Hydroperoxyl Radicals (HOO.): Vitamin E Regeneration and H-Bond Effects on the Hydrogen Atom Transfer

Article abstract of DOI:10.1002/chem.201603722

Hydroperoxyl (HOO^.) and alkylperoxyl (ROO^.) radicals show a different behavior in H-atom-transfer processes. Both radicals react with an analogue of α-tocopherol (TOH), but HOO^., unlike ROO^., is able to regenerate TOH by a fast H-atom transfer: TO^.+HOO^.→TOH+O₂. The kinetic solvent effect on the H-atom transfer from TOH to HOO^.is much stronger than that observed for ROO^.because noncovalent interactions with polar solvents (Solv???HOO^.) destabilize the transition state.

Full text of DOI:10.1002/chem.201603722

DOI: 10.1002/chem.201603722
Communication
&
Reactive Oxygen Species
C
Hydroperoxyl Radicals (HOO ): Vitamin E Regeneration and H-
Bond Effects on the Hydrogen Atom Transfer
Jakub Cedrowski,[a] Grzegorz Litwinienko,*[a] Andrea Baschieri,[b] and Riccardo Amorati*[b]
ly in the protonated form and the presence of superoxide can
C
C
Abstract: Hydroperoxyl (HOO ) and alkylperoxyl (ROO )
radicals show a different behavior in H-atom-transfer pro-
cesses. Both radicals react with an analogue of a-toco-
be neglected. Autoxidation of CHD to benzene is a well-known
C
chain process, in which HOO acts as propagating radical (see
Scheme 1 and Figure 1).[9]
C
C
pherol (TOH), but HOO , unlike ROO , is able to regenerate
C
C
TOH by a fast H-atom transfer: TO +HOO !TOH+O2.
The kinetic solvent effect on the H-atom transfer from
C
TOH to HOO is much stronger than that observed for
C
ROO because noncovalent interactions with polar solvents
C
(Solv···HOO ) destabilize the transition state.
C
Hydroperoxyl radicals (HOO ) are mediators of many processes
of wide current interest, such as atmospheric pollutant degra-
dation,[1] photocatalysis,[2] and molecular oxygen activation on
metal surfaces[3] or in enzymes.[4] While its conjugated base (su-
Cꢀ
C
peroxide, O2 ) is inactive as an oxidizer,[5] HOO is a source of
Scheme 1. Autoxidation mechanism of 1,4-cyclohexadiene[9] initiated by
AIBN (2,2’-azobis(isobutyronitrile)); R1 =(CH3)2(CN)C.
oxidative damage in biological systems. Its formation is related
to degenerative pathologies and aging.[6] HOO is believed to
C
be essentially similar to alkylperoxyl radicals in H-atom transfer
(HAT) reactions.[6,7] The HOOꢀH bond dissociation enthalpy
(BDE) is slightly higher (87.5 kcalmolꢀ1, gas phase)[7] than the
BDE of ROOꢀH (ꢁ85 kcalmolꢀ1, gas phase).[7] On the other
C
hand, the knowledge about reducing properties of HOO is still
very limited. The hydroperoxyl radical has an exceptionally
weak HꢀOO BDE (49.2 kcalmolꢀ1),[7] which allows us to consid-
C
C
er HOO as potentially good H-atom donating agent. Despite
C
Cꢀ
the great role of the HOO /O2 pair in biology, the study of the
C
HOO reactivity with phenolic antioxidants has been somewhat
neglected,[7] mainly because this radical is hard to be generat-
ed in solution in experimental systems and its reactivity is very
difficult to be followed by common spectroscopic methods.[8]
To address this lack of knowledge, we studied the reaction of
C
HOO with 2,2,5,7,8-pentamethyl-6-chromanol (TOH), an ana-
logue of a-tocopherol (the main component of vitamin E), by
following the autoxidation rate of 1,4-cyclohexadiene (CHD) in
Figure 1. Oxygen consumption measured during autoxidation experiments
in chlorobenzene initiated by AIBN (0.05m) at 308C with the following reac-
tants: a) styrene (2.1m); b) CHD (cyclohexadiene, 0.26m); c) styrene (2.1m)
and TOH (5 mm); d) CHD (0.26m) and TOH (6.2 mm). The points are the nu-
merical fitting of trace d.
C
different organic solvents. In our system, HOO exists exclusive-
[a] J. Cedrowski, Prof. G. Litwinienko
Faculty of Chemistry, University of Warsaw
Pasteura 1, 02-093 Warsaw (Poland)
E-mail: litwin@chem.uw.edu.pl
In the presence of TOH the rate of the CHD autoxidation,
measured as the rate of O2 consumption, was slowed down
[b] Dr. A. Baschieri, Dr. R. Amorati
C
(Figure 1b,d) because of the trapping of HOO by TOH
Department of Chemistry “G. Ciamician”, University of Bologna
Via S. Giacomo 11, 40126 Bologna (Italy)
E-mail: riccardo.amorati@unibo.it
[Eq. (1)].
k1
C
C
TOH þ HOO
TO þ HOOH
ð1Þ
ƒ!
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201603722.
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C
C
To compare the chemistry of HOO and ROO radicals, the
rate of the reaction of styrylperoxyl with TOH [Eq. (2)] was also
determined by studying the autoxidation of styrene (Fig-
ure 1a,c).[10]
stance Figure 1d for PhCl). Since the propagation and termina-
tion rate constants of CHD and styrene are known (see the
Supporting Information for the kinetic details),[9] the values of
k1, k2, and the k3b/k3a ratio could be obtained (see Table 1).
k2
C
C
TOH þ ROO
TO þ ROOH
ð2Þ
ƒ!
Table 1. Rate constants for the reaction of TOH with hydroperoxyl (k1) or
with styrylperoxyl (k2) radicals and competition between reduction and
The chain-breaking effect of TOH was more clearly visible in
styrene, because this substrate has a lower propagation rate
C
C
oxidation of TO by HOO radicals (k3b/k3a).
constant than CHD (41[11] vs. 1400[9]
M
ꢀ1 sꢀ1 in chlorobenzene,
H
[a]
Solvent (b2
)
k1 [mꢀ1 sꢀ1
]
k2 [mꢀ1 sꢀ1
]
k3b/k3a
respectively). In CHD, however, the length of the inhibition
period was up to 10 times longer (corresponding to ꢁ20 radi-
cals quenched by each TOH molecule) than in styrene. Analysis
of the products formed in the mixture of TOH, AIBN (2,2’-azobis-
(isobutyronitrile)), and CHD in the presence of O2 (Figure 1S in
CCl4 (0.00)
PhCl (0.09)
Dioxane[b] (0.41)
MeCN (0.44)
THF[b] (0.51)
(1.6ꢂ0.4)ꢁ107
(1.6ꢂ0.1)ꢁ106
(1.1ꢂ0.1)ꢁ105
(6.8ꢂ0.7)ꢁ104
(2.5ꢂ0.5)ꢁ104
(4.0ꢂ0.4)ꢁ106
(2.7ꢂ0.3)ꢁ106
(5.0ꢂ0.1)ꢁ105
(6.8ꢂ0.6)ꢁ105
(6.2ꢂ1.0)ꢁ105
9.9ꢂ3.5
8.3ꢂ0.5
5.2ꢂ0.9
2.2ꢂ1.0
0.5ꢂ0.1
C
the Supporting Information) showed that in such system HOO
[a] From ref. [17b]. [b] Co-oxidation of the solvent was also considered,
see the Supporting Information.
acts as the propagating radical (no products were formed by
reaction of TOH with peroxyl radicals derived from AIBN) and
that TOH was consumed more slowly than expected, suggest-
C
C
ing that HOO may reduce TO radicals. This double-faced be-
The data presented in Table 1 indicate that in a non-H-bond-
C
havior of HOO was confirmed by performing autoxidation ex-
C
accepting solvent like CCl4 the HOO radical is about four times
periments (in PhCl) in the presence of 3,5-di-tert-butyl-ortho-
quinone. In styrene, this compound did not modify the rate of
the O2 uptake, as expected from the absence of phenolic OH
groups. However, when CHD was oxidized instead of styrene,
a strong inhibition was observed and this effect can be only
explained as originating from the reduction of the orthoqui-
C
more reactive than ROO towards TOH, in agreement with the
larger BDE for HOOꢀH than for ROOꢀH. In chlorobenzene, the
C
C
reactivity of HOO is halved compared to that of ROO , while it
becomes 1/25 in THF. The different susceptibility of these two
radicals on the kinetic solvent effect (KSE) is in contrast to the
general assumption that the decrease of the rate constant for
an H-atom transfer (kS) from a phenol to a radical depends
only on the ability of a phenol to form a H-bond with an H-
bond-accepting solvent.[16a–d] Thus, kS in any solvent can be
correlated with the rate constant in a non-H-bonding solvent
C
none by HOO (see Figure 2S in the Supporting Information for
details).[12] Therefore, the unusual stoichiometric factor of the
TOH inhibition of the CHD autoxidation can be attributed to
C
C
C
the reduction of TO by HOO . Based on BDE values for HꢀOO
and TOꢀH (49.2[7] and 77.1[13] kcalmolꢀ1, respectively), this reac-
tion is substantially exothermic (DH8ꢁꢀ28 kcalmolꢀ1). With
this thermodynamic justification, a competition between the
addition (k3a)[14] and reduction (k3b), can be reasonably pro-
posed (Scheme 2).
H
H
k0 via Equation (3),[16a] in which a2 and b2 represent the rela-
tive ability of the substrate to donate an H-bond (range 0 to
1.0)[17a] and the relative ability of the solvent to accept a H-
bond (range 0 to 1.0), respectively.[17b]
H
logðkS mꢀ1 sꢀ1Þ ¼ logðk0 mꢀ1 sꢀ1Þꢀ8:3 a2H b2
ð3Þ
According to Equation (3), the magnitude of the KSE does
not depend on the nature of the abstracting radical,[16a] as de-
picted by pathways a and b in Scheme 3.
The KSE mechanism holds for organic radicals, such as alkox-
yl, alkyl, alkylperoxyl, and hydrazyl radicals in almost any sol-
vent,[16a–d] with a few exceptions.[16d,e,18] If the logarithm of the
[16a]
C
C
rate constants for the reaction of TOH with ROO , tBuO ,
and
[16b]
C
2,2’-diphenylpicrylhydrazyl (dpph )
radicals is plotted as
H
a function of the solvent parameter b2 (Figure 2), nearly paral-
lel straight lines are observed in agreement with Equa-
tion (3).[19] A much bigger slope for the HOO line indicates
C
Scheme 2. Different reaction pathways between hydroperoxyl radicals
C
that the reaction of TOH with the HOO radicals has a stronger
C
C
(HOO ) and a-tocopheroxyl radicals (TO ).
KSE than predicted by Equation (3).
The solvents used in our experiments allowed us to exclude
+
C
C
Cꢀ
The autoxidation plots were subsequently analyzed by a ki-
netic simulation software by taking into account the two possi-
a deprotonation equilibrium (HOO ÐH +O2 ), which may di-
minish the concentration of HOO radicals in the system, be-
C
ble pathways for the TO decay, reactions 3a and 3b
cause dioxane and THF are not ionization-supporting sol-
H
(Scheme 2).[15] A very good fitting of the experimental O2
traces was obtained in all the investigated solvents (see for in-
vents.[16d] Linearity of the log(k1) versus b2 relationship
(Figure 2), in opposition to the scattered dependence between
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Scheme 3. Reaction between HOO and TOH in the presence of an H-bond-
C
C
accepting solvent (S). The S···HOO complex is less reactive than HOO
(kSHOO <kHOO).
log(k1) and the dielectric constant (see Figure 3S in the Sup-
Figure 2. The kinetic solvent effect observed for the reaction of TOH with
porting Information), indicates a prominent role of the H-bond
C
C
C
C
tBuO (~), ROO (*), dpph (2,2’-diphenylpicrylhydrazyl, !), and HOO (*)
in CCl4, PhCl, MeCN, dioxane, and THF. The slopes are ꢀ1.5, ꢀ1.8, and ꢀ2.0
C
formed between HOO and the solvent. Therefore, the most
C
C
C
C
for tBuO , ROO , and dpph , respectively. For TOH reacting with HOO the
C
probable justification of the anomalous KSE of HOO in respect
slope is ꢀ5.0.
C
to ROO is that some solvents, besides accepting the H-bond
C
C
from TOH, also interact with HOO by forming a S···HOO com-
C
plex that is less reactive than free HOO (shown by reactions c
and d in Scheme 3). The decrease of reactivity of the H-
ods (see details in the Supporting Information).[20] The reaction
was modelled by using (non solvated) phenol and HCN as ana-
logues of TOH and acetonitrile, respectively. In Figure 3 it is
C
bonded HOO is indeed a general characteristic of this radical.
Also the logarithm of the rate constant for its reaction with
CHD, measured by Howard and Ingold, and by Sawyer et al.,[9]
C
shown that the HCN···HOO interaction makes the HAT reaction
gives excellent straight lines when plotted against the b2 of
more endothermic by 4.6 kcalmolꢀ1 and increases the activa-
H
tion energy by 2.6 kcalmolꢀ1 compared to free HOO as H-
C
the solvent (see Figure 4S in the Supporting Information).
C
C
The effect of the S···HOO complex formation on the H-atom
atom abstracting radical. Interestingly, in the HCN···HOO com-
abstraction was further investigated by computational meth-
plex the length of the H-bond increases during the reaction
C
C
Figure 3. Reaction of HOO with phenol, with or without HCN as H-bond acceptor in the S···HOO complex, at the M05/6-311 g(2df,2p) level of theory. The
length of the H-bond is indicated.
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C
ucts. This clearly implies that HOO is a much better H-bond
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[7]
C
siderably weaker acid than HOO (pKa =4.7). This explanation
C
agrees with the known ability of HOO to donate H-bonds to
water and organic polar molecules.[1,21,22] A similar reactivity
decrease occurs in general when the stabilization of a radical is
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autoxidation in several solvents are in excellent agreement with each
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measured in n-decane by Howard and Ingold, probably because of low
C
explained by the inability of the H-bonded complex S···HOO to
C
reduce TO (Scheme 2, reaction 3b), while reaction 3a should
be less dependent on the solvent. Considering that the rate
constant of the phenoxyl–alkylperoxyl recombination is usually
high (ꢁ108 mꢀ1
s
ꢀ1),[24] k3b is roughly 109 mꢀ1 sꢀ1 in apolar sol-
vents.
In conclusion, the present work provides new insights into
the reactivity of hydroperoxyl radicals with a phenolic antioxi-
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C
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C
is triggered by the fraction of HOO able to penetrate the bi-
layer.[6,8c,25a] In our model system, the antioxidant action, i.e.,
C
HOO trapping by an a-tocopherol analogue, is strongly en-
C
C
hanced by H-atom abstraction from HOO by TO radicals, a pro-
cess resulting in the regeneration of TOH. This additional pro-
cess can be biologically important, since a-tocopheroxyl radi-
cals formed during the antioxidant action of vitamin E are pres-
ent at the water–lipid boundary region,[25] which can be easily
C
HOO can be estimated to be both exothermic. In case of unsubstituted
orthoquinone (Q): Q+HOO !QH +O2, DH8=ꢀ17.5 kcalmolꢀ1; QH +
C
C
C
HOO !QH2 +O2, DH8=ꢀ31.5 kcalmolꢀ1. L. Valgimigli, R. Amorati, M. G.
C
Fumo, G. A. DiLabio, G. F. Pedulli, K. U. Ingold, D. A. Pratt, J. Org. Chem.
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363; b) P. Mendes, D. B. Kell, Bioinformatics 1998, 14, 869–883. This soft-
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ref. [10a].
C
Cꢀ
accessed by HOO (and to a different extent by O2 , which is
also able to regenerate the a-tocopheroxyl radical).8c The
strong kinetic solvent effect on the k3b/k3a, however, suggests
that in H-bond-accepting solvents this reaction is not so effi-
C
cient to dominate over the addition of HOO to a-tocopheroxyl
radicals, as predicted by the conventional mechanism of the
antioxidant action of a-tocopherol.[8c]
[16] a) D. W. Snelgrove, J. Lusztyk, J. T. Banks, P. Mulder, K. U. Ingold, J. Am.
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Lastly, the kinetic solvent effect observed for the H-atom
C
transfer from TOH to HOO is much stronger than for the TOH/
C
C
ROO pair, because of an H-bond formation between HOO and
H-bond-accepting solvents.
Acknowledgements
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The authors gratefully acknowledge financial support from the
National Science Center of Poland (NCN grant No. 2014/15/B/
ST4/04835) and from the University of Bologna (FARB project
FFBO123154). Computing facilities were provided to R.A. by
CINECA (IsC35 project SPRING).
C
C
C
[19] Experimental slopes for tBuO , dpph (taken from ref. [16a,b]) and ROO
(measured herein) are in good agreement with each other, but are
H
somewhat smaller than expected from Equation (3), by using the a2 of
TOH of 0.37 (8.3ꢁ0.37=3.1) taken from ref. [16a].
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Keywords: hydrogen atom transfer · hydroperoxyl radicals ·
reactive oxygen species · solvent effects · tocopherol
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Received: August 3, 2016
Published online on && &&, 0000
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COMMUNICATION
Role reversal: Hydroperoxyl radicals
&
Reactive Oxygen Species
C
(HOO ) are able to recycle an a-toco-
J. Cedrowski, G. Litwinienko,* A. Baschieri,
R. Amorati*
pherol analogue, increasing the inhibi-
tion period up to 10 times, and exhibit
a strong kinetic solvent effect arising
from noncovalent interactions between
&& – &&
C
Hydroperoxyl Radicals (HOO ): Vitamin
C
HOO and H-bond-accepting solvents.
E Regeneration and H-Bond Effects on
the Hydrogen Atom Transfer
&
&
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!