Organochalcogen substituents in phenolic antioxidants

Article abstract of DOI:10.1021/ol100683u

Little is known about the ED/EW character of organochalcogen substituents and their contribution to the O-H bond dissociation enthalpy (BDE) in phenolic compounds. A series of ortho- and para-(S,Se,Te)R-substituted phenols were prepared and investigated by EPR, IR, and computational methods. Substituents lowered the O-H BDE by >3 kcal/mol in the para position, while the ortho-effect was modest due to hydrogen bonding (～3 kcal/mol) to the O-H group.

Full text of DOI:10.1021/ol100683u

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2326-2329
Organochalcogen Substituents in
Phenolic Antioxidants
Riccardo Amorati,† Gian Franco Pedulli,† Luca Valgimigli,*,† Henrik Johansson,‡
and Lars Engman*,‡
Department of Organic Chemistry “A. Mangini”, UniVersity of Bologna, Via S.
Giacomo 11, I-40126 Bologna, Italy, and Department of Biochemistry and Organic
Chemistry, Uppsala UniVersity, Box 576, SE-751 23 Uppsala, Sweden
luca.Valgimigli@unibo.it; lars.engman@biorg.uu.se
Received March 23, 2010
ABSTRACT
Little is known about the ED/EW character of organochalcogen substituents and their contribution to the O-H bond dissociation enthalpy
(BDE) in phenolic compounds. A series of ortho- and para-(S,Se,Te)R-substituted phenols were prepared and investigated by EPR, IR, and
computational methods. Substituents lowered the O-H BDE by >3 kcal/mol in the para position, while the ortho-effect was modest due to
hydrogen bonding (∼3 kcal/mol) to the O-H group.
Phenolic antioxidants such as synthetic butylated hydroxyanisole
(BHA, 1) have been used for more than 60 years to preserve
oxidizable products in all kinds of man-made materials.
Similarly, nature has selected a number of phenolic
compounds such as R-tocopherol (2) to protect living
organisms from oxidative stress.1
Their antioxidant activity stems from the ability to transfer
the phenolic hydrogen to chain-propagating (peroxyl) radicals
more rapidly than these would react with the oxidizable
The rate of formal hydrogen transfer to peroxyl radicals
is dictated mainly by the O-H bond dissociation enthalpy
(BDEOH).1 In R-tocopherol as well as in other phenolic
material to propagate the oxidative chain.
(2) (a) Lind, J.; Shen, X.; Eriksen, T. E.; Mere´nyi, G. J. Am. Chem.
Soc. 1990, 112, 479. (b) Pratt, D. A.; DiLabio, G. A.; Mulder, P.; Ingold,
K. U. Acc. Chem. Res. 2004, 37, 334. (c) Lucarini, M.; Pedrielli, P.; Pedulli,
G. F. J. Org. Chem. 1996, 61, 9259. (d) Wright, J. S.; Johnson, E. R.;
DiLabio, G. A. J. Am. Chem. Soc. 2001, 123, 1173.
† University of Bologna.
‡ Uppsala University.
(1) Burton, G. W.; Ingold, K. U. Acc. Chem. Res. 1986, 19, 194.
10.1021/ol100683u  2010 American Chemical Society
Published on Web 04/20/2010

antioxidants, BDEOH is sensitive to the electronic contribution
from ring substituents.2 Thus, ortho and para electron-
donating (ED) groups decrease the BDEOH and increase the
reactivity, while the opposite is true for electron-withdrawing
(EW) groups.3 Substituent contributions are approximately
additive,2c and they are conserved also in ring-modified
derivatives such as 3-pyridinols (3) and 5-pyrimidinols (4).4
Indeed, knowledge about substituent contributions on the
BDEOH has been the key to rational design and development
of novel and more effective antioxidants and radical scav-
engers during the last two decades.
would give rise to persistent aryloxyl radicals or that are
sufficiently stable under continuous UV irradiation; none of
these requirements were actually satisfied by compounds
5-10.
In order to find out about substituent effects, we synthe-
sized the electron-rich ortho-alkylchalcogeno BHA analogues
11-13 by bromination of 1, followed by in situ lithiation of
the resulting bromophenol and addition of di-n-octyl ditel-
luride, -diselenide, and -disulfide, respectively (Scheme 1).
We have for some time tried to design and synthesize
chalcogen-substituted regenerable antioxidants, which could
perform in a catalytic fashion in the presence of thiol-
reducing agents and combine the chain-breaking activity with
a GPx-like peroxide decomposing activity.5 Our work,
however, had to proceed on a trial-and-error basis due to
the absence of literature data on the contribution of heavy
(Se, Te) organochalcogen substituents on BDEOH of phenolic
compounds. Knowledge about the ED/EW character of alkyl-
(S, Se, Te) substituents or their ability to delocalize an
unpaired electron would also be vital in the design of radical
conductors based on heavy chalcogens6 or to rationalize
antioxidant effects in complex biological systems.7
Scheme 1. Synthesis of Compounds 11-13
We have recently reported on pyridinols 5-10 bearing
ortho- or para-organochalcogen substituents. Some of them,
such as 7, bearing an ortho-alkyltelluro group, showed
improved antioxidant characteristics:8 a feature difficult to
rationalize without knowledge about the electronic contribu-
tion of alkylchalcogen substituents. Despite its relevance, we
were unable to aquire this piece of information by using the
well-established method of EPR radical equilibration that has
proven to be the most accurate approach for phenolic
compounds.2b,c,3–5 It requires equilibrating compounds that
To extend the investigation to some para alkyl-(S, Te)
groups, we included compound 14, available from previous
studies,9 and 15, which could be accessed in 90% overall
yield from 2,6-di-tert-butylphenol (see Supporting Informa-
tion). Reference data for para-alkyl-Se substituents could
be extracted from previous work.5
Compounds 11-13 were sufficiently electron-rich to
produce EPR-detectable concentrations of the corresponding
phenoxyl radicals when their 0.01 M solutions in benzene,
containing 20-30% di-tert-butyl peroxide, were exposed to
ambient light inside the cavity of an EPR spectrometer. Very
moderate UV irradiation using the unfocused beam from a
high-pressure Hg lamp yielded intense spectra (Figure 1),
whose deconvolution afforded the hyperfine splitting con-
stants (HSCs) collected in Table 1. Spin delocalization on
the chalcogen is witnessed by the increasing g-factor on
going from S to Te, and by the magnitude of spin coupling
with protons in the ortho-X-CH2 moiety. A slight increase
in the intensity of UV irradiation caused rapid detelluration
of compound 13, followed by formation of dimeric phenoxyl
radicals, while prolonged irradiation was needed to produce
similar results with phenols 1, 11, and 12 (see Supporting
Information).
(3) Brigati, G.; Lucarini, M.; Mugnaini, V.; Pedulli, G. F. J. Org. Chem.
2002, 67, 4828.
(4) (a) Pratt, D. A.; DiLabio, G. A.; Brigati, G.; Pedulli, G. F.;
Valgimigli, L. J. Am. Chem. Soc. 2001, 123, 4624. (b) Valgimigli, L.;
Brigati, G.; Pedulli, G. F.; DiLabio, G. A.; Mastragostino, M.; Arbizzani,
C.; Pratt, D. A. Chem.sEur. J. 2003, 9, 4997. (c) Wijtmans, M.; Pratt,
D. A.; Valgimigli, L.; DiLabio, G. A.; Pedulli, G. F.; Porter, N. A. Angew.
Chem., Int. Ed. 2003, 42, 4370.
(5) (a) Shanks, D.; Amorati, R.; Fumo, M. G.; Pedulli, G. F.; Valgimigli,
L.; Engman, L. J. Org. Chem. 2006, 71, 1033. (b) Kumar, S.; Johansson,
H.; Engman, L.; Valgimigli, L.; Amorati, R.; Fumo, M. G.; Pedulli, G. F.
J. Org. Chem. 2007, 72, 2583. (c) Kumar, S.; Engman, L.; Valgimigli, L.;
Amorati, R.; Fumo, M. G.; Pedulli, G. F. J. Org. Chem. 2007, 72, 6046.
(6) (a) Risto, M.; Reed, R. W.; Robertson, C. M.; Oilunkaniemi, R.;
Laitinen, R. S.; Oakley, R. T. Chem. Commun. 2008, 3278. (b) Leitch, A. A.;
Yu, X.; Winter, S. M.; Secco, R. A.; Dube, P. A.; Oakley, R. T. J. Am.
Chem. Soc. 2009, 131, 7112.
(7) Jacob, C.; Giles, G. I.; Giles, N. M.; Sies, H. Angew. Chem., Int.
Ed. 2003, 42, 4742.
(8) Kumar, S.; Johansson, H.; Kanda, T.; Engman, L.; Muller, T.;
Bergenudd, H.; Jonsson, M.; Pedulli, G. F.; Amorati, R.; Valgimigli, L. J.
Org. Chem. 2010, 75, 716.
(9) Amorati, R.; Fumo, M. G.; Menichetti, S.; Mugnaini, V.; Pedulli,
G. F. J. Org. Chem. 2006, 71, 6325.
Org. Lett., Vol. 12, No. 10, 2010
2327

Figure 1. EPR spectra of phenoxyl radicals originated from phenols 1 and 11-13 in benzene (with 20% di-tert-butyl peroxide) at 298 K.
Table 1. EPR Spectral Parameters for Aryloxyl Radicals from
Investigated Compounds in Benzene (containing 20% v/v
di-tert-butyl peroxide) at 298 K
Table 2. Bond Dissociation Enthalpies of Investigated Phenols
(UPhOH) from EPR Equilibrations in Benzene (containing 20%
v/v di-tert-butyl peroxide) at 298 Ka
HSCs/Gauss
UPhOH
RPhOH
Keq
BDEOH (kcal/mol)b
compound
orthoa
meta
para
g-factor
1
11
12
TBP
DBHT
TBP
DBHT
DBHA
DBHA
DBHA
0.78 ( 0.24
0.31 ( 0.10
1.89 ( 0.25
1.25 ( 0.10
0.058 ( 0.016
0.26 ( 0.08
0.093 ( 0.040
80.3 ( 0.2
80.6 ( 0.1
1
11
12
13
14
15
6.06 (1H) 0.96 (1H); 0.74 (1H) 1.65 (3H) 2.0048
1.32 (2H) 1.36 (1H); 0.35 (1H) 1.40 (3H) 2.0053
0.79 (2H) 1.32 (1H); 0.35 (1H) 1.41 (3H) 2.0081
1.27 (2H) 1.35 (1H); 0.30 (1H) 1.42 (3H) 2.0104
79.8 ( 0.1
78.9 ( 0.2
78.0 ( 0.3c
78.6 ( 0.3
13
14
15
DBP
1.30 (2H)
∼0.7 (2H)
2.20(3H) 2.0055
∼1.5(2H) 2.0122
81.7b 2c
,
a Coupling with tert-bulyl H-nuclei was unresolved (HSC ∼0.1-0.3
a DBP ) 2,6-di-tert-butylphenol; TBP ) 2,4,6-tri-tert-butylphenol;
DBHT ) 2,6-di-tert-butyl-4-methylphenol; DBHA ) 2,6-di-tert-butyl-4-
methoxyphenol. b Values corrected for revised BDE of phenol (86.7 ( 0.7
kcal; ref 10). c Literature value 78.3 kcal/mol (ref 9).
G) and led to spectral line broadening.
When EPR spectra were recorded on mixtures of com-
pounds 1 or 11-15 with variable amounts of reference
phenols, rapid equilibration was established.
The resulting EPR spectra were a superimposition of those
of the equilibrating phenoxyl radicals, and their analysis
allowed determination of the corresponding equilibrium
constant, Keq.2c,3 Since the entropy change associated with
the equilibrium is negligible, knowledge of its Gibbs energy
change affords the BDEOH of the unknown phenols according
to eqs 1-3.2c,3
cm-1, indicative of phenolic O-H groups involved in
intramolecular H-bonding exceeding ca. 2.5 kcal/mol in
strength (see Supporting Information).
To obtain deeper insight into the effects of organochal-
cogen substituents on the BDEOH of investigated compounds,
DFT calculations12 at the B3LYP/LANL2DZdp level were
performed.13,14 As the BDE-lowering effect of Bu groups
t
is difficult to reproduce by theoretical methods,15 calculations
were performed on the corresponding CH3-substituted com-
pounds, as illustrated in the Supporting Information. Results
are compared in Table 3 with the experimentally determined
contributions from ortho- and para-organochalcogen sub-
stituents obtained from Table 2, except for the para-SeR
substitution that was estimated from previous work on
selenochromanol analogues.5a,b
Keq
R
R
UPhOH + PhO• y z UPhO• + PhOH
(1)
∆G ) ∆H - T∆S ) -RTlnKeq
BDE(UPhOH) ) BDE(RPhOH) - ∆H
(2)
(3)
Data collected in Table 2 show that alkyl-S and alkyl-Se
groups in the ortho position (compounds 11 and 12) produced
only a modest variation in the strength of the phenolic O-H
bond as compared with the unsubstituted parent 1, while
alkyl-Te substitution (13) significantly decreased the BDEOH
(-1.4 kcal/mol). In contrast, para substitution with orga-
nochalcogen (S or Te) groups lowered the BDEOH by more
than 3 kcal/mol as compared with unsubstituted 2,6-di-tert-
butylphenol: a behavior we attribute to intramolecular
H-bonding to chalcogen in ortho-substituted phenols. This
would increase the BDEOH thereby (partly) compensating for
the electron-donating character of organochalcogen substit-
uents.11 To test this hypothesis, we turned to IR spectroscopy;
while BHA (1) showed a sharp peak at 3613 cm-1 in the
O-H stretching region, such a signal was absent in the
spectra of ortho-substituted derivatives 11-13, which instead
showed almost superimposable broad signals at 3375 ( 4
Calculated substituent contributions reproduced experi-
mental data within (0.6 kcal/mol, except in the case of
ortho-TeR, which was overestimated by 1.1 kcal/mol (vide
infra). More interestingly, DFT calculations very nicely
reproduced the experimental trends: when the chalcogen-
containing substituents are in the para position, their ability
(10) Mulder, P.; Korth, H. G.; Pratt, D. A.; Di Labio, G. A.; Valgimigli,
L.; Pedulli, G. F.; Ingold, K. U. J. Phys. Chem. A 2005, 109, 2647.
(11) Amorati, R.; Catarzi, F.; Menichetti, S.; Pedulli, G. F.; Viglianisi,
C. J. Am. Chem. Soc. 2008, 130, 237.
(12) All calculations were carried out with Gaussian 03: Frisch, M. J.;
Gaussian 03, revision D.02; Gaussian, Inc.: Wallingford, CT, 2004 (see
Supporting Information for the full list of authors).
(13) Check, C. E.; Faust, T. O.; Bailey, J. M.; Wright, B. J.; Gilbert,
T. M.; Sunderlin, L. S. J. Phys. Chem. A 2001, 105, 8111
(14) Shanks, D.; Frisell, H.; Ottosson, H.; Engman, L. Org. Biomol.
Chem. 2006, 4, 846
.
.
(15) Wright, J. S.; Johnson, E. R.; DiLabio, G. A. J. Am. Chem. Soc.
2001, 123, 1173.
2328
Org. Lett., Vol. 12, No. 10, 2010

in all the phenols, while it is reduced to 0° in the phenoxyl
radicals (Figure 2). The perpendicular conformation allows
hydrogen bond formation with the phenolic OH in ortho-
substituted compounds as clearly shown by IR spectra. MSEs
can be viewed as summations of the intrinsic effects of
substituents, essentially identical for para or ortho substit-
uents, and the contribution from intramolecular H-bonding,
the strength of which, according to data in Table 3, is
approximately constant among S-, Se-, and Te-Me groups
(≈3 kcal/mol). Surprisingly, in ortho-XMe phenols, RSEs
show a notable increase while passing from S to Te. We
hypothesize that this is due to a favorable electrostatic
interaction between the sigma hole on Se and Te atoms and
the lone pairs of the phenoxyl oxygen: possibly, the
contribution of such an interaction for Te is overestimated
by our DFT method, which would explain the poorer
agreement between calculated and exprimental ∆BDEOH
values for the ortho-TeR substituent (vide supra).
Interaction of the sigma hole with the phenol π system
(Figure 2a) suggests that S-, Se-, and Te-alkyl substituents
would show EW behavior, which becomes ED upon rotation
in the phenoxyl radical (Figure 2b). This counterintuitive
prediction is confirmed by IR measurements in para-XR
phenols 14 and 15. It has been suggested that the O-H
stretching frequency for a series of 4-substituted 2,6-di-tert-
butylphenols depends on the electronic contribution from the
substituent.17 Indeed, using literature data,17 we found that
a plot of νOH versus the substituents constants σ18 for the
corresponding group in the para position is linear (r2 )
0.996) with νOH (cm-1) ) 3645.3 - 14.5 σ. If the measured
values for compounds 14 (νOH ) 3643 cm-1) and 15 (νOH
) 3641 cm-1) are used in this correlation, the resulting σ
values for -SR and -TeR substituents are 0.14 and 0.28,
respectively, confirming the predicted EW behavior in the
parent phenols.19
Table 3. Calculated Substituent Contribution as ∆BDEOH
,
Molecule Stabilization Energy (MSE), and Radical Stabilization
Energy (RSE), Compared to Experimental ∆BDEOH (kcal/mol)a
b
c
substituent
∆BDEexp
∆BDEcalc
MSEcalc
RSEcalc
ortho-SR
ortho-SeR
ortho-TeR
para-SR
para-SeR
para-TeR
+0.3
-0.5
-1.4
-3.7
(-3.4)
-3.1
-0.3
-0.8
-2.5
-4.3
-3.5
-2.9
2.5
3.4
3.3
-0.6
0.4
0.5
2.8
4.2
5.8
3.7
3.9
3.4
a∆BDE ) MSE-RSE.
bArOH-XMe + C6H6 MSE8 ArOH + C6H5-XMe.
cArO•-XMe + C6H6 RSE8 ArO• + C6H5-XMe.
to lower the BDEOH decreases on descending the periodic
table from S to Te, while the trend is the opposite when the
substituents are in the ortho position. These trends prompted
us to partition the ∆BDEOH values into contributions from
the molecule and radical stabilization energies, MSEs and
RSEs, respectively (see footnotes in Table 3).2b The energies
in Table 3 show that X-Me substituents in the para position
have a nearly constant RSE (≈3.7 kcal/mol), while MSE is
weakly negative (destabilizing) for SMe and positive (sta-
bilizing) for SeMe and TeMe. This can be ascribed to an
electron-deficient zone along the outer side of the S-, Se-,
and Te-CH3 bond, the so-called “sigma hole” (Figure 2),
In conclusion, B3LYP/LANL2DZdp calculations very
nicely reproduced experimental findings and could be a
valuable tool to estimate the role of organochalcogen
substituents when experimentally not accessible. We believe
that the experimental thermodynamic and spectroscopic data
obtained in this investigation will significanly aid the rational
design of organochalcogen-substitued functional phenols.
Figure 2. Electrostatic potential on the molecular surface of
2-MeTe-4-MeO-6-MeC6H3OH (a) and the corresponding phenoxyl
radical (b) (red, negative; blue, positive). Arrows indicate regions
of positive electron density (sigma holes) located along the Te-Me
and Te-Ar bonds.
Acknowledgment. We thank MIUR (Rome) and the
Swedish Research Council for financial support, and Prof.
M. Lucarini (Bologna) for access to EPR software.
Supporting Information Available: Synthesis proce-
dures, spectroscopy, and computational data. This material
is available free of charge via the Internet at http://pubs.acs.org.
which becomes important as the atom size increases (i.e., S
< Se < Te).16 Heavy chalcogen atoms can interact with the
π system either with the filled p orbital or with the sigma
hole by rotation around the Ar-X bond by about 90°.
Actually, optimized geometries show that the dihedral angle
between the aromatic ring and the X-Me bond is about 90°
OL100683U
(17) Ingold, K. U. Can. J. Chem. 1960, 38, 1092.
(18) Hansh, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165.
(19) A small EW behavior of -SR in the phenol is espected to reflect
a small but positive (stabilizing) MSE value, at variance with our calculated
-0.6 for para-SR in Table 3. This suggests that our DFT approach possibly
underestimates the contribution of the sigma hole for sulfur.
(16) Politzer, P.; Murray, J. S.; Lane, P. Int. J. Quantum Chem. 2007,
107, 3046.
Org. Lett., Vol. 12, No. 10, 2010
2329