Regenerable Radical-Trapping Tellurobistocopherol Antioxidants

Article abstract of DOI:10.1021/acs.joc.6b02450

Tellurobistocopherols 9-11 were prepared by lithiation of the corresponding bromotocopherols, reaction with tellurium tetrachloride and reductive workup. Compounds 9-11 quenched linoleic-acid-derived peroxyl radicals much more efficiently than α-tocophero

Full text of DOI:10.1021/acs.joc.6b02450

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Regenerable Radical-Trapping Tellurobistocopherol Antioxidants
Jia-fei Poon, Jiajie Yan, Vijay Pal Singh, Paul J. Gates, and Lars Engman
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02450 • Publication Date (Web): 17 Nov 2016
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Regenerable RadicalꢀTrapping Tellurobistocopherol Antioxidants
Jiaꢀfei Poon, † Jiajie Yan,† Vijay P. Singh,† Paul J. Gates‡ and Lars Engman*,†
†Uppsala University, Department of Chemistry – BMC, Box 576, SEꢀ751 23 Uppsala,
Sweden
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‡University of Bristol, School of Chemistry, Bristol, BS8 1TS, United Kingdom
Abstract: Tellurobistocopherols 9ꢀ11 were prepared by lithiation of the corresponding
bromotocopherols, reaction with tellurium tetrachloride and reductive workꢀup.
Compounds 9ꢀ11 quenched linoleic acidꢀderived peroxyl radicals much more
efficiently than αꢀtocopherol in a chlorobenzene/water twoꢀphase system.
NꢀAcetylcysteine or tris(2ꢀcarboxylethyl)phosphine as coꢀantioxidants in the aqueous
phase could regenerate the tellurobistocopherols and increase their inhibition times.
Antioxidant 11 inhibited peroxidation for sevenꢀfold longer than recorded with
αꢀtocopherol. Thiolꢀconsumption in the aqueous phase was monitored and found to be
inversely related to the inhibition time.
Oxidative stress is characterized by an imbalance between the production of reactive
oxygen species (ROS) and the antioxidant defense systems in favour of the former.1
ROS is known to target lipids in biological systems and this is generally known as lipid
peroxidation, an undesired free radical process whereby organic substances, RH, are
oxidized to the corresponding hydroperoxides, ROOH (eq 1).
Vitamin E, the most important lipidꢀsoluble antioxidant in man, offers protection
against lipid peroxidation. Briefly, vitamin E (AH) competes with the propagation
event and scavenges peroxyl radicals, ROO·, by hydrogenꢀatom transfer (HAT) with a
rate kinh >> kprop (eq 2). The resulting resonanceꢀstabilized radical A· is unable to
propagate the reaction.
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Vitamin E was first reported by Evans and Bishop in 19222 but its antioxidant
properties were revealed by Emerson and coꢀworkers when they showed that it could
slow down the autoxidation of fats.3 Vitamin E is a collective name for a family of
compounds including four tocopherols and four tocotrienols. Structurally, they are all
6ꢀchromanols. They differ in the number and position of methyl groups in the phenolic
part and in the sideꢀchain which is saturated in tocopherols 1ꢀ4 and triply unsaturated in
the corresponding tocotrienols. In the tocopherol family, αꢀtocopherol (1) is the most
reactive compound (kinh = 3.2 x 106 Mꢀ1sꢀ1).4
1 αꢀTocopherol R1= R2 = Me
2 βꢀTocopherol R1 = Me; R2 = H
3 γꢀTocopherol R1 = H; R2 = Me
4 δꢀTocopherol R1 = R2 = H
Considerable efforts have been invested in order to improve the reactivity of 1. Ingold
and coworkers found that compound 5 was a slightly more reactive antioxidant (kinh
=
4.7 x 106 Mꢀ1sꢀ1) 5 due to better overlap between the chromane oxygen lone pair and the
aromatic ring, resulting in a lower bond dissociation energy, BDEOꢀH, of the phenol.
More recently, Pratt and coworkers introduced nitrogen into the aromatic ring of
αꢀtocopherol. Thus, strongly electronꢀdonating groups such as amines could be
installed to lower the BDEOꢀH while the ionization potential of the compound did not
drop below the critical point where electron transfer to dioxygen becomes a problem.
Naphthyridinols 6, representing compounds of this type, were recently found to
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efficiently quench peroxyl radicals in lipid bilayers.6 Suitably positioned chalcogens
(Se, S) have also been found to increase the radical trapping activity of phenolic
compounds.7
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Recently, our group showed that alkyltelluro substituted ßꢀ, γꢀ and δꢀtocopherols 7aꢀ7d
were at least 10ꢀfold more reactive as radicalꢀtrapping agents than their respective
parents.8
Computational studies on alkyltelluro phenols suggested that oxygenꢀatom transfer
from the peroxyl radical to tellurium is a key step in the antioxidant mechanism. The
resulting alkoxyl radical in the solvent cage can then abstract a hydrogenꢀatom from the
phenolic OꢀH.9 Regeneration of the antioxidant from the phenoxyl radical/telluroxide
formed was brought about by thiols (Figure 1). Indeed, the inhibition time for
compound 7 was 6.5ꢀfold longer than recorded with αꢀtocopherol in a twoꢀphase lipid
peroxidation system.
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Figure 1. Proposed catalytic mechanism for quenching of peroxyl radicals by
2ꢀ(alkyltelluro)phenols in the presence of thiols.
It occurred to us that it may be possible to benefit even more from the unusual reactivity
of the heteroatom. The idea that emerged was to link two molecules of a tocopherol to
tellurium. Surprisingly, only very few compounds of this kind are reported in the
literature. They include the methanoꢀ and ethano dimers 8.10 To the best of our
knowledge, dimers linked together by a chalcogen are as yet unknown.
Synthesis: Symmetrical diorganyl tellurides can be obtained in high yields by
copperꢀinduced detelluration of the corresponding diorganyl ditellurides.11 This
procedure was tried for the preparation of tellurobistocopherol 9. Although the
ditelluride required was conveniently obtained from 5ꢀbromoꢀδꢀtocopherol by
dilithiation, Teꢀinsertion into the CꢀLi bond and airꢀoxidation, extrusion of tellurium
was unsuccessful. Instead, we were pleased to find that a similar strategy, using TeCl4
in place of elemental tellurium, provided compound 9 in low yield after reductive
workꢀup (eq 3).
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In a similar fashion, 7ꢀbromoꢀβꢀtocopherol and 7ꢀbromoꢀδꢀtocopherol provided the
corresponding tellurobistocopherols 10 and 11 in 33% and 26% yield, respectively.
Curious to study the effects of the phytyl chain, the methyl groups and the
benzannulated cyclic ether on antioxidant capacity, compounds 12 and 13 were
prepared using a similar procedure.
Evaluation: To determine the radicalꢀtrapping capacity and regenerability, all
tellurobisphenolic antioxidants were evaluated in a twoꢀphase lipid peroxidation
system
reminiscent
of
a
biological
membrane.12
Briefly,
azobis(2,4ꢀdimethylvaleronitrile) (AMVN) was added as an initiator to chlorobenzene
at 42°C containing the antioxidant and linoleic acid as the oxidizable substrate. The
aqueous phase contained Nꢀacetylcysteine (NAC) or tris(2ꢀcarboxylethyl)phosphine
(TCEP) which could serve as coꢀantioxidants and continuously regenerate the
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antioxidants in the lipid phase. The chlorobenzene phase was assayed by HPLC every
20 minutes and the concentration of conjugated diene, formed by peroxidation of
linoleic acid, was determined by HPLC with UVꢀdetection at 234 nm. Initially, lipid
peroxidation is efficiently inhibited by the antioxidant and the rate of conjugated diene
formation, Rinh, is low. After some time, when the antioxidant is all consumed, the
Rꢀvalue increases considerably to a value corresponding to uninhibited peroxidation.
This point is referred to as the inhibition time, Tinh, of the antioxidant. Our reference
compound, αꢀtocopherol, at 40 ꢀM could inhibit peroxidation efficiently (Rinh = ca. 25
ꢁM/h) for ca. 100 min in the presence of aqueous phase NAC or TCEP (Figure 1 and
Table 1). The similar Tinhꢀ and Rinhꢀvalues recorded in the absence of the coꢀantioxidant
show that αꢀtocopherol is not regenerable under the conditions of the twoꢀphase model.
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In the absence of NAC/TCEP, all organotellurium antioxidants tested quenched peroxyl
radicals at least (Rinh = 7 – 25 ꢁM/h), as efficiently as 1. For compounds 9ꢀ11 the
Tinhꢀvalues (165ꢀ214 min) were significantly longer than recorded for αꢀtocopherol.
8000
7000
α-Tocopherol
6000
5000
4000
3000
2000
1000
0
11
0
200
400
600
800
1000
Time (min)
Figure 2. Peroxidation traces (conjugated diene concentration vs time) recorded using
compound 11 and αꢀtocopherol as antioxidants in chlorobenzene and NAC (1 mM) in
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the aqueous phase.
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When NAC (1 mM) was present in the aqueous phase, the Rinhꢀvalues were
significantly lower for all compounds (Rinh = 1 – 4 ꢁM/h) and the Tinhꢀvalues longer
(Table 1). 7,7’ꢀTellurobisꢀδꢀtocopherol (11) inhibited peroxidation for 742 min or
7.6ꢀfold longer than recorded for 11 (Figure 2). This is the longest inhibition time we
have ever recorded in the twoꢀphase model. Removal of the phytyl chain and the
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Table 1. Inhibited Rates of Conjugated Diene Formation (Rinh) and Inhibition Times
(Tinh) in the Presence and Absence of NAC (1.0 mM) or TCEP (0.5 mM) in the
Twoꢀphase Model
Antioxidants
With NAC
With TCEP
Without NAC/TCEP
a
b
a
b
a
b
(40 ꢀM)
Rinh
Tinh
Rinh
Tinh
Rinh
Tinh
(ꢁM/h)
(ꢁM/h)
(ꢁM/h)
(min)
(min)
451 ± 9
510 ± 5
507 ± 8
208 ± 10
125 ± 13
123 ± 7
(min)
170
165
214
92
9
1 ± 1
2 ± 0
4 ± 1
1 ± 1
2 ± 1
25 ± 1
634 ± 9
653 ± 12
742 ± 13
544 ± 4
365 ± 6
97 ± 15
2 ± 0
2 ± 1
2 ± 0
2 ± 1
3 ± 1
21 ± 2
8
7
10
11
21
25
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28
12
13
49
αꢀTocopherol
109
aRate of peroxidation during the inhibited phase (uninhibited rate ca. 479 µM/h). Errors
b
correspond to ± SD for triplicates. Inhibited phase of peroxidation. Reactions were
monitored for 880 min. Errors correspond to ± SD for triplicates.
2,2´,8,8´ methyls caused a drop in the inhibition time (compound 12; Tinh = 544 min),
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which continued upon further simplification of the structure (compound 13; Tinh = 365
min). We speculate that this is a lipophilicity effect or the result of an increasing
BDEOꢀH (vide infra).
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When TCEP (0.5 mM) was used as a coꢀantioxidant, similarly low Rinhꢀvalues were
recorded as with NAC (Table 1). Whereas the inhibition times were generally shorter,
the similar trend was seen when the compounds were arranged according to falling Tinh.
We were also curious to see how quickly NAC was consumed during a normal
peroxidation experiment. Following a recently described procedure,13 the aqueous
phase was sampled every 30 minutes and the thiol was allowed to react with
bisꢀ4ꢀpyridyl disulfide. The concentration of pyridineꢀ4ꢀthiol formed (eq 4), as
determined by UVꢀspectroscopy at 324 nm, was used for monitoring the disappearance
of NAC with time.
For αꢀtocopherol, the rate of NACꢀconsumption (33 µM/h) was low and essentially the
same as recorded in control experiments (nothing but NAC in the twoꢀphase system or
NAC + linoleic acid + AMVN; Table 2). When a telluride antioxidant was present, the
NAC was consumed more quickly. In the presence of tellurobistocopherols 9ꢀ11, 119 –
131 µM/h of the thiol was consumed. The rate increased to 150 and 164 µM/h,
respectively, with compounds 12 and 13.
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Table 2. NACꢀConsumption in the Aqueous Phase during Peroxidation Inhibited by
5
6
Telluriobisphenol Antioxidants
7
8
9
Antioxidant
Rate of NACꢀConsumption
(µM/h)a
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(40 µM)
131 ± 4
125 ± 10
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164 ± 4
33 ± 4
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10
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13
αꢀTocopherol
b
_
37 ± 8
c
_
27 ± 5
aErrors correspond to ± SD for triplicates. Linoleic acid and AMVN in the
b
c
chlorobenzene and NAC in the aqueous phase. Nothing in the chlorobenzene and
NAC in the aqueous phase.
Thus, the rate of thiol consumption is inversely related to the Tinh recorded in the
twoꢀphase model. Extrapolation in the NACꢀconcentration vs time plots to find the time
where the aqueous phase was depleted of NAC, showed that this always fell short of the
corresponding Tinh. It therefore seems that the availability of aqueousꢀphase NAC is a
limiting factor for the inhibition time.
In an attempt to see if the turnover number of catalyst 11 could be increased, the
concentration was lowered from the standard 40 ꢀM to 30, 20, 10 and 5 ꢀM. As shown
in Figure 3, this was not the case. When the concentration was lowered, the Tinh was
accordingly reduced. A similar trend was seen with TCEP.
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800
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600
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0
NAC
y = 18.217x - 28.159
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TCEP
y = 9.928x + 84.311
0
5
10
15
20
25
30
35
40
45
Antioxidant Concentration (µM)
Figure 3. Inhibition times recorded for 11 at different concentrations in the presence of
NAC (1.0 mM) or TCEP (0.5 mM).
Concluding Remarks
As observed previously with the “monomeric” tocopherol derivatives 7, the “dimeric”
tellurobistocopherols 9ꢀ11 showed considerable antioxidant capacity also in the
absence of a coꢀantioxidant. This may be because the heteroatom is sterically protected.
Otherwise, residual amounts of linoleic acid hydroperoxide tend to oxidize the telluride
antioxidant to the corresponding telluroxide, which is considerably less reactive
towards peroxyl radicals.
In the presence of NAC as a coꢀantioxidant, Tinhꢀvalues for the “dimers” 9ꢀ11 were
always longer but never close to twice as long as recorded for the
corresponding ”monomers” 7aꢀ7d. 8b The largest improvement, +38%, was seen with
δꢀtocopherol derivative 9 (634 min instead of 458 min for the corresponding monomer
7c). For compounds 10 (653 min instead of 591 min for 7a) and 11 (742 min instead of
630 min for 7d) the increase in Tinh was only modest. On the other hand, diaryl
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tellurides are chemically more robust than alkyl aryl tellurides. Some time ago we
probed the stabilizing capacity of a series of electronꢀrich diaryl tellurides is polymeric
materials.14 As determined by thermogravimetric analysis many of the compounds
were stable at least up to 210o C. Diaryl tellurides as well as alkyl aryl tellurides are
easily oxidized to the corresponding telluroxides. In case the system is depleted in
reducing agents, there is a risk that the alkyl aryl telluroxide (but not the diaryl
telluroxide) may decompose via a telluroxide elimination reaction.15
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The reactivity of the tellurobistocopherols did not change much upon removal of the
phytyl chain, the 2,2’,8,8’ꢀmethyls and the benzannulated cyclic ether. However, a
noteworthy drop in the Tinh was recorded for compounds 12 and 13. This could be a
lipophilicity effect. Highly lipophilic antioxidants would distribute almost exclusively
into the lipid phase and give a maximal antioxidant protection there. Removal of the
benzannulated cyclic ether and any methyl groups flanking the aromatic OH would also
be expected to cause an increase in the BDEOꢀH (electron donating substituents here are
known to weaken the OꢀH bond). This would increase leakage of chainꢀpropagating
alkoxyl radicals from the solvent cage into the bulk of the solution (Figure 1).
Whenever this happens, 2 equivalents of thiol are wasted in order to regenerate the
catalyst. In fact, such an increase in the rate of thiol consumption was observed for
compounds 12 and 13.
Experimental Section
13
13
1H and C NMR spectra were recorded on 400 MHz (1H: 399.97 MHz; C 100.58
MHz) and 500 MHz (1H: 499.93 MHz; 13C: 125.70 MHz) spectrometers, using the
13
residual solvent peaks of CDCl3 (1H: δ 7.26; C: δ 77.0) as an indirect reference to
TMS. 125Te NMR spectra were recorded on a 400 MHz spectrometer (125Te: 126.19
MHz) using Ph2Te2 (423 ppm) as external standard. The melting points are uncorrected.
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Flash column chromatography was performed using silica gel (0.04 – 0.06 mm).
Tetrahydrofuran was dried in a solvent purification system by passing it through an
activated alumina column. 5ꢀBromoꢀδꢀtocopherol,8b 7ꢀbromoꢀδꢀtocopherol8b and
7ꢀbromoꢀβꢀtocopherol8b and 6ꢀbromochromane16 were prepared according to literature
procedures.
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General procedure: Synthesis of tellurobisphenols
To a solution of the appropriate 2ꢀbromophenol derivate (1.0 eq.) in anhydrous THF (10
mL) at ꢀ78 oC under nitrogen, tertꢀbutyl lithium (1.7 M in pentane, 3.0 eq.) was added.
After stirring for 2 hours at ꢀ78 oC, tellurium tetrachloride (0.5 eq.) was added and the
solution was allowed to stir for overnight at ambient temperature. After addition of
Na2SO3 (aq., 20 mL) and extraction with diethyl ether (25 mL x 3), the organic layer
was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The
residue was purified by column chromatography (pentane/ethyl acetate = 90:10) to give
the title compound.
5,5´ꢀTellurobisꢀδꢀtocopherol (9). 5ꢀBromoꢀδꢀtocopherol (964 mg, 2.0 mmol),
tertꢀbutyl lithium (1.7 M in pentane, 3.5 mL, 6.0 mmol) and tellurium tetrachloride
(269 mg, 1.0 mmol) were reacted according to the general procedure to give the title
compound as a yellow oil (225 mg, 24%). 1H NMR (400 MHz, CDCl3): δ 6.71 (s, 2H),
6.33 (s, 2H), 2.82 (m, 4H), 2.14 (s, 6H), 1.78 (m, 4H), 1.08ꢀ1.58 (several peaks, 48H),
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0.87ꢀ0.91 (several peaks, 24H). C NMR (100 MHz, CDCl3): δ 150.9, 146.3, 130.4,
125.5, 114.5, 102.0, 75.2, 39.7, 39.4, 37.5, 37.4, 37.3, 32.8, 32.7, 32.2, 28.7, 28.0, 24.8,
24.4, 23.7, 22.7, 22.6, 21.0, 19.8, 19.6, 16.3. 125Te NMR (126 MHz, CDCl3): δ ꢀ3.
HRMS (TOF MS EI+) m/z calcd for C54H90O4Te [M]+: 932.5901. Found: 932.5928.
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7,7´ꢀTellurobisꢀβꢀtocopherol (10). 7ꢀBromoꢀβꢀtocopherol (496 mg, 1.0 mmol),
tertꢀbutyl lithium (1.7 M in pentane, 1.8 mL, 3.0 mmol) and tellurium tetrachloride
(134 mg, 0.5 mmol) were reacted according to the general procedure to give the title
compound as a yellow oil (158 mg, 33%). 1H NMR (400 MHz, CDCl3): δ 5.73 (s, 2H),
2.62 (t, J = 6.4 Hz, 4H), 2.42 (s, 6H), 2.12 (s, 6H), 1.77 (m, 4H), 1.01ꢀ1.56 (several
peaks, 48H), 0.83ꢀ0.88 (several peaks, 24H).13C NMR (125 MHz, CDCl3): δ 148.6,
145.5, 129.1, 123.1, 119.1, 105.3, 75.0, 39.8, 39.4, 37.4, 37.3, 32.8, 32.7, 31.4, 28.0,
24.8, 24.4, 23.7, 22.7, 22.6, 21.2, 21.1, 20.9, 19.8, 19.6, 12.6. 125Te NMR (126 MHz,
CDCl3): δ 33. HRMS (MALDI) m/z calcd for C56H94O4Te [M]+: 960.6214. Found:
960.6217.
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7,7´ꢀTellurobisꢀδꢀtocopherol (11). 7ꢀBromoꢀδꢀtocopherol (964 mg, 2.0 mmol),
tertꢀbutyl lithium (1.7 M in pentane, 3.5 mL, 6.0 mmol) and tellurium tetrachloride
(269 mg, 1.0 mmol) were reacted according to the general procedure to give the title
compound as a yellow oil (238 mg, 26%). 1H NMR (400 MHz, CDCl3): δ 6.65 (s, 2H),
6.61 (s, 2H), 2.68 (m, 4H), 2.52 (s, 6H), 1.75 (m, 4H), 1.06ꢀ1.60 (several peaks, 48H),
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0.88ꢀ0.92 (several peaks, 24H). C NMR (100 MHz, CDCl3): δ 150.5, 145.4, 132.5,
124.0, 111.5, 105.9, 76.0, 40.1, 39.4, 37.4, 37.3, 32.8, 32.7, 31.2, 28.0, 24.8, 24.4, 24.0,
22.7, 22.6, 22.5, 22.4, 21.0, 19.7, 19.6. 125Te NMR (126 MHz, CDCl3): δ 49. HRMS
(TOF MS ESI) m/z calcd for C54H90O4Te [M+Na]+: 955.5794. Found: 955.5801.
6ꢀChromanol. To a mixture of magnesium turnings (248 mg, 10.2 mmol) and iodine
(90 mg, 0.35 mmol) in THF (4 mL) under nitrogen was added a solution of
6ꢀbromochromane (378 mg, 1.8 mmol) in anhydrous THF (2 mL). After heating at 60
°C for 20 min, a solution of 6ꢀbromochromane (1.14 g, 5.3 mmol) in anhydrous THF (6
mL) was added dropwise over a period of 50 min at 30 °C. The Grignard reagent was
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transferred to a solution of trimethyl borate (0.79 mL, 7.1 mmol) in anhydrous THF (4
mL) at ꢀ10 °C over a period of 1 hour. The reaction mixture was allowed to stir for 30
min prior to hydrolysis with HCl (2 M, 12 mL) and extraction with diethyl ether (10
mL). The organic phase was washed with water (10 mL x 2) and then transferred to a
twoꢀneck roundꢀbottomed flask. To the solution, peracetic acid (1.2 mL, 39% in acetic
acid) was added dropwise at 0°C under nitrogen. After stirring at ambient temperature
for 3 hours, the reaction mixture was quenched with NaHSO3 (10% aq., 30 mL) and
extracted with diethyl ether (30 mL x 3). The organic layer was dried over magnesium
sulfate, filtered and evaporated under reduced pressure. The residue was purified by
column chromatography (pentane/ethyl acetate = 95:5) to give the title compound as a
white solid. 1H NMR (400 MHz, CDCl3): 6.67 (d, J = 8.8 Hz, 1H), 6.57 (dd, J = 2.8, 8.8
Hz, 1H), 6.53 (d, J = 2.8 Hz, 1H), 4.40 (s, 1H), 4.13 (t, J = 4.8 Hz, 2H), 2.74 (d, J = 6.4
Hz, 2H), 1.98 (m, 2H). 13C NMR (100 MHz, CDCl3): 148.9, 148.8, 123.0, 117.3, 115.8,
114.3, 66.3, 25.0, 22.4. 1H and 13C spectra were in accord with the literature.17
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5ꢀBromoꢀ6ꢀchromanol. To a solution of 6ꢀchromanol (651 mg, 4.3 mmol) in
dichloromethane (50 mL), a solution of tetrabutylammonium tribromide (2.1 g, 4.3
mmol) in dichloromethane (50 mL) was added dropwise. After stirring for one hour, the
solution was evaporated and the residue was purified by column chromatography
(pentane/ethyl acetate = 95:5) to give the title compound as a white solid (685 mg,
70%). 1H NMR (400 MHz, CDCl3): δ 6.82 (d, J = 6.8 Hz, 1H), 6.73 (d, J = 6.8 Hz, 1H),
5.16 (s, 1H), 4.08 (m, 2H), 2.73 (t, J = 5.6 Hz, 2H), 2.02 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 149.5, 146.1, 1221, 116.8, 113.9, 112.6, 65.8, 26.3, 22.3. 1H and 13C spectra
were in accord with the literature.17
5,5'ꢀTellurobisꢀ6ꢀchromanol (12). 5ꢀBromoꢀ6ꢀchromanol (458 mg, 2.0 mmol),
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tertꢀbutyl lithium (1.7 M in pentane, 3.5 mL, 6.0 mmol) and tellurium tetrachloride
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(269 mg, 1.0 mmol) were reacted according to the general procedure to give the title
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compound as a red solid (135 mg, 32%). Mp = 158ꢀ160 °C. H NMR (500 MHz,
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CDCl3): δ 6.79 (d, J = 9.0 Hz, 2H), 6.73 (d, J = 9.0 Hz, 2H), 6.23 (s, 2H), 4.03 (t, J = 5.0
Hz, 4H), 2.80 (t, J = 7.0 Hz, 4 H), 1.98 (m, 4H). 13C NMR (125 MHz, CDCl3): δ 151.9,
149.1, 127.5, 120.0, 113.0, 106.4, 65.7, 31.2, 23.2. 125Te NMR (126 MHz, CDCl3) δ
216. HRMS (TOF MS EI+) m/z calcd for C18H18O4Te [M]+: 428.0267. Found:
428.0272.
2,2´ꢀTellurobisphenol (13). 2ꢀBromophenol (692 mg, 4.0 mmol), tertꢀbutyl lithium
(1.7 M in pentane, 7.0 mL, 12.0 mmol) and tellurium tetrachloride (538 mg, 2.0 mmol)
were reacted according to the general procedure to give the title compound as a pale
yellow solid (270 mg, 44%). 1H NMR (500 MHz, CDCl3): δ 7.52 (dd, J = 2.0, 8.0 Hz,
2H), 7.26 (m, 2H), 6.96 (dd, J = 1.5, 8.5 Hz, 2H), 6.78 (m, 2H), 5.92 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ 156.9, 139.5, 131.3, 122.2, 114.2, 102.2. 125Te NMR (126 MHz,
CDCl3) δ 285. The 1H spectrum was in accord with the literature.18
HPLC Peroxidation Assay. The experimental setup for the twoꢀphase lipid
peroxidation model for determination of Rinh and Tinh has been recently described.12 The
values for Rinh and Tinh in the presence of NAC and TCEP are reported as means ± SD
based on triplicates. The initial concentration of linoleic acid hydroperoxide was ca.
175 ꢁM at the beginning of each experiment.
NACꢀconsumption Assay. The experimental setup for determination of the rate of
NACꢀconsumption in the twoꢀphase lipid peroxidation model was recently described.13
The values reported are means ± SD based on triplicates.
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ASSOCIATED CONTENT
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Supporting Information
1H, 13C and 125Te NMR data for all new compounds prepared. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: Lars.Engman@kemi.uu.se
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
Stiftelsen ÅꢀForsk (16ꢀ364) and Stiftelsen Olle Engkvist Byggmästare (2016/159) are
gratefully acknowledged for financial support.
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Graphical Abstract
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