On 'Is vitamin E the only lipid-soluble, chain-breaking antioxidant in human blood plasma and erythrocyte membranes?' by Graham W. Burton, Anne Joyce, Keith U. Ingold.

Application of a time-tested quantitative method of measuring peroxyl radical production in conjunction with the determination of the stoichiometry of the reaction of peroxyl radicals with α-tocopherol has permitted the conclusion that α-tocopherol is the major lipid-soluble chain-breaking antioxidant in human plasma and red cell membranes.

An outbreak of hepatitis A virus infection in a secondary school in England with no undetected asymptomatic transmission among students.

In June 2019 the Health Protection Team in Yorkshire and Humber, England, was notified of cases of hepatitis A virus (HAV) infection in staff at a secondary school. Investigation revealed that an earlier case worked as a food handler in the school kitchen. Indirect transmission through food from the canteen was considered the most likely route of transmission. Cases were described according to setting of exposure. Oral fluid was obtained from students for serological testing. Environmental investigations were undertaken at settings where food handling was considered a potential transmission risk. Thirty-three confirmed cases were linked to the outbreak. All of those tested (n = 31) shared the same sequence with a HAV IB genotype. The first three cases were a household cluster and included the index case for the school. A further 19 cases (16 students, 3 staff) were associated with the school and consistent with indirect exposure to the food handler. One late onset case could not be ruled out as a secondary case within the school and resulted in vaccination of the school population. Five cases were linked to a bakery where a case from the initial household cluster worked as a food server. No concerns about hygiene standards were noted at either the school or the bakery. Oral fluid samples taken at the time of vaccination from asymptomatic students (n = 219, 11-16 years-old) showed no evidence of recent or current infection. This outbreak included household and foodborne transmission but limited (and possibly zero) person-to-person transmission among secondary school students. Where adequate hygiene exists, secondary transmission within older students may not occur.

Why are sec-alkylperoxyl bimolecular self-reactions orders of magnitude faster than the analogous reactions of tert-alkylperoxyls? The unanticipated role of CH hydrogen bond donation.

High-level ab initio calculations are used to identify the mechanism of secondary (and primary) alkylperoxyl radical termination and explain why their reactions are much faster than their tertiary counterparts. Contrary to existing literature, the decomposition of both tertiary and non-tertiary tetroxides follows the same asymmetric two-step bond cleavage pathway to form a caged intermediate of overall singlet multiplicity comprising triplet oxygen and two alkoxyl radicals. The alpha hydrogen atoms of non-tertiary species facilitate this process by forming unexpected CHO hydrogen bonds to the evolving O2. For non-tertiary peroxyls, subsequent alpha hydrogen atom transfer then yields the experimentally observed non-radical products, ketone, alcohol and O2, whereas for tertiary species, this reaction is precluded and cage escape of the (unpaired) alkoxyl radicals is a likely outcome with important consequences for autoxidation.

Why are organotin hydride reductions of organic halides so frequently retarded? Kinetic studies, analyses, and a few remedies.

Kinetic data for reduction of organic halides (RX) by tri-n-butylstannane (SnH) reveal a serious flaw in the current view of the kinetic radical chain: the tacit but unproven assumption that the speed of reaction is determined by the slowest propagation step. Our results show this is rarely true for reductive chains and that the observed rate is in fact controlled by unseen side-reactions of propagating R(•) and Sn(•) radicals with the solvent (notably, benzene!) or solvent impurities (e.g., trace benzophenone dryness indicator in THF) or, crucially, with allylic-CH and conjugated unsaturated groups in substrates and products. Most R(•) and/or Sn(•) radicals are therefore converted into relatively inert delocalized species A(•) and/or B(•) that inhibit the chain. Retardation in the degraded chain is given by a simple sum of terms, each being the ratio of the chain-transfer rate divided by the rate of chain-return. The model kinetic equation is linear and easy to ratify, interpret, and apply: to calculate retarding rate constants, optimize reaction conditions, and identify additives or "remedies" that repair the chain and accelerate reaction. The present work is thus expected to have a helpful impact on the practice and design of SnH radical chain based (and related) syntheses.

New insights into the mechanism of amine/nitroxide cycling during the hindered amine light stabilizer inhibited oxidative degradation of polymers.

High-level ab initio molecular orbital theory calculations are used to identify the origin of the remarkably high inhibition stoichiometric factors exhibited by dialkylamine-based radical-trapping antioxidants. We have calculated the free energy barriers and reaction energies at 25, 80, and 260 °C in the gas phase and in aqueous solution for a broad range of reactions that might, potentially, be involved in amine/nitroxide cycling, as well as several novel pathways proposed as part of the present work, including that of N-alkyl hindered amine light stabilizer activation. We find that most of the literature nitroxide regeneration cycles should be discarded on either kinetic or thermodynamic grounds; some are even inconsistent with existing experimental observations. We therefore propose a new mechanistic cycle that relies on abstraction of a ß-hydrogen atom from an alkoxyamine (R(1)R(2)NOCHR(3)R(4)). Our results suggest that this cycle is energetically feasible for a range of substrates and provides an explanation for previously misinterpreted or unexplained experimental results. We also explore alternative mechanisms for amine/nitroxide cycling for cases where the alkoxyamines do not possess an abstractable ß-hydrogen.

The frequently overlooked importance of solvent in free radical syntheses.

This tutorial review is designed to dispel the myth, still believed by many synthetic organic chemists, that radical-based syntheses are free from significant solvent effects. However, many synthetically valuable radical reactions do exhibit large kinetic solvent effects. It is therefore important to select the solvent for any proposed radical synthesis with considerable care if good product yields are to be achieved.

Accurate O-H bond dissociation energy differences of hydroxylamines determined by EPR spectroscopy: computational insight into stereoelectronic effects on BDEs and EPR spectral parameters.

Differences in O-H bond dissociation enthalpies (ΔBDEs) between the hydroxylamine of (15)N-labeled TEMPONE and 10 N,N-di-tert-alkyl hydroxylamines were determined by EPR. These ΔBDEs, together with the g and a(N) values of the derived nitroxide radicals, are discussed in relation to various geometric, intramolecular dipole/dipole, and steric effects and in relation to the results from DFT calculations. We find that dipole/dipole interactions are the dominant factors in dictating a(N) values and O-H BDEs in all of these structurally similar nitroxides and hydroxylamines, respectively. The importance of including the Boltzmann distribution of conformations for each nitroxide in the a(N) calculations is emphasized.

Influence of "remote" intramolecular hydrogen bonds on the stabilities of phenoxyl radicals and benzyl cations.

Remote intramolecular hydrogen bonds (HBs) in phenols and benzylammonium cations influence the dissociation enthalpies of their O-H and C-N bonds, respectively. The direction of these intramolecular HBs, para --> meta or meta --> para, determines the sign of the variation with respect to molecules lacking remote intramolecular HBs. For example, the O-H bond dissociation enthalpy of 3-methoxy-4-hydroxyphenol, 4, is about 2.5 kcal/mol lower than that of its isomer 3-hydroxy-4-methoxyphenol, 5, although group additivity rules would predict nearly identical values. In the case of 3-methoxy-4-hydroxybenzylammonium and 3-hydroxy-4-methoxybenzylammonium ions, the CBS-QB3 level calculated C-N eterolytic dissociation enthalpy is about 3.7 kcal/mol lower in the former ion. These effects are caused by the strong electron-withdrawing character of the -O(*) and -CH(2)(+) groups in the phenoxyl radical and benzyl cation, respectively, which modulates the strength of the HB. An O-H group in the para position of ArO(*) or ArCH(2)(+) becomes more acidic than in the parent molecules and hence forms stronger HBs with hydrogen bond acceptors (HBAs) in the meta position. Conversely, HBAs, such as OCH(3), in the para position become weaker HBAs in phenoxyl radicals and benzyl cations than in the parent molecules. These product thermochemistries are reflected in the transition states for, and hence in the kinetics of, hydrogen atom abstraction from phenols by free radicals (dpph(*) and ROO(*)). For example, the 298 K rate constant for the 4 + dpph(*) reaction is 22 times greater than that for the 5 + dpph(*) reaction. Fragmentation of ring-substituted benzylammonium ions, generated by ESI-MS, to form the benzyl cations reflects similar remote intramolecular HB effects.

beta-Carotene: an unusual type of lipid antioxidant.

The mechanism of lipid peroxidation and the manner in which antioxidants function is reviewed. beta-Carotene is a purported anticancer agent, which is believed by some to have antioxidant action of a radical-trapping type. However, definitive experimental support for such action has been lacking. New experiments in vitro show that beta-carotene belongs to a previously unknown class of biological antioxidants. Specifically, it exhibits good radical-trapping antioxidant behavior only at partial pressures of oxygen significantly less than 150 torr, the pressure of oxygen in normal air. Such low oxygen partial pressures are found in most tissues under physiological conditions. At higher oxygen pressures, beta-carotene loses its antioxidant activity and shows an autocatalytic, prooxidant effect, particularly at relatively high concentrations. Similar oxygen-pressure-dependent behavior may be shown by other compounds containing many conjugated double bonds.

Intramolecular and intermolecular hydrogen bond formation by some ortho-substituted phenols: some surprising results from an experimental and theoretical investigation.

The effects produced by addition of various concentrations of the strong hydrogen bond (HB) acceptor, dimethyl sulfoxide (DMSO), on the OH fundamental stretching region of the IR spectra of several o-methoxy, o-nitro, and o-carbonyl phenols in CCl(4) are reported. In most of these phenols the intramolecular HB is not broken by the DMSO. Instead, the DMSO acts as a HB acceptor to the intramolecular HB forming a bifurcated intra/intermolecular HB. For o-methoxyphenols the bifurcated HBs are observed as new IR bands at much lower wavenumbers (Deltanu(OH) approximately -300 cm(-1)) than the band due to their intramolecular HB. The formation of bifurcated HBs and the large frequency shift of their OH bands in o-methoxyphenols are well reproduced by theoretical modeling. In contrast to the o-methoxyphenols DMSO has little effect (other than causing some broadening) on the intramolecular HB OH bands of o-nitro and o-carbonyl phenols, with the single exception of 2,4-dinitrophenol. In this case, but not for 2,4-diformylphenol, the intramolecular HB OH band decreases as the DMSO concentration increases and a new absorption grows in at lower wavenumbers, indicating that DMSO can break this intra-HB and form an inter-HB, a result well reproduced by theory. Although DMSO has little effect on the O-H stretching band of 2-nitrophenol, theory indicates extensive formation (90%) of bifurcated HBs with OH stretching bands at slightly higher wavenumbers (Deltanu(OH) approximately +20 cm(-1)) than that for the intramolecular HB OH group and 10% of a "simple" intermolecular HB in which the intramolecular HB has been broken. Theory also indicates that, with DMSO, 2-formylphenol also forms a bifurcated HB (Deltanu(OH) approximately +150 cm(-1)), whereas 2,4-diformylphenol forms both intermolecular HBs (Deltanu(OH) approximately -130 cm(-1)) and bifurcated HBs (Deltanu(OH) approximately +165 cm(-1)). The IR spectrum of 2-methoxymethylphenol shows that although an intramolecular HB conformer is dominant there is a small percentage of a "free" OH, non-HB conformer (2.1% in CCl(4), 1.5% in cyclohexane). These results are quantitatively reproduced by theory. We conclude that theory can provide important insights into the formation and structure of inter, intra, and bifurcated HBs, and into their OH stretching frequencies, that are not always revealed by IR studies alone.

Social-ecological network analysis for sustainability sciences: a systematic review and innovative research agenda for the future.

Social-ecological network (SEN) concepts and tools are increasingly used in human-environment and sustainability sciences. We take stock of this budding research area to further show the strength of SEN analysis for complex human-environment settings, identify future synergies between SEN and wider human-environment research, and provide guidance about when to use different kinds of SEN approaches and models. We characterize SEN research along a spectrum specifying the degree of explicit network representation of system components and dynamics. We then systematically review one end of this spectrum, what we term "fully articulated SEN" studies, which specifically model unique social and ecological units and relationships. Results show more focus on methodological advancement and applied ends. While there has been some development and testing of theories, this remains an area for future work and would help develop SENs as a unique field of research, not just a method. Authors have studied diverse systems, while mainly focused on the problem of social-ecological fit alongside a scattering of other topics. There is strong potential, however, to engage other issues central to human-environment studies. Analyzing the simultaneous effects of multiple social, environmental, and coupled processes, change over time, and linking network structures to outcomes are also areas for future advancement. This review provides a comprehensive assessment of (fully articulated) SEN research, a necessary step that can help scholars develop comparable cases and fill research gaps.

Improving network approaches to the study of complex social-ecological interdependencies.

Achieving effective, sustainable environmental governance requires a better understanding of the causes and consequences of the complex patterns of interdependencies connecting people and ecosystems within and across scales. Network approaches for conceptualizing and analyzing these interdependencies offer one promising solution. Here, we present two advances we argue are needed to further this area of research: (i) a typology of causal assumptions explicating the causal aims of any given network-centric study of social-ecological interdependencies; (ii) unifying research design considerations that facilitate conceptualizing exactly what is interdependent, through what types of relationships, and in relation to what kinds of environmental problems. The latter builds on the appreciation that many environmental problems draw from a set of core challenges that re-occur across contexts. We demonstrate how these advances combine into a comparative heuristic that facilitates leveraging case-specific findings of social-ecological interdependencies to generalizable, yet context-sensitive, theories based on explicit assumptions of causal relationships.

Absolute rate constants for some intermolecular reactions of alpha-aminoalkylperoxyl radicals. Comparison with alkylperoxyls.

Seven alpha-aminoalkylperoxyl radicals have been generated by 355 nm laser flash photolysis (LFP) of oxygen-saturated di-tert-butyl peroxide containing mono-, di-, and trialkylamines and a dialkylarylamine. All these peroxyls possess absorptions in the near-UV (strongest for the trialkylamine-derived peroxyls) which permits direct monitoring of the kinetics of their reactions with many substrates. The measured rate constants for hydrogen atom abstraction from some phenols and oxygen atom transfer to triphenylphosphine demonstrated that all seven alpha-aminoalkylperoxyls have similar reactivities toward each specific substrate. More importantly, a comparison with literature data for alkylperoxyls shows that alpha-aminoalkylperoxyls and these alkylperoxyls have essentially the same reactivities. The combination of LFP and alkylamines provides a quick, reliable method for determining absolute rate constants for alkylperoxyl radical reactions, an otherwise laborious task.

Reaction of phenols with the 2,2-diphenyl-1-picrylhydrazyl radical. Kinetics and DFT calculations applied to determine ArO-H bond dissociation enthalpies and reaction mechanism.

The formal H-atom abstraction by the 2,2-diphenyl-1-picrylhydrazyl (dpph(*)) radical from 27 phenols and two unsaturated hydrocarbons has been investigated by a combination of kinetic measurements in apolar solvents and density functional theory (DFT). The computed minimum energy structure of dpph(*) shows that the access to its divalent N is strongly hindered by an ortho H atom on each of the phenyl rings and by the o-NO(2) groups of the picryl ring. Remarkably small Arrhenius pre-exponential factors for the phenols [range (1.3-19) x 10(5) M(-1) s(-1)] are attributed to steric effects. Indeed, the entropy barrier accounts for up to ca. 70% of the free-energy barrier to reaction. Nevertheless, rate differences for different phenols are largely due to differences in the activation energy, E(a,1) (range 2 to 10 kcal/mol). In phenols, electronic effects of the substituents and intramolecular H-bonds have a large influence on the activation energies and on the ArO-H BDEs. There is a linear Evans-Polanyi relationship between E(a,1) and the ArO-H BDEs: E(a,1)/kcal x mol(-1) = 0.918 BDE(ArO-H)/kcal x mol(-1) - 70.273. The proportionality constant, 0.918, is large and implies a "late" or "product-like" transition state (TS), a conclusion that is congruent with the small deuterium kinetic isotope effects (range 1.3-3.3). This Evans-Polanyi relationship, though questionable on theoretical grounds, has profitably been used to estimate several ArO-H BDEs. Experimental ArO-H BDEs are generally in good agreement with the DFT calculations. Significant deviations between experimental and DFT calculated ArO-H BDEs were found, however, when an intramolecular H-bond to the O(*) center was present in the phenoxyl radical, e.g., in ortho semiquinone radicals. In these cases, the coupled cluster with single and double excitations correlated wave function technique with complete basis set extrapolation gave excellent results. The TSs for the reactions of dpph(*) with phenol, 3- and 4-methoxyphenol, and 1,4-cyclohexadiene were also computed. Surprisingly, these TS structures for the phenols show that the reactions cannot be described as occurring exclusively by either a HAT or a PCET mechanism, while with 1,4-cyclohexadiene the PCET character in the reaction coordinate is much better defined and shows a strong pi-pi stacking interaction between the incipient cyclohexadienyl radical and a phenyl ring of the dpph(*) radical.

Impaired ability of patients with familial isolated vitamin E deficiency to incorporate alpha-tocopherol into lipoproteins secreted by the liver.

Plasma and lipoprotein alpha-tocopherol concentrations of four patients with familial isolated vitamin E deficiency and six control subjects were observed for 4 d after an oral dose (approximately 15 mg) of RRR-alpha-tocopheryl acetate labeled with six deuterium atoms (d6-tocopherol). Chylomicron d6-tocopherol concentrations were similar in the two groups. d6-Tocopherol concentrations of plasma, very low (VLDL), low (LDL), and high (HDL) density lipoproteins were similar in the two groups only during the first 12 h; then these were significantly lower, and the rate of disappearance faster, in the patients. The times (tmax) of the maximum chylomicron d6-tocopherol concentrations were similar for the two groups, but tmax values in the controls increased in the order: chylomicrons less than VLDL less than or equal to LDL approximately HDL, while the corresponding values in the patients were similar to the chylomicron tmax. Thus, plasma d6-tocopherol in controls increased during chylomicron and VLDL catabolism, whereas in patients it increased only during chylomicron catabolism, thereby resulting in a premature and faster decline in the plasma tocopherol concentration due to a lack of d6-tocopherol secretion from the liver. We suggest that these patients are lacking or have a defective liver "tocopherol binding protein" that incorporates alpha-tocopherol into nascent VLDL.

Bond strengths: the importance of hyperconjugation.

[Structure: see text] Gronert (J. Org. Chem. 2006, 71, 1209) has challenged the importance of hyperconjugation in determining C-H bond dissociation enthalpies (BDEs) in alkanes. Electron paramaganetic resonance spectra of H3CCH2*, (H3C)2CH*, and (H3C)3C* show significant positive spin on their beta-H3C groups' hydrogens. A 55%/45% partitioning of these spins between hyperconjugation and spin polarization mechanisms linearly correlates with the C-H BDEs in methane, ethane, propane, isobutane and propene. Hyperconjugation is an important factor determining alkane C-H BDEs.

Antioxidant and co-antioxidant activity of vitamin C. The effect of vitamin C, either alone or in the presence of vitamin E or a water-soluble vitamin E analogue, upon the peroxidation of aqueous multilamellar phospholipid liposomes.

Thermally labile azo-initiators, dissolved in either the aqueous or lipid phase, have been used to generate peroxyl radicals at a known, steady rate in an aqueous dispersion of dilinoleoylphosphatidylcholine multilamellar liposomes at 37 degrees C in order to study the antioxidant behaviour of ascorbate itself and ascorbate in combination with either alpha-tocopherol or a water-soluble alpha-tocopherol analogue (TROLOX(-]. It is found that ascorbate is an effective inhibitor of peroxidations initiated in the aqueous phase, with each ascorbate terminating 0.6 radical chains (i.e., n = 0.6), but it is a very poor inhibitor of peroxidations initiated in the lipid phase. Peroxidations initiated in the lipid-phase in the presence of either alpha-tocopherol or TROLOX(-) indicate that ascorbate is an excellent synergist with both phenolic antioxidants (n = 0.4). In peroxidations initiated in the aqueous phase ascorbate acts as a co-antioxidant with TROLOX(-) (n = 0.7), but the interpretation of the approximately additive effect obtained in the presence of alpha-tocopherol is complicated by the fact that under the experimental conditions employed alpha-tocopherol alone does not give a distinct, measurable inhibition period. The latter problem is shown to be due to a non-uniform distribution of the water-soluble initiator within the liposome. Other examples of the complicating effects of non-uniform distributions of reactants in kinetic studies of the autoxidation of organic substrates dispersed in water are described.

Hydrolysis of stereoisomeric alpha-tocopheryl acetates catalyzed by bovine cholesterol esterase.

The kinetics of the bovine cholesterol esterase-catalyzed hydrolysis of three stereoisomers of alpha-tocopheryl acetate (alpha T-Ac) have been examined in vitro at 37 degrees C in the presence of dimyristoylphosphatidylcholine and sodium cholate. In contrast to in vivo results obtained earlier in rats (Ingold, K.U., Burton, G.W., Foster, D.O., Hughes, L., Lindsay, D.A. and Webb, A. (1987) Lipids 22, 163-172), 2R,4'R,8'R-alpha T-Ac (RRR-alpha T-Ac) is hydrolyzed (to form 'natural' vitamin E) more slowly (by a factor of approx. 7) than SRR- (and SSS-)alpha T-Ac. It is concluded that chirality at position 2 plays the dominant role in determining Vmax. The Km values show that RRR-alpha T-Ac is 2.1- and 2.7-times more strongly bound to the enzyme than are the SRR- and SSS-alpha T-Ac, respectively. The reaction is subject to competitive inhibition by the product with RRR-alpha T being 2.3-times as powerful an inhibitor as SRR-alpha T.

Vitamin E in young and old human red blood cells .

Young and old human red blood cells contain about the same amount of alpha-tocopherol, a compound which has previously been shown to be the major lipid-soluble, chain-breaking antioxidant present in such cells. Since red blood cells lose up to ca. 20% of lipid material from their membrane as they age, the alpha-tocopherol/membrane-lipid ratio actually rises with age rather than declining as might have been expected on the basis of the free radical theory of aging. The alpha-tocopherol/arachidonic acid moiety ratios increase in the order: young red blood cells less than old red blood cells less than plasma, which argues against the suggested membrane stabilizing effect of alpha-tocopherol/arachidonic acid moiety complexes.

The antioxidant efficiency of vitamin C is concentration-dependent.

The inhibition of autoxidation of plasma lipids by vitamin C (ascorbic acid) has been studied. The ascorbate stoichiometric factor, n, i.e., the number of peroxyl radicals trapped by each ascorbate molecule, decreases as the concentration of ascorbate increases. This is attributed to the fact that ascorbate not only acts as a radical-trapping antioxidant, but can also undergo autoxidation. The data indicate that n----2.0 as [ascorbate]----0 and that n----0 as [ascorbate]----infinity. This concentration-dependent behaviour accounts for the wide variation of n values reported in the literature. It is suggested that this autoxidative destruction of ascorbate may play a role regulating its concentration in blood plasma.