Do Peroxyl Radicals Obey the Principle That Kinetic Solvent Effects on H-Atom Abstraction Are Independent of the Nature of the Abstracting Radical?

Full text of DOI:10.1021/jo971944i

J . Org. Chem. 1998, 63, 4497-4499
4497
from phenols by cumyloxyl, tert-butoxyl, and DPPH
radicals (eq 2). Thus, when X is the cumyloxyl radical
and AH is phenol, k2 at 25 °C is 86, 28, 0.58, and 0.36107
M-1 s-1 in CCl4, C6H6, CH3CN, and (CH3)3COH, respec-
tively.5 This solvent effect has been found to be es-
sentially identical for the same substrate and indepen-
dent of the nature of the attacking radical and has been
attributed to hydrogen-bond formation between the
substrate AH and hydrogen-bond-accepting solvents.5 A
dependence on the nature of the medium has also been
found in the reactivity of peroxyl radicals toward phenols.
Thus, R-tocopherol (R-TOH) reacts very rapidly with
peroxyl radical in organic solvents (3.2 × 106 M-1 s-1 at
30 °C in styrene),6 while the rate of this reaction is about
100 and 1000 times lower in SDS micelles (3.7 × 104 M-1
s-1 at 40 °C) and in phospholipid bilayers (3 × 103 M-1
s-1 at 25 °C).7,8 Although the reduced reactivity observed
in the latter systems might be attributed to solvent
effects due to the formation of hydrogen bonding between
R-TOH and water in the proximity of the polar interface,9
recent results are not consistent with this interpreta-
tion,10 since the rate constant for the reaction of peroxyl
radicals with R-tocopherol in water has been estimated
to be as large as 8 × 105 M-1 s-1. However, it should be
pointed out that this estimate has been obtained from
the absolute rate constant for hydrogen atom abstraction
by tert-butoxyl radicals from 6-hydroxy-2,5,7,8-tetram-
ethylchroman-2-acetic acid,10 i.e., the water-soluble model
of R-tocopherol, by assuming that the kinetic solvent
effect on reaction 1 is independent of the nature and
reactivity of the abstracting radical X.5 This implies that
any interaction of the abstracting radical with the solvent
does not substantially affect its reactivity and that the
solvent effect is only due to the complexation of the
substrate by the solvent. Since the estimated value of
k2 in water is much larger than that found in SDS
micelles or in liposomes, it seems likely that only a small
fraction of the observed rate reduction in SDS and
phospholipid bilayers can be attributed to hydrogen
bonding of R-tocopherol to water.
Do P er oxyl Ra d ica ls Obey th e P r in cip le
Th a t Kin etic Solven t Effects on H-Atom
Abstr a ction Ar e In d ep en d en t of th e Na tu r e
of th e Abstr a ctin g Ra d ica l?
Marco Lucarini,* Gian Franco Pedulli,* and
Luca Valgimigli*
Dipartimento di Chimica Organica “A. Mangini”, Universita`
di Bologna, Via S. Donato 15, I-40127 Bologna, Italy
Received October 21, 1997
The oxidation by molecular oxygen of lipids containing
polyunsaturated fatty acids or their esters, a reaction
called autoxidation or peroxidation, has important effects
on the structural and functional properties of biomem-
branes. Many pathological events, such as heart disease,
cancer, atherosclerosis, rheumatoid arthritis, as well as
the degenerative processes associated with aging and
with the action of foreign toxic substances, are often
related to the membrane damage caused by lipid peroxi-
dation, which is believed to represent the major pathway
by which free radicals mediate their cytotoxic effects.1-3
In the autoxidation of lipids, RH, activated C-H bonds
(those in a bisallylic position) are cleaved by peroxyl
radicals, ROO, to give an hydroperoxide molecule, ROOH,
and a lipid radical, R, which by reaction with O2 regener-
ates the peroxyl radical (Scheme 1). Phenolic antioxi-
Sch em e 1
Ri
initiator
9
8 ROO•
kp
ROO• + RH
9
8 ROOH + R•
R• + O2 f ROO•
2kt
2ROO• 8 products
It must be emphasized that the assumption that the
kinetic solvent effect for peroxyl radicals is negligible as
for other radicals has not yet been unambiguously
proved.11 Indeed, suggestions contradicting this assump-
tion have been proposed by various authors, who pointed
out that peroxyl radicals are likely to be hydrogen-bonded
dants (AH), such R-tocopherol (vitamin E), are able to
inhibit this reaction by scavenging the chain carrying
peroxyl radicals by transfer of a hydrogen atom (eq 1);
the resulting radical from the antioxidant, A, is generally
too unreactive to continue the chain.
k1
ROO• + AH
X• + AH
9
8 ROOH + A•
(1)
(2)
(5) (a) Valgimigli, L.; Banks, J . T.; Ingold, K. U.; Lusztyk, J . J . Am.
Chem. Soc. 1995, 117, 9966. (b) Avila, D. V.; Ingold, K. U.; Lusztyk,
J .; Green, W. H.; Procopio, D. P. J . Am. Chem. Soc. 1995, 117, 2929.
(6) Burton, G. W.; Doba, T.; Gabe, E. J .; Hughes, L.; Lee, F. L.;
Prasad, L.; Ingold, K. U. J . Am. Chem. Soc. 1985, 107, 7053.
(7) (a) Barclay, L. R. C.; Baskin, K. A.; Locke, S. J .; Schaeffer, T. D.
Can. J . Chem. 1987, 65, 2529. (b) Pryor, W. A.; Strickland, T.; Church,
D. F. J . Am. Chem. Soc. 1988, 110, 2224. (c) Castle, L.; Perkins, M. J .
J . Am. Chem. Soc. 1986, 108, 6381.
(8) (a) Barclay, L. R. C.; Baskin, K. A.; Locke, S. J .; Vinquist, M. R.
Can. J . Chem. 1989, 67, 1366. (b) Barclay, L. R. C.; Baskin, K. A.;
Dakin, K. A.; Locke, S. J .; Vinquist, M. R. Can. J . Chem. 1990, 68,
2258.
k2
9
8 XH + A•
Although only a negligible dependence on solvent is
commonly observed in atom-transfer homolytic reac-
tions,4 the occurrence of dramatic solvent effects has been
recently reported on the rates of hydrogen abstraction
(1) Halliwell, B.; Gutteridge, J . M. C. Free Radicals in Biology and
Medicine; Clarendon Press: Oxford, 1989.
(2) Comporti, M. In Free Radicals: From Basic Science to Medicine;
Poli, G., Albano, E., Dianzani, M. U., Eds.; Birkhauser Verlag: Basel,
1993.
(3) Scott, G. Chem. Brit. 1995, 879-882.
(4) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry,
2nd ed.; VCH: Weinheim, 1988.
(9) Iwatsuki, M.; Tsachiya, J .; Komuro, E.; Yamamoto, Y.; Niki, E.
Biochim. Biophys. Acta 1994, 1200, 19.
(10) Valgimigli, L.; Ingold, K. U.; Lusztyk, J . J . Am. Chem. Soc.
1996, 118, 3545.
(11) The ratio between the rate constants k2 (RO• + R-tocopherol)
measured in benzene and in tert-butyl alcohol is 17, while the ratio
between the rate constant k1 (ROO• + R-tocopherol) in styrene and in
tert-butyl alcohol is 14.
S0022-3263(97)01944-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/30/1998

4498 J . Org. Chem., Vol. 63, No. 13, 1998
Notes
Ta ble 1. Oxid iza bility Va lu es a n d Absolu te Ra te Con sta n ts for P r op a ga tion , kp , a n d Ter m in a tion , 2kt, Mea su r ed for th e
Au toxid a tion of Cu m en e (1.1 M) in Va r iou s Solven ts a t 50 °C (Th e In itia tion Ra te (Ri) Wa s Mea su r ed for Ea ch
Exp er im en t a n d th e Ra n ge Em p loyed Is Rep or ted )
solvent
isooctane
Ri /s-1
kp/(2kt)1/2/M-1/2 s-1/2
2kt/M-1 s-1
kpa/M-1 s-1
(0.81-1.21) × 10-8
(0.95-1.75) × 10-7
(0.85-1.32) × 10-7
(0.83-1.42) × 10-7
(1.23-2.72) × 10-7
1.99 × 10-3
1.54 × 10-3
1.97 × 10-3
1.03 × 10-3
1.23 × 10-3
2.5 × 105
2.4 × 105
1.4 × 105
6.0 × 105
4.5 × 105
0.99 ( 0.17
0.75 ( 0.09
0.74 ( 0.08
0.80 ( 0.07
0.82 ( 0.08
benzene
acetonitrile
tert-butyl alcohol
pyridine
a
Errors correspond to twice the standard deviation (2σ). True uncertainties are believed to be at least twice as big.
in hydroxylic solvents and this could, in principle, reduce
their reactivity.8,9,12 Experimental data making the
picture more confusing are those recently reported on
hydrogen abstraction reaction from hydrocarbons by
DPPH, a radical related to peroxyls in its electronic
structure.13 The rate of this reaction, although largely
solvent independent, is higher in tert-butyl alcohol than
in the other investigated solvents, including isooctane
and benzene.
To check if peroxyl radicals obey the principle that
kinetic solvent effects on hydrogen abstraction are inde-
pendent of the nature of the abstracting radical, we have
measured the rate constants for the H-abstraction from
cumene by peroxyl radicals, kp, in five solvents character-
ized by different hydrogen-bond-donating/accepting prop-
erties (isooctane, R ) 0, â ) 0; benzene, R ) 0, â ) 0.10;
acetonitrile, R ) 0.19, â ) 0.31; tert-butyl alcohol, R )
0.68, â ) 0.5; pyridine, R ) 0, â ) 0.64).14 This reaction
was chosen because it has been recently demonstrated
that the H-abstraction from hydrocarbons by cumyloxyl
radicals does not show any measurable kinetic solvent
effect.15
F igu r e 1. Oxygen consumption observed during the autoxi-
dation of 1.1 M cumene in tert-butyl alcohol in the presence of
4.6 × 10-2 M AIBN and 8.0 × 10-5 M R-tocopherol, at 50 °C.
The two different slopes correspond to the inhibited and
uninhibited autoxidation, the latter being observed when
R-tocopherol is completely consumed. The time, τ, at which
this change is observed corresponds to the induction period
that provides the value of Ri by means of the following
equation, Ri ) 2[R-tocopherol]/τ.
d[O2] k [RH] R
x
p
i
-
)
+ Ri
(3)
× 10-3 M-1/2 s-1/2) and the larger (1.99 × 10-3 M-1/2 s-1/2
)
dt
2k
x
t
being found in tert-butyl alcohol and isooctane, respec-
tively. Since the observed variations could be due to a
difference in the values of either kp or kt or of both,17 we
determined the value of 2kt, under the same conditions
employed in the autoxidation experiments, by following
the decay of the EPR signal due to the peroxyl radical
that consists of a single broad line (peak to peak width
ca. 12 G) centered at g ) 2.0149. The cumylperoxyl
radicals were generated by photolyzing oxygen-saturated
solutions of tert-butyl peroxide in the presence of a large
amount of cumene.
The values of kp have been determined by studying the
azoisobutyronitrile (AIBN)-initiated oxidation of cumene,
a well-known free-radical chain autoxidation reaction.
The oxidation rate is given by eq 3, where RH is the
cumene concentration, 2kt is the chain termination rate
constant, and Ri is the rate of free-radical chain initiation
that was measured in each solvent using a phenolic
antioxidant (see Table 1). The rate of oxygen consump-
tion has been measured in a closed tube using a method
based on the variation of the EPR spectral line width of
a stable nitroxide radical dissolved in solution, as de-
scribed elsewhere.16 Figure 1 shows, as an example, the
decrease with time of the oxygen concentration observed
during the autoxidation of cumene at 50 °C in benzene
containing AIBN and 2,2,6,6-tetramethylpiperidine-1-
oxyl (TEMPO), while the oxidizability, kp/(2kt)1/2, of
cumene obtained in the five investigated solvents is
reported in Table 1.
The decay traces followed good second-order kinetics
in all cases (see Figure 2), but the measured rate
constants showed some variation with cumene concen-
tration.18 This effect was previously observed and was
attributed to the occurrence of the reactions shown in
Scheme 2, the relative importance of which depends on
the cumene concentration.19 Although the true value of
2kt could, in principle, be determined by analyzing the
decay traces using the cumbersome equation that has
been worked out from the complete kinetic treatment,19
we preferred to carry out the decay experiments under
An examination of the oxidizability values shows that
these are slightly solvent dependent, the smaller (1.03
(12) Roberts, B. P. J . Chem. Soc., Perkin Trans. 2 1996, 2719.
(13) Valgimigli, L.; Ingold, K. U.; Lusztyk, J . J . Org. Chem. 1996,
61, 7947.
(14) Kamlet, M. J .; Abbound, J . L.; Abraham, M. H.; Taft, R. W. J .
Org. Chem. 1983, 48, 2877 and references therein.
(15) Avila, D. V.; Brown, C. E.; Ingold, K. U.; Lusztyk, J . J . Am.
Chem. Soc. 1992, 114, 6576.
(16) (a) Cipollone, M.; Di Palma, C.; Pedulli, G. F. Appl. Magn.
Reson. 1992, 3, 99. (b) Pedulli, G. F.; Lucarini, M.; Pedrielli, P.; Sagrini,
M.; Cipollone, M. Res. Chem. Intermed. 1996, 22, 1.
(17) Experimental data for the autoxidation of styrene in different
solvents have been previously reported (Howard, J . A.; Ingold, K. U.
Can. J . Chem. 1964, 42, 1044) and the observed differences attributed
to changes in the rate constant for chain propagation.
(18) The EPR measured values of 2kt at 50 °C in benzene are 9.0,
5.4, 3.0, 2.4, and 1.9 × 105 M-1 s-1, at cumene concentrations of 0.125,
0.25, 0.87, 1.1, and 1.81 M, respectively.
(19) Howard, J . A. In Free Radicals; Kochi, J . K., Ed.; Wiley-
Interscience: New York, 1975; Vol. 2, Chapter 12.

Notes
J . Org. Chem., Vol. 63, No. 13, 1998 4499
solvent and the hydroxylic proton of the substrate. Thus,
it can be concluded that peroxyl radicals do obey the
principle that kinetic solvent effects on H-atom abstrac-
tion are independent of the nature of the abstracting
radical.5a This enforces the estimated value of 8 × 105
M-1 s-1 for the rate constant for the hydrogen asbstrac-
tion from R-tocopherol by peroxyl radical in water.
On this basis, it is inferred that the dramatic reduction
of reactivity of peroxyl radicals toward R-tocopherol
observed in SDS micelles and in liposomes with respect
to hydrocarbons can be only partially due to hydrogen
bonding of the phenol by water molecules. This low
reactivity should instead be attributed largely to other
factors, specifically, as Castle and Perkins pointed out,7c,10
and which we consider probable, to the physical inacces-
sibility of much of the R-tocopherol to the attacking
peroxyl radicals. This inaccessibility has been attributed
to the fact that only a small fraction of micelles and
liposomes contain at least a molecule of antioxidant and
that the hydrophobic phytyl chain inhibits the transfer
of R-tocopherol between micelles or between liposomes,
this leaving the majority of them unprotected.
F igu r e 2. Trace of the growth and the decay of cumylperoxyl
radicals photolytically generated from a 1.1 M solution of
cumene in oxygen-saturated benzene in the presence of 1.0 M
tert-butyl peroxide at 50 °C. Insert: second-order plot of the
decay curve observed when shutting off the light.
Sch em e 2
Exp er im en ta l Section
Typically, six to eight experiments were performed in each
solvent on samples consisting of oxygen-purged solutions of
cumene (1.1 M) containing di-tert-butyl peroxide (1.0 M) that
were photolyzed with the unfiltered light from a 500 W high-
pressure mercury lamp directly inside the cavity of a Bruker
ESP 300 EPR spectrometer equipped with a ER033M field
frequency lock. The temperature was controlled by standard
variable-temperature accessories. The decay traces of the EPR
signals were collected on a dedicated computer using time
constants ranging from 4 to 12 ms. Radical concentrations were
measured with respect to a solution of DPPH of known concen-
tration using the signal from a ruby crystal as internal standard.
The measurement of oxidizability (kp/(2kt)1/2) was accomplished
by following the autoxidation of 1.1 M cumene at 50 °C according
to a previously described EPR method.16 Typically, six to eight
experiments for each solvent were performed on sealed air-
saturated solutions containing AIBN ((0.1-1) × 10-2 M), TEMPO
or TEMPO-d6 (0.5-1.0 × 10-5 M) as spin probe. R-Tocopherol
((5-9) × 10-5 M) has been added in each experiment in order
to determine Ri by the inhibitor method (see Figure 1).
the same experimental conditions employed in the au-
toxidation of cumene, i.e., at 50 °C and at 1.1 M cumene,20
using the termination rate constants measured under
these conditions to calculate the kp values reported in
Table 1.
The constancy of kp in the five solvents examined
demonstrates that there is no significant kinetic solvent
effect on hydrogen atom abstraction from cumene by
cumyl peroxyl radicals and that the small dependence
on solvent of the oxidizability of cumene is due entirely
to variations of the termination rate constant. Therefore,
in the reaction of peroxyl radicals with phenols, the
solvent effects reported in homogeneous systems can be
attributed to the formation of hydrogen bonding between
Ack n ow led gm en t. This work was supported by
MURST and by the University of Bologna (Progetto
d′Ateneo: Biomodulatori Organici). We also wish to
thank Dr. K. U. Ingold for reading the manuscript and
for helpful discussions.
(20) Measurements made over a wide range of steady-state concen-
trations of peroxyl radicals did not show any appreciable difference in
the apparent rate constant 2kt in the same solvent.
J O971944I