Multi-faceted reactivity of alkyltellurophenols towards peroxyl radicals: Catalytic antioxidant versus thiol-depletion effect

Article abstract of DOI:10.1002/chem.201300451

Hydroxyaryl alkyl tellurides are effective antioxidants both in organic solution and aqueous biphasic systems. They react by an unconventional mechanism with ROO^. radicals with rate constants as high as 10⁷ M^-1 s^-1 at 303 K, outperforming common phenols. The reactions proceed by oxygen atom transfer to tellurium followed by hydrogen atom transfer to the resulting RO^. radical from the phenolic OH. The reaction rates do not reflect the electronic properties of the ring substituents and, because the reactions occur in a solvent cage, quenching is more efficient when the OH and TeR groups have an ortho arrangement. In the presence of thiols, hydroxyaryl alkyl tellurides act as catalytic antioxidants towards both hydroperoxides (mimicking the glutathione peroxidases) and peroxyl radicals. The high efficiency of the quenching of the peroxyl radicals and hydroperoxides could be advantageous under normal cellular conditions, but pro-oxidative (thiol depletion) when thiol concentrations are low. Anti- and pro-oxidants: Hydroxyaryl alkyl tellurides are unconventional antioxidants able to quench chain-carrying peroxyl radicals with rate constants as high as 10⁷ M^-1 s^-1 by a mechanism involving oxygen atom transfer to tellurium followed by reaction of the RO^. radical with the phenol (see figure). They can also catalytically decompose both the ROO^. radical and H₂O₂ in the presence of excess thiols. Copyright

Full text of DOI:10.1002/chem.201300451

DOI: 10.1002/chem.201300451
Multi-faceted Reactivity of AlkyltelluACTHNUGRTNEUNGrophenols Towards Peroxyl Radicals:
Catalytic Antioxidant Versus Thiol-Depletion Effect
Riccardo Amorati,[a] Luca Valgimigli,*[a] Peter Dinꢀr,[b] Khadijeh Bakhtiari,[b]
Mina Saeedi,[b] and Lars Engman*[b]
Abstract: Hydroxyaryl alkyl tellurides
are effective antioxidants both in or-
ganic solution and aqueous biphasic
systems. They react by an unconven-
The reaction rates do not reflect the
electronic properties of the ring sub-
stituents and, because the reactions
occur in a solvent cage, quenching is
more efficient when the OH and TeR
groups have an ortho arrangement. In
the presence of thiols, hydroxyaryl
alkyl tellurides act as catalytic antioxi-
dants towards both hydroperoxides
(mimicking the glutathione peroxi-
AHCTUNGTRENNdGUN ases) and peroxyl radicals. The high
C
tional mechanism with ROO radicals
efficiency of the quenching of the per-
oxyl radicals and hydroperoxides could
be advantageous under normal cellular
conditions, but pro-oxidative (thiol de-
pletion) when thiol concentrations are
low.
with rate constants as high as 107 mꢀ1 sꢀ1
at 303 K, outperforming common phe-
nols. The reactions proceed by oxygen
atom transfer to tellurium followed by
hydrogen atom transfer to the resulting
Keywords: antioxidants · kinetics ·
pro-oxidants · radicals · tellurium
C
RO radical from the phenolic OH.
Introduction
from considering tellurium compounds for drug develop-
ment. Although some adverse effects of both inorganic and
organic tellurium compounds have been reported,[5] there is
no intrinsic toxicity associated with the element.[6] Rather,
the toxicity of tellurium seems to vary depending on the oxi-
dation state of the chalcogen and whether it is organic or in-
organic.
The glutathione peroxidases, GPx, are a small family of
selenoenzymes that catalyse the reduction of hydrogen per-
oxide and organic hydroperoxides to water and alcohols, re-
spectively, by using glutathione, GSH, as the stoichiometric
reducing agent. In the proposed mechanism of action, sele-
nium at the active site of selenocysteine traverses the sele-
nol, selenenic acid and selenosulfide oxidation states as hy-
drogen peroxide is reduced to water and two molecules of
glutathione are oxidised to the corresponding disulfide,
GSSG.[7] Redox cycling of tellurium between the oxidation
states +II and +IV occurs very readily. Thus, the divalent
organotellurium compounds R2Te could mimic the action of
the glutathione peroxidases and catalyse the decomposition
of hydrogen peroxide and organic hydroperoxides in the
presence of thiols, as outlined in Scheme 1.[8–10]
Although tellurium is as rare as gold and silver in the crust
of the earth (27 ppb), the element is readily available. This
is because it occurs in copper ores. During electrolytic refin-
ing of 500 tons (508ꢀ103 kg) of ore, typically as much as one
pound (453 g) of tellurium is produced.[1] The organic chem-
istry of tellurium has been extensively explored during the
last century and a volume concerning the preparation and
transformations of organotellurium compounds appeared in
the Houben Weyl series in 1990.[2] However, very few re-
ports on the applications or effects of organotelluriums in
biological systems have appeared. Unlike the lighter chalco-
gens, sulfur and selenium, tellurium does not seem to be an
essential element to mammals. Thus, although the adminis-
tration of radiolabelled (75Se)selenite to rat liver hepatocytes
resulted in the formation of radiolabelled selenoproteins, no
such incorporation of the chalcogen was observed when
(
121Te)tellurite was used.[3] Organic and inorganic derivatives
of tellurium have a reputation for being toxic to humans.[4]
Such concerns may have led the pharma industry to desist
Diorganyl selenides similarly can undergo redox cy-
cling.[11] However, for those cases in which comparison has
been made, the tellurium series clearly shows superior cata-
lytic performance.[12,13]
As a result of their interesting redox properties, organo-
tellurium compounds have recently been probed as redox
chemotherapeutics.[14] Their capacity to inhibit both human
and malaria parasite thioredoxin reductase was proposed as
an explanation for their anti-cancer[12,15] and anti-malari-
al[16,17] properties. It has recently been proposed that redox-
active organotellurium compounds, depending on the cellu-
[a] Dr. R. Amorati, Dr. L. Valgimigli
Department of Chemistry “Ciamician”, University of Bologna
Via S. Giacomo 11, 40126-Bologna (Italy)
Fax : (+39)051-209-5688
E-mail: luca.valgimigli@unibo.it
[b] Dr. P. Dinꢁr, Dr. K. Bakhtiari, Dr. M. Saeedi, Prof. L. Engman
Department of Chemistry - BMC, Uppsala University
Box 576, 751 23 Uppsala (Sweden)
E-mail: lars.engman@kemi.uu.se
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300451.
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FULL PAPER
(BDEOH),[23b,24b] which holds for virtually any (other) phe-
nolic antioxidant.[25] This indicated an unconventional mech-
anism for the trapping of the peroxyl radical, related to the
redox chemistry of the neighbouring tellurium, which still
remains obscure. Furthermore, most compounds 1–8 showed
an additional mode of chain-breaking antioxidant behav-
iour: in the presence of a stoichiometric or excess amount
of reducing agents like thiols, they were fully regenerated
from their oxidation products formed upon quenching per-
oxyl radicals, thereby renovating their chain-breaking anti-
oxidant behaviour. In other words, they could act as catalyt-
ic chain-breaking antioxidants.[23,24] This behaviour is not
common in chalcogen-substituted phenols and its mecha-
nism is far from understood. Its relevance is, however, easy
to appreciate in the light of the capacity of organotelluriums
to serve as redox sensors/effectors able to recognise the oxi-
dative stress status and act either as pro- or antioxidants.[18]
To shed more light on the complex antioxidant chemistry
of these compounds we prepared two simple model alkyltel-
lurophenols and their corresponding methyl ethers (com-
pounds 9–12) and investigated their reactivity by employing
Scheme 1. GPx-mimicking preventive antioxidant behaviour of diorganyl
tellurides R2Te.
lar oxidative stress status, could either act as anti- or pro-ox-
idants.[18] For example, in cancer cells, in which the levels of
superoxide and hydrogen peroxide are elevated, these or-
ACHTUNGTRENNUNGganACHTUNGTRENNUNGotellurium compounds may catalyse the oxidation of key
proteins and trigger apoptosis, the preferred mode of cancer
cell death. On the other hand, in healthy cells, in which oxi-
dant concentrations are low and the levels of glutathione
are high, the same compounds would serve as protective an-
tioxidants. In support of the potential damaging effect of
catalytic amounts of organotelluriums, hydroperoxide causes
the release of zinc from the sulfur clusters in metallothio-
nein[19] and the thiols of a zinc finger protein Sp1 fragment
were similarly oxidatively modified.[20]
During the last decade we have designed, prepared and
studied organochalcogen redox-active agents with the ability
C [21–24]
a
combination of experimental and computational ap-
to quench peroxyl radicals, ROO ,
the main effectors of
proaches.
oxidative damage in biological systems (and materials).[25]
Several such compounds (e.g., 1–8) show remarkable chain-
breaking antioxidant behaviour, being able to inhibit lipid
peroxidation (or the autoxidation of organic substrates like
styrene) similarly or even more effectively than reference
phenolic antioxidants such as BHT (butylated hydroxyl
ACHTUNGTNERtNUNG ol-
ACHTUNGTRENNUNGuene), BHA (butylated hydroxyanisole) or a-tocopherol
whilst maintaining good GPx-like preventive antioxidant be-
haviour.[21–24]
Results
Synthesis: Several strategies were considered for the intro-
duction of an octyltelluro group next to the phenolic moiety
in 2-tert-butylphenol. The most straightforward approach
seemed to involve ortho bromination, lithiation and reaction
with electrophilic tellurium in the form of di-n-octyl ditellu-
AHCTUNGTRENNUNG
ride or elemental tellurium (Scheme 2).[24b] Lithium telluro-
lates, similar to those resulting from the latter approach,
have previously been oxidised to ditellurides and converted
into aryl alkyl tellurides by sodium borohydride reduction
followed by alkylation (Scheme 2). Selective ortho bromina-
tion of 2-tert-butylphenol was achieved by using in situ pre-
pared N-bromodimethylamine as previously described
(Scheme 2).[26]
Certain alkyltellurophenols and -pyridinols (such as 6–8)
showed reactivities towards peroxyl radicals much higher
than predicted by the well-established Evans–Polanyi rela-
tionship between kinh (the rate constant for peroxyl radical
However, although the dilithiated phenol reacted as ex-
pected with either di-n-octyl ditelluride or elemental telluri-
um, the desired compound 9 was always contaminated by
chromatographically inseparable byproducts. In a slightly
modified approach, the bromophenol was O-methylated[27]
ꢀ
trapping) and the bond dissociation enthalpy of ArO H
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L. Valgimigli, L. Engman et al.
Scheme 3. Preparation of compound 10.
Inhibition studies in the two-phase lipid peroxidation
system: We have previously designed and thoroughly vali-
dated a two-phase controlled lipid peroxidation system that
allows the study of lipid-soluble antioxidants either alone or
in the presence of water-soluble co-antioxidants during the
azo-initiated peroxidation of linoleic acid.[29] Regeneration
of the main lipid-soluble antioxidant by the co-antioxidant is
most often the reason for synergistic antioxidant behaviour
and can be visualised by the extension of the inhibition
period, tinh, during which linoleic acid is “protected” from
oxidation.[21–24,30] In the experimental setup, linoleic acid
Scheme 2. Preparation of compound 9.
prior to lithiation and the two methods for the introduction
of the octyltelluro group were attempted starting from the
monolithiated anisole. In this way, pure compound 11 was
isolated in yields of 84 and 35% by using di-n-octyl ditellu-
ACHTUNGTRENNUNGride and elemental tellurium as the sources of chalcogen, re-
spectively. We have previously used boron tribromide for
the demethylation of anisole derivatives carrying an alkyl-
AHCTUNGTREG(NNNU L-H) and the antioxidant (40 mm) to be evaluated were stir-
A
red in chlorobenzene at 428C with an aqueous solution of
N-acetylcysteine (NAC). 2,2’-Azobis(2,4-dimethylvaleroni-
trile) (AMVN) was used as initiator in the organic phase
and the progress of the peroxidation [formation of the con-
jugated diene hydroperoxide, Eq. (1)] was monitored by
HPLC.
zo[b]selenophenes).[22b] However, to the best of our knowl-
edge, successful demethylation of aryl methyl ethers con-
taining an alkyltelluro group has not been previously report-
ed. We were therefore pleased to find that compound 11,
upon stirring with a two-fold excess of BBr3 in methylene
chloride, afforded the desired phenol 9 in a modest isolated
yield of 43% after aqueous workup and chromatographic
purification. Although boron is likely to chelate both
oxygen and tellurium, the subsequent nucleophilic attack of
bromide probably occurs with less steric hindrance on the
methyl group.
Selective para bromination of 2-tert-butylphenol was
brought about by using tetrabutylammonium tribromide in
chloroform, as recently described.[28] Fortunately, the lithia-
tion strategy used for the preparation of the ortho com-
pound cleanly produced the desired phenolic compound 10
(Scheme 3). Thus, treatment of the para-bromophenol with
three equivalents of tert-butyllithium followed by the addi-
tion of di-n-octyl ditelluride afforded compound 10 in a
yield of 79% after chromatographic purification. For refer-
ence purposes, anisole 12, the O-methylated analogue of
compound 10, was also prepared. As outlined in Scheme 2,
lithiation of 4-bromo-2-tert-butylanisole followed by the ad-
dition of di-n-octyl ditelluride provided the desired alkyl
aryl telluride in a yield of 84%.
From the inhibited rate of peroxidation, Rinh, determined
by least-squares methods from absorbance–time plots, and
from tinh, determined graphically as the cross-point of the in-
hibited and uninhibited lines (Figure 1), both antioxidant ca-
pacity and regenerability could be studied. a-Tocopherol
was used as a reference compound (Table 1). Under the
conditions used, a-tocopherol inhibited the peroxidation ef-
ficiently with a value of Rinh of 24 mmhꢀ1. However, irrespec-
tive of whether N-acetylcysteine was present or not, the in-
hibition time was essentially the same (87–90 min). 2-tert-
Butylphenol did not quench the peroxyl radicals efficiently
enough that an inhibited phase of peroxidation could be dis-
tinguished. Rather, it acted as a retarder of the peroxida-
tion, that is, the autoxidation proceeded significantly albeit
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Reactivity of Alkyltellurophenols Towards Peroxyl Radicals
FULL PAPER
11 and 62 min for the para compound 12. The inhibited
rates of peroxidation were 27 and 18 mmhꢀ1, respectively,
and thus in the same range as that recorded for a-tocopher-
ol. Although the occurrence of regeneration (paralleled by
NAC consumption in the aqueous phase) indicates catalytic
antioxidant behaviour of the organotelluriums, the overall
efficiency of the radical trapping (that is, the number of per-
oxyl radicals trapped for each NAC molecule) was substan-
tial only for compound 9 (0.33), whereas it was very modest
for the other compounds (0.09, 0.09 and 0.06 for 10, 11 and
12, respectively).
Figure 1. Concentration of linoleic acid hydroperoxide versus time using
antioxidants 9, 10 and a-tocopherol (40 mm) in the chlorobenzene layer,
in the presence of NAC (1 mm) in the aqueous phase.
Thiol peroxidase activity: Diorganyl tellurides are readily
oxidised by a variety of mild oxidising agents (e.g., hydrogen
peroxide, organic hydroperoxides and peroxynitrite). The re-
sulting tetravalent species, present as tellurium(IV) dihy-
Table 1. Inhibited rates of linoleic acid peroxidation (Rinh) and inhibition
times (tinh) for antioxidants 9–12 and a-tocopherol in the two-phase
model with and without N-acetylcysteine (1mm) in the aqueous phase.
ACHUTNGERNdNUG roxHCATUNGTRNEiNUGN des in an aqueous environment, are reduced by mild
reducing agents such as ascorbate or thiols to regenerate the
diorganyl telluride. Thus, as previously discussed, organotel-
luriums can mimic the action of selenium-containing gluta-
thione peroxidase enzymes (see Scheme 1).[8–10]
A simple assay for glutathione peroxidase activity is
based on monitoring the initial rate of formation of diphenyl
disulfide in methanol by UV spectroscopy in the reaction of
hydrogen peroxide, thiophenol and catalyst.[31] As shown in
Table 2, both compounds 9 and 10 efficiently decompose hy-
With N-acetylcysteine
Without N-acetylcysteine
[b]
[c]
[c]
Antioxidant[a]
Rinh [mmhꢀ1
]
tinh [min] Rinh[b] [mmhꢀ1
]
tinh [min]
9
10ꢁ5
12ꢁ2
27ꢁ6
18ꢁ4
361ꢁ1
94ꢁ1
93ꢁ10
62ꢁ1
90ꢁ1
340
390
553
565
0
0
0
0
10
11
12
a-tocopherol[d] 24ꢁ2
24ꢁ2
87ꢁ7
[a] [Antioxidant]=40 mm. [b] Rate of peroxidation during the inhibited
phase (uninhibited rate ca. 650 mmhꢀ1). Data are the meanꢁSD of three
or four experimental runs. Estimated errors for inefficient catalysts are
ꢁ20%. Absolute values depend on the experimental setup, but they are
reproducible for comparison under identical settings. [c] Inhibited phase
of peroxidation. Data are the meanꢁSD for three experimental runs.
[d] From ref. [23b].
Table 2. Thiol peroxidase activity of organotelluriums 9 and 10.
Catalyst
Thiol peroxidase activity[a] [mmminꢀ1
]
9
10
24ꢁ2
16ꢁ1
[a] Initial rate of hydrogen peroxide reduction in the presence of thiophe-
nol and catalyst in methanol at ambient temperature. Data are the
meanꢁSD for three experimental runs.
at a reduced rate in the presence of this phenolic inhibitor.
As shown in Table 1, similar results were obtained when
compounds 9 and 10 were tested in the absence of the thiol
co-antioxidant as it was not possible to distinguish an inhibi-
tion phase of the peroxidation. However, in contrast to 2-
tert-butylphenol, in the presence of N-acetylcysteine in the
aqueous phase, both compounds 9 and 10 inhibited peroxi-
dation significantly more efficiently than a-tocopherol. This
behaviour parallels that of other ortho-alkyltellurophenols
and -pyridinols investigated and has been attributed to the
rapid oxidation of the telluride moiety to the corresponding
telluroxide by hydroperoxides already present as impurities
even in purified samples of linoleic acid.[23,24] Because tellur-
oxide is a much less effective antioxidant,[23] some thiol is
needed in the aqueous phase to maintain the antioxidant in
the telluride oxidation state, as shown in Scheme 1. When it
comes to the ability to regenerate, 10 outperformed a-toco-
drogen peroxide although the ortho-substituted compound 9
(initial rate=24 mmminꢀ1) is a better GPx mimic than the
corresponding para derivative 10 (initial rate=16 mmminꢀ1).
Both compounds clearly outperformed diphenyl diselenide
(initial rate=0.7 mmminꢀ1), which is commonly used as a
control when glutathione peroxidase activity is assessed.
Considering that oxidation is rate-determining for the GPx
activity, it is surprising that the sterically more congested or-
ganotellurium 9 is a better catalyst than 10. However, it may
be that the ortho-hydroxy group preorganises the reacting
partners by hydrogen bonding to H2O2 and thus facilitates
nucleophilic attack from tellurium on oxygen.
pherol (not regenerated by thiols) only slightly (tinh
94 min), whereas the ortho-substituted derivative 9 (tinh
=
=
Homogeneous phase autoxidation studies: Aryl alkyl tellu-
361 min) showed a much longer inhibition period than a-to-
copherol.
ACHTUNGTRENNUNG
Compounds 11 and 12, the O-methylated analogues of tel-
lurides 9 and 10, also did not inhibit the peroxidation in the
absence of thiol. However, in the presence of the co-antioxi-
dant, the inhibition time was 93 min for the ortho derivative
N
ACHTUNGTRENNUNG
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L. Valgimigli, L. Engman et al.
unchanged for compound 10, whereas it increases for com-
pound 9, which suggests that the rate-determining step for
C
the reaction of 9 and 10 with ROO is not a HAT process.
To gain confirmation of this, we measured the deuterium
kinetic isotope effect (DKIE) for the reaction of the tellu-
AHCTUNGTREGrNNUN ides with peroxyl radicals. This was achieved by the well-es-
tablished method of adding 1% D2O to the autoxidating
mixture to achieve dynamic OH!OD exchange in the phe-
nolic moiety. No significant DKIE was observed (kH/kD =
1.2ꢁ0.4) in either PhCl or MeCN, which confirms that hy-
drogen-atom transfer is not the rate-limiting step.[34–36]
The addition of a lipid-soluble thiol (N-tert-butoxycarbo-
nylcysteine methyl ester; LipCys) to the autoxidating mix-
ture inhibited by 9 or 10 extended the inhibition period in a
concentration-dependent fashion only in the case of 10,
which allowed the catalytic efficiency of peroxyl radical
trapping by the thiol to be estimated as 0.09, in line with the
data recorded in the two-phase system (Figure 3). In con-
Figure 2. Oxygen consumption during the autoxidation of styrene in PhCl
initiated by AIBN (50 mm) at 308C inhibited by 9 (30 mm), 10 (30 mm), a-
TOH (6.3 mm) or in the absence of inhibitor (dashed line).
Inhibition rate constants, kinh, for 9 and 10, that is, the ap-
C
parent rate constant for ROO quenching to give non-radical
products, were determined to be (1.0ꢁ0.2)ꢀ107 and (1.6ꢁ
0.2)ꢀ106 mꢀ1 sꢀ1, respectively, in homogeneous chloroben-
zene solution. These values are particularly high in compari-
son with other phenolic antioxidants, as shown in Table 3.
On the other hand, the overall antioxidant performance was
limited by the modest stoichiometric factor n (the number
of peroxyl radicals trapped by each antioxidant molecule),
which is less than unity for 9 and 10.
Table 3. Rate constants, kinh, and stoichiometric factors, n, for the inhibi-
tion of homogeneous-phase autoxidation of 4.3m styrene at 303 K.
Chlorobenzene
kinh [mꢀ1 sꢀ1
Acetonitrile
kinh [mꢀ1 sꢀ1
]
n
]
n
9
10
N
ACHTUNGTRENNUNG
(1.6ꢁ0.2)ꢀ106 0.30ꢁ0.05
ACHTUNGTRENNUNG
a-Tocopherol[a] 3.2ꢀ106
2
Figure 3. A) Oxygen consumption plot during the autoxidation of styrene
(4.3m) initiated by AIBN (0.05m) at 308C inhibited by 10 (1.6ꢀ10ꢀ5 m) in
the presence of increasing amounts of LipCys. B) Length of the induction
period as a function of LipCys concentration.
[a] From ref. [35].
To gain information about the reaction mechanism, the
solvent was changed from the relatively apolar non-hydro-
gen-bonding PhCl to the more polar and hydrogen-bond-ac-
cepting (HBA) MeCN. The formation of a hydrogen bond
between the phenolic OH and MeCN is expected to slow
the reaction if the rate-limiting step occurs by a (formal) hy-
drogen-atom-transfer (HAT) mechanism.[25] The data in
Table 3 show that on changing from PhCl to MeCN, kinh is
trast, no significant co-antioxidant behaviour was recorded
with the more effective antioxidant 9. Addition of a large
excess (20-fold) of the thiol to the autoxidating mixture in
fact tended to decrease the length of the inhibition period,
possibly due to interference of the thiol with other antioxi-
dant chemistry of the ortho-tellurium-substituted compound
(see below).
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Reactivity of Alkyltellurophenols Towards Peroxyl Radicals
FULL PAPER
Computational studies: In previous work we suggested that
the reaction of peroxyl radicals with the title compounds, on
the basis of their chain-breaking antioxidant behaviour
[Eq. (6)], may occur by hydrogen-atom abstraction from the
phenolic OH to give a hydroperoxide or by oxygen-atom
transfer to tellurium to give a telluroxide and an alkoxyl
radical that would then react with the phenolic hydroxy
group.[23,24] To gain deeper mechanistic insight, we per-
formed a computational study on both reaction paths, in-
cluding methyltellurophenols with an ortho and para ar-
The methoxyl radical can react in two different ways with
IIb. One involves the addition to the telluroxide to form III
with an activation enthalpy of 14.9 kcalmolꢀ1 (TSIII). Intra-
molecular hydrogen-atom transfer from the phenolic group
with subsequent elimination of methanol (TSIV) then yields
product IV, in which MeOH donates a hydrogen bond to
the Te=O oxygen. The alternative reaction of IIb involves a
direct hydrogen-atom transfer to the methoxyl radical. The
calculated activation enthalpy for this process is merely
2.0 kcalmolꢀ1, which is substantially lower than that calcu-
lated for the path involving addition to the telluroxide.
The other main pathway considered for the transforma-
tion of SM into IV involves proton-coupled electron transfer
(PCET), which was previously investigated computationally
by DiLabio and Johnson.[41] Three different transition states
(transoid TSIa’, gauche TSIb’ and cisoid TSIc’) were consid-
ered. The favoured process involves complex formation to
give Ib’ (ꢀ3.1 kcalmolꢀ1), which equilibrates with cisoid Ic’
(ꢀ1.5 kcalmolꢀ1) to allow reaction via the cisoid transition
state TSIc’ (1.3 kcalmolꢀ1) to
C
rangement of the aromatic substituents and the MeOO per-
oxyl radical. All the compounds were calculated at the
B3LYP/6-311+GACHTUNGTRENNUNG(d,p) level of theory for carbon, hydrogen
and oxygen, whereas the ECP basis set SDB-cc-pVTZ was
used for tellurium because it has previously been used with
success in calculations on organotellurium compounds.[37–39]
The enthalpies, DH, for the steps in the reaction of the
ortho compound (SM) are shown in Scheme 4. Oxygen-
atom transfer in TSI proceeds via the intermediate complex
afford complex IIc’ (ꢀ7.9 kcal
molꢀ1) with an activation barri-
er comparable to that calculat-
ed for the oxygen-atom-transfer
(OAT) process. Note here that
complexes Ia’ and Ic’ are con-
ceivable only for phenols un-
substituted at the 6-position
(see the Supporting Informa-
tion), whereas the only possible
arrangement for compounds
such as 9, with a bulky tert-
butyl at the 6-position, would
be complex Ib’, which has to
undergo PCET via TSIb’ with a
barrier of 6.1 kcalmolꢀ1.
Complex IIc’ (or IIb’) can
then dissociate into the free
phenoxyl radical and methyl
hydroperoxide (II’+MeOOH:
ꢀ1.1 kcalmolꢀ1) or undergo fur-
ther reaction by oxygen transfer
from methyl hydroperoxide to
the phenoxyl radical via TSII’
Scheme 4. Reaction enthalpies for the pathways considered computationally for the reaction of ortho-methyl-
tellurophenol with the methylperoxyl radical at the B3LYP/6-311+G(d,p) level of theory for the carbon, hy-
drogen and oxygen atoms, and at the B3LYP/SDB-cc-pVTZ level of theory for the tellurium atom.
to form the methoxide ion com-
plexed to the protonated tellur-
oxide (III’) in an exothermic
AHCTUNGTRENNUNG
process
(ꢀ24.5 kcalmolꢀ1).
I with a low activation enthalpy, which is in agreement with
the previously obtained experimental rate constant,
108 mꢀ1 sꢀ1.[40] Owing to the stability of the tellurium oxygen
bond, the formation of complex IIa is strongly exothermic
(ꢀ24.4 kcalmolꢀ1 relative to SM). Complex IIa can then dis-
sociate to the free telluroxide and methoxyl radical (II+
Proton transfer then occurs in a barrierless process (activa-
tion energy: 0.5 kcalmolꢀ1, activation enthalpy: ꢀ1.9 kcal
molꢀ1) to the methoxide ion to form the complex IV’ in
which MeOH donates a hydrogen bond to the phenoxyl
oxygen. The activation enthalpy for this kind of telluroxide
formation is 11.2 kcalmolꢀ1, and thus the calculations show
that the pathway involving OAT followed by intermolecular
hydrogen-atom transfer (HAT) proceeds by a lower-energy
rate-limiting step. An overview of the energetics of the two
MeO : ꢀ22.0 kcalmolꢀ1) or rearrange to complex IIb
C
(ꢀ20.5 kcalmolꢀ1) in which the intramolecular hydrogen
bond between the hydroxy group and telluroxide is broken.
Chem. Eur. J. 2013, 19, 7510 – 7522
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7515

L. Valgimigli, L. Engman et al.
Product analysis by ESI-MS:
To gain further information
about the species involved in
the radical chemistry, com-
pounds 9 and 10 were treated
with peroxyl radicals obtained
by the thermal decomposition
of AIBN in MeCN (i.e., paral-
lel autoxidation experiments
but performed in the absence
of an oxidisable substrate) and
the products were analysed by
negative ESI-MS spectrometry
at various intervals of time
after dilution of collected sam-
ples in MeOH.[42] As the reac-
tion proceeded, the peak corre-
sponding to the starting organo-
telluriums, m/z=391 [MꢀH]ꢀ,
progressively decreased, where-
as the peak at m/z=453 due to
the acetal (dimethyl from the
solvent) of the corresponding
Figure 4. Reaction enthalpy diagram for the pathways considered computationally for the reaction of ortho-
methyltellurophenol with the methylperoxyl radical at the B3LYP/6-311+G(d,p) level of theory for the
carbon, hydrogen and oxygen atoms, and at the B3LYP/SDB-cc-pVTZ level of theory for the tellurium atom.
AHCTUNGTRENNUNG
telluroxide
increased
(see
reaction paths considered is provided in Figure 4. The over-
all transformation of SM into IV’ (or IV) is strongly exo-
thermic: ꢀ41.9 kcalmolꢀ1 (or ꢀ30.3 kcalmolꢀ1).
ortho-Alkyltellurophenols and -pyridinols quench peroxyl
radicals more efficiently than the corresponding para-substi-
tuted isomers. Therefore we extended our calculations to in-
clude a para-substituted compound. Because we have al-
ready established that the pathway involving OAT followed
by HAT is energetically favoured, we only investigated this
route for the para isomer (Scheme 5). Oxygen transfer
occurs with a similar activation enthalpy (TSI’’; 5.9 kcal
molꢀ1) to that calculated for the ortho isomer to form com-
plex IIa’’ in an exothermic reaction (ꢀ19.1 kcalmolꢀ1). This
complex can rearrange to form IIc’’ or the methoxyl radical
adds to the telluroxide via TSIII’’ to form complex III’’. The
activation enthalpy for this process is 16.7 kcalmolꢀ1. To
arrive at a more stable telluroxide, hydrogen-atom transfer
must either take place intermolecularly (this process has not
been considered in this work) or complex IIa’’ must dissoci-
ate into free telluroxide IIb“ and the methoxyl radical
(ꢀ17.8 kcalmolꢀ1) followed by complexation (IIc’’;
ꢀ22.2 kcalmolꢀ1) and abstraction of the phenolic hydrogen
Scheme 5. Reaction enthalpies for the pathways considered computation-
ally for the reaction of para-methyltellurophenol with the methylperoxyl
radical at the B3LYP/6-311+GACTHUNRTGNEUNG(d,p) level of theory for the carbon, hy-
drogen and oxygen atoms, and at the B3LYP/SDB-cc-pVTZ level of
theory for the tellurium atom.
at the para position. This process proceeds with a low acti-
vation enthalpy (1.7 kcalmolꢀ1). The overall transformation
of SM into IV” is again strongly exothermic (ꢀ37.2 kcal
molꢀ1). Although the overall energetics of the reactions of
the ortho- and para-substituted phenols are similar, the
ortho compound has a definite advantage in that HAT can
occur intramolecularly between the methoxyl radical and
the phenolic hydroxy group without dissociation.
Figure 5). Only in the case of 9 was the peak at m/z=407
[MꢀH]ꢀ observed for the telluroxide. A peak at m/z=278
was also detected during autoxidation for both compounds 9
and 10.
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Reactivity of Alkyltellurophenols Towards Peroxyl Radicals
FULL PAPER
Scheme 6. Negative ions detected by negative ESI-MS during the reac-
tion between 9 and AIBN, and proposed structures for the adduct
formed after the addition of C12H25SH.
Figure 5. ESI-MS spectra of 9 and AIBN at 608C in methanol A) imme-
diately after mixing the reactants, B) after 60 min of reaction and
C) after 60 min of reaction followed by the addition of C12H25SH.
Discussion
This peak at m/z=278 can be attributed to the radical
anion of a telluroquinone, which may be formed by the
elimination of an alkyl radical from the phenoxyl radical or
by one-electron reduction of the telluroquinone during ESI
ionisaton. Because its intensity varies significantly with cone
voltage, it is conceivable that, at least in part, it is formed as
an in-source fragment ion of intact 9 or 10 during ESI ioni-
sation. A signal at m/z=279, which corresponds to an arene-
The antioxidant behaviour of phenolic compounds stems
ꢀ
from the reactivity of the phenolic Ar OH with chain-carry-
C
ing peroxyl radicals ROO to form the corresponding phe-
ꢀ
C
noxyl radical, Ar O , and hydroperoxide, ROOH. The diffu-
sion-controlled reaction of the phenoxyl radical with a
second peroxyl radical is responsible for the stoichiometric
factor n=2 normally encountered with phenolic antioxi-
dants. The rate-limiting transfer of the phenolic hydrogen
atom to the peroxyl radical has been shown to occur by
proton-coupled electron-transfer, a one-step bimolecular
process with a rate constant, kinh, that is inversely related to
ꢀ
ꢀ
tellurol, Ar Te H, also became quite intense during the ox-
idation of 9, whereas it remained a minor product in the
case of 10. The arenetellurol may be formed by a elimina-
tion from the intact alkyl telluride, probably during ESI ion-
isation. Interestingly, a signal at m/z=295 was also detected
in the later stages of the radical-mediated oxidation. Its in-
tensity grew significantly in the reaction of 9, whereas it re-
mained very weak in the reaction of the para isomer 10.
This peak can be attributed to an (ortho or para) aryltellu-
ꢀ
the bond dissociation enthalpy of the phenolic O H
(BDEOH) by the linear Evans–Polanyi relationship between
logkinh and BDEOH. Electron-donating (ED) substituents in
the aromatic ring lower the BDEOH in an approximately ad-
ditive fashion, consequently they enhance the reactivity of
the phenolic compound towards peroxyl radicals. By consid-
ering the contribution of ring substituents, as determined in
previous EPR studies (i.e., DBDE=ꢀ1.4 and ꢀ3.1 kcal
molꢀ1 for ortho- and para-alkyltelluro, respectively, and
ꢀ1.9 kcalmolꢀ1 for ortho- or para-tert-butyl),[24a,43] the values
of BDEOH for compounds 9 and 10 were estimated to be
83.4 and 81.7 kcalmolꢀ1, respectively. Neither the excellent
antioxidant behaviour recorded for 9 and 10 in the two-
phase system (comparable to or better than the reference a-
tocopherol, see Table 1) nor the rate of reaction with perox-
yl radicals, measured in homogeneous phase autoxidation
reactions in chlorobenzene at 303 K as 1.0ꢀ107 and 1.6ꢀ
106 mꢀ1 sꢀ1 for 9 and 10, respectively (see Table 3) can be jus-
tified on these grounds. These values exceed those expected
from Evans–Polanyi correlations for common phenolic anti-
oxidants by one to three orders of magnitude (see the Sup-
porting Information). For the sake of comparison, a-toco-
pherol, with kinh =3.2ꢀ106 mꢀ1 sꢀ1 under identical settings,
has a BDEOH =77.8 kcalmolꢀ1,[44,45] that is, 5.6 and 3.9 kcal
ꢀ
ꢀ
ACHTUNGTRENNUNGrenic acid, Ar Te OH, produced by a Cope-type elimina-
tion of the telluroxides of 9 or 10.
The addition of excess thiol (C12H25SH, 20 mm) to the
mixture led to the disappearance of the peaks assigned to
the telluroxide, its corresponding acetal and tellurenic acid,
whereas the signal for the arenetellurol at m/z=279 was sig-
nificantly enhanced with compound 9 and the signal at
m/z=278 was enhanced with both compounds 9 and 10.
Furthermore, a new signal at m/z=479 appeared, which
ꢀ
ꢀ ꢀ
we have attributed to a tellurosulfide (Ar Te S C12H25),
formed from tellurenic acid and thiol with loss of water. The
structures of the identified products are presented in
Scheme 6. Mixing our antioxidants 9 and 10 with a slight
excess of tBuOOH in methanol caused the slow appearance
of peaks corresponding to tellurium(IV) compounds (m/z=
407 and 453). After the addition of a thiol, these peaks dis-
appeared and the signal due to the tellurosulfide (m/z=479)
appeared.
Chem. Eur. J. 2013, 19, 7510 – 7522
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7517

L. Valgimigli, L. Engman et al.
molꢀ1 lower than 9 and 10, respectively. More importantly,
consideration of the relative BDEOH values of 9 and 10 fails
to explain the much higher reactivity of the ortho-tellurium-
substituted 9. We had previously encountered similar
“anomalous” behaviour in our on-going research into chal-
oxidation chain (by reactive RO ) and depletion of the anti-
C
oxidant (the telluroxide is known to be a much less effective
antioxidant[23]). This explains the small stoichiometric factor
recorded for compounds 9 and 10 compared with typical
phenolic antioxidants (n=0.4–0.6 compared with n=2, see
C
cogen-containing antioxidants. Indeed, we observed that
Table 3). Furthermore, the reaction of RO with the phenolic
both in the phenolic BHA[24] and 3-hydroxypyridine scaf-
folds,[23] ring substitution with alkyltelluro groups dramati-
cally increased the antioxidant activity when the substitution
was ortho to the phenolic OH whereas the effect was much
less pronounced in the para position. Furthermore, it is in-
teresting to recall that the very high rate constant for the re-
action with peroxyl radicals recorded here in homogeneous
chlorobenzene for the very “simple” ortho-tellurium-substi-
tuted compound 9 is almost identical to that previously
measured for compounds 6 (kinh =1.0ꢀ107 mꢀ1 sꢀ1), 7 (1.0ꢀ
107 mꢀ1 sꢀ1) and 8 (0.9ꢀ107 mꢀ1 sꢀ1) with significantly different
ring substitution patterns, electronic properties and BDEOH
values, which suggests that tellurium-substituted phenol-type
antioxidants might react with peroxyl radicals by a substan-
tially different mechanism in comparison with conventional
phenolic antioxidants. Our current DFT calculations show
that, in addition to the formal HAT from the phenolic OH
(Scheme 7, path A), which would be impeded in compound
OH is expectedly more favoured with ortho-alkyltellurophe-
nol 9 than with the para isomer 10, in line with the higher
stoichiometric factor recorded for 9. Path B also explains
the modest DKIE recorded with alkyltellurophenols.
Indeed, the rate-determining step is the OAT, whereas the
HAT from the phenolic OH occurs in a later “downhill”
process in line with the value kH/kD ꢂ1.2. Further experi-
mental support for path B comes from the observed kinetic
solvent effect (KSE) in the reactions of 9 and 10 with perox-
yl radicals. At variance with common phenolic antioxidants,
the reactivities of which are impaired in hydrogen-bond-ac-
cepting solvents by hydrogen-bond donation of the reactive
OH group,[25] we recorded an increased reactivity of com-
pound 9 on passing from chlorobenzene to acetonitrile,
which is justified by the polar transition state in the rate-lim-
iting oxygen-atom transfer. The absence of a KSE for the
para isomer 10 might therefore arise from compensation be-
tween the negative KSE expected for path A and the posi-
tive KSE in path B. In principle, the KSE and the small
DKIE might also suggest that the reaction proceeds by a se-
quential electron transfer (ET)/proton transfer (PT) mecha-
nism in which the ET step is rate-limiting.[46] Although this
mechanism could actually be relevant to some extent in the
aqueous biphasic system (see below), we believe it is unlike-
ly to justify rate constants as high as 107 mꢀ1 sꢀ1 in homogene-
ous chlorobenzene.
One important point in the antioxidant chemistry of alkyl-
tellurophenols is their ability to be regenerated from their
oxidation products by thiols as co-antioxidants. Comparison
of the efficiency of this process for the ortho and para iso-
mers in the aqueous two-phase system and in homogeneous
solution suggests that it could actually occur by different
mechanisms in the two environments. In the two-phase
system it is conceivable that regeneration at the aqueous/or-
ganic interface (by water-soluble NAC) occurs mainly by
ET. The standard reduction potential for the RSSR/RSH
couple for NAC is estimated to be E8=ꢀ0.15 V versus
NHE at the pH of the aqueous interface in our experiments
(pHꢂ3.8),[22b] whereas the reduction potentials for the
Scheme 7. Reaction mechanism that explains the high reactivity of ortho-
alkyltellurophenols.
9 due to steric hindrance from the tert-butyl substituent
omitted in the calculations, another preferred reaction path
is available for the reaction of peroxyl radicals with alkyltel-
lurophenols: a rate-limiting oxygen-atom transfer to the tel-
luride group to form an alkoxyl radical that would “immedi-
ately” undergo an almost barrierless, highly exothermic
HAT from the phenolic OH (path B). This mechanism is
supported by product studies, which revealed the prominent
formation of the telluroxide (m/z=407) or its solvated form
(m/z=453) in the negative ESI-MS analysis of the autoxidis-
ing mixture. In this reaction sequence, the rate-determining
OAT is a reaction known to proceed with a rate constant of
108 mꢀ1 sꢀ1 with diaryl tellurides,[40] which accounts for the
very high reactivity of these antioxidants with peroxyl radi-
cals and the poor correlation of the antioxidant activity with
the ring substitution pattern and BDEOH values.
C
PhO /PhOH couples of 9 and 10 are expectedly close to
those measured for the analogous compounds 5–7 as E8ꢂ +
0.8 V versus HNE at pH 12,[23b] which needs to be corrected
by +0.3 V for pH 3.8[47] resulting in E8ꢂ +1.1 V versus
NHE. A similar mechanism might also account for the anti-
oxidant behaviour observed for the O-methylated deriva-
tives 11 and 12 in the presence of NAC, as illustrated in
Scheme 8.
Reaction path B relies on the in-cage reaction of the
formed alkoxyl radical with the phenolic OH, however, dif-
fusion of the alkoxyl radical into the bulk solution is always
a competing process and would result in the start of a new
On the other hand, we suggest that the regeneration of
antioxidant 10 by the thiol co-antioxidant in homogeneous
chlorobenzene occurs by formal HAT to the phenoxyl radi-
cal followed by reduction of the telluroxide, as illustrated in
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Reactivity of Alkyltellurophenols Towards Peroxyl Radicals
FULL PAPER
ESI-MS analysis revealed the formation of other inter-
mediates not previously considered in the antioxidant chem-
ꢀ
ꢀ
istry of hydroxyaryl tellurides: the tellurenic acid Ar Te
OH, which is known to arise from the decomposition
(Cope-type elimination of an olefin) of alkyl telluroxides.[50]
ꢀ
ꢀ
The relevance of Ar Te OH formation is much greater
with ortho-tellurium-substituted 9, possibly due to the stabi-
lisation of the tellurenic acid by intramolecular hydrogen
bonding to the neighbouring OH group. Some of us have re-
Scheme 8. Suggested mechanism for the antioxidant activity of com-
pounds 11 and 12 in the presence of thiols in aqueous heterogeneous en-
vironments.
ꢀ
cently shown that homologous sulfenic acids (RS OH),
formed by Cope elimination from plant-derived thiosulfi-
nates (RS(O)SR), are potent antioxidants and are responsi-
ble for the well-known protecting activity of garlic and other
Allium species.[42,51] DFT calculations suggest that aryltellu-
Scheme 9A. This mechanism appears thermodynamically
feasible considering the reported BDESH of cysteine (calc.
87.8 kcalmolꢀ1 at the G3 level)[48] and the BDEOH values of
AHCTUNGTRENrNGUN enic acids have BDEOH values substantially higher than al-
kylsulfenic acids (e.g., ca.
80 kcalmolꢀ1 by B3LYP), but
low enough to justify a reaction
with chain-carrying peroxyl rad-
icals
(BDEROOH ꢂ88 kcal
molꢀ1). It is currently unclear
whether such intermediate spe-
cies contribute to the observed
very high reactivity with perox-
yl radicals, however, it is clear
that hydroxyaryl tellurides have
a
redox chemistry far more
complex than their phenolic
nature would suggest (a sum-
mary of the reactions and inter-
mediates potentially involved is
given in the Supporting Infor-
mation).
Scheme 9. Proposed mechanisms for the reactions of thiols with the oxidation products obtained from antioxi-
dants A) 10 or B) 9 in homogeneous apolar solution.
90.1 and 86.4 kcalmolꢀ1 calculated here (by B3LYP) for the
telluroxides of compounds 9 and 10, respectively. Following
this line, the reason for the non-regeneration of the ortho-
hydroxyaryl telluride 9 in chlorobenzene, at variance with
the corresponding para isomer, can be attributed to the ad-
dition of the incipient thiyl radical to the neighbouring tel-
luroxide to start a cascade of radical reactions (Scheme 9B)
that would ultimately yield the dealkylated tellurosulfide
Conclusion
Alkyltellurophenols are very promising multi-faceted anti-
oxidants. They maintain GPx-like thiol peroxidase activity,
typical of divalent organotelluriums, acting as preventive an-
tioxidants able to catalytically decompose hydrogen perox-
ide and organic hydroperoxides. In parallel, they are very ef-
fective chain-breaking antioxidants and even the very
simple compounds presented in this work show a reactivity
towards peroxyl radicals comparable to or higher than refer-
ence phenolic antioxidants such as a-tocopherol, albeit with
a substantially different mechanism that involves the redox
chemistry of tellurium. In the presence of thiol co-antioxi-
dants, they can be regenerated from their oxidation prod-
ucts, thereby acting as catalytic chain-breaking antioxidants,
at variance with common phenols. The efficiency of this
process in aqueous two-phase systems is significantly higher
for compounds with an ortho arrangement of phenolic and
alkyltelluro moieties. This type of reactivity can, however,
turn the investigated alkyltellurophenols into effective pro-
oxidants, which is very interesting in the light of the pro-
ꢀ
ꢀ
Ar Te SR, as observed in ESI-MS product studies. In this
reduction product, the chain-breaking reactivity with perox-
yl radicals is impaired by the strong intramolecular hydro-
gen bond between the OH group and sulfur. Note also that
this process causes a depletion of the thiol co-antioxidant
and produces alkyl radicals that, in the presence of oxygen,
would rapidly form peroxyl radicals and initiate new oxida-
tive chains. In other words, the reduction of the oxidised
products formed from antioxidant 9 by thiols might result in
pro-oxidant activity in homogeneous apolar environments
rather than in catalytic antioxidant activity as expressed in
aqueous two-phase systems.[49]
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7519

L. Valgimigli, L. Engman et al.
layer was dried over MgSO4 and concentrated at reduced pressure. The
crude bis(3-tert-butyl-2-methoxyphenyl) ditelluride was dissolved in
EtOH (15 mL). NaBH4 (0.07 g, 1.83 mmol) was added in portions to this
solution under N2 until the reaction mixture turned colourless. Octyl bro-
mide (0.19 mL, 1.1 mmol) was added and stirring continued for 2 h. The
mixture was poured onto brine and extracted with EtOAc. Purification
was then performed as described in method A to afford the title com-
pound as an oil (0.28 g, 35%).
posed pro-oxidant/antioxidant behaviour of or
ACHTUNGTRENNUNG
ACHTUNGTNERgNUNG an-
otelluriums in biological systems.[17,18] In normal cells rich in
glutathione, organotelluriums can act both in a preventive
and chain-breaking fashion to quench both radical (peroxyl
radicals of lipid and other origin) and non-radical (such as
hydrogen peroxide, organic hydroperoxides, peroxynitrite
and hypochlorite) reactive oxygen species. On the other
hand, if the natural antioxidant defence is overwhelmed and
the concentrations of reactive oxygen compounds are elevat-
ed, alkyltellurophenols can rapidly “waste” the remaining
amounts of thiols and induce apoptosis. The reduction of
each molecule of hydroperoxide occurs at the expense of
two thiols, whereas peroxyl radicals can be eliminated at the
“cost” of several thiol molecules.
2-tert-Butyl-6-(octyltelluro)phenol (9): Boron tribromide (2 mL, 1m in
CH2Cl2, 2 mmol) was added dropwise to a solution of 2-tert-butyl-6-(oc-
tyltelluro)anisole (0.32 g, 0.8 mmol) in dichloromethane (10 mL) under
N2 at ꢀ788C and stirred at the same temperature for 1 h. The mixture
was allowed to warm to room temperature and stirred for 1 h. It was
then poured into a saturated aqueous sodium hydrogen carbonate solu-
tion and extracted with chloroform. The organic layer was washed with
brine, dried over anhydrous sodium sulfate and the solvent was removed
under reduced pressure. The title compound (0.13 g, 43%) was obtained
as a yellow oil by silica gel column chromatography using n-pentane as
eluent. 1H NMR (400 MHz, CDCl3): d=0.89 (t, J=6.8 Hz, 3H), 1.25–
1.42 (several signals, 19H), 1.69 (m, 2H), 2.71 (t, J=7.6 Hz, 2H), 6.67 (s,
1H), 6.70 (t, J=7.6 Hz, 1H), 7.30 (dd, J=1.2, 7.6 Hz, 1H), 7.68 ppm (dd,
J=1.6, 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=155.8, 140.2, 134.6,
129.1, 120.6, 103.7, 35.1, 31. 6, 31.5, 31.3, 29.2, 29.0, 28.7, 22.5, 13.9,
9.9 ppm; elemental analysis calcd (%) for C18H30OTe: C 55.4, H 7.8;
found: C 55.7, H 7.8.
Experimental Section
General: All NMR experiments were run in deuterated chloroform as
solvent using a Varian Unity 400 MHz spectrometer (400 MHz for 1H
and 100 MHz for 13C spectra). NMR chemical shifts are reported in ppm
1
2-tert-Butyl-4-(octyltelluro)phenol (10): tBuLi (0.6 mL 1.7m in pentane,
0.99 mmol) was added dropwise to a solution of 4-bromo-2-tert-butylphe-
nol (0.076 g, 0.33 mmol) in dry THF (2 mL) under an inert atmosphere at
ꢀ788C. The solution was stirred for 2 h at this temperature and a solu-
tion of di-n-octyl ditelluride (0.31 g, 0.66 mmol) in THF (1 mL) was
added. The cooling bath was then removed and stirring was continued
for an additional 4 h at room temperature before quenching with a satu-
rated solution of NaHCO3. The mixture was extracted with diethyl ether
and washed with brine. The organic layer was dried over MgSO4 and con-
centrated at reduced pressure. The title compound was obtained as an oil
( 0.101 g, 79%) after silica gel column chromatography with n-pentane/
EtOAc (95:5) as eluent. 1H NMR (400 MHz, CDCl3): d=0.89 (t, J=
7.6 Hz, 3H), 1.27–1.43 (several peaks, 19H), 1.76 (m, 2H), 2.82 (t, J=
7.6 Hz, 2H), 4.70 (s, 1H), 6.51 (d, J=8 Hz, 1H), 7.46 (dd, J=2, 8 Hz,
1H), 7.65 ppm (d, J=2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=154.5,
138.8, 138.5, 137.5, 117.9, 101.1, 34.8, 32.1, 32.09, 32.02, 29.7, 29.4, 29.1,
22.9, 14.3, 9.3 ppm; elemental analysis calcd (%) for C18H30OTe: C 55.4,
H 7.8; found: C 55.8, H 7.8.
referenced to the solvent peak of CDCl3 (7.26 ppm for H, 77.16 ppm for
13C). MS spectra were obtained with a Micromass ZMD (ESI-MS), and
an AB-SCIEX TripleTOF 5600 (HRMS). Unless otherwise noted, all sol-
vents and chemicals were of the highest grade available from Fluka-
Sigma-Aldrich and were used without further purification. Tetrahydrofu-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
um hydride before use. Styrene (Aldrich) was percolated twice through
activated basic alumina and once through silica followed by vacuum dis-
tillation before use.2-Bromo-6-tert-butylphenol,[26] 2-bromo-6-tert-butyla-
nisole,[27] 4-bromo-2-tert-butylphenol[28] and di-n-octyl ditelluride[52] were
prepared according to literature methods. 4-Bromo-2-tert-butylanisole
was prepared in a yield of 87% in analogy to the preparation of 2-
bromo-6-tert-butylanisole.[27] Their 1H and 13C NMR data were in good
agreement with the literature.[53]
Synthesis of 2-tert-butyl-6-(octyltelluro)anisole (11)
Method A: tBuLi (2.3 mL 1.7m in pentane, 4 mmol) was added dropwise
to a solution of 1-bromo-6-tert-butylanisole (0.49 g, 2 mmol) in dry THF
(15 mL) under an inert atmosphere at ꢀ788C. The solution was stirred
for 45 min at this temperature and a solution of di-n-octyl ditelluride
(1.17 g, 2.45 mmol) in THF (3 mL) was added. The cooling bath was then
removed and stirring was continued for an additional 4 h at room temper-
ature before quenching with a saturated solution of NH4Cl. The mixture
was extracted with ethyl acetate and washed with brine. The organic
layer was dried over MgSO4 and concentrated at reduced pressure. The
title compound was obtained as an oil (0.68 g, 84%) after silica gel
column chromatography using n-pentane as eluent. 1H NMR (400 MHz,
CDCl3): d=0.91 (t, J=6.8 Hz, 3H), 1.29–1.46 (several signals, 19H), 1.84
(t, J=7.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 3.87 (s, 3H), 6.92 (t, J=
7.6 Hz, 1H), 7.26 (dd, J=1.6, 8.0 Hz, 1H), 7.42 ppm (dd, J=1.2, 7.2 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=161.0, 143.3, 134.8, 127.1, 125.0,
110.2, 62.0, 35.5, 32.4, 32.1, 31.7, 31.4, 29.4, 29.2, 22.9, 14.4, 7.8 ppm.
HRMS (TOF MS ES+): m/z calcd for C19H32OTe: 406.1515 [M]+; found:
406.1540.
2-tert-Butyl-4-(octyltelluro)anisole (12): tBuLi (1.4 mL 1.7m in pentane,
2.4 mmol) was added dropwise to a solution of 4-bromo-2-tert-butylani-
sole (0.30 g, 1.24 mmol) in dry THF (8 mL) under an inert atmosphere at
ꢀ788C. The solution was stirred for 45 min at this temperature and then
a solution of di-n-octyl ditelluride (0.9 g, 1.86 mmol) in THF (2 mL) was
added. The cooling bath was then removed and stirring was continued
for an additional 2.5 h at room temperature before quenching with brine.
The mixture was extracted with ethyl acetate and washed with water.
The organic layer was dried over MgSO4 and concentrated at reduced
pressure. The title compound was obtained as an oil (0.68 g, 84%) after
silica gel column chromatography with n-pentane/ethyl acetate as eluent.
1H NMR (400 MHz, CDCl3): d=0.87 (t, J=6.4 Hz, 3H), 1.25–1.44 (sever-
al peaks, 19H), 1.77 (q, J=7.6 Hz, 2H), 2.83 (t, J=7.6 Hz, 2H), 3.83 (s,
3H), 6.72 (d, J=8.4 Hz, 1H), 7.57 (dd, J=2.0, 8.4 Hz, 1H), 7.64 ppm (d,
J=2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=158.7, 139.3, 138.4,
138.0, 112.6, 100.8, 55.0, 34.9, 32.0, 31.9, 31.9, 29.7, 29.3, 29.0, 22.8,14.2,
9.1 ppm; HRMS (TOF MS ES+): m/z calcd for C19H32OTe: 406.1515
[M]+; found: 406.1522.
Method B: tBuLi (2.3 mL, 1.7m in pentane, 4 mmol) was added dropwise
to a solution of 1-bromo-6-tert-butylanisole (0.49 g, 2 mmol) in dry THF
(15 mL) under nitrogen at ꢀ788C. The solution was stirred for 45 min at
this temperature before elemental tellurium (0.4 g, 3.1 mmol) was added.
The cooling bath was then removed and stirring was continued for an ad-
ditional 4 h at room temperature. The reaction was then poured onto
crushed ice and kept in the open air overnight. The solution was filtered
through a pad of Celite, which was washed with CHCl3. The organic
HPLC peroxidation assay: In the experimental setup, linoleic acid and
the antioxidant to be evaluated were vigorously stirred in chlorobenzene
at 428C in the presence of an aqueous solution of N-acetylcysteine
(NAC). 2,2ꢃ-Azobis(2,4-dimethylvaleronitrile) (AMVN) was added as an
initiator in the organic phase and the progress of the peroxidation was
monitored by HPLC (conjugated diene hydroperoxide formation). For
comparison of the catalyst efficiency, inhibition times, tinh, and inhibited
7520
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Chem. Eur. J. 2013, 19, 7510 – 7522

Reactivity of Alkyltellurophenols Towards Peroxyl Radicals
FULL PAPER
rates of peroxidation, Rinh, were determined by least-squares methods
[4] C. W. Nogueira, G. Zeni, J. B. T. Rocha, Chem. Rev. 2004, 104,
6255–6285.
from absorbance/time plots as previously described.[21,22a]
[5] For example, see: a) J. F. Goodrum, Neurochem. Res. 1998, 23,
1313–1319; b) B. P. Laden, T. D. Porter, J. Lipid Res. 2001, 42, 235–
240.
[6] L. A. Ba, M. Dçring, V. Jamier, C. Jacob, Org. Biomol. Chem. 2010,
8, 4203–4216.
[7] K. P. Bhabak, G. Mugesh, Acc. Chem. Res. 2010, 43, 1408–1419 and
refs cited therein.
[8] C.-M. Andersson, A. Hallberg, R. Brattsand, I. A. Cotgreave, L.
Engman, J. Persson, Bioorg. Med. Chem. Lett. 1993, 3, 2553–2558.
[9] L. Engman, D. Stern, M. Pelcman, C. M. Andersson, J. Org. Chem.
1994, 59, 1973–1979.
[10] Y. You, K. Ahsan, M. R. Detty, J. Am. Chem. Soc. 2003, 125, 4918–
4927.
[11] V. Nascimento, E. E. Alberto, D. W. Tondo, D. Dambrowski, M. R.
Detty, F. Nome, A. L. Braga, J. Am. Chem. Soc. 2012, 134, 138–141.
[12] M. McNaughton, L. Engman, A. Birmingham, G. Powis, I. A. Cot-
greave, J. Med. Chem. 2004, 47, 233–239.
Assay for thiol peroxidase activity: Thiol peroxidase activity was deter-
mined spectrophotometrically as previously described.[22b]
Inhibition studies in homogeneous solution: Autoxidation experiments
were performed in a two-channel oxygen-uptake apparatus based on a
Validyne DP 15 differential pressure transducer described previously.[32]
In a typical experiment, an air-saturated chlorobenzene (or acetonitrile)
solution of styrene containing AIBN (0.05m) was equilibrated with an
identical reference solution containing an excess of a-tocopherol (0.1–
1 mm) in the same solvent at 308C. When constant oxygen consumption
was observed, a concentrated solution of the antioxidant was injected
into the sample flask and the oxygen consumption was measured, after
calibration of the apparatus, from the differential pressure recorded with
time between the two channels.[22–24] a-Tocopherol was also used as a ref-
erence antioxidant to measure the rate of initiation Ri.35 Oxygen con-
sumption traces were analysed by using Equation (9), the integrated
form of Equation (8), in which t is the length of the inhibited period.[25]
[13] a) B. K. Sarma, D. Manna, M. Minoura, G. Mugesh, J. Am. Chem.
Soc. 2010, 132, 5364–5374; b) X. Ren, Y. Xue, J. Liu, K. Zhang, J.
Zheng, G. Luo, C. Guo, Y. Mu, J. Shen, ChemBioChem 2002, 3,
356–363; c) T. G. Back, D. Kuzma, M. Parvez, J. Org. Chem. 2005,
70, 9230–9236; d) Y.-Q. Hao, X.-C. Liu, J.-Q. Liu, Y.-Q. Wu, Mole-
cules 2009, 14, 904–916.
[14] G. T. Wondrak, Antioxid. Redox Signaling 2009, 11, 3013–3069.
[15] L. Engman, N. Al-Maharik, M. McNaughton, A. Birmingham, G.
Powis, Bioorg. Med. Chem. 2003, 11, 5091–5100, and referencess
cited therein.
[16] P. J. McMillan, E. M. Patzewitz, S. E. Young, G. D. Westrop, G. H.
Coombs, L. Engman, S. Mꢄller, Parasitology 2009, 136, 27–33.
[17] S. Mecklenburg, S. Shaaban, L. A. Ba, T. Burkholz, T. Schneider, B.
Diesel, A. K. Kiemer, A. Rçseler, K. Becker, J. Reichrath, A. Stark,
W. Tilgen, M. Abbas, L. A. Wessjohann, F. Sasse, C. Jacob, Org.
Biomol. Chem. 2009, 7, 4753–4762.
[18] V. Jamier, L. A. Ba, C. Jacob, Chem. Eur. J. 2010, 16, 10920–10928.
[19] C. Jacob, G. E. Arteel, T. Kanda, L. Engman, H. Sies, Chem. Res.
Toxicol. 2000, 13, 3–9.
D½O2ꢃt ¼ ðkp½RHꢃ=kinhÞln ð1ꢀt=tÞ
ð9Þ
Product studies: A 1 mm acetonitrile solution of 9 or 10 was stirred
under air at 40–608C for 300 min in the presence of AIBN (0.05m). After
periods of time, aliquots of the reaction mixture were diluted 1:10 with
MeOH, cooled to 208C, and analysed by mass spectrometry using elec-
trospray ionisation (ESI) by direct liquid injection at a flow rate of
15 mLminꢀ1. The reactions with hydroperoxides were studied by incubat-
ing 9 or 10 (0.1 mm) with tBuOOH (1 mm) in methanol followed by
direct injection into the ESI-MS spectrometer. In some experiments, do-
decanethiol (10 mm) was added to the autoxidating system after 30–
60 min and then subjected to ESI-MS after 1–10 min. The instrument em-
ployed was a Micromass ZMD spectrometer equipped with a single
quadrupole analyser and a Z-spray source. The most appropriate instru-
mental settings were as follows: ESI type, negative ions; desolvation gas,
N2, 242 Lhꢀ1; cone gas (skimmer), 33 Lhꢀ1; desolvation temperature,
1208C, source block temperature, 808C; capillary voltage, 3.00 kV; cone
voltage, 10–40 V; hexapole extractor, 3 V.
[20] N. M. Giles, N. J. Gutowski, G. I. Giles, C. Jacob, FEBS Lett. 2003,
535, 179–182.
Computational details: Reactants and transition states were optimised by
using the Gaussian 09 program[54] with B3LYP[55–58] and the 6-311+G-
[21] J. Malmstrçm, M. Jonsson, I. A. Cotgreave, L. Hammarstrçm, M.
Sjçdin, L. Engman, J. Am. Chem. Soc. 2001, 123, 3434–3440.
[22] a) D. Shanks, R. Amorati, M. G. Fumo, G. F. Pedulli, L. Valgimigli,
L. Engman, J. Org. Chem. 2006, 71, 1033–1038; b) S. Kumar, H. Jo-
hansson, L. Engman, L. Valgimigli, R. Amorati, M. G. Fumo, G. F.
Pedulli, J. Org. Chem. 2007, 72, 2583–2595; c) S. Kumar, L.
Engman, L. Valgimigli, R. Amorati, M. G. Fumo, G. F. Pedulli, J.
Org. Chem. 2007, 72, 6046–6055.
[23] a) S. Kumar, H. Johansson, T. Kanda, L. Engman, T. Mꢄller, M.
Jonsson, G. F. Pedulli, S. Petrucci, L. Valgimigli, Org. Lett. 2008, 10,
4895–4898; b) S. Kumar, H. Johansson, T. Kanda, L. Engman, T.
Mꢄller, H. Bergenudd, M. Jonsson, G. F. Pedulli, R. Amorati, L.
Valgimigli, J. Org. Chem. 2010, 75, 716–725.
ACHTUNGTRENNUNG
(d,p)[59, 60] basis set for carbon, oxygen and hydrogen, and an effective
core potential (SDB-cc-pVTZ)[61,62] basis set for the tellurium atoms. All
geometries were characterised as minima or saddle points on the poten-
tial-energy surface (PES) by using the sign of the eigenvalues of the
force-constant matrix obtained from a frequency calculation. Transition
states with one imaginary frequency were confirmed to describe the cor-
rect movement on the PES by mode analysis. Intrinsic reaction coordi-
nate (IRC) calculations[63] were performed for all transition states at the
DFT level of theory to connect each transition state (TS) with its corre-
sponding reactant and product.
[24] a) R. Amorati, G. F. Pedulli, L. Valgimigli, H. Johansson, L.
Engman, Org. Lett. 2010, 12, 2326–2329; b) H. Johansson, D.
Shanks, L. Engman, R. Amorati, G. F. Pedulli, L. Valgimigli, J. Org.
Chem. 2010, 75, 7535–7541.
[25] L. Valgimigli, D. A. Pratt in Encyclopedia of Radicals in Chemistry,
Biology and Materials (Eds.: C. Chatgilialoglu, A. Studer) Wiley,
Chichester, 2012, pp. 1623–1677.
[26] T.-J. Kim, S.-K. Kim, B.-J. Kim, J. S. Hahn, M.-A. Ok, J. H. Song, D.-
H. Shin, J. Ko, M. Cheong, J. Kim, H. Won, M. Mitoraj, M. Srebro,
A. Michalak, S. O. Kang, Macromolecules 2009, 42, 6932–6943.
[27] S. Sarkar, A. R. Carlson, M. K. Veige, J. M. Falkowski, K. A.
Abboud, A. S. Veige, J. Am. Chem. Soc. 2008, 130, 1116–1117.
[28] A. B. Williams, P. T. Weiser, R. N. Hanson, J. R. Gunther, J. A. Kat-
zellenbogen, Org. Lett. 2009, 11, 5370–5373.
Acknowledgements
Financial support from the University of Bologna and MIUR, Rome
(grant PRIN 2011, prot. 2010PFLRJR project PROXI), the Swedish Re-
search Council and the Wennergren Foundations are gratefully acknowl-
edged. P.D. thanks the National Supercomputing Center (NSC) for com-
putational resources.
[1] Selenium Tellurium Development Association, http://www.stda.org/.
[2] K. J. Irgolic in Houben Weyl Methods of Organic Chemistry,
Vol. E12b, 4th ed. (Ed.: D. Klamann), Georg Thieme Verlag, Stutt-
gart, 1990.
[3] P. Garberg, L. Engman, V. Tolmachev, H. Lundqvist, R. G. Gerdes,
I. A. Cotgreave, Int. J. Biochem. Cell Biol. 1999, 31, 291–301.
[29] K. Vessman, M. Ekstrçm, M. Berglund, C.-M. Andersson, L.
Engman, J. Org. Chem. 1995, 60, 4461–4467.
Chem. Eur. J. 2013, 19, 7510 – 7522
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7521

L. Valgimigli, L. Engman et al.
[30] a) R. Amorati, F. Ferroni, M. Lucarini, G. F. Pedulli, L. Valgimigli,
J. Org. Chem. 2002, 67, 9295–9303; b) R. Amorati, F. Ferroni, G. F.
Pedulli, L. Valgimigli, J. Org. Chem. 2003, 68, 9654–9658.
[31] M. Iwaoka, S. Tomoda, J. Am. Chem. Soc. 1994, 116, 2557–2561.
[32] a) M. Lucarini, G. F. Pedulli, L. Valgimigli, R. Amorati, F. Minisci, J.
Org. Chem. 2001, 66, 5456–5462; b) R. F. Enes, A. C. Tomꢁ, J. A. S.
Cavaleiro, R. Amorati, M. G. Fumo, G. F. Pedulli, L. Valgimigli,
Chem. Eur. J. 2006, 12, 4646–4653.
[33] a) L. Valgimigli, R. Amorati, M. G. Fumo, G. A. DiLabio, G. F. Pe-
dulli, K. U. Ingold, D. A. Pratt, J. Org. Chem. 2008, 73, 1830–1841;
b) R. Amorati, G. F. Pedulli, D. A. Pratt, L. Valgimigli, Chem.
Commun. 2010, 46, 5139–5141; c) R. Amorati, G. F. Pedulli, L. Val-
gimigli, Org. Biomol. Chem. 2011, 9, 3792–3800.
[34] With a common phenol-type antioxidant reacting by a pure HAT or
PCET mechanism, kH/kD values in the range of 3–10 have typically
been observed by using the same experimental approach. See, for
example, refs. [16,24,25].
[35] G. W. Burton, T. Doba, E. J. Gabe, L. Hughes, F. L. Lee, L. Prasad,
K. U. Ingold, J. Am. Chem. Soc. 1985, 107, 7053–7065.
[36] a) D. A. Pratt, G. A. DiLabio, G. Brigati„ G. F. Pedulli, L. Valgimi-
gli, J. Am. Chem. Soc. 2001, 123, 4625–4626; b) L. Valgimigli, R.
Amorati, S. Petrucci, G. F. Pedulli, D. Hu, J. J. Hanthorn, D. A.
Pratt, Angew. Chem. 2009, 121, 8498–8501; Angew. Chem. Int. Ed.
2009, 48, 8348–8351.
[37] R. L. Longo, P. H. Menezes in Pataiꢀs Chemistry of Functional
Groups: Theoretical and Computational Aspects of Organotellurium
Compounds, Wiley, 2011, DOI: 10.1002/9780470682531.pat0570.
[38] C. Bleiholder, D. B. Werz, H. Kçppel, R. Gleiter, J. Am. Chem. Soc.
2006, 128, 2666–2674.
[39] C. Bleiholder, R. Gleiter, D. B. Werz, H. Kçppel, Inorg. Chem.
2007, 46, 2249–2260.
[40] L. Engman, J. Persson, G. Merenyi, J. Lind, Organometallics 1995,
14, 3641–3648.
[41] G. A. DiLabio, E. R. Johnson, J. Am. Chem. Soc. 2007, 129, 6199–
6203.
[42] R. Amorati, P. T. Lynett, L. Valgimigli, D. A. Pratt, Chem. Eur. J.
2012, 18, 6370–6379.
[43] M. Lucarini, P. Pedrielli, G. F. Pedulli, S. Cabiddu, C. Fattuoni, J.
Org. Chem. 1996, 61, 9259–9259.
[44] The original value reported in ref. [43] needs to be downscaled by
1.1 kcalmolꢀ1 to take into account the revised value for the BDEOH
of phenol, as discussed in ref. [45].
[45] P. Mulder, H.-G. Korth, D. A. Pratt, G. A. DiLabio, L. Valgimigli,
G. F. Pedulli, K. U. Ingold, J. Phys. Chem. A 2005, 109, 2647–2655.
[46] J. M. Mayer, Annu. Rev. Phys. Chem. 2004, 55, 363–390.
[47] C. Li, M. Z. Hoffman, J. Phys. Chem. B 1999, 103, 6653–6656.
[48] M. V. Roux, C. Foces-Foces, R. Notario, M. A. V. Ribeiro da Silva,
M. D. M. C. Ribeiro da Silva, A. F. L. O. M. Santos, E. Juaristi, J.
Phys. Chem. B 2010, 114, 10530–10540.
ceivably due to the preferred orthogonal orientation (in the oxidised
phenoxyl radical) of the Te=O bond with respect to the aromatic
ꢀ ꢀ
plane (O=Te C C angle=888 by B3LYP/LANL2DZdp), which im-
pairs the concerted addition of the thiyl radical to tellurium as de-
picted in Scheme 7B (see the Supporting Information).
[50] a) H. Lee, M. P. Cava, J. Chem. Soc., Chem. Commun. 1981, 277–
278; b) S. Uemura, S.-I. Fukuzawa, J. Am. Chem. Soc. 1983, 105,
2748–2752; K. Selvakumar, H. B. Singh, N. Goel, U. P. Singh, Orga-
nometallics 2011, 30, 3892–3896.
[51] a) A. J. McGrath, G. E. Garrett, L. Valgimigli, D. A. Pratt, J. Am.
Chem. Soc. 2010, 132, 16759–16761; see also: b) P. T. Lynett, K.
Butts, V. Vaidya, G. E. Garrett, D. A. Pratt, Org. Biomol. Chem.
2011, 9, 3320; c) V. Vaidya, K. U. Ingold, D. A. Pratt, Angew. Chem.
2009, 121, 163–166.
[52] Y. Li, L. C. Silverton, R. Haasch, Y. Y. Tong, Langmuir 2008, 24,
7048–7053.
[53] a) M. Steele, M. Watkinson, A. Whiting, J. Chem. Soc., Perkin
Trans. 1 2001, 2001, 588–598; b) B. Charpentier, J. M. Bernardon, J.
Eustache, C. Millois, B. Martin, S. Michel, B. Shroot, J. Med. Chem.
1995, 38, 4993–5006.
[54] Gaussian 09, Revision C.01, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V.
Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X.
Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-
nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven,
J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J.
Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J.
Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar,
J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A.
Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, ꢅ.
Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian,
Inc., Wallingford CT, 2009.
[55] S. H. Vosko, L. Wilk, M. Nusair, Can. J. Phys. 1980, 58, 1200–1211.
[56] C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789.
[57] A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652.
[58] P. J. Stephens, F. J. Devlin, C. F. Chabalowski, M. J. Frisch, J. Phys.
Chem. 1994, 98, 11623–11627.
[59] R. Krishnan, J. S. Binkley, R. Seeger, J. A. Pople, J. Chem. Phys.
1980, 72, 650–654.
[60] M. J. Frisch, J. A. Pople, J. S. Binkley, J. Chem. Phys. 1984, 80, 3265–
3269.
[61] A. Bergner, M. Dolg, W. Kꢄchle, H. Stoll, H. Preuß, Mol. Phys.
1993, 80, 1431–1441.
[62] J. M. L. Martin, A. Sundermann, J. Chem. Phys. 2001, 114, 3408–
3420.
[49] As the only exception observed during our on-going investigation,
ortho-hydroxy-3-pyridyl tellurides showed remarkable catalytic
chain-breaking behaviour in homogeneous chlorobenzene (similar
or better to that observed in the two-phase system).[23b] This is con-
[63] C. Gonzalez, H. B. Schlegel, J. Chem. Phys. 1989, 90, 2154–2161.
Received: February 4, 2013
Published online: April 10, 2013
7522
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