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.
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