Skip to main content
NCBI home page
Molecules logoLink to Molecules
. 2009 May 11;14(5):1762–1772. doi: 10.3390/molecules14051762

Synthesis of Hydroxytyrosyl Alkyl Ethers from Olive Oil Waste Waters

Andrés Madrona 1, Gema Pereira-Caro 2, Raquel Mateos 2, Guillermo Rodríguez 3, Mariana Trujillo 1, Juan Fernández-Bolaños 3, José L Espartero 1,*
PMCID: PMC6254267  PMID: 19471196

Abstract

The preparation of a new type of derivatives of the naturally occurring antioxidant hydroxytyrosol is reported. Hydroxytyrosyl alkyl ethers were obtained in high yield by a three-step procedure starting from hydroxytyrosol isolated from olive oil waste waters. Preliminary results obtained by the Rancimat method have shown that these derivatives retain the high protective capacity of free hydroxytyrosol.

Keywords: Ethers, hydroxytyrosol, natural products, antioxidants, olive oil, waste waters

1. Introduction

In the production of Virgin Olive Oil (VOO) 80% of the olive fruit is discarded [1]. In this way, over 10 million tons per year of solid or semisolid wastes are produced worldwide in the olive industry, whose storage and/or recycling represent a serious environmental problem due to its high content in organic matter [2]. These wastes are rich in polyphenols, including hydroxytyrosol (1), which are scarcely soluble in the VOO extracted in the process [3]. On the other hand, the small fraction of liposoluble hydroxytyrosol derivatives passing into the VOO is sufficient to protect it from oxidation and rancidity throughout their lifespan [4]. In fact, it has been shown that hydroxytyrosol is superior in protecting fatty foods against oxidation than other antioxidants used in food such as butylated hydroxytoluene (BHT) or α–tocopherol [5]. So, in an effort to exploit this natural residue, several procedures for the isolation and purification of hydroxytyrosol from olive industry wastes have been reported [6,7,8,9,10,11,12,13]. Simultaneously, an explosion in research into the biological properties of hydroxytyrosol has occurred during the past few years, and, as a consequence, it has been demonstrated that this biophenol presents diverse interesting activities, including antimicrobial, hypotensive, hypoglycemic, platelet anti-aggregation, cardioprotective, and anti-inflammatory activities, and also inhibition of several lipoxygenases, and apoptosis induction in HL-60 cells, among others [14,15,16,17,18]. Moreover, an effort in the synthesis of hydroxytyrosyl derivatives with a better hydrophile/lipophile balance (HLB) has been carried out, for their possible use in the protection of fatty foods against oxidation, as well as to increase its bioavailability in the body. In this sense, the syntheses of isochromans [19,20,21] and esters [22,23,24,25,26,27] derivatives have been published in recent years. Such derivatives have shown similar or even improved activities [28] with respect to hydroxytyrosol itself, proving to be, in most cases, more liposolubles. In this short communication, the synthesis of a new type of hydroxytyrosol derivative is presented: alkyl hydroxytyrosyl ethers (4a–h).

2. Results and Discussion

For their syntheses, hydroxytyrosol isolated from olive oil waste waters (OOWW) was used in order to give an added value to this type of residue. Pure hydroxytyrosol (1) was transformed into its known dibenzyl derivative (2) [29] by reaction with benzyl bromide/potassium carbonate in acetone. Alkylation of the free alcoholic group with the corresponding alkyl iodides yielded the intermediate compounds 3a–h, in good to excellent yields. The desired alkyl hydroxytyrosyl ethers 4a–h were obtained in excellent yields after hydrogenolytic cleavage of the protecting Bn groups (Scheme 1). The results are summarized in Table 1.

Scheme 1.

Scheme 1

Open in a new tab

Synthesis of alkyl hydroxytyrosyl ethers.

Table 1.

Yields (%) of pure compounds obtained.

entry n Alkylation Product (R = Bn) Yield (%) Deprotection Product (R = H) Yield (%)
1 0 3a 91 4a 96
2 1 3b 86 4b 88
3 2 3c 78 4c 91
4 3 3d 84 4d 98
5 5 3e 82 4e 91
6 7 3f 80 4f 83
7 11 3g 67 4g 82
8 17 3h 60 4h 98
Open in a new tab

New compounds (3a–h and 4a–h) were characterized by their elemental analyses, and their structures were determined by spectroscopic (NMR and MS) methods. As it can be seen in Table 1, the alkylation step yields decreased as the length of the alkyl chain increased, as a result of the worse solubility of the corresponding alkyl iodide in the media. In fact, in the cases of using n-dodecyl (entry 7) and n-octadecyl iodide (entry 8), reactions were conducted at 50°C instead of room temperature.

Results on the antioxidant activity of 4a–h have shown that these derivatives maintain the high protective capacity of free hydroxytyrosol [30]. In this way, selected results obtained by the Rancimat® method are shown in Figure 1. As it can be seen, all new compounds 4a–h show similar induction time (IT) values than hydroxytyrosol (1) and significantly higher than both BHT and α–tocopherol.

Figure 1.

Figure 1

Open in a new tab

Oxidative stability of lipid matrices spiked with 0,5 mM of hydroxytyrosyl ethers (4a–h), hydroxytyrosol (1), BHT and α–tocopherol (Vit E). Each value is the mean of duplicate measurements ± standard deviation. Results are expressed as Induction Time (IT) in hours. Data with a different letter are statistically different (p < 0.05).

3. Experimental

3.1. General

All solvent and reagents were of analytical grade unless stated otherwise. Benzyl bromide, palladium over charcoal (Pd/C), and the alkyl iodides (methyl, ethyl, n-propyl, n-buthyl, n-hexyl, n-octyl, n-dodecyl and n-octadecyl iodides) were from Sigma-Aldrich (Steinheim, Germany), as well as 2,6-di-tert-butyl-4-metylphenol (BHT) and α-tocopherol. NMR spectra were recorded on a Bruker Avance 500 spectrophotometer operating at 500.13 MHz (1H) and 125.75 MHz (13C). Chemical shifts are given in ppm with the residual solvent signals (2.49 ppm for 1H and 39.5 ppm for 13C) as references. Samples were dissolved (10 mg/mL) in hexadeuterated methylsulfoxide (DMSO-d6), and spectra were recorded at 303 K. Elemental analyses were made on a Leco CHNS-932 apparatus. High-resolution EI, CI and FAB mass spectra were obtained on a Micromass AUTOSPECQ spectrometer.

3.2. Isolation and purification of hydroxytyrosol from olive oil waste waters (OOWW)

OOWW samples were supplied by the ‘Oleícola El Tejar’ oil extraction factory in Córdoba, Spain. These waste samples were partially de-stoned, partially de-oiled (after secondary centrifugal processing to obtain the residual olive oil), and had a high water content (70% of moisture). Thermal treatment between 140 and 180°C, using an operating pressure of 6–10 Kg/cm2, for 0.5–1.5 hour was performed in a new semi industrial reactor to allow the maximum phenolic solubilization. Under these conditions a high hydroxytyrosol concentration of up to 2–4 g/L was found in the filtered aqueous phase. After the natural phenolic antioxidant was purified by a patented industrial system in the pilot plant of the Instituto de la Grasa (CSIC, Seville), giving a hydroxytyrosol purity of at least 94% [10]. Further purification by column chromatography using mixtures (1:1 and 2:1) of ethyl ether/hexane as eluants yielded pure hydroxytyrosol (1).

3.3. Synthetic procedures

2-(3,4-bis(benzyloxy)phenyl)ethanol (2): To a solution of pure 1 (0.8 g, 5,2 mmol) in dry acetone (25 mL), benzyl bromide (1.4 mL, 11.8 mmol) and potassium carbonate (2.9 g, 20.8 mmol) were added and the resulting mixture heated to reflux for 24 h. The obtained suspension was filtered and concentrated to yield a crude residue, which was further purified by column chromatography, using a 1:2 mixture of diethyl ether/hexane as eluent. The desired product 2 was obtained as a white solid (1.16 g, 67%). M.p.: 55-57°C. All spectroscopic data were in good accordance with those previously reported [29].

3.3.1. General procedure for alkylation of hydroxytyrosol

A mixture of 2 (334 mg, 1 mmol), KOH (335 mg) and the corresponding alkyl iodide (3 mmol) in methyl sulfoxide (12 mL) was stirred at room temperature until completion of reaction (TLC). 3M HCl (25 mL) was added and the mixture extracted with CHCl3 (3 ° 25 mL). The organic phase was washed with 2% NaHSO3 (25 mL) and water (25 mL), dried over Na2SO4, filtered and evaporated. The desired products 3a–h were purified by flash column chromatography over silica gel.

1,2-bis(Benzyloxy)-4-(2-methoxyethyl)benzene (3a): colourless liquid (91% yield); 1H-NMR δ ppm 7.37 (m, 10H, 2 x Ph), 6.95 (d, J = 2.0 Hz, 1H, H4), 6.93 (d, J = 8.2 Hz, 1H, H7), 6.72 (dd, J = 2.0 Hz, J = 8.2 Hz, 1H, H8), 5.09 (s, 2H, CH2Ph in pos. 5), 5.07 (s, 2H, CH2Ph in pos. 6), 3.46 (t, J = 7.0 Hz, 2H, H1), 3.21 (s, 3H, H1’), 2.69 (t, J = 7.0 Hz, 2H, H2); 13C-NMR δ ppm 148.1 (C5), 146.6 (C6), 137.5 and 137.4 (Cipso, Bn groups), 132.1 (C3), 128.3-127.4 (C3, C4 and C5, Bn groups), 121.3 (C8), 115.4 (C4), 114.7 (C7), 72.9 (C1), 70.3 (CH2Ph in pos. 6), 70.1 (CH2Ph in pos. 5), 57.7 (C1’), 34.8 (C2); Elem. anal. calc. for C23H24O3 C, 79.28; H, 6.94; found: C, 78.75; H, 6.87; HRMS, 348.172247 (0.9 ppm).

1,2-bis(Benzyloxy)-4-(2-ethoxyethyl)benzene (3b): colourless liquid (86% yield); 1H-NMR δ ppm 7.37 (m, 10H, 2 x Ph), 6.96 (d, J = 2.0 Hz, 1H, H4), 6.93 (d, J = 8.2 Hz, 1H, H7), 6.72 (dd, J = 2.0 Hz, J = 8.2 Hz, 1H, H8), 5.09 (s, 2H, CH2Ph in pos. 5), 5.07 (s, 2H, CH2Ph in pos. 6), 3.49 (t, J = 7.0 Hz, 2H, H1), 3.39 (q, J = 7.0 Hz, 2H, H1’), 2.69 (t, J = 7.0 Hz, 2H, H2), 1.07 (t, J = 7.0 Hz, 3H, H2’); 13C- NMR δ ppm 148.1 (C5), 146.6 (C6), 137.5 and 137.4 (Cipso, Bn groups), 132.2 (C3), 128.3-127.4 (C3, C4 and C5, Bn groups), 121.3 (C8), 115.4 (C4), 114.7 (C7), 70.7 (C1), 70.2 (CH2Ph in pos. 6), 70.1 (CH2Ph in pos. 5), 65.1 (C1’), 35.1 (C2), 15.0 (C2’); Elem. anal. calc. for C24H26O3 x ½ H2O C, 77.60; H, 7.33; found: C, 77.99; H, 6.91; HRMS, 362.189060 (2.4 ppm).

1,2-bis(Benzyloxy)-4-(2-propoxyethyl)benzene (3c): colourless liquid (78% yield); 1H-NMR δ ppm 7.37 (m, 10H, 2 x Ph), 6.96 (d, J = 2.0 Hz, 1H, H4), 6.93 (d, J = 8.2 Hz, 1H, H7), 6.72 (dd, J = 2.0 Hz, J = 8.2 Hz, 1H, H8), 5.09 (s, 2H, CH2Ph in pos. 5), 5.07 (s, 2H, CH2Ph in pos. 6), 3.49 (t, J = 7.1 Hz, 2H, H1), 3.30 (t, J = 6.6 Hz, 2H, H1’), 2.69 (t, J = 7.1 Hz, 2H, H2), 1.47 (m, 2H, H2’), 0.83 (t, J = 7.4 Hz, 3H, H3’); 13C-NMR δ ppm 148.1 (C5), 146.6 (C6), 137.4 and 137.3 (Cipso, Bn groups), 132.2 (C3), 128.3-127.4 (C3, C4 and C5, Bn groups), 121.3 (C8), 115.5 (C4), 114.7 (C7), 71.5 (C1’), 70.9 (C1), 70.2 (CH2Ph in pos. 6), 70.1 (CH2Ph in pos. 5), 35.1 (C2), 22.4 (C2’) , 10.4 (C3’); Elem. anal. calc. for C25H28O3 C, 79.75; H, 7.50; found: C, 79.15; H, 6.88; HRMS, 376.205160 (3.5 ppm).

1,2-bis(Benzyloxy)-4-(2-butoxyethyl)benzene (3d): colourless liquid (84% yield); 1H-NMR δ ppm 7.37 (m, 10H, 2 x Ph), 6.96 (d, J = 2.0 Hz, 1H, H4), 6.93 (d, J = 8.2 Hz, 1H, H7), 6.72 (dd, J = 2.0 Hz, J = 8.2 Hz, 1H, H8), 5.08 (s, 2H, CH2Ph in pos. 5), 5.07 (s, 2H, CH2Ph in pos. 6), 3.49 (t, J = 7.0 Hz, 2H, H1), 3.34 (t, J = 6.5 Hz, 2H, H1’), 2.69 (t, J = 7.0 Hz, 2H, H2), 1.44 (m, 2H, H2’), 1.28 (m, 2H, H3’), 0.85 (t, J = 7.4 Hz, 3H, H4’); 13C-NMR δ ppm 148.1 (C5), 146.6 (C6), 137.5 and 137.4 (Cipso, Bn groups), 132.2 (C3), 128.3-127.4 (C3, C4 and C5, Bn groups), 121.3 (C8), 115.5 (C4), 114.7 (C7), 71.0 (C1), 70.2 (CH2Ph in pos. 6), 70.1 (CH2Ph in pos. 5), 69.6 (C1’), 35.1 (C2), 31.3 (C2’), 18.8 (C3’), 13.7 (C4’); Elem. anal. calc. for C26H30O3 C, 79.97; H, 7.74; found: C, 79.52; H, 7.38; HRMS, 390.218471 (2.6 ppm).

1,2-bis(Benzyloxy)-4-(2-(hexyloxy)ethyl)benzene (3e): colourless liquid (82% yield); 1H-NMR δ ppm 7.37 (m, 10H, 2 x Ph), 6.96 (d, J = 2.0 Hz, 1H, H4), 6.93 (d, J = 8.2 Hz, 1H, H7), 6.72 (dd, J = 2.0 Hz, J = 8.2 Hz, 1H, H8), 5.08 (s, 2H, CH2Ph in pos. 5), 5.07 (s, 2H, CH2Ph in pos. 6), 3.49 (t, J = 7.0 Hz, 2H, H1), 3.33 (t, J = 6.5 Hz, 2H, H1’), 2.69 (t, J = 7.0 Hz, 2H, H2), 1.45 (m, 2H, H2’), 1.24 (m, 6H, H3’−H5’), 0.84 (t, J = 7.0 Hz, 3H, H6’); 13C-NMR δ ppm 148.1 (C5), 146.6 (C6), 137.5 and 137.4 (Cipso, Bn groups), 132.2 (C3), 128.3-127.4 (C3, C4 and C5, Bn groups), 121.3 (C8), 115.5 (C4), 114.7 (C7), 71.0 (C1), 70.2 (CH2Ph in pos. 6), 70.1 (CH2Ph in pos. 5), 69.9 (C1’), 35.1 (C2), 31.0 (C4’), 29.1 (C2’), 25.3 (C3’), 22.0 (C5’), 13.8 (C6’); Elem. anal. calc. for C28H34O3 C, 80.35; H, 8.19; found: C, 79.55; H, 7.86; HRMS, 418.250377 (1.0 ppm).

1,2-bis(Benzyloxy)-4-(2-(octyloxy)ethyl)benzene (3f): white solid (80% yield); mp 52−54°C; 1H- NMR δ ppm 7.37 (m, 10H, 2 x Ph), 6.96 (d, J = 2.0 Hz, 1H, H4), 6.93 (d, J = 8.2 Hz, 1H, H7), 6.72 (dd, J = 2.0 Hz, J = 8.2 Hz, 1H, H8), 5.08 (s, 2H, CH2Ph in pos. 5), 5.07 (s, 2H, CH2Ph in pos. 6), 3.49 (t, J = 7.0 Hz, 2H, H1), 3.33 (t, J = 6.5 Hz, 2H, H1’), 2.69 (t, J = 7.0 Hz, 2H, H2), 1.45 (m, 2H, H2’), 1.23 (m, 10H, H3’−H7’), 0.84 (t, J = 7.0 Hz, 3H, H8’); 13C-NMR δ ppm 148.1 (C5), 146.6 (C6), 137.4 and 137.3 (Cipso, Bn groups), 132.2 (C3), 128.2-127.4 (C3, C4 and C5, Bn groups), 121.3 (C8), 115.4 (C4), 114.7 (C7), 71.0 (C1), 70.2 (CH2Ph in pos. 6), 70.1 (CH2Ph in pos. 5), 69.9 (C1’), 35.1 (C2), 31.2 (C6’), 29.1 (C2’), 28.7 (C4’), 28.6 (C5’), 25.7 (C3’), 22.0 (C7’), 13.8 (C8’); Elem. anal. calc. for C30H38O3 C, 80.68; H, 8.58; found: C, 79.93; H, 8.75; HRMS, 446.282509 (0.9 ppm).

1,2-bis(Benzyloxy)-4-(2-(dodecyloxy)ethyl)benzene (3g): white solid (67% yield); mp 42−45°C; 1H- NMR δ ppm 7.37 (m, 10H, 2 x Ph), 6.96 (d, J = 2.0 Hz, 1H, H4), 6.93 (d, J = 8.2 Hz, 1H, H7), 6.72 (dd, J = 2.0 Hz, J = 8.2 Hz, 1H, H8), 5.08 (s, 2H, CH2Ph in pos. 5), 5.06 (s, 2H, CH2Ph in pos. 6), 3.49 (t, J = 7.0 Hz, 2H, H1), 3.33 (t, J = 6.5 Hz, 2H, H1’), 2.69 (t, J = 7.0 Hz, 2H, H2), 1.45 (m, 2H, H2’), 1.22 (m, 18H, H3’−H11’), 0.84 (t, J = 7.0 Hz, 3H, H12’); 13C-NMR δ ppm 148.1 (C5), 146.6 (C6), 137.4 and 137.3 (Cipso, Bn groups), 132.2 (C3), 128.2-127.4 (C3, C4 and C5, Bn groups), 121.3 (C8), 115.4 (C4), 114.7 (C7), 70.9 (C1), 70.3 (CH2Ph in pos. 6), 70.1 (CH2Ph in pos. 5), 69.9 (C1’), 35.1 (C2), 31.2 (C10’), 29.1 (C2’), 29.0−28.6 (C4’−C9’), 25.7 (C3’), 22.0 (C11’), 13.8 (C12’); Elem. anal. calc. for C34H46O3 C, 81.23; H, 9.22; found: C, 81.01; H, 9.07; HRMS, 502.344735 (0.1 ppm).

1,2-bis(Benzyloxy)-4-(2-(octadecyloxy)ethyl)benzene (3h): white solid (60% yield); mp 57−59°C; 1H-NMR δ ppm 7.37 (m, 10H, 2 x Ph), 6.96 (d, J = 2.0 Hz, 1H, H4), 6.93 (d, J = 8.2 Hz, 1H, H7), 6.72 (dd, J = 2.0 Hz, J = 8.2 Hz, 1H, H8), 5.08 (s, 2H, CH2Ph in pos. 5), 5.06 (s, 2H, CH2Ph in pos. 6), 3.49 (t, J = 7.0 Hz, 2H, H1), 3.33 (t, J = 6.5 Hz, 2H, H1’), 2.69 (t, J = 7.0 Hz, 2H, H2), 1.45 (m, 2H, H2’), 1.22 (m, 30H, H3’−H17’), 0.84 (t, J = 7.0 Hz, 3H, H18’); 13C-NMR δ ppm 148.1 (C5), 146.6 (C6), 137.4 and 137.3 (Cipso, Bn groups), 132.2 (C3), 128.2-127.4 (C3, C4 and C5, Bn groups), 121.3 (C8), 115.5 (C4), 114.7 (C7), 70.9 (C1), 70.2 (CH2Ph in pos. 6), 70.1 (CH2Ph in pos. 5), 69.8 (C1’), 35.0 (C2), 31.2 (C16’), 29.1 (C2’), 29.0−28.6 (C4’−C15’), 25.6 (C3’), 22.0 (C17’), 13.8 (C18’); Elem. anal. calc. for C40H58O3 C, 81.86; H, 9.96; found: C, 81.77; H, 10.00; HRMS, 586.438530 (0.1 ppm).

3.3.2. General procedure for cleavage of Bn protective groups

Palladium over charcoal (Pd-C) was added to a solution of the corresponding ether (3a–h, 1 mmol) in THF (20 mL) and the mixture was hydrogenated at 4 bar with magnetic stirring. After 24 h at room temperature the catalyst was filtered off and solvent was evaporated in vacuum, yielding the desired compound in each case (4a–h) that was purified by column chromatography.

4-(2-Methoxyethyl)benzene-1,2-diol (4a): colourless liquid (96% yield); 1H-NMR δ ppm 6.60 (d, J = 8.0 Hz, 1H, H7), 6.58 (d, J = 2.1 Hz, 1H, H4), 6.43 (dd, J = 2.1 Hz, J = 8.0 Hz, 1H, H8), 3.42 (t, J = 7.0 Hz, 2H, H1), 3.21 (s, 3H, H1’), 2.60 (t, J = 7.0 Hz, 2H, H2); 13C-NMR δ ppm 144.9 (C5), 143.4 (C6), 129.7 (C3), 119.3 (C8), 116.2 (C4), 115.3 (C7), 73.2 (C1), 57.7 (C1’), 35.0 (C2); Elem. anal. calc. for C9H12O3 C, 64.27; H, 7.19; found: C, 63.74; H, 6.94; HRMS, 168.079247 (3.6 ppm).

4-(2-Ethoxyethyl)benzene-1,2-diol (4b): colourless liquid (88% yield); 1H-NMR δ ppm 6.60 (d, J = 8.0 Hz, 1H, H7), 6.58 (d, J = 2.1 Hz, 1H, H4), 6.44 (dd, J = 2.1 Hz, J = 8.0 Hz, 1H, H8), 3.45 (t, J = 7.2 Hz, 2H, H1), 3.40 (q, J = 7.0 Hz, 2H, H1’), 2.59 (t, J = 7.2 Hz, 2H, H2), 1.08 (t, J = 7.0 Hz, 3H, H2’); 13C- NMR δ ppm 144.9 (C5), 143.2 (C6), 129.7 (C3), 119.3 (C8), 116.2 (C4), 115.3 (C7), 71.1 (C1), 65.1 (C1’), 35.0 (C2), 15.0 (C2’); Elem. anal. calc. for C10H14O3 C, 65.91; H, 7.74; found: C, 65.39; H, 7.44; HRMS, 182.094382 (0.5 ppm).

4-(2-Propoxyethyl)benzene-1,2-diol (4c): white solid (91% yield); mp 93−95°C; 1H-NMR δ ppm 6.60 (d, J = 8.0 Hz, 1H, H7), 6.58 (d, J = 2.1 Hz, 1H, H4), 6.44 (dd, J = 2.1 Hz, J = 8.0 Hz, 1H, H8), 3.45 (t, J = 7.2 Hz, 2H, H1), 3.31 (t, J = 6.6 Hz, 2H, H1’), 2.60 (t, J = 7.2 Hz, 2H, H2), 1.48 (m, 2H, H2’), 0.83 (t, J = 7.4 Hz, 3H, H3’); 13C-NMR δ ppm 144.9 (C5), 143.3 (C6), 129.7 (C3), 119.3 (C8), 116.2 (C4), 115.3 (C7), 71.5 (C1’), 71.3 (C1), 35.0 (C2), 22.4 (C2’), 10.5 (C3’); Elem. anal. calc. for C11H16O3 x ⅓ H2O C, 65.32; H, 8.31; found: C, 65.29; H, 7.76; HRMS, 196.109392 (2.8 ppm).

4-(2-Butoxyethyl)benzene-1,2-diol (4d): white solid (98% of yield); mp 66−68°C; 1H-NMR δ ppm 6.60 (d, J = 8.0 Hz, 1H, H7), 6.58 (d, J = 2.1 Hz, 1H, H4), 6.44 (dd, J = 2.1 Hz, J = 8.0 Hz, 1H, H8), 3.45 (t, J = 7.2 Hz, 2H, H1), 3.34 (t, J = 6.6 Hz, 2H, H1’), 2.59 (t, J = 7.2 Hz, 2H, H2), 1.45 (m, 2H, H2’), 1.29 (m, 2H, H3’), 0.85 (t, J = 7.4 Hz, 3H, H4’); 13C-NMR δ ppm 144.8 (C5), 143.3 (C6), 129.7 (C3), 119.3 (C8), 116.2 (C4), 115.3 (C7), 71.4 (C1), 69.6 (C1’), 35.0 (C2), 31.3 (C2’), 18.8 (C3’), 13.7 (C4’); Elem. anal. calc. for C12H18O3 C, 68.54; H, 8.63; found: C, 68.09; H, 8.54; HRMS, 210.125280 (1.5 ppm).

4-(2-(Hexyloxy)ethyl)benzene-1,2-diol (4e): colourless liquid (91% yield); 1H-NMR δ ppm 6.60 (d, J = 8.0 Hz, 1H, H7), 6.58 (d, J = 2.1 Hz, 1H, H4), 6.44 (dd, J = 2.1 Hz, J = 8.0 Hz, 1H, H8), 3.45 (t, J = 7.2 Hz, 2H, H1), 3.34 (t, J = 6.6 Hz, 2H, H1’), 2.59 (t, J = 7.2 Hz, 2H, H2), 1.45 (m, 2H, H2’), 1.24 (m, 6H, H3’−H5’), 0.85 (t, J = 7.1 Hz, 3H, H6’); 13C-NMR δ ppm 144.9 (C5), 143.3 (C6), 129.7 (C3), 119.3 (C8), 116.2 (C4), 115.3 (C7), 71.4 (C1), 69.9 (C1’), 35.0 (C2), 31.0 (C4’), 29.1 (C2’), 25.3 (C3’), 22.0 (C5’), 13.8 (C6’); Elem. anal. calc. for C14H22O3 x ⅓ H2O C, 68.82; H, 9.35; found: C, 69.22; H, 8.88; HRMS, 238.157767 (3.7 ppm).

4-(2-(Octyloxy)ethyl)benzene-1,2-diol (4f): colourless liquid (83% yield); 1H-NMR δ ppm 6.60 (d, J = 8.0 Hz, 1H, H7), 6.58 (d, J = 2.1 Hz, 1H, H4), 6.43 (dd, J = 2.1 Hz, J = 8.0 Hz, 1H, H8), 3.44 (t, J = 7.2 Hz, 2H, H1), 3.33 (t, J = 6.6 Hz, 2H, H1’), 2.59 (t, J = 7.2 Hz, 2H, H2), 1.45 (m, 2H, H2’), 1.23 (m, 10H, H3’−H7’), 0.85 (t, J = 7.0 Hz, 3H, H8’); 13C-NMR δ ppm 144.8 (C5), 143.3 (C6), 129.7 (C3), 119.3 (C8), 116.1 (C4), 115.3 (C7), 71.4 (C1), 69.9 (C1’), 35.0 (C2), 31.2 (C6’), 29.1 (C2’), 28.7 (C4’), 28.6 (C5’), 25.6 (C3’), 22.0 (C7’), 13.8 (C8’); HRMS, 266.188001 (0.7 ppm).

4-(2-(Dodecyloxy)ethyl)benzene-1,2-diol (4g): white solid (82% yield); mp 39−41°C; 1H-NMR δ ppm 6.60 (d, J = 8.0 Hz, 1H, H7), 6.57 (d, J = 2.1 Hz, 1H, H4), 6.43 (dd, J = 2.1 Hz, J = 8.0 Hz, 1H, H8), 3.44 (t, J = 7.2 Hz, 2H, H1), 3.33 (t, J = 6.6 Hz, 2H, H1’), 2.59 (t, J = 7.2 Hz, 2H, H2), 1.45 (m, 2H, H2’), 1.23 (m, 18H, H3’−H11’), 0.84 (t, J = 7.0 Hz, 3H, H12’); 13C-NMR δ ppm 144.8 (C5), 143.3 (C6), 129.7 (C3), 119.3 (C8), 116.1 (C4), 115.3 (C7), 71.4 (C1), 69.9 (C1’), 35.0 (C2), 31.2 (C10’), 29.1 (C2’), 28.9−28.6 (C4’−C9’), 25.6 (C3’), 22.0 (C11’), 13.8 (C12’); Elem. anal. calc. for C20H34O3 C, 74.49; H, 10.63; found: C, 74.11; H, 10.64; HRMS, 322.250251 (1.7 ppm).

4-(2-(Octadecyloxy)ethyl)benzene-1,2-diol (4h): white solid (98% yield); mp 65−67°C; 1H-NMR δ ppm 6.60 (d, J = 8.0 Hz, 1H, H7), 6.57 (d, J = 2.1 Hz, 1H, H4), 6.43 (dd, J = 2.1 Hz, J = 8.0 Hz, 1H, H8), 3.44 (t, J = 7.2 Hz, 2H, H1), 3.33 (t, J = 6.6 Hz, 2H, H1’), 2.59 (t, J = 7.2 Hz, 2H, H2), 1.45 (m, 2H, H2’), 1.23 (m, 30H, H3’−H17’), 0.84 (t, J = 7.0 Hz, 3H, H18’); 13C-NMR δ ppm 144.9 (C5), 143.3 (C6), 129.7 (C3), 119.3 (C8), 116.1 (C4), 115.3 (C7), 71.4 (C1), 69.9 (C1’), 35.0 (C2), 31.2 (C16’), 29.2 (C2’), 29.0−28.6 (C4’−C15’), 25.6 (C3’), 22.0 (C17’), 13.8 (C18’); Elem. anal. calc. for C26H46O3 x ⅓ H2O C, 75.68; H, 11.40; found: C, 75.77; H, 12.20; HRMS, 406.344308 (1.0 ppm).

3.4. Evaluation of oxidative stability of lipid matrices

The oxidative stability of a lipid matrix, obtained from commercial sunflower oil, was evaluated by an automated test using the Rancimat apparatus (Model 743, Metrohm Co. Basel, Switzerland). Aliquots of the purified glyceridic matrix [30] were spiked with 0.5 mM of antioxidant and subjected to accelerated oxidation. A flow of air (15 L/h) was bubbled successively through the matrices and heated at 90°C. In this process, the volatile oxidation products are stripped from the oil and dissolved in the water, increasing the water conductivity. The time taken until there is a sharp increase of conductivity is named induction time (IT) and is expressed in hours. All determinations were carried out by duplicate. Data were subjected to a one-way analysis of variance (ANOVA) using Statistix 8.0. Differences were considered significant when p < 0.05.

4. Conclusions

In conclusion, we have designed and easily synthesized new alkyl hydroxytyrosyl ethers (4a–h) in high yield as potential antioxidant additives. All the new compounds have been completely characterized by spectroscopic methods. Free hydroxytyrosol recovered and purified from olive oil waste waters has been used as starting material. Results obtained by the Rancimat method have shown that these derivatives maintain the high protective capacity of free hydroxytyrosol, and further studies are being carried out to determine the bioavailability and toxicity of these derivatives.

Acknowledgements

We thank the Ministerio de Educación y Ciencia of Spain for financial support (grant no. AGL2007-66373).

Footnotes

Samples Availability: Samples of compounds 3a–h and 4a–h are available from authors.

References and Notes

  • 1.Alburquerque J.A., Gonzalvez J., Garcıa D., Cegarra J. Agrochemical characterisation of "alperujo", a solid by-product of the two-phase centrifugation method for olive oil extraction. Bioresource Technol. 2004;91:195–200. doi: 10.1016/S0960-8524(03)00177-9. [DOI] [PubMed] [Google Scholar]
  • 2.Arvanitoyannis I.S., Kassaveti A., Stefanatos S. Olive oil waste treatment: a comparative and critical presentation of methods, advantages and disadvantages. Crit. Rev. Food Sci. Nutr. 2007;47:187–229. doi: 10.1080/10408390600695300. [DOI] [PubMed] [Google Scholar]
  • 3.Mateos R., Espartero J.L., Trujillo M., Ríos J.J., Leon M., Alcudia F., Cert A. Determination of phenols, flavones, and lignans in virgin olive oils by solid-phase extraction and high-performance liquid chromatography with diode array ultraviolet detection. J. Agric. Food Chem. 2001;49:2185–2192. doi: 10.1021/jf0013205. [DOI] [PubMed] [Google Scholar]
  • 4.Mateos R., Domínguez M.M., Espartero J.L., Cert A. Antioxidant effect of phenolic compounds, α-tocopherol, and other minor components in virgin olive oil. J. Agric. Food Chem. 2001;51:7170–7175. doi: 10.1021/jf034415q. [DOI] [PubMed] [Google Scholar]
  • 5.Chimi H., Sadik A., Le Tutour B., Rahmani M. Comparative study of antioxidant abilities of tyrosol, hydroxytyrosol, caffeic acid, oleuropein and BHT in olive oil. Laboratory note. Rev. Franc. Corps Gras. 1988;35:339–344. [Google Scholar]
  • 6.Servili M., Montedoro G.F. Recovery of polyphenols from olive vegetation waters and evaluation of their antioxidative capacities. Ind. Alimentari. 1989;28:14–18. [Google Scholar]
  • 7.Capasso R., Evidente A., Visca C. Production of hydroxytyrosol from olive oil vegetation waters. Agrochim. 1994;38:165–171. [Google Scholar]
  • 8.Fernandez-Bolanos J., Rodriguez G., Rodriguez R., Heredia A., Guillen R., Jimenez A. Production in large quantities of highly purified hydroxytyrosol from liquid-solid waste of two-phase olive oil processing or "alperujo". J. Agric. Food Chem. 2002;50:6804–6811. doi: 10.1021/jf011712r. [DOI] [PubMed] [Google Scholar]
  • 9.Allouche N., Fki I., Sayadi S. Toward a high yield recovery of antioxidants and purified hydroxytyrosol from olive mill wastewater. J. Agric. Food Chem. 2004;52:267–273. doi: 10.1021/jf034944u. [DOI] [PubMed] [Google Scholar]
  • 10.Fernandez-Bolanos J., Heredia A., Rodriguez G., Rodriguez R., Jimenez A., Guillen R. Method for obtaining purified hydroxytyrosol from products and by-products derived from the olive tree. US 6849770 B2. 2005
  • 11.Agalias A., Magiatis P., Skaltsounis A.L., Mikros E., Tsarbopoulos A., Gikas E., Spanos I., Manios T. A new process for the management of olive oil mill waste water and recovery of natural antioxidants. J. Agric. Food Chem. 2007;55:2671–2676. doi: 10.1021/jf063091d. [DOI] [PubMed] [Google Scholar]
  • 12.Japon-Lujan R., Luque M.D. Static-dynamic superheated liquid extraction of hydroxytyrosol and other biophenols from alperujo (a semisolid residue of the olive oil industry) J. Agric. Food Chem. 2007;55:3629–3634. doi: 10.1021/jf0636770. [DOI] [PubMed] [Google Scholar]
  • 13.Garcia-Granados A., Parra A. Method for the industrial recovery of tyrosol and hydroxytyrosol contained in the solid by-products of industrial olive crushing. PCT Int. Appl. WO 2007093659. 2007
  • 14.Visioli F., Galli C., Galli G., Caruso D. Biological activities and metabolic fate of olive oil phenols. Eur. J. Lipid Sci. Technol. 2002;104:677–684. doi: 10.1002/1438-9312(200210)104:9/10&#x0003c;677::AID-EJLT677&#x0003e;3.0.CO;2-M. [DOI] [Google Scholar]
  • 15.Tuck K.L., Hayball P.J. Major phenolic compounds in olive oil: metabolism and health effects. J. Nutr. Biochem. 2002;13:636–644. doi: 10.1016/S0955-2863(02)00229-2. [DOI] [PubMed] [Google Scholar]
  • 16.Bianco A., Ramunno A. The Chemistry of Olea europaea. In: Atta-ur-Rahman, editor. Studies in Natural Products Chemistry. Vol. 33. Elsevier; The Netherlands: 2006. pp. 859–903. [Google Scholar]
  • 17.Covas M.I., Ruiz-Gutiérrez V., De La Torre R., Kafatos A., Lamuela-Raventós R.M., Osada J., Owen R.W., Visioli F. Minor components of olive oil: evidence to date of health benefits in humans. Nutr. Rev. 2006;64:S20–S30. doi: 10.1111/j.1753-4887.2006.tb00260.x. [DOI] [Google Scholar]
  • 18.Bendini A., Cerretani L., Carrasco-Pancorbo A., Gomez-Caravaca A.M., Segura-Carretero A., Fernandez-Gutierrez A., Lercker G. Phenolic molecules in virgin olive oils: a survey of their sensory properties, health effects, antioxidant activity and analytical methods. An overview of the last decade. Molecules. 2007;12:1679–1719. doi: 10.3390/12081679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Guiso M., Marra C., Cavarischia C. Isochromans from 2-(3',4'-dihydroxy)phenylethanol. Tetrahedron Lett. 2001;42:6531–6534. [Google Scholar]
  • 20.Bianco A., Coccioli F., Guiso M., Marra C. The occurrence in olive oil of a new class of phenolic compounds: hydroxy-isochromans. Food Chem. 2002;77:405–411. doi: 10.1016/S0308-8146(01)00366-1. [DOI] [Google Scholar]
  • 21.Lorenz P., Zeh M., Martens-Lobenhoffer J., Schmidt H., Wolf G., Horn T.F.W. Natural and newly synthesized hydroxy-1-aryl-isochromans: a class of potential antioxidants and radical scavengers. Free Rad. Res. 2005;39:535–545. doi: 10.1080/10715760500073733. [DOI] [PubMed] [Google Scholar]
  • 22.Gordon M. H., Paiva-Martins F., Almeida M. Antioxidant activity of hydroxytyrosol acetate compared with that of other olive oil polyphenols. J. Agric. Food Chem. 2001;49:2480–2485. doi: 10.1021/jf000537w. [DOI] [PubMed] [Google Scholar]
  • 23.23. Alcudia F., Cert A., Espartero J.L., Mateos R., Trujillo M. Process for the preparation of hydroxytyrosol esters for use as additives in food, cosmetics and pharmaceutical compositions. PCT Int. Appl. WO 2004005237. 2004 [Google Scholar]
  • 24.Torregiani E., Seu G., Minassi A., Appendino G. Cerium(III) chloride-promoted chemoselective esterification of phenolic alcohols. Tetrahedron Lett. 2005;46:2193–2196. doi: 10.1016/j.tetlet.2005.02.042. [DOI] [Google Scholar]
  • 25.Torres A., Penalver P., Rondon D., Morales J.C. Efficient lipase-catalyzed synthesis of new lipid antioxidants based on a catechol structure. Tetrahedron. 2005;61:7654–7660. doi: 10.1016/j.tet.2005.05.100. [DOI] [Google Scholar]
  • 26.Grasso S., Siracusa L., Spatafora C., Renis M., Tringali C. Hydroxytyrosol lipophilic analogues: Enzymatic synthesis, radical scavenging activity and DNA oxidative damage protection. Bioorg. Chem. 2007;35:137–152. doi: 10.1016/j.bioorg.2006.09.003. [DOI] [PubMed] [Google Scholar]
  • 27.Bernini R., Mincione E., Barontini M., Crisante F. Convenient synthesis of hydroxytyrosol and its lipophilic derivatives from tyrosol or homovanillyl alcohol. J. Agric. Food Chem. 2008;56:8897–8904. doi: 10.1021/jf801558z. [DOI] [PubMed] [Google Scholar]
  • 28.Trujillo M., Mateos R., Collantes L., Espartero J.L., Cert R., Jover M., Alcudia F., Bautista J., Cert A., Parrado J. Lipophilic hydroxytyrosyl esters. Antioxidant activity in lipid matrices and biological systems. J. Agric. Food Chem. 2006;54:3779–3785. doi: 10.1021/jf060520z. [DOI] [PubMed] [Google Scholar]
  • 29.Hamada A., Yaden E.L., Horng J.S., Ruffolo R.R., Patil P.N., Miller D.D. N-Substituted imidazolines and ethylenediamines and their action on α- and β-adrenergic receptors. J. Med. Chem. 1985;28:1269–1273. doi: 10.1021/jm00147a026. [DOI] [PubMed] [Google Scholar]
  • 30.Pereira-Caro G., Madrona A., Bravo L., Espartero J.L., Alcudia F., Cert A. Mateos., R. Antioxidant activity evaluation of alkyl hydroxytyrosyl ethers, a new class of hydroxytyrosol derivatives. Food Chem. 2009;115:86–91. doi: 10.1016/j.foodchem.2008.11.069. [DOI] [Google Scholar]

Articles from Molecules are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

RESOURCES