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Bicarbonate and Alkyl Carbonate Radicals: Their Structural Integrity and Reactions with Lipid Components Michael Buehl, Peter Dabell, David W

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Bicarbonate and Alkyl Carbonate Radicals: Their Structural Integrity and Reactions with Lipid Components Michael Buehl, Peter Dabell, David W Subscriber access provided by Brought to you by ST ANDREWS UNIVERSITY LIBRARY Article Bicarbonate and Alkyl Carbonate Radicals: Their Structural Integrity and Reactions with Lipid Components Michael Buehl, Peter DaBell, David W. Manley, Rory P. McCaughan, and John C. Walton J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b10693 • Publication Date (Web): 01 Dec 2015 Downloaded from http://pubs.acs.org on December 2, 2015 Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. 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Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts. Journal of the American Chemical Society is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties. Page 1 of 14 Journal of the American Chemical Society Bicarbonate and Alkyl Carbonate Radicals: Their Structural Integrity and Reactions with Lipid Components. 1 2 Michael Bühl,* Peter DaBell, David W. Manley,† Rory P. McCaughan and John C. Walton.* 3 4 University of St. Andrews, EaStCHEM School of Chemistry, St. Andrews, Fife, KY16 9ST, UK 5 6 Supporting information 7 8 9 ABSTRACT: The elusive neutral bicarbonate radical and the carbonate radical anion form an acid/conjugate base pair. 10 We now report experimental studies for a model of bicarbonate radical, namely methyl carbonate (methoxycarbonyloxyl) 11 radical, complemented by DFT computations at the CAM-B3LYP level applied to the bicarbonate radical itself. Methyl 12 carbonate radicals were generated by UV irradiation of oxime carbonate precursors. Kinetic EPR was employed to meas- 13 ure rate constants and Arrhenius parameters for their dissociation to CO2 and methoxyl radicals. With oleate and choles- 14 terol lipid components methyl carbonate radicals preferentially added to their double bonds; with linoleate and linolenate 15 substrates abstraction of the bis-allylic H-atoms competed with addition. This contrasts with the behavior of ROS such as 16 hydroxyl radicals that selectively abstract allylic and/or bis-allylic H-atoms. The thermodynamic and activation parame- 17 ters for bicarbonate radical dissociation, obtained from DFT computations, predicted it would indeed have substantial 18 lifetime in gas and non-polar solvents. The acidity of bicarbonate radicals was also examined by DFT methods. A note- 19 worthy linear relationship was discovered between the known pK as of strong acids and the computed numbers of mi- 20 crosolvating water molecules needed to bring about their ionization. DFT computations with bicarbonate radicals, solv- ated with up to 8 water molecules, predicted that only 5 water molecules were needed to bring about its complete ioniza- 21 tion. On comparing with the correlation, this indicated a pK of about -2 units. This marks the bicarbonate radical as the 22 a strongest known carboxylic acid. 23 24 25 26 As shown in Scheme 1, the carbonate radical anion 2 forms a 27 INTRODUCTION conjugate base/acid pair with the neutral bicarbonate radical 28 Carbonic acid is a weak, diprotic acid formed upon dissolu- 1. Apart from attempts to determine its pK a, virtually nothing 29 tion of carbon dioxide in water. While its acid/base equilibria is known about the chemistry or biochemistry of the neutral 6 30 are well understood, its radical chemistry is not. Deprotona- bicarbonate radical itself. It was shown to be a strong acid, − and a computational study 7 suggested its pK might be as low 31 tions produce the bicarbonate anion HCO 3 (pKa = 6.38) and a 2− as -4 units. Because of this acidity it is generally assumed 32 then carbonate dianion CO 3 (pK a = 10.25) (See Scheme 1). 33 that carbonate radical anions 2 are the dominant partner of the pair in biological fluids. Carbonate radical anion 2 is a reac- 34 Scheme 1. Formation of Carbonic Acid and Associat- tive oxygen species (ROS) that contributes to oxidative 35 ed Anions and Radicals. stress. 8 It is an important oxidizing agent in aqueous solu- 36 tion, 9 and its main bio-targets are polar species such as bio- 37 thiols, nucleic acids, metalloproteins/proteins and glutathi- 38 one. 10 − 39 Because HOCO 2• is neutral, whereas OCO 2• is negatively 40 charged, and the two radicals have very different extents of 41 electron delocalization, their preferred reaction channels and reactivity are expected to be markedly different. Thus 2 is 42 lipophobic, with the majority of its physiological reactions 43 taking place in polar environments. Therefore, it should be a 44 poor initiator of lipid peroxidation, due to its low diffusibility 45 These species play important roles in geology, oceanology, in hydrophobic environments. The neutral protonated radical 46 atmospheric chemistry and of course in physiology. In blood 1 could well be the dominant form in non-polar hydrophobic 47 serum and intracellular media these equilibria constitute the lipid rich situations. Initiation of peroxidation is the likely 48 ‘bicarbonate buffer system’. This is critical for maintaining role of 1 in structures such as membranes, vesicles, low- 49 the pH constant within the range 7.35-7.45 which is essential density lipo-protein particles (LDL) or lipid microdomains. for optimum functioning of enzymes. 1 Approximately 70 % However, as of yet, there is no research reporting peroxida- 50 tion of lipids by 1. One reason for this is that the carbonate of CO 2 is transported as bicarbonate in the human body (25.0 51 2 and bicarbonate precursors of 1 are only soluble in polar sol- 52 mM in serum and 14.4 mM in intracellular media). When an electron is removed from bicarbonate or carbonate respective- vents so that even when 1 is formed it immediately deproto- 53 ly, neutral bicarbonate radicals 1 or carbonate radical anions 2 nates to 2. No lipid soluble precursor for 1 is currently 54 are created. There are several enzymatic (and possibly non- known. To understand oxidative lipid and cell damage, with 55 enzymatic) ways these radicals can be produced in biological the resultant functional decline and associated degenerative conditions, a thorough study of the chemistry and biochemis- 56 fluids. For example CO 2 is one of peroxynitrite’s primary 3 try of both components of the carbonate/bicarbonate radical 57 biological targets producing NO 2 and 2. Xanthine oxidase pair is much needed. 58 turnover of acetaldehyde and other substrates is also known 4 5 59 to produce 2. Similarly it is recognized that the Cu,Zn- Radical 1 may be viewed as the first member of a homolo- gous series with alkyl carbonate radicals: 60 superoxide dismutase/H 2O2 system also generates 2. HOC(O)O, MeOC(O)O, C nH2n-1OC(O)O ACS Paragon Plus Environment Journal of the American Chemical Society Page 2 of 14 These neutral alkyl carbonate radicals are structurally similar were purged with N 2 and UV irradiated in the resonant cavity 1 to 1 so they, and particularly the methyl carbonate radical ( 7), of an EPR spectrometer. Neither MeOC(O)O • radicals nor 2 are suitable models for 1. Several members of this series MeO • radicals will be directly detectable by EPR in solu- 3 have been generated and precursors soluble in organic sol- tion. 11a,17 The spectra actually disclosed the corresponding vents, that is dialkyl peroxydicarbonates 11 and oxime car- iminyl radical together with a second species having g = 4 12 5 bonates, are known. However, to our knowledge, the sim- 2.0026, a(1H) = 34.5, a(1H) = 13.1, a(1H) = 9.3, a(1H) = 8.1, plest member, methyl carbonate, has not yet been reported. 6 a(1H) = 2.8 G. By analogy with literature data for other alkyl carbonate radicals 11,12 we identify this as the meta -adduct 7 The objectives of this research were first to weigh up lipid- soluble precursors for radical 1. Second to investigate the radical 8 from addition of 7 to the solvent (see Scheme 3). 8 structural integrity of 1, and of model MeOC(O)O • and relat- Scheme 3. Generation and Reactions of Methyl 9 ed species, particularly in respect of the ease with which they Carbonate Radicals 7. 10 decarboxylate: 11 1 • 1 • R UV, R OC(O)O → R O + CO 2 O 12 O O MAP Im An examination of specific reactions of these species with Me N Ph + MeO 13 PhBu- t O lipid components was also a priority. In each case both exper- O 14 imental and quantum-mechanical (QM) computational meth- 6a; R=H 7 15 ods were employed.
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