Free radical scavenging properties of thienyl and furyl linalool analogues: an experimental and DFT/B3LYP study Agnieszka Stobiecka,* Radoslaw Bonikowski and Józef Kula ABSTRACT: In the present study, thiophene (2a-b) and furane (3a-b) linalool analogues were screened for antioxidant/pro-oxidant activity using experimental and theoretical methods. The new compounds were subjected to two different types of assays: a hydrogen transfer-based test (i.e. ORAC FL measurements) and an electron transfer-based test (i.e. ABTS assay), respectively. Furthermore, the PM3 semi-empirical method and the density functional theory (DFT) method with the hybrid B3LYP exchange- correlation functional have been applied to investigate the free radical scavenging properties of synthetic compounds. The experimental results showed that linalool and its analogues possessed an almost identical ability to neutralize peroxyl radicals. In contrast, new compounds were better ABTS •+ scavenges in comparison with the starting compound but they, in general, exerted very weak antiradical activity in comparison with the synthetic antioxidant, i.e. Trolox. Taking into account the DFT-predicted reaction enthalpies associated with two possible mechanisms which might be responsible for the antioxidant activity of investigated compounds, i.e. the single electron and proton transfer process (SET-PT) and the direct H-atom transfer (HAT) mechanism, it could be concluded that the latter mechanism should be favoured in the polar medium. The theoretical results also revealed that the new odourants may exhibit pro-oxidant activity by auto-oxidation. The antioxidant and pro-oxidant properties of linalool and its analogues were determined by the low bond dissociation enthalpy of a C-H bond located at allylic carbon atom 5C and the relatively low ionization potential, respectively. Copyright © 2014 John Wiley & Sons, Ltd. Keywords: synthetic odourants; linalool analogues; antioxidant/pro-oxidant properties; DFT/B3LYP calculations; HAT mechanism Introduction Linalool (3,7-dimethyl-1,6-octadien-3-ol), with its sweet, floral and woody scent, is one of the most widely used fragrance ingredients. Linalool naturally occurs in the essential oils of over 200 species and belongs to the family of bioactive compounds. [1–6] It has been reported as being one of the most potent antimicrobial agents in the group of acyclic monoter- pene alcohols. Linalool also possesses weak antimalarial activity and is significantly less toxic towards human kidney cells than the other allylic alcohols that are present in essential oils (e.g. geraniol and nerolidol). [5] Linalool belongs to the group of natural compounds exerting both antioxidant and pro-oxidant activity. The antiradical scavenging activity of linalool seems to be dependent on the applied experimental conditions, mainly the concentration and the incubation or exposure time. For example, pure linalool was reported as being one of the weakest 1,1-diphenyl-2- picrylhydrazyl radical (DPPH) scavengers among the most abun- dant essential oil constituents. [5] In contrast, the DPPH radical scavenging activity of linalool in the essential oil matrix may be significantly increased most probably as a result of the synergy between the specific oil’s constituents. [6] The reducing power of linalool evaluated by the Prussian Blue method was re- ported to be lower in comparison with decanal and sweet orange oil but higher in comparison with valencene. [7] According to Ruberto and Baratta, linalool as opposed to other allylic alcohols (e.g. nerol, verbenol and geraniol) showed pro-oxidant activity in the thiobarbituric acid reactive species (TBARS) assay and it was inactive in the prevention of linoleic acid oxidation. [8] Interestingly, very recently Aazza et al. who used the same TBARS method found quite an opposite effect, i.e. antioxidant activity for linalool. [9] It should be also mentioned that linalool may be considered as a powerful antimutagenic and antioxidant agent which exhibits strong capacity to prevent H 2 O 2 -induced oxidative DNA damage. [10] On the other hand, owing to its noticeable pro-oxidant activity resulting in the cytotoxicity towards various cancer cell lines, linalool is also considered as a potent antitumour agent as well as the lead molecule for the synthesis of new anticancer drugs. [6,7,11] As a result of its interesting olfactory properties, linalool is mainly used in the floral and fancy fragrance compositions of decorative and skin care cosmetics as well as in fragrances for detergents and cleaners. In its pure form this unsaturated alcohol can be obtained by synthesis from α- and β-pinene. Its annual production exceeds 1000 metric tons. [2] It should also be noted that linalool is included in the list of 26 allergens of the European Commission’s Scientific Committee on Cosmetic and Other Non-Food Products. [12] According to reported results of ex- perimental studies, exposition of pure linalool to the air results in the formation of two main oxidation products, i.e. 7-hydroperoxy- 3,7-dimethyl-octa-1,5-diene-3-ol and 8-hydroperoxy-3,7-dimethyl- * Correspondence to: Agnieszka Stobiecka, Institute of General Food Chemistry, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90–924 Lodz, Poland. E-mail: agnieszka.stobiecka@p.lodz.pl Institute of General Food Chemistry, Department of Biotechnology and Food Science, Lodz University of Technology, Stefanowskiego 4/10, 90- 924 Lodz, Poland Flavour Fragr. J. 2014, 29, 325–333 Copyright © 2014 John Wiley & Sons, Ltd. Research Article Received: 12 April 2014, Revised: 28 May 2014, Accepted: 10 June 2014 Published online in Wiley Online Library: 6 July 2014 (wileyonlinelibrary.com) DOI 10.1002/ffj.3208 325