A valuable upgrade to the portfolio of cycloaddition reactions

The author thanks EaStCHEM for financial support.Recently Antonchick and Manna described a unique annulation that knits together three acetophenones to construct cyclopropanes. The cascade is mediated by organo-copper 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.PostprintPeer reviewe

Dissociations of free radicals to generate protons, electrophiles or nucleophiles : role in DNA strand breaks

Thanks to the University of St. Andrews and the EaStCHEM Research Computing Facility for financial and computational support.The concept behind the research described in this article was that of marrying the 'soft' methods of radical generation with the effectiveness and flexibility of nucleophile/electrophile synthetic procedures. Classic studies with pulse radiolysis and laser flash photolysis had shown that free radicals could be more acidic than their closed shell counterparts. QM computations harmonised with this and helped to define which radical centres and which structural types were most effective. Radicals based on the sulfonic acid moiety and on the Meldrum's acid moiety (2,2-dimethyl-1,3-dioxane-4,6-dione) were found to be extreme examples in the superacid class. The ethyne unit could be used as a very effective spacer between the radical centre and the site of proton donation. The key factor in promoting acidity was understood to be the thermodynamic stabilisation of the conjugate anion-radicals released on deprotonation. Solvation played a key part in promoting this and theoretical microhydration studies provided notable support. A corollary was that heterolytic dissociations of free radicals to yield either electrophiles or nucleophiles were also enhanced relative to non-radical models. The most effective radical types for spontaneous releases of both these types of reagents were identified. Ethyne units were again effective as spacers. The enhancement of release of phosphate anions by adjacent radical centres was an important special case. Reactive oxygen species and also diradicals from endiyne antibiotics generate C4 '-deoxyribose radicals from nucleotides. Radicals of these types spontaneously release phosphate and triphosphate and this is a contributor to DNA and RNA strand breaks.Publisher PDFPeer reviewe

Radical-stimulated nucleophile release

J.C.W. thanks EaStCHEM for financial support.Experimental and computational results have shown that deprotonation was enhanced for precursors containing radical centers (RED-shift). An examination of whether the inverse heterolytic dissociations that release nucleophiles instead of electrophiles could also be stimulated by suitably sited radicals is reported in this paper. A DFT method was employed to assess the free energies of heterolytic dissociations releasing C-centered and O-centered nucleophiles. In most instances a radical adjacent to the incipient positive charge in the precursors led to significant enhancement of heterolytic dissociation, but inhibition was found in some cases. Greater enhancements were obtained with C-centered rather than O-centered radicals. Exergonic dissociations for both O- and C-centered nucleophiles could be achieved with fluorenylmethyl- and cyclohepta-2,4,6-trienylmethyl-containing precursors. Heterolytic phosphate release from ribose and deoxyribose nucleotide C4' radicals was also found to be enhanced. This provided supporting evidence of the importance of these radicals in DNA and RNA strand breaking. The effect of ethyne, ethene, and phenyl spacer units between the radical center and the incipient positive charge was examined. Evidence was obtained that the key factor promoting heterolytic dissociation was the resonance stabilization of the coreleased radical-cations.PostprintPeer reviewe

Electron spin resonance study of free radicals generated from retinyl- and ionyl-derivatives

Free radicals generated from α- and β-ionyl bromides gave well resolved ESR spectra, but retinyl bromide and chloride gave only broad signals. Delocalised radicals were also spectrosopically observed on hydrogen abstraction from α-ionane, α-ionyltrimethylsilylether and buten-3-ynyl-2,6,6-trimethyl-2-cyclohexene. Retinyl and β-ionyl radicals, derived from the corresponding xanthates, were successfully spin trapped with nitrosodurene. The results suggested that the secondary sites C(7) and C(9) were the most reactive in the β-ionyl radicaland that the secondary sites C(7) and C(11) and probably the primary site C(15) were the most reactive in the retinyl radical

Identification of products from canthaxanthin oxidation

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.PostprintPeer reviewe

EPR and preparative studies of 5-endo cyclizations of radicals derived from alkenyl NHC-boranes bearing tert-butyl ester substituents

J.C.W. thanks EaStCHEM for financial support, and D.P.C. thanks the US National Science Foundation. Computational support was provided through the EaStCHEM Research Computing Facility.Radical H atom abstraction from a set of N-heterocyclic carbene (NHC) complexes of alkenylboranes bearing two tert-butyl ester substituents was studied by EPR spectroscopy. The initial boraallyl radical intermediates rapidly ring closed onto the O atoms of their distal ester groups in 5-endo mode to yield 1,2-oxaborole radicals. Unexpectedly, two structural varieties of these radicals were identified from their EPR spectra. These proved to be two stable rotamers, in which the carbonyl group of the tert-butyl ester was oriented toward and away from the NHC ring. These rotamers were akin to the s-trans and s-cis rotamers of α,β-unsaturated carbonyl compounds. Their stability was attributed to the quasi-allylic interaction of their unpaired electrons with the carbonyl units of their adjacent ester groups. EPR spectroscopic evidence for two rotamers of the analogous methyl ester containing NHC-oxaborole radicals was also obtained. An improved synthetic procedure for preparing rare NHC-boralactones was developed involving treatment of the alkenyl NHC-boranes with AIBN and tert-dodecanethiol.PostprintPeer reviewe

Enhanced proton loss from neutral free radicals : toward carbon-centered superacids

J.C.W. thanks EaStCHEM for financial support.Radical centers close to protons are known to enhance their dissociation. Investigation of the generality of this radical enhanced deprotonation (RED-shift) phenomenon, and the kinds of structures in which it operates, are reported. The pKas for sulfinic, sulfonic, pentan-2,4-dione, and Meldrum's acid species, with adjacent radicals centered on C-, N-, and O atoms, were computed by a DFT method from free energies of deprotonation. All series showed significant RED-shifts that increased with the electronegativity of the radical center. The hugely negative pKa obtained for a Meldrum's acid with an alkoxyl radical substituent showed it to belong to the superacid class. The ethyne unit was found to be uniquely effective at enhancing acidity and conducting RED-shifts through chains up to and beyond 20 atoms. These connector units enable a radical center to alter the pKa of a spatially remote acidic group. RED-shifted species were characterized by conjugate radical anions displaying site exchange of spin with electronic charge.PostprintPeer reviewe

EPR studies on the addition of ligated boryl radicals to carbonyl compounds

J.C.W. thanks EaStCHEM for financial support and D.P.C. thanks the US National Science Foundation. Computational support was provided through the EaStCHEM Research Computing Facility.The boron-centered radicals derived from alkenyl N-heterocyclic carbene (NHC)-boranes bearing ester substituents were recently found to ring close in 5-endo mode by addition to the oxygen atoms of the ester substituents. The inference from this was that NHC-boryl radicals might add intermolecularly to carbonyl-containing substrates. Several different NHC-boryl radicals were generated by H-atom abstraction from NHC-ligated trihydroborates. Electron paramagnetic resonance (EPR) spectroscopy proved that these did indeed add to the oxygen atoms of diaryl ketones with production of the corresponding bora-ketyl radicals. The same unusual regioselectivity of addition was observed with monoaryl ketones, but no bora-ketyls were observed with dialkyl ketones. Similarly, no bora-ketyl adduct radicals were observed with esters, even esters of benzoic acid. EPR spectroscopic evidence suggested that NHC-boryl radicals were also added to the O-atoms of aromatic aldehydes. Amine-boryl and phosphine-boryl radicals were also observed to add to the O-atom of benzophenone with production of the corresponding ketyl radicals.PostprintPeer reviewe

Radical-enhanced acidity : why bicarbonate, carboxyl, hydroperoxyl, and related radicals are so acidic

J.C.W. thanks EaStCHEM for financial support.Comparison of accepted pKa values of bicarbonate, carboxyl, and hydroperoxyl radicals, with those of models having the unpaired electron replaced by H atoms, implied the acidity of the radicals was greatly increased. A Density Functional Theory computational method of estimating pKas was developed and applied to a set of radicals designed to probe the phenomenon of radical-enhanced deprotonation (RED-shift) and its underlying causes. Comparison of the computed pKa values of 12 acid radicals to those of the corresponding model acids confirmed the intensified acidity of the title radicals and also pin-pointed the carboxy-ethynyl (HO2CC≡C•) and the carboxy-aminyl (HO2CNH•) radicals as having enhanced acidity. The underlying cause was found to be extensive charge distribution away from the anionic O atoms of the conjugate radical anions, coupled with spin density displaced toward these O atoms. Ethyne spacers, between the radical and carboxylate centers, transmitted the effect extremely efficiently such that measurable enhancement was detectable up to at least six alkyne units. The bicyclo[1.1.1]pent-1-yl-3-carboxylic acid radical also displayed enhanced acidity, but additional cage units drastically attenuated the effect. Nitroxide radicals with suitably situated carboxylic acid substituents also exhibited enhanced acidity. Several families of potentially persistent radicals with enhanced acidity were identified.PostprintPeer reviewe