DOI: 10.1002/chem.201100983 Probing Lipid Peroxidation by Using Linoleic Acid and Benzophenone Inmaculada Andreu, [a] Dmytro Neshchadin, [b] Enrique Rico, [a] Markus Griesser, [b] Abdelouahid Samadi, [a] Isabel M. Morera, [a] Georg Gescheidt,* [b] and Miguel A. Miranda* [a] Introduction Peroxidation of polyunsaturated fatty acids plays a crucial role in many oxidative processes and is responsible for food deterioration and numerous diseases, including Alzheimers disease, atherosclerosis, and cancer rheumatoid arthritis. [1] It is generally accepted that a key step in lipid peroxidation (type I mechanism) is hydrogen abstraction of the allylic hy- drogen atoms from fatty acids by reactive free radicals, such as hydroxyl, alkyl, alkoxyl, peroxyl radicals, and carbonyl triplets. [2] After oxygen trapping, the fatty acid free-radical forms hydroperoxide, which in turn can initiate the peroxi- dation chain cycle through the generation of hydroxyl and alkoxyl radicals. [3] The reaction of the benzophenone (BZP) triplet excited state with allylic hydrogen atoms has attracted considerable interest during recent decades. Hydrogen abstraction and p quenching have been found to be the most important deacti- vation processes. [4] Herein, we build up the knowledge of lipid peroxidation by starting with 1,4-cyclohexadiene (CHD) and its deriva- tives as simple models and then move on to linoleic acid (LA), which serves as a realistic paradigm for lipid peroxi- dation. Studies performed by combining HPLC and laser flash photolysis (LFP) on tiaprofenic acid, which is a benzo- phenone-derived, nonsteroidal anti-inflammatory drug, have demonstrated that LA photoperoxidation is mediated by both type I and type II mechanisms through hydrogen ab- straction and singlet oxygen production, respectively. [5] Irra- diation of BZP in the presence of 1,4-cyclohexadienes (CHDs) as models for LA leads to a complex mixture of photoproducts arising from hydrogen abstraction, via triplet radical pairs. [6] Interestingly, with enantiomerically pure BZP--CHD model dyads, a significant stereodifferentation Abstract: A thorough mechanistic study has been performed on the reac- tion between benzophenone (BZP) and a series of 1,4-dienes, including 1,4-cyclohexadiene (CHD), 1,4-dihy- dro-2-methylbenzoic acid (MBA), 1,4- dihydro-1,2-dimethylbenzoic acid (DMBA) and linoleic acid (LA). A combination of steady-state photolysis, laser flash photolysis (LFP), and photo- chemically induced dynamic nuclear polarization (photo-CIDNP) have been used. Irradiation of BZP and CHD led to a cross-coupled sensitizer–diene product, together with 6, 7, and 8. With MBA and DMBA as hydrogen donors, photoproducts arising from cross-cou- pling of sensitizer and diene radicals were found; compound 7 was also ob- tained, but 6 and o-toluic acid were only isolated in the irradiation of BZP with MBA. Triplet lifetimes were deter- mined in the absence and in the pres- ence of several diene concentrations. All three model compounds showed similar reactivity (k q  10 8 m 1 s 1 ) to- wards triplet excited BZP. Partly rever- sible hydrogen abstraction of the allylic hydrogen atoms of CHD, MBA, and DMBA was also detected by photo- CIDNP on different timescales. Polari- zations of the diamagnetic products were in full agreement with the results derived from LFP. Finally, LA also un- derwent partly reversible hydrogen ab- straction during photoreaction with BZP. Subsequent hydrogen transfer be- tween primary radicals led to conjugat- ed derivatives of LA. The unpaired electron spin population in linoleyl rad- ical (LAC) was predominantly found on HACHTUNGTRENNUNG(1-5) protons. To date, LA-related radicals were only reported upon hy- drogen transfer from highly substituted model compounds by steady-state EPR spectroscopy. Herein, we have experi- mentally established the formation of LAC and shown that it converts into two dominating conjugated isomers on the millisecond timescale. Such pro- cesses are at the basis of alterations of membrane structures caused by oxida- tive stress. Keywords: dienes · hydrogen ab- straction · photochemistry · photol- ysis · transient absorption spectros- copy [a] Dr. I. Andreu, E. Rico, Dr. A. Samadi, Dr. I. M. Morera, Prof. Dr. M. A. Miranda Departamento de Química-Instituto de Tecnología Química UPV- CSIC Universidad PolitØcnica de Valencia, Camino de Vera s/n 46022, Valencia (Spain) Fax: (+ 34) 96-387-9349 E-mail: mmiranda@qim.upv.es [b] Dr. D. Neshchadin, M. Griesser, Prof. Dr. G. Gescheidt Institute of Physical and Theoretical Chemistry Technical University Graz, Technikerstrasse 4/I, 8010 Graz (Austria) E-mail : g.gescheidt-demner@tugraz.at Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201100983. Chem. Eur. J. 2011, 17, 10089 – 10096  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 10089 FULL PAPER