Boosting effect of ortho-propenyl substituent on the antioxidant activity of natural phenols

Article abstract of DOI:10.1016/j.foodchem.2015.09.007

Seven new antioxidants derived from natural or synthetic phenols have been designed as alternatives to BHT and BHA antioxidants. Influence of various substituents at the ortho, meta and para positions of the aromatic core of phenols on the bond dissociation enthalpy of the ArO-H bond was evaluated using a DFT method B3LYP/6-311++G(2d,2p)//B3LYP/6-311G(d,p). This prediction highlighted the ortho-propenyl group as the best substituent to decrease the bond dissociation enthalpy (BDE) value. The rate constants of hydrogen transfer from these phenols to DPPH radical in a non-polar and non-protic solvent have been measured and were found to be in agreement with the BDE calculations. For o-propenyl derivatives from 2-tert-butyl-4-methylphenol, BHA, creosol, isoeugenol and di-o-propenyl p-cresol, fewer radicals were trapped by a single phenol molecule, i.e. a lower stoichiometric number. Reaction mechanisms involving the evolution of the primary phenoxyl radical ArO are proposed to rationalise these effects.

Full text of DOI:10.1016/j.foodchem.2015.09.007

Food Chemistry 196 (2016) 418–427
Contents lists available at ScienceDirect
Food Chemistry
journal homepage: www.elsevier.com/locate/foodchem
Boosting effect of ortho-propenyl substituent on the antioxidant activity
of natural phenols
Clémentine Marteau a,b, Romain Guitard a, Christophe Penverne a, Dominique Favier b,
Véronique Nardello-Rataj a, , Jean-Marie Aubry a,
⇑
⇑
a Université de Lille, Sciences et Technologies, Unité de Catalyse et de Chimie du Solide – UMR CNRS 8181 Bâtiment C6, F-59655 Villeneuve d’Ascq Cedex, France
b International Flavors & Fragrances Research and Development, 61 rue de Villiers, 95253 Neuilly-sur-Seine Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 April 2015
Received in revised form 5 August 2015
Accepted 4 September 2015
Available online 9 September 2015
Seven new antioxidants derived from natural or synthetic phenols have been designed as alternatives to
BHT and BHA antioxidants. Influence of various substituents at the ortho, meta and para positions of the
aromatic core of phenols on the bond dissociation enthalpy of the ArO–H bond was evaluated using a DFT
method B3LYP/6-311++G(2d,2p)//B3LYP/6-311G(d,p). This prediction highlighted the ortho-propenyl
group as the best substituent to decrease the bond dissociation enthalpy (BDE) value. The rate constants
of hydrogen transfer from these phenols to DPPHÅ radical in a non-polar and non-protic solvent have been
measured and were found to be in agreement with the BDE calculations. For o-propenyl derivatives from
2-tert-butyl-4-methylphenol, BHA, creosol, isoeugenol and di-o-propenyl p-cresol, fewer radicals were
trapped by a single phenol molecule, i.e. a lower stoichiometric number. Reaction mechanisms involving
the evolution of the primary phenoxyl radical ArOÅ are proposed to rationalise these effects.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Phenol
Antioxidant
Autoxidation
BDE
DPPH radical
ortho-Propenyl group
1. Introduction
the most widely used antioxidants in food and fragrances. They
act as chain-breaking antioxidants by transferring a hydrogen
Many authors have demonstrated the beneficial effects of
antioxidants for foodstuff preservation and in human health since
it is clearly established that lipid peroxidation is responsible for the
rancidification of fats and oils as well as for age related degenera-
tive diseases (Halliwell, Aeschbach, Löliger, & Aruoma, 1995;
Hussain et al., 2003). In contrast, less work has been devoted to
antioxidants for the preservation of flavours and fragrances
although several families of raw materials such as terpenes, ethers
or aldehydes are known to be very sensitive towards oxidation
while they are very common in end-use formulations (Dupont,
1940; Hagvall et al., 2007; Marteau, Ruyffelaere, et al., 2013).
Indeed, they suffer from an autoxidation process by molecular oxy-
gen 3O2 accelerated by metal traces, heat or light (Denisov &
Afanas’ev, 2005; Marteau, Ruyffelaere, et al., 2013). This degrada-
tion phenomenon has dramatic consequences on the functional
properties of the final product, since it can induce bad odour, col-
our and/or pH modifications, as well as the formation of allergenic
molecules. To avoid autoxidation and accordingly product degra-
dation, preservative agents are necessary. Phenol derivatives are
atom to peroxyl radicals (Eq. (1) with Z = ArO) at a rate higher than
the propagation reaction (Eq. (1) with Z = allyl or carbonyl) con-
verting thus peroxyl ROOÅ or acylperoxyl RC(O)OO radicals into
non-radical products (Denisov & Afanas’ev, 2005; Lucarini &
Pedulli, 2010).
Kinh
ROOÅ þ Z—H ꢀ! ROOH þ ZÅ
ð1Þ
Generally speaking, efficient antioxidants exhibit low bond dis-
sociation enthalpy (BDE) of the phenolic bond (Eq. (2)) compared
to that of the allylic (Eq. (3)) and aldehydic (Eq. (4)) bonds making
them competitive in propagation reactions (Burton & Ingold, 1986;
Denisov & Khudyakov, 1987; Hussain et al., 2003).
ArO—H ! ArOÅ þ HÅ
ð2Þ
ð3Þ
C H
C
+ H
O
C
H
O
ð4Þ
+ H
C
⇑
Corresponding authors.
E-mail addresses: veronique.rataj@univ-lille1.fr (V. Nardello-Rataj), jean-marie.
Moreover, a phenolic antioxidant is effective because the reaction
aubry@univ-lille1.fr (J.-M. Aubry).
of peroxyl radicals with OAH bonds is much faster than that with
http://dx.doi.org/10.1016/j.foodchem.2015.09.007
0308-8146/Ó 2015 Elsevier Ltd. All rights reserved.

C. Marteau et al. / Food Chemistry 196 (2016) 418–427
419
CAH bonds. However, some of the most popular synthetic phenolic
antioxidants, such as butylated hydroxyanisole (BHA) and butylated
hydroxytoluene (BHT), are or are about to be banned because of
their toxicity on animals (Ito, Fukushima, Hagiwara, Shibata, &
Ogiso, 1983; Saito, Sakagami, & Fujisawa, 2003). Industrial suppliers
of foods, fragrances and cosmetics are thus forced to find substi-
tutes for these synthetic antioxidants. A first way to circumvent this
issue is to resort to natural antioxidants (Amorati & Valgimigli,
2012; Goupy, Dufour, Loonis, & Dangles, 2003; Rice-Evans, Miller,
ethylenetetramine (Fluka, 99.5%), THF (Acros P99%, distilled
before use), triphenylphosphine (Alfa Aesar, 99%), ethyl bromide
(Fluka, 98%). DPPHÅ (Sigma–Aldrich, 97%), toluene (Sigma–Aldrich,
ChromasolvÒ, 99.9%), ethyl acetate (Verbièse, 99%), octane (Sigma–
Aldrich, 99%) and decanal (IFF, 97%).
2.2. BDE calculation
The so-called BDE of the OAH bonds in a phenol, which corre-
sponds in fact to the bond dissociation enthalpy, is given by the dif-
ference between the enthalpy of the phenoxyl radical (plus that of
the hydrogen atom) and that of the starting phenol as described by
Eq. (5).
&
Paganga, 1996; Sanchez-Moreno, Larrauri, & Saura-Calixto,
1998; Villaño, Fernández-Pachón, Moyá, Troncoso, & García-Parrilla,
2007). However, these phenols suffer from two main drawbacks: they
are relatively costly and some of their oxidation products are coloured
which is unacceptable for applications such as fine perfumery
(Dangles, Fargeix, & Dufour, 1999). Another way would consist in
using some phenolic flavour and fragrance molecules themselves as
antioxidants (Marteau, Nardello-Rataj, Favier, & Aubry, 2013; Suja,
Jayalekshmy, & Arumughan, 2004). For instance, the antioxidant
properties of eugenol and isoeugenol have already been reported
(Brand-Williams, Cuvelier, & Berset, 1995). Finally, a third approach
would be to simply develop new phenolic antioxidants with high
hydrogen transfer capacity on the basis of theoretical effects of various
substituents that could be easily grafted onto phenols (Johansson
et al., 2010; Wijtmans et al., 2003).
We followed herein this latter strategy by modifying the chem-
ical structure of some phenolic flavours and fragrances so as to
increase their antioxidant activity. The design of such new antiox-
idants consisted of three steps: (1) selection of fragrant phenols
which exhibit, or could exhibit after chemical modification, a sig-
nificant antioxidant activity (Wijtmans et al., 2003), (2) identifica-
tion of the structural parameters able to decrease the BDE of
ArOAH bond and to stabilise the phenoxyl radical and (3) grafting
onto the selected phenols the most relevant substituent, chosen
among those frequently encountered in fragrant phenols. Thus,
seven new antioxidants derived from common phenols were
designed by grafting a propenyl group onto the phenyl core. The
rate constants of hydrogen transfer from these phenols to the
DPPHÅ radical and the number of H atoms that can be donated by
each phenol were compared to those of the starting phenols.
BDE
ArO—H þ XÅ ꢀ! ArOÅ þ X—H
ð5Þ
BDEðArO—HÞ ¼ H0f ðArOÅÞ þ Hf0ðHÅÞ ꢀ Hf0ðArO—HÞ
All the calculations were performed with Gaussian 03 packages
(Szymusiak & Zielinski, 2003). The geometries of all the parent
molecules were firstly optimised with the PM3 method and then
the DFT one by using the B3LYP/6-311G(d,p) basis set. The first
method was used to speed up the convergence of the optimisation
by the second one. The frequency has been calculated to verify that
the structure corresponds to an energy minimum. Moreover, the
zero-point energy (ZPE) was taken into account to correct the BDE
values. Geometries from this method were used as inputs to the
final energy B3LYP/6-311G ++(2d,2p) calculation. For species having
several conformers, all of them were investigated. The conformer
with the lowest electronic energy was used in this work. For radi-
cals, the optimisation also used the PM3 step plus the final
UB3LYP/6-311G(d,p) method. Geometries were then used as inputs
to the final UB3LYP/6-311G++(2d,2p) calculation. Calculations were
performed in toluene. The method is described as B3LYP/6-311++G
(2d,2p)//B3LYP/6-311G(d,p).
2.3. General synthesis of o-propenyl phenols
The o-alkylation of phenols 1–6 by the alkyl bromide
(1.1 equiv.) was carried out with an excess of K2CO3 (10 equiv.)
in refluxing acetone giving the allylic ether A. The Claisen rear-
rangement of A was performed by heating at 220 °C for 2 h without
solvent under microwaves giving phenol B. Isomerization was car-
ried out by heating at 150 °C for 3 h under microwaves with an
excess of KOH in methanol (10 equiv.) (Eq. (6)). The microwaves
apparatus is a Biotage initiator device (Biotage, Uppsala, Sweden).
2. Materials and methods
2.1. Materials
O
OH
OH
OH
R1
allyl bromide
K2CO3
R1
R2
R1
R2
R1
R2
microwaves
2h
KOH, MeOH
microwaves, 3h
ð6Þ
R4
R4
R4
Acetone, 12h
R2
R4
R3
R3
R3
R3
1-6
A
B
P
Chemicals used in this work included p-cresol 1 (IFF, 99%), 2-
tert-butyl-4-methylphenol (Sigma–Aldrich, 99%), BHA
Analytical thin layer chromatography (TLC) was performed on
silica gel plates (Merck 60F254 visualised with UV lamp
2
3
)
a
(Sigma–Aldrich P98%), guaiacol 4 (Fluka, P98%), creosol 5 (IFF,
98%), isoeugenol 6 (IFF, 98%), alkyl bromide (Alfa Aesar, 99%),
K2CO3 (Carlo Erba, 99%), acetone (Verbiese, 99%), KOH (Sigma–
Aldrich, 98%), methanol (Sigma–Aldrich, ChromasolvÒ, 99.99%),
petroleum ether (Verbiese), TFA (Alfa Aesar, 99%), hexam-
(254 nm). Flash chromatography was performed on silica gel
(40–60 mesh) using a mixture of ethyl acetate and petroleum ether
(1:9 v/v). For the synthesis of phenol 1PP, the starting phenol was
the o-allylphenol 1PA and isomerization was performed by
increasing the microwaves reaction time.

420
C. Marteau et al. / Food Chemistry 196 (2016) 418–427
2.4. Determination of the rate constants for hydrogen transfer from
phenols to DPPHÅ radical
Knowledge of BDEs has been accumulated over the past
20 years. More precisely, experimental methods, such as electro-
chemical measurements, radical equilibrium electron paramag-
netic resonance REqEPR method, pulse radiolysis and quantum
chemical calculations using large basis sets have been combined.
Perez-Gonzalez et al. and Leopoldini et al. published interesting
work concerning BDE calculation of polyphenols (Leopoldini,
Russo, & Toscano, 2010; Perez-Gonzalez, Rebollar-Zepeda, Leon-
Carmona, & Galano, 2012). As explained by Lukes et al., Moller–
Plesset (MP) methods significantly underestimate substituent
Solutions of DPPHÅ were prepared in toluene at a concentration
of ca. 5 mM by sonicating the mixture until all DPPHÅ crystals were
dissolved. The solutions were then maintained under argon at
20 °C. For phenols, solutions were also prepared in toluene at a
concentration of ca. 50–200 mM by sonicating until all crystals
were dissolved. Typically, 10–500
lL of the phenol solutions were
added to 500
l
L of DPPHÅ solution in a glass reactor of 50 mL
equipped with a UV fibre containing 20 mL of deoxygenated sol-
vent maintained at 20 °C. The hydrogen-transfer reaction from
phenol to DPPHÅ radical was accompanied by a change in the
UV–visible spectrum and was monitored at 517 nm with a Varian
spectrophotometer (Cary 50, 10 pts/s). The loss of DPPHÅ absor-
bance in the presence of an excess of phenol follows pseudo-first
order kinetics. The rate constants were determined for at least five
different phenol concentrations plotting kDPPH versus [phenol]. It is
the case for phenols 2, 3, 5, 6, 8 and 2P, 3P, 5P, 6P. In the case of all
other phenols (1, 4, 7 and 1P, 1PP, 4P), the reaction with DPPHÅ
radical is very fast and the rate constants were determined by
using stoichiometric conditions at 517 nm considering second-
order kinetics ([DPPHÅ]/[tocopherol] = 1/1). For these phenols, solu-
tions were prepared in toluene at a concentration of ca. 5 mM by
sonicating until all crystals were dissolved. Values of the rate con-
stants are given in the Supporting information (see Table S1).
effects (Klein & Lukes, 2006; Klein, Lukes, Cibulkova, &
Polovkova, 2006) whereas DFT methods reflect the effect of sub-
stituents on BDE satisfactorily. We can notice that if we compare
our theoretical calculated BDE values with the literature, we can
find some discrepancies. For example, in the case of phenol, the
DFT calculation gives 82.2 kcal molꢀ1 while the most reliable gas-
phase BDE reported in the literature by Mulder et al. is
86.7 kcal molꢀ1 (Mulder et al., 2005). Moreover, other theoretical
BDE values of phenol were found such as 90.3 kcal molꢀ1 (Klein
& Lukes, 2006). Thereby, these theoretical results are basis set
and solvent dependent (Brinck, Haeberlein, & Jonsson, 1997). How-
ever, it is known that a systematic underestimation of about
5 kcal molꢀ1 can arise from the DFT calculation but it is generally
reliable for predicting substituent effects on OAH BDE. Hence, it
is better to consider the
DBDE values instead of the theoretical
BDEs of phenols as reported in Table 1. These values are consistent
with published theoretical values except for OMe substituent
(Table 1, entry 12) which is underestimated. Theoretical values
for phenolic antioxidants are also consistent with experimental
values reported by Lucarini and Pedulli (2010) (r2 = 0.97) and the-
oretical data found in literature (Table 2).
The effect of electron-donating and electron-withdrawing sub-
stituents was studied in numerous experimental and theoretical
works for more than 20 years, from the early 1990s (Lucarini &
Pedulli, 2010; Wright et al., 2001). In a previous work, we have also
shown that electron-donating groups decrease the BDE values, in
particular at the ortho- or para-positions (Marteau, Nardello-
Rataj, et al., 2013). In this work, we have extended the study by cal-
culating with the same and more appropriate DFT method
described as B3LYP/6-311++G(2d,2p)//B3LYP/6-311G(d,p), the
BDE of ArOAH bond of phenol itself and of 12 phenol derivatives
bearing different substituents at the ortho-, meta- or para-
positions frequently encountered in natural phenols (i.e. methyl,
ethyl, methoxy, allyl, propenyl) or in synthetic antioxidants (i.e.
tert-butyl). Results are given in Table 1.
Under these conditions,
e
and e0 values are 11 800 L molꢀ1 cmꢀ1
and 24 L molꢀ1 cmꢀ1 for DPPHÅ and DPPH-H respectively.
2.5. Determination of the stoichiometric number for the reaction of
phenols with DPPHÅ
Solutions of DPPHÅ were prepared in toluene at a concentration
of ca. 0.1 mM by sonicating the mixture until all DPPHÅ crystals
were dissolved. The solutions were then maintained under argon
at 20 °C. For phenols, solutions were also prepared in toluene at
a concentration of ca. 5–50 mM by sonicating until all crystals
were dissolved. Typically, 10–30 lL of the phenol solutions were
added to 2.8 mL of a DPPHÅ solution in a UV cell stirred and main-
tained at 20 °C. The absorbance change was monitored at 517 nm
by using the UV–Visible Cary 60. Final Af and initial A0 absorbances
were used to determine the stoichiometric number
r according to
Eq. (14). Final absorbances were collected when constant values
were reached for at least 30 min. Values of the stoichiometric num-
ber
r are given in the Supporting information (see Table S2).
Comparison of entries 1, 2, 5, 6 and 11 confirms that the
decrease of the BDE values is even more important when the
electro-donating substituent effect is stronger (Wright et al.,
2001). The ortho-effect includes steric effects and intramolecular
hydrogen bonding. Moreover, substituents in meta-position are
really unfavourable (see Table 1, entries 3, 9 and 12) compared
to substituents in ortho- (see Table 1, entries 2, 8 and 11) and
para-positions (see Table 1, entries 4, 10 and 13) and, accordingly,
the BDE increases. This unfavourable effect has already been
shown by some authors (Chandra & Uchimaru, 2002; Zhang, Sun,
& Chen, 2001). Finally, the BDE of phenols substituted by a prope-
nyl group (entries 8, 9, 10) is substantially lower than the one of
phenol substituted by an allyl group (entry 7) because the conjuga-
tion of the propenyl with the aromatic ring allows a better delocal-
isation of the free electron of the phenoxyl radical.
3. Results and discussion
3.1. Design and synthesis of new phenolic antioxidants
To design new effective phenolic antioxidants, it is necessary to
identify which substituent and which position can improve the
antioxidant activity of the starting phenol. As a rule of thumb, phe-
nolic compounds with low ArOAH BDE are efficient as antioxidants
(Wright, Johnson, & DiLabio, 2001; Zhang, 1998). They can easily
transfer a hydrogen atom to radicals and thus inhibit the chain
propagation step induced by the peroxyl ROOÅ or acylperoxyl RC
(O)OOÅ radicals involved in terpene and aldehyde oxidation,
respectively (Lucarini
&
Pedulli, 2010). BHA, BHT and
a
-
Since the antioxidant activity of phenols generally increases
when the BDE value of the phenolic OH bond decreases and when
the ionisation potential value is relatively high (Klein & Lukes,
2006), we conducted the evaluation of the antioxidant properties
of 7 phenols (1P to 1PP), including 1 or 2 propenyl groups at the
ortho or para positions. These compounds were synthesised from
tocopherol which have low BDE values (80.0, 79.9 and
77.1 kcal molꢀ1 respectively) (Lucarini & Pedulli, 2010) are the
most frequently encountered antioxidants in perfumery. However,
BHA is already banned, BHT is likely to be and
much more expensive than these two synthetic antioxidants.
a-tocopherol is

C. Marteau et al. / Food Chemistry 196 (2016) 418–427
421
Table 1
Contributions to the BDE values of the ArO–H bond of phenols in toluene bearing different ortho (o), meta (m) or para (p) substituents calculated by a DFT method B3LYP/6-311+
+G(2d,2p)//B3LYP/6-311G(d,p). Comparison with theoretical data found in literature.
Entry
Substituent
Position
BDE (kcal molꢀ1
)
D
BDE (kcal molꢀ1
)
Literature
–
D )
BDE (kcal molꢀ1
1
2
3
4
5
6
7
8
9
10
11
12
13
AH
ACH3
ACH3
ACH3
–
o
m
p
o
o
o
o
m
p
o
82.2
80.2
82.2
80.1
80.1
79.3
80.2
79.2
83.5
77.3
80.4
83.1
77.6
–
ꢀ2.0
ꢀ2.15a, ꢀ1.9b
0
ꢀ0.48a, ꢀ0.4b, ꢀ0.4d
ꢀ2.1
ꢀ2.1
ꢀ2.9
ꢀ2.0
ꢀ3.0
+1.3
ꢀ4.9
ꢀ1.8
+0.9
ꢀ4.6
ꢀ2.15a, ꢀ2.1b, ꢀ2.0c, ꢀ2.5d
AC2H5
nd
AC(CH3)3
ACH2ACH@CH2
ACH@CHACH3
ACH@CHACH3
ACH@CHACH3
AOCH3
ꢀ3.2d
nd
nd
nd
nd
ꢀ1.4d
AOCH3
AOCH3
m
p
ꢀ1.2a, ꢀ1.2b, ꢀ1.2d
ꢀ5.74a, ꢀ5.9b, ꢀ5.8c, ꢀ6.1d
nd: Not determined.
a
From Klein and Lukes (2006).
From Chandra and Uchimaru (2002).
From Lucarini, Mugnaini, Pedulli, and Guerra (2003).
From Wright et al. (2001).
b
c
d
Table 2
Calculated bond dissociation enthalpies (BDE) of ArO–H in toluene and
D
BDE compared to the phenol value (82.2 kcal molꢀ1), comparison with theoretical and experimental data
found in literature, rate constants k of hydrogen transfer from ArOH to DPPHÅ in toluene at 20 °C, stoichiometric numbers of H atoms
toluene at 20 °C and mechanisms rtheo involved during the abstraction of H atoms from ArOH by DPPHÅ.
r
exp determined with an excess of DPPHÅ in
Phenols
BDE
D
BDE
D
BDE (kcal molꢀ1
)
k (Mꢀ1 sꢀ1
)
rexp
Tentative mechanisms (rtheo)
(kcal molꢀ1
80.4
)
Literature
SOKa
FOKb
a
(2HÅ)
b (2HÅ)
c
(2HÅ)
d (3HÅ)
e
(1HÅ)
u (1HÅ)
1
ꢀ1.8
ꢀ2.1c, ꢀ2.15d
–
0.5
1.6
x
x
ꢀ2.1e, ꢀ2.0f, ꢀ2.5g
1P
1PP
2
2P
3
3P
4
4P
5
5P
6
6P
7
76.5
72.8
78.1
73.3
73.0
ꢀ5.7
ꢀ9.4
ꢀ4.1
ꢀ8.9
ꢀ9.2
nd
nd
nd
nd
–
–
6.3
53.9
2.7
–
–
–
0.5
3.1
5.5
–
–
–
1.6
0.8
2.5
0.8
2.1
0.8
1.6
1.5
2.2
1.1
1.1
0.5
2.1
2.0
x
x
x
x
x
x
x
3.1
4.0
135
218
–
x
x
x
x
x
ꢀ7.2c, ꢀ8.9d
x
69.5
80.4
77.3
78.4
75.7
75.7
73.6
72.4
69.1
ꢀ12.7
ꢀ1.8
ꢀ4.9
ꢀ3.8
ꢀ6.5
ꢀ6.5
ꢀ8.6
ꢀ9.8
ꢀ13.1
nd
ꢀ2.5c, ꢀ3.34h
nd
–
ꢀ4.4c
5.7
39.1
30.1
246
–
x
x
x
nd
ꢀ4.09h
nd
x
x
ꢀ7.3c
0.18
–
x
8
ꢀ10.1c, ꢀ11.3d
2570
x
nd: Not determined
a
SOK: second order kinetics ([DPPH]0 = [ArOH]0).
b
c
d
e
f
FOK: pseudo-first order kinetics ([ArOH]0 ꢁ [DPPHÅ]0).
Experimental data from radical equilibrium electron paramagnetic resonance REqEPR method (Lucarini & Pedulli, 2010).
From Klein and Lukes (2006).
From Chandra and Uchimaru (2002).
From Lucarini et al. (2003).
From Wright et al. (2001).
g
h
From Murakami et al. (2007).
the fragrant phenols p-cresol 1, guaiacol 4, creosol 5 and isoeu-
genol 6. The synthetic phenol BHA 3 was also selected to compare
the possible beneficial effect of the substitution on a synthetic
antioxidant with an available ortho-position. Finally, 2-tert-butyl-
4-methylphenol 2, a synthetic phenol, was also retained because
its chemical structure is close to those of BHA 3 and creosol 5
(Fig. 1).
2% for the second step. Therefore, for the second and third steps,
we resorted to microwave activation in the presence of potassium
hydroxide in methanol as outlined in Eq. (6). This route provides
better yields and shorter reaction times (see section 2.3).
3.2. Kinetics of hydrogen transfer from phenols to DPPH radical
The synthesis of the ortho-propenyl phenols 1P–6P starting
from phenols 1–6 respectively has been adapted from the method
described by De Kimpe and Srikrishna (Fletcher & Tarbell, 1943;
The antioxidant activity of phenols is generally predicted by cal-
culating the BDE values of the ArOAH bond and assessed by mea-
suring the rate constant for H-atom transfer from the phenol to the
peroxyl radical (Litwinienko & Ingold, 2007). Indeed, the logarithm
of the rate constant of hydrogen transfer from a phenol to a radical
is correlated to the BDE in non-polar non-protic solvents such as
aliphatic and aromatic hydrocarbons as it is a radical pathway,
the so-called HAT mechanism (Foti, Daquino, Mackie, DiLabio, &
Ingold, 2008). Furthermore, it has been shown that there is a strong
correlation between the rate constant of hydrogen transfer from
Nguyen Van, Debenedetti,
& De Kimpe, 2003; Srikrishna &
Satyanarayana, 2006). It consists of three steps. The o-alkylation
of the phenols 1–6 was accomplished by treatment with an alkyl
bromide in refluxing acetone giving the ether A. A Claisen rear-
rangement of A gives the ortho-allylphenol B which is further iso-
merised with potassium tert-butoxide at room temperature. This
protocol does not work for all phenols and gives yields lower than

422
C. Marteau et al. / Food Chemistry 196 (2016) 418–427
OH
OH
OH
OH
OH
OH
O
O
O
O
1
2
3
4
5
6
p-cresol
2-tert-butyl-4-methylphenol
BHA
Guaiacol
Creosol
Isoeugenol
OH
OH
OH
OH
OH
OH
O
O
O
O
1P
2P
3P
4P
5P
6P
OH
OH
HO
O
C16H33
1PP
7
8
BHT
α−tocopherol
Fig. 1. Chemical structures of the starting phenols (1–6, 1P) and their corresponding derivatives bearing a propenyl group in the ortho position (1P–6P, 1PP). BHT 7 and
-tocopherol 8 are used as references.
a
½DPPHÅꢂ0 ꢀ ½DPPHÅꢂf
½ArOHꢂ0
A0 ꢀ Af
phenols to peroxyl (ROOÅ) and to DPPHÅ radicals (Foti et al., 2002;
Litwinienko & Ingold, 2007). As the DPPHÅ test is a simple and rel-
evant method, the radical-scavenging capacity of phenols has been
evaluated by determining the rate constants k of hydrogen transfer
for all phenols 1–6 and 1P–6P with DPPHÅ in toluene (Eq. (7)).
rexp
¼
¼
ð14Þ
its
ð
e
ꢀ
e0Þ½ArOHꢂ0
where A0, Af are the DPPHÅ absorbance at t0 and tf respectively,
e
molar absorption coefficient at 517 nm, e0 is molar absorption
O2N
O2N
O
OH
H
k
N
N
NO2
N
N
NO2
+
+
ð7Þ
O2N
O2N
R
R
DPPH (Purple)
DPPH-H (Yellow)
coefficient of DPPH-H at 517 nm and [ArOH]0 the initial phenol
concentration.
Two different methods were used to measure k, depending on
the reactivity of phenols. For the highly reactive phenols 2, 3, 6,
8 and their propenylated derivatives, equal molar amounts of phe-
nols and DPPHÅ were allowed to react in toluene. Under these con-
ditions, the second order kinetics can be described by Eqs. (8)–(10).
For less reactive phenols 1, 4, 5, 7 and derivatives, k was deter-
mined in the presence of excess amounts of phenols to increase the
rate of reaction. In this case, [ArOH] ꢃ [ArOH]0 and the pseudo-first
order kinetics is described by Eq. (11).
d½DPPHÅꢂ
¼ ꢀk½DPPHÅꢂ½ArOHꢂ
ð8Þ
ð9Þ
At 517 nm, DPPHÅ and DPPH-H exhibit a strong (
e) and a weak
dt
(
e0) molar absorption coefficient respectively which allow monitor-
ing the disappearance of DPPHÅ (Eq. (7)). Eqs. (10) and (11) can be
expressed in terms of absorbance A, A0 and Af giving Eqs. (12) and
(13) which provide the rate constants k and k[ArOH]0 as the slopes
of the linearised curves obtained by plotting 1/(A ꢀ Af) and ln
(A ꢀ Af)/(A0 ꢀ Af), respectively, versus time. In the latter case, the
experiment was performed with various concentrations of ArOH
to determine k.
d½DPPHÅꢂ
2
¼ ꢀk½DPPHÅꢂ
dt
1
1
ꢀ
¼ kt
ð10Þ
ð11Þ
ð12Þ
½DPPHÅꢂ ½DPPHÅꢂ0
½DPPHÅꢂ ¼ ½DPPHÅꢂ0 expfꢀk½ArOHꢂ0tg
2-tert-butyl-4-methylphenol 2 with an intermediate reactivity
was studied with both methods to check their consistency. Fig. 2
shows the curves obtained with the second method (large excess
of 2). The results obtained with the first method (equal concentra-
tion of 2 and DPPHÅ) are displayed in Fig. S1 (see Supporting infor-
mation). The rate constant k for phenol 2 was found to be
2.7 Mꢀ1 sꢀ1 and 3.1 Mꢀ1 sꢀ1 using the first and second methods
1
1
k
ꢀ
¼
ꢀ
t
A ꢀ Af A0 ꢀ Af
e
e0
A ꢀ Af
Ln
¼ ꢀk½ArOHꢂ0t
ð13Þ
A0 ꢀ Af

C. Marteau et al. / Food Chemistry 196 (2016) 418–427
423
1.4
1.2
1
3.5
3
14
(a)
(b)
13
12
11
10
9
2.5
2
8
0.8
0.6
0.4
0.2
0
7
6
1.5
1
5
2
2.5
3
3.5
4
4.5
5
[2]0 (mM)
0.5
0
0
100
200
300
400
500
Time (s)
600
700
800
900
1000
Fig. 2. (a) Evolution of the absorbance of DPPHÅ in the presence of an excess of 2-tert-butyl-4-methylphenol 2 (5 mM (blue), 4 mM (red), 3 mM (green), 2 mM (black)) in
toluene and linearised curves according to pseudo-first order kinetics, (b) variation of the apparent rate constant k[ArOH]0 as a function of initial concentrations of 2. (For
interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
respectively. Rate constants obtained for all phenols are sum-
marised in Table 2.
4
8
When considering the kinetic analysis of the reaction between
3
DPPHÅ and ArOH, it is assumed that during the first minutes, only
the reaction of DPPHÅ with the phenolic hydrogen occurs (Eq.
6P
3P
(7)). During this period, the curves corresponding to the DPPHÅ con-
sumption are well fitted by second order (SOK) or pseudo-first
order (FOK) kinetics. The logarithm of the rate constants k is fairly
well correlated with the calculated BDE values (r2 = 0.95) for phe-
nols 1–8 (black dots), provided that the sterically hindered phenol
7 (white dot) is discarded (Fig. 3).
2
1
3
5P
1PP
6
5
2
1P
2P
4P
0
4
1
7
ortho-Propenylated derivatives 1P–6P are more reactive than
the parent phenols 1–6 towards DPPHÅ in agreement with the
decrease of the BDE values (Table 2). This is also the case when
comparing phenols 1PP to 1P. However, we can notice significant
differences when comparing the effect of the o-propenyl group
on logk (see Fig. 4), due to steric hindrance of bulky substituents
and intra-molecular hydrogen bond between phenolic hydrogen
and o-methoxy group.
-1
68
70
72
74
76
78
80
82
BDE toluene (kcal.mol-1)
Fig. 4. Comparison of the logarithm of the rate constants (logk) for the reaction
between DPPHÅ and phenols 1–8 (black line) and propenylated derivatives 1P–6P
and 1PP (blue, green and red lines) in toluene as a function of the calculated BDE of
the ArO–H bond in toluene. (For interpretation of the references to colour in this
figure legend, the reader is referred to the web version of this article.)
Actually, grafting one or two propenyl groups on non-ortho-
substituted p-cresol 1 (red line) and on o-methoxy phenols 1, 1P,
4, 5 and 6 (blue lines) leads to an increase of the reactivity with
the radical DPPHÅ which follows the tendency given by the phenols
1–6 and 8 (black line). In contrast, the addition of a propenyl group
on the tert-butyl phenols 2 and 3 (green lines) has only a moderate
accelerating effect because the combined hindrance effects of the
ortho-tert-butyl and propenyl groups dominate over the electronic
effect of propenyl group and make the phenolic hydrogen less
accessible.
3.3. Stoichiometric number (
r
) of phenols A and D
of an antioxidant is defined as the
4
The stoichiometric number
r
8
3.5
3
maximum number of radicals trapped by one antioxidant mole-
cule. It is determined with the DPPHÅ test by using the final absor-
bance reached by DPPHÅ in the presence of a large excess of DPPHÅ
with respect to the antioxidant (Eq. (14)) (Goupy et al., 2003).
All the stoichiometric numbers rexp determined for the differ-
ent phenols (see Table S2 in the Supporting information) are sum-
marised in Table 2. They range from 0.5 for 6P to 2.5 for 2,
depending on the nature of the substituents at the ortho and para
positions for the phenol group. The determination of the stoichio-
y = -0.32x + 25.73
R² = 0.99
2.5
2
3
6
1.5
1
5
0.5
0
2
4
1
-0.5
-1
metric number
r can help in giving an idea of the major reaction
7
pathway but, usually, several competitive pathways are simultane-
ously involved making the interpretation not straightforward
(Bondet, Brand-Williams, & Berset, 1997). The first step of the
interaction between an antioxidant and a radical (ROOÅ or DPPHÅ)
is always the abstraction of the phenolic hydrogen. Then, the
obtained phenoxyl radical ArOÅ may, in turn, transfer a second
68
70
72
74
76
78
80
82
BDE toluene (kcal.mol-1)
Fig. 3. Plots of the logarithm of the rate constants (logk) for the reaction between
DPPHÅ and phenols 1–8 (s sterically hindered phenol BHT 7, d other phenols) in
toluene at 25.0 °C as a function of the calculated BDE of the ArO–H bond in toluene.

424
C. Marteau et al. / Food Chemistry 196 (2016) 418–427
hydrogen or dimerise. Such reactions (Eqs. (15)–(19)) have already
been reported in the literature by several authors who analysed the
products formed during the oxidation of common antioxidants.
Analysis of oxidation products is beyond the scope of the present
work. Nevertheless, attempts to rationalise our results are entirely
based on data collected from the literature.
a
-Tocopherol 8 and BHT 7 are known to transfer a second
hydrogen from the p- or o-methyl group leading to a p- or o-
quinone-methide derivative, consistent with stoichiometric
number of 2 (Eqs. (15) and (16)) (Wright, Carpenter, McKay, &
a
r
Ingold, 1997). These p- and o-quinone-methide derivatives 9 and
10 are electrophilic compounds capable of reacting with the start-
R
O
H
8
O
O
H
17
R
ð15Þ
R
+ 2 DPPH-H
+ 2 DPPH
α
Very slow
reaction
O
O
O
O
R
8
10
O
O
H
O
O
7
18
2
H
DPPH-
+
2
ð16Þ
+
DPPH
O
Very slow
reaction
β
H
9
7
H
O
O
O
O
O
H
+ 4 DPPH-H
2
+ 4 DPPH
ð17Þ
ð18Þ
γ
O
3
11
OH
O
O
O
H
O
O
O
2
2
+
DPPH
2
H
DPPH-
+
O
ε
O
15
O
6
Non-reactive dimer
14
H
O
O
2
H
DPPH-
+
+ 2 DPPH
ð19aÞ
ð19bÞ
β
H
12
2
H
O
O
O
H
6 H
DPPH-
2
+
+ 6 DPPH
δ
H
2
13

C. Marteau et al. / Food Chemistry 196 (2016) 418–427
425
H
O
O
O
2
+ 2 DPPH-H
2
+ 2 DPPH
O
O
O
3P
ϕ
ð20Þ
O
+ 2 DPPH-H
O
16
ing phenols 7 and 8 to form the dimers 17 and 18 (Boehmdorfer,
Patel, Netscher, Gille, & Rosenau, 2011; Bolon, 1970; Bowry &
Ingold, 1995). Nevertheless, quinone-methides 10 and 9 react very
(Montellano, 2010). These results suggest that either coloured
products are formed or corresponding dimers are not as reactive
as the BHA dimer. Phenol 2 is the most effective compound to inhi-
bit radicals since it can scavenge 2.5 radicals per molecule. In the
case of this specific phenol, we propose a competition between 2
pathways. The first one is based on the BHT mechanism b (stoi-
chionetry of 2), whereas the second one results from an ortho-
dimerisation (stoichiometry of 3) (Kaeding, 1963) as depicted in
Eqs. (19a) and (19b) respectively. The different mechanisms likely
to take place during hydrogen transfers for all the investigated
phenols are summarised in Table 2.
slowly with
a-tocopherol 8 and BHT 7, respectively. Therefore,
under our experimental conditions, dimerisation does not take
place and compounds 17 and 18 are not obtained. BHA 3, which
has no methyl substituent, preferentially dimerises at the ortho–
ortho positions, giving a diphenol with antioxidant activity which
may transfer two hydrogen atoms (Eq. (17)) (Kadoma, Ito, Yokoe,
& Fujisawa, 2008; Omura, 1995). The radical-scavenging capacity
of isoeugenol 6 is totally different from that of the other phenols,
since it only traps one radical per molecule (r = 1). Indeed, its phe-
noxyl radical dimerises giving dehydrodiisoeugenol 15 (Eq. (18)),
the antioxidant activity of which, evaluated by the DPPHÅ test,
was reported to be very weak and practically negligible, compared
to that of isoeugenol (Bortolomeazzi, Verardo, Liessi, & Callea,
2010). The formation of a non-reactive dimer implies a stoichio-
metric number of 1. Another possible explanation is that the ary-
loxyl radical adds onto a second phenol molecule to form a
redox-inert dimeric product.
As far as the o-propenyl-phenols 2P, 3P, 5P, 6P and 1PP are con-
cerned, their stoichiometric numbers are lower than those of the
starting phenols 2, 3, 5, 6 and 1P (Table 2). On the contrary, phe-
nols 1P and 4P with a free ortho or para position exhibit the same
stoichiometric number as the parent phenols 1 and 4. In the case of
4. Conclusions
The protection against flavour and fragrance oxidation is essen-
tial to maintain their sensorial properties during storage. Synthetic
or natural antioxidants, such as a-tocopherol, BHT and BHA are the
most frequently used antioxidants but the synthetic ones are or
will be prohibited because of their suspected toxicity and natural
ones are more expensive. For instance, it is known that the toxicity
of BHT is linked to its tendency to form quinone methides that
form covalent linkages to biological molecules. Sometimes, some
phenolic compounds naturally occurring in natural oils can exhibit
antioxidant properties, allowing a reduction of the antioxidant
quantity in a formulation (e.g. isoeugenol in ylang-ylang oil). The
BDE calculations predict that the introduction of a propenyl group
at the ortho-position should enhance the antioxidant properties of
this kind of phenolic compound. The kinetics study of the DPPHÅ
reaction with initial and synthetic phenols allowed confirmation
that this group does increase the hydrogen transfer capacity of
phenols. However, complementary experiments to determine the
stoichiometric number by the DPPHÅ test showed that fewer radi-
cals can be inhibited by the substituted phenols because of the
inhibition of the dimerisation reaction of the phenoxyl radicals.
The DPPH test highlighted two opposite effects in the antioxidant
activity of an ortho-substitution of a propenyl group on the pheno-
lic ring. Indeed, this substituent dramatically increases the rate of
the first hydrogen transfer from phenol group making it more reac-
tive but reduces the number of hydrogen atoms available per phe-
nol molecule.
3P and 5P, stoichiometric numbers
r are about half that of phenols
3 and 5, i.e. they trap only one radical per antioxidant molecule
although they are much more reactive with DPPHÅ. As proposed
previously, dimerisation at the ortho position according to Eq.
(17) cannot take place. Instead, phenoxyl radicals can be delo-
calised on the propenyl substituent and may react by a coupling
reaction giving the dimer 16 without significant antioxidant activ-
ity like dehydrodiisoeugenol (Eq. (20)) (Bortolomeazzi et al., 2010).
In this case, the stoichiometric number would be reduced to ꢃ1.
Another explanation could be the formation of dimers with CAO
linkages when the two ortho-positions on phenolic cycle are occu-
pied (Bolon, 1970). The proposed coupling reaction is based on the
oxidation products of isoeugenol 6 identified by Bortolomeazzi
et al. (2010). For phenol 2P, the stoichiometric number decrease
is higher than for the others because the dimer of 2 is supposed
to reduce 2 or 4 radicals per molecule.
The antioxidant property of phenols depends on the BDE values
and indirectly on the hydrogen transfer capacity and vice versa but
also on the initial structure of the phenol. Indeed, if the introduc-
tion of suitable substituents effectively increases the kinetics of
the hydrogen transfer reaction during oxidation, it disrupts or
inhibits some coupling reactions between phenolic radicals that
lead to oxidation products which are themselves antioxidants.
For p-cresol 1 and guaiacol 4, stoichiometric numbers are lower
than 2. Ordoudi et al. have studied the reactivity of guaiacol deriva-
tives with DPPHÅ in ethanol and obtained stoichiometric numbers
from 0.6 to 1.5 (Ordoudi, Tsimidou, Vafiadis, & Bakalbassis,
2006). However, guaiacol can provide a coloured dimeric product,
i.e. a quinone which can alter the absorbance determination

426
C. Marteau et al. / Food Chemistry 196 (2016) 418–427
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molecule is thereby reduced. The effect on the antioxidant
properties induced by propenyl substitution is significant when
the phenolic ring can transfer easily a second hydrogen atom or
be coupled at the para-position. Even if this grafting leads to
opposite effects, the results show that the development of new
antioxidants with dual properties, i.e. antioxidant activity coupled
with flavouring or odorous properties, is possible but requires an
intimate knowledge of all the mechanisms.
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Appendix A. Supplementary data
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