl groups cyclize in moderate yields.

3-Methylcyclohexa-1,4-diene-3-carboxylic acid and 2-methyl-2,5-dihydrofuran-2-carboxylic acid were prepared by Birch reduction and alkylation of benzoic and furoic acid respectively and converted to alkyl esters. Cyclohexadienyl and 2,5-dihydrofuranyl radicals were generated by hydrogen abstraction and characterised by EPR spectroscopy. The esters decomposed thermally in the presence of a radical initiator to generate alkyl radicals which could be trapped with moderate efficiency by halogen donors or alkenes. Loss of methyl to afford an alkyl benzoate was an important side reaction at higher temperatures. From the thermal reaction of hex-5-enyl 3-methylcyclohexa-1,4-diene-3-carboxylate the rate constant for hydrogen abstraction from the ester by hexenyl radicals was determined to be 0.82 × 105 dm3 mol-1 s-1 at 140 °C.

The activation energies of unimolecular homolytic reactions (Er) are predicted to correlate linearly with the mid-point temperatures (Tmid) defined as the temperature at which the rearranged and unrearranged species are of equal concentration, for photochemically initiated processes under EPR conditions. A linear relationship (Er/kcal mol–1 = 0.044Tmid + 0.22) has been demonstrated from experimental data and shown to hold for a range of solvents and instrumental configurations. The relationship will facilitate the determination of kinetic parameters, particularly for processes where the spectra of the intermediates are of low intensity.

Hydrogen abstraction from N-alkoxycarbonyldihydropyridines generated azacyclohexadienyl radicals (pyridinyl radicals) which are characterised by EPR spectroscopy. In the presence of peroxide initiators, N-alkoxycarbonyl-1,2-dihydropyridines decomposed with production of pyridine, the corresponding alkyl formate, alkyl benzoate and alkanol being formed as the major products. Absence of cyclised products in experiments with substrates containing hex-5-enyl, pent-4-enyloxy etc. units demonstrates that radical production must be minor and that N-alkoxycarbonylazacyclohexadienyl radicals do not readily undergo β-scission of the exocyclic N–C bond. The most probable mechanism is a direct 1,2-elimination of formate. The alcohols which accompanied the other products are probably formed by hydrolysis of the formates and benzoates. Analogous chemistry is displayed by N-alkoxycarbonyl-1,4-dihydropyridines at higher temperatures where 1,4-elimination of formate is too rapid for homolytic radical production to compete.

An urgent search is being made for generic reagents that promote free radical synthetic transformations as means of banishing the toxic threat of organotin hydrides. Although second-generation tin reagents are beguiling, organosilanes and a range of thiocarbonyl compounds are more intrinsically benign. Metal-free radical chain sequences based around cyclohexadiene derivatives are being developed (see reaction scheme), and tetrathiafulvalenes mimic metals and allow a crossover from homolytic to ionic chemistry. Z=alkene.

Cascade, domino, or tandem processes, that link together two or more transformations in one pot, are increasing in popularity because they lead to improvements in synthetic efficiency and decreases in environmental impact. Not only do these cascades contain choice mechanistic gems but they also deliver compact and elegant syntheses of complex natural products. Longer cascades require more functional groups precisely configured within carefully designed initial molecular architectures. Such "purposeful" molecules can be thought of as chemical algorithms.This article surveys the phenomenal range of unimolecular free-radical cascades. A convenient system for classifying free-radical cascades is described that is useful for evaluating and comparing cascades and aids the design of synthetic routes to polycyclic structures.Double cyclization cascades lead to cyclopentylcyclopentane or bicyclo[3.3.0]octane derivatives. Precursors that contain a ring as a template have been used to control stereochemistry in syntheses of triquinanes and many related compounds. Of the cascades containing ring-cleavage steps, the most useful are the ring expansions which have opened up new synthetic routes to medium ring polycycles.The key design features of three-stage unimolecular free-radical cascades that yielded steroid structures, are linear arrays of radical acceptor units associated with methyl groups distributed every fifth C-atom in the precursor polyenes. Ring cleavage is the reverse of cyclization. In special, symmetrical structures, therefore, this led to sequences that were reversible, thus launching endlessly repeating cascades supported by delightfully fluxional structures. The science of "programming" organic molecules to achieve particular target structures is maturing rapidly. Coordination and classification of the welter of information in this area is intended to facilitate design and hence to extend the range and complexity of attainable structures.

Synthetic routes to pure 1-phenylcyclohexa-2,5-diene-1-carboxylic acid and derived esters were developed. Esters containing appropriately unsaturated side chains generated the corresponding alkenyl radicals and hence gave good yields of 5-exo ring closure products in organotin-free reactions. Extrusion of phenyl radicals from the intermediate cyclohexadienyl type radicals was not observed, and this alternative β-scission did not compete under any conditions. Yields from alkylations of olefins in analogous intermolecular processes were, however, poor. As a spin-off from the research, it was found that 1-phenylcyclohexa-2,5-diene-1-carboxylic acid (6) was a useful source of hydroxyformyl (formate) radicals in organic solvents.

Undue influence: N-heterocyclic carbenes (NHCs) were found to reduce the strength of the B-H bonds of borane by a surprisingly large amount upon the formation of NHC-BH(3) complexes. This property was exploited in the development of a suite of NHC-borane complexes for the reduction of xanthates in radical-mediated Barton-McCombie-type deoxygenation reactions (see scheme). AIBN = azobisisobutyronitrile, Bn = benzyl.

Acyl oximes derived from a variety of indolylalkanones underwent a ring closure sequence during FVP to afford 9H-pyrido[2,3-b]indoles. Unlike UV light promoted reactions of oxime esters, the mechanism is almost certainly not mediated by iminyl radicals but probably involves tautomerism, elimination of acetic acid, and a final electrocyclic ring closure.