Hydroquinone-Based Biarylic Polyphenols as Redox Organocatalysts for Dioxygen Reduction: Dramatic Effect of Orcinol Substituent on the Catalytic Activity

Article abstract of DOI:10.1002/adsc.201600819

A series of 18 new biaryls has been synthesized and investigated with regard to their organocatalytic efficiency. They consist of a hydroquinone core linked to a phenol or a resorcinol moiety. It is shown that the resorcinol moiety substituted on its meta position has a strong impact on the catalytic activities of these compounds towards the reduction of dioxygen by diethylhydroxylamine (DEHA) in aqueous medium. While the derivative consisting of the two cores spaced by three methylene units is completely inactive, substitution on the hydroquinone part leads to tremendously active catalysts, especially the biaryl consisting of methoxyhydroquinone-orcinol. Two mechanisms are proposed to explain the dramatic efficiency of the novel hydroquinone-based biarylic polyphenols for the catalytic reduction of dioxygen, both considering the influence of the orcinol moiety on the semiquinone anion intermediate. As a first hypothesis, this substituent could promote its direct reduction by DEHA to regenerate the hydroquinone, which will react again to regenerate the semiquinone. On the other hand, an intramolecular hydrogen bond could enhance the reactivity of the semiquinone anion toward dioxygen by an addition–elimination mechanism. In this case, the elimination would provide the corresponding quinone but, since the reduction of the quinones by DEHA is much slower than the observed kinetics, a reduction by DEHA prior to the elimination has to be considered to generate the semiquinone anion instead of the quinone. (Figure presented.).

Full text of DOI:10.1002/adsc.201600819

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DOI: 10.1002/adsc.201600819
Hydroquinone-Based Biarylic Polyphenols as Redox Organocata-
lysts for Dioxygen Reduction: Dramatic Effect of Orcinol Sub-
stituent on the Catalytic Activity
a
a
a,
Raphaꢀl Lebeuf, Vꢁronique Nardello-Rataj, and Jean-Marie Aubry *
a
Univ. Lille, CNRS, ENSCL, Centrale Lille, Univ. Artois, UMR 8181 – UCCS – Unitꢁ de Catalyse et Chimie du Solide,
F-59000 Lille, France
Fax : (+33)-3-2047-0599; phone: (+33)-3-2033-6364; e-mail: jean-marie.aubry@univ-lille1.fr
Received: July 26, 2016; Revised: November 21, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600819.
Abstract: A series of 18 new biaryls has been synthe- a first hypothesis, this substituent could promote its
sized and investigated with regard to their organoca- direct reduction by DEHA to regenerate the hydro-
talytic efficiency. They consist of a hydroquinone quinone, which will react again to regenerate the
core linked to a phenol or a resorcinol moiety. It is semiquinone. On the other hand, an intramolecular
shown that the resorcinol moiety substituted on its hydrogen bond could enhance the reactivity of the
meta position has a strong impact on the catalytic ac- semiquinone anion toward dioxygen by an addition–
tivities of these compounds towards the reduction of elimination mechanism. In this case, the elimination
dioxygen by diethylhydroxylamine (DEHA) in aque- would provide the corresponding quinone but, since
ous medium. While the derivative consisting of the the reduction of the quinones by DEHA is much
two cores spaced by three methylene units is com- slower than the observed kinetics, a reduction by
pletely inactive, substitution on the hydroquinone DEHA prior to the elimination has to be considered
part leads to tremendously active catalysts, especially to generate the semiquinone anion instead of the
the biaryl consisting of methoxyhydroquinone-orci- quinone.
nol. Two mechanisms are proposed to explain the
dramatic efficiency of the novel hydroquinone-based
biarylic polyphenols for the catalytic reduction of di- Keywords: diethylhydroxylamine; dioxygen; hydro-
oxygen, both considering the influence of the orcinol quinones; organocatalysts; polyphenols; semiqui-
moiety on the semiquinone anion intermediate. As nones
Introduction
from aqueous solutions. This property can be of inter-
[12]
est for industrial boilers to impede their corrosion.
The oxidation of hydroquinones produce quinones,
The organic hydroquinone/benzoquinone redox
couple is one of the most studied systems due to its which can be reduced back to hydroquinones, either
fundamental biological implication in several biosyn- electrochemically, or chemically using various com-
thetic pathways. In addition to the biological activity pounds such as NADH in biological systems thanks
of quinonoid compounds, other relevant application to oxidoreductases, dihydrogen in the presence of
domains of these molecules are the preservation of metal catalysts, sulfite, etc. Among them, N,N-di-
raw materials thanks to the antioxidant properties of ethylhydroxylamine 4 (DEHA) can act as an efficient
hydroquinone reported for lipids, styrene, acrylic reducer for this transformation in a preparative syn-
acid or acrylate esters, hydrogen peroxide produc- thetic pathway.
tion through the anthraquinone process, and other react slowly with dioxygen, it reduces much faster
[
1]
[2]
[
3]
[13]
[
14]
[15]
[
4]
[5]
[
6]
[16]
Although DEHA is also able to
[
7]
[17]
emerging ones like for catalytic processes by their use the semiquinone 3 formed as an intermediate during
[8]
as co-catalysts as well as energy production acting the oxidation of the corresponding hydroquinone 1 by
[
9]
[10]
as possible electron carriers or reservoirs. More- dioxygen in basic aqueous media. Thus, this allows
over, the ability of hydroquinone to react with ground the establishment of a full organocatalytic cycle for
[11]
state dioxygen
can be used to suppress dioxygen the reduction of dioxygen in water, in which the hy-
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the reduction of dioxygen. For that purpose, the struc-
ture of the biaryl 7, which has shown until now the
higher reactivity, was rebuilt step by step starting
from hydroquinone. The simplest hydroquinone-
based biarylic structure corresponds in fact to the
phenylhydroquinone 8, which is largely available. The
two isomeric biaryls 9 and 10 consisting of a hydroqui-
none substituted by a phenolic group have been syn-
thesized in order to assess the influence of the posi-
tion of an additional hydroxy function. A fourth
phenol function was also added through the resorcinol
derivative 11, which presents the closer structure to 7
Scheme 1. Organocatalytic reduction of dioxygen by hydro-
quinone regenerated by DEHA, in basic aqueous solutions. (Figure 1).
droquinone moiety is the pivot and DEHA the final
[
18]
reducer (Scheme 1).
Recently, we have shown that this catalytic cycle
could be kinetically improved by using resorcinol de-
[
19]
rivatives as co-catalysts. From a mechanistic view-
point, this finding may be ascribed to the formation
of a highly active heterodimer resulting from the con-
densation of benzoquinone with orcinol (Scheme 2).
Figure 1. Set of hydroquinone-based biaryls investigated as
catalysts for dioxygen reduction by DEHA.
2
2
The crucial role of the C(sp )–C(sp ) biarylic link-
age has also been investigated with the compound 12,
in which the hydroquinone and resorcinol rings are
separated by an alkyl chain of a suitable length in
order to favour possible electronic charge transfer be-
tween the electron-poor semi-hydroquinone inter-
mediate and the electron-rich resorcinol core
Scheme 2. Catalytic activity of hydroquinone and an orcinol- (Scheme 3). It was expected that such stabilization
based heterodimer toward dioxygen reduction by DEHA in
would favour the formation of the semi-hydroquinone
water. [catalyst]=1 mM, [DEHA]=840 mM, [O ]ꢀ275 mM,
2
or its oxidation to the quinone.
À1 [19]
pH 10.1, T=258C. TOF in mMmin .
2
2
Finally, the C(sp )–C(sp ) biaryls based on hydro-
quinone-resorcinol units have been modified on each
Based on this interesting finding, we decided to
extend the scope of these promising organocatalytic
biarylic systems. It is noteworthy that very few hetero-
dimers composed of resorcinol and hydroquinone de-
rivatives have been described in the literature so far,
and none of them have been studied for their reactivi-
[
20]
ty toward dioxygen. Pummerer and Huppmann in
[
21]
1
927 and Stjernstrçm in 1963 reported a hydroqui-
none-resorcinol based compound. Acylhydroquinone-
[
22]
resorcinol has been reported by Eugster, a hydroxy-
hydroquinone-resorcinol has been described by
[23]
Musso
by Gꢃmez and De la Hoz.
The aim of this study was thus to determine the
and finally a hydroquinone-phloroglucinol
[
24]
structure-activity relationships of the biaryls in regard Scheme 3. Designed catalyst for dioxygen reduction by
to their substituents and to their ability to catalyze DEHA with possible electron charge transfer effects.
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part, varying the steric and the electronic effects, in of activated methylenic compounds with benzoqui-
[
25]
order to extend the scope of this new type of catalysts none have been adapted to synthesize most of the
and to find more effective catalysts exhibiting both targeted biaryls based on hydroquinone and resorci-
higher activity and better stability.
nol (Scheme 4). In alkaline media (Method A), the
mixture turned immediately black upon addition of
the resorcinol derivative to the quinone, with forma-
tion of oligo-/polymers, even in the presence of only
one equivalent of base for the deprotonation of the
resorcinol, and under anaerobic conditions to avoid
the oxidation of the formed hydroquinone. The ben-
Results and Discussion
Synthesis of the Hydroquinone-Based Biaryls
[
21]
Both the acidic conditions used by Stjernstrçm for zoquinone was totally consumed in a few seconds.
the coupling of benzoquinone with resorcinol and the Mass spectrometric analysis of the crude products
basic ones used by other authors for the condensation (see the Supporting Information, S15) allowed iden-
Scheme 4. Synthesized hydroquinone-resorcinol-based biaryls.
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tification of oligomers with up to 6 orcinol and hydro-
quinone units. Among them, the signal at m/z=337
can be attributed to two hydroquinones grafted to
one orcinol, the signal at m/z=445 is assumed to be
the same product with a third hydroquinone, one
being oxidized to quinone, and finally, the signal at
m/z=353 would correspond to two orcinols grafted to
one hydroquinone. This means that some oxidation
occurs during the reaction to generate quinones for
further condensation, probably by benzoquinone
itself. This assumption is supported by the isolation of
hydroquinone at the end of the reaction. These un-
avoidable subsequent condensations lead to relatively
poor yields (between 4 and 36%). Nevertheless, the
products could be isolated in only one synthetic step
after acidification, extraction and purification through
silica gel. Under acidic conditions (Method B), the re-
Scheme 5. Regioselectivity of the reactions between substi-
tuted quinones and orcinol.
action media remained homogeneous even after pro- on its opposite position in a 1:2 ratio (22a, b), as for
longed reaction times, with an orange-red coloration a methoxy, for which it occurs in a selective manner
probably due to the formation of quinone traces. Less (23b).
oligomers were present in the mass spectra (see the
Supporting Information, S16) but the isolated yields tron-donating power of the substituent until it be-
were only slightly improved (10 to 30%). comes totally regioselective in the case of methoxy-
The increase of the regioselectivity follows the elec-
The attack of benzoquinone by the meta-substituted benzoquinone. Based on the mechanism proposed in
resorcinols preferentially occurs at the position 4 Scheme 6, this can be explained by the formation of
rather than position 2, e.g., rather at the otho-para the intermediate (a) keeping a donor-acceptor conju-
than the ortho-ortho positions relative to the two hy- gated system.
droxy groups. This last regioisomer could not be un-
1
ambiguously identified by H NMR but its formation
would be less than 10%. These regioselectivities are
in accordance with the ones observed for Pech-
[26]
mann and Friedel–Crafts reactions carried out with
[
27]
resorcinol derivatives.
The change of the position of the substituents on
the resorcinol moiety did not impede the formation of
the heterodimer as shown by the use of 2-methylre-
sorcinol (13) and 4-methylresorcinol (14). Since sub-
stituents at the meta position of resorcinol enhance
the catalytic activity for dioxygen reduction by
DEHA using hydroquinone and resorcinol derivatives
Scheme 6. Regioselectivity of the addition of orcinol to me-
thoxybenzoquinone under basic conditions.
[19]
as co-catalysts,
this position was preferentially
modified by a chlorine (15), phenyl (16), and a fused-
benzene (17) substituent. In the case of 3,5-dihydro-
benzoic acid, the resulting heterodimer lactonized
Although the condensation of orcinol on disubsti-
during the purification over silica gel (18). More com- tuted 2,5-dimethylbenzoquinone and 2,6-dimethylben-
plex resorcinol derivatives could also be grafted to zoquinone failed under basic conditions, a reaction
benzoquinone like resveratrol providing compound occurs with 2,5-dimethylbenzoquinone under acidic
1
9.
Variability of the substituents on the quinone was oxidation, provides the quinone 24 with a 14% yield
also investigated. Orcinol attacks the non-substituted (Scheme 7).
conditions leading to a complex mixture which, after
side of the benzoquinones, apart for chlorobenzoqui-
Under acidic conditions, dehydration can occur as
none under basic conditions (25). Directing effects shown during the reaction of 2-methylnaphtoquinone
could be observed following the substituent under (29, menadione) with orcinol (28) for which three
basic conditions (Scheme 5). Whereas the two re- compounds were isolated (Scheme 8). The two re-
gioisomers were formed in nearly equal amounts gioisomers 30a and 30b could be separated by chro-
using methylbenzoquinone (20a, b) and phenylbenzo- matography. The quinone 26 was formed without ad-
quinone (21a, b), a tert-butyl group favours the attack dition of external oxidant, either by the action of di-
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Scheme 7. Reaction of orcinol with 2,5-dimethylbenzoqui-
none under acidic conditions.
Scheme 10. Synthesis of trihydroxylated biaryl by Suzuki–
Miyaura reaction.
3
1
4 and 2-bromoanisole 35 afforded the heterodimer
0 after demethylation with boron tribromide.
Alternatively, the para-isomer 9 could be obtained
by the addition of the diazonium salt formed from
para-methoxyaniline and benzoquinone according to
[
28]
the procedure of Brassard and L’Ecuyer, followed
[
16]
by reduction with DEHA
Scheme 11).
and demethylation
(
Scheme 8. Condensation of orcinol to menadione under
acidic conditions.
oxygen during the work-up procedure or by the start-
ing naphthoquinone during the reaction.
Interestingly, the condensation reaction can occur
under acidic conditions with simple phenols like 3,5-
dimethylphenol 32 (Scheme 9). Again, the quinone 33
was directly obtained instead of the hydroquinone,
more probably by oxidation during the work-up pro-
cedure as observed by the colour change from orange
to red-brown.
Scheme 11. Biaryl synthesis through direct addition of diazo-
nium salt on benzoquinone.
A palladium-catalyzed cross-coupling reaction was
required for the selective coupling of the phenol on
Lastly, product 12 with the two aryl moieties sepa-
its ortho-position (Scheme 10). The Suzuki–Miyaura rated by an alkyl chain which could be obtained by
reaction between (1,4-dimethoxy)phenylboronic acid a Suzuki–Miyaura coupling between 5-iodo-1,3-dime-
thoxybenzene and allyl-1,4-dimethoxybenzene 40 re-
[29]
acted with 9-borabicyclononane (Scheme 12).
The
product 40 was obtained by a Claisen rearrangement
from 4-methoxyphenol 39, followed by methylation.
The product resulting from the coupling was deme-
thylated in a last step.
Having all the biaryls in hand, we investigated their
catalytic reactivity toward dioxygen.
Scheme 9. Condensation of 3,5-dimethyphenol to benzoqui-
none
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Figure 2. Turnover and reaction rate of several catalysts
1 mM) for the reduction of dissolved dioxygen in buffered
Scheme 12. Synthesis of biaryl 12.
(
water (pH 10.1, NaHCO =10 mM, Na CO =16 mM) by
3
2
3
DEHA (0.84 mM) at 258C.
Hydroquinone-Based Biaryls as Catalysts for the
Reduction of Dioxygen by DEHA
a more rapid degradation of the catalyst. On the
The mechanism by which the polyphenols catalyze other hand, an opposite trend is observed when the
the reduction of dioxygen by DEHA in basic aqueous phenol is at the ortho-position (10), i.e., the reaction
media is complex and the rate-limiting step is un- is more sluggish compared to phenylhydroquinone,
known as yet. Indeed, several reaction steps have to but the amount of consumed dioxygen is slighlty im-
be considered: (i) the reaction of hydroquinone with proved thanks to a better robustness of the catalyst.
dioxygen, (ii) the regeneration of hydroquinone by Using the resorcinol-derived biaryl (11), a higher con-
DEHA either from the quinone or from the semiqui- version than with hydroquinone was obtained despite
none anion and (iii) the reactivity of the superoxide an initial reaction rate around 3 times lower. The ben-
radical anion formed after a first electron transfer. efit of the ortho-substitution can be exploited to
Typically, a rapid decrease of the dioxygen concentra- obtain more active catalysts with an ortho-ortho’ dis-
tion occurs when the polyphenol is added to an aerat- ubstituted biaryl as shown by the orcinol-based com-
ed solution of DEHA ([O ] ꢀ275 mM). Then, the rate pound (7), which showed a much higher activity,
2
0
of reaction slows down because of catalyst degrada- around four-fold faster than hydroquinone and with
[
30]
tion by the hydrogen peroxide
formed during the a turnover of 213 instead of 30 under the tested con-
[31]
reaction and by the hydroxide anions from the ditions.
Thus, both the initial reaction rate This ortho-ortho’ substitution effect on the hydro-
[19a]
basic buffer.
and the turnover have to be considered to compare quinone-based biaryl would be more conformational
the effectiveness of the catalysts. The reaction rate is than electronic. Indeed, comparing the biaryls
directly related to the reactivity of the polyphenol (Figure 2, in red) consisting of 2-methylresorcinol
toward dioxygen or to its ease of regeneration, where- (13), 4-methylresorcinol (14) and 5-methylresorcinol
as the turnover reflects the robustness of the catalyst (orcinol, 7), this last one is much more active. Even if
toward degradation. Figure 2 and Table S1 (in the the methyl at the ortho’ position entails a more elec-
Supporting Information) report the reaction rate Vmax tron-donating core, the conformational effect is
as a function of the turnover for a series of biaryls. proved by the activity of the biaryl constituted of 3,5-
The values were corrected of the slow background re- dimethylphenol (33). Indeed, the compound 33 with
action between DEHA and dissolved dioxygen with- a methyl group instead of a hydroxy is a bit less elec-
out catalyst, which cannot be neglected for poorly re- tron-rich than the resorcinol-based biaryl 11 but pres-
active catalysts.
ents a much higher reaction rate. This is in agreement
The influence of the substitution of hydroquinone with the results above which show that the para-
1
by more and more electron-rich aromatics within phenol reduces the activity of the catalyst compared
the phenyl, phenol and resorcinol series was first in- to a simple phenyl group. The significant difference of
vestigated (in black). Compared to hydroquinone reactivity between the two biaryls with 2-methylresor-
itself, phenylhydroquinone 8 is less active both in cinol (13) and 4-methylresorcinol (14) might be ex-
terms of reaction rate and turnover. When a phenol plained by a more difficult rotation of the CÀO bond
group is grafted onto hydroquinone in its para-posi- of the hydroxy group at the ortho position in the case
tion (9), the reaction rate is similar to that of phenyl- of 13, which might impede the formation of intramo-
hydroquinone 8 but the turnover is lower, indicating lecular hydrogen bondings. The crucial importance of
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2
2
the C(sp )–C(sp ) biarylic linkage is shown unambigu-
ously by the catalyst 12 consisting of the two aromatic
moieties separated by three methylenes since almost
no catalytic activity was observed for this compound
at 1 mM. Three such methylene spacers have been
shown to favour the formation of charge transfer
[32]
complexes,
however, instead of the expected in-
creasing of reactivity toward dioxygen through the fa-
vouring of the semiquinone or quinone formation
(
Scheme 3), such stabilization would rather prevent
their reduction by DEHA, impeding the regeneration
of the catalysts, but not their decomposition by the
hydroxide ions of the buffer.
Since the hydroquinone-based biaryls with substi-
tuted resorcinol moities at the meta position gave the Figure 3. Consumption of dissolved dioxygen (ꢀ275 mM) by
DEHA (840 mM) in the presence of different catalysts
best results, several functional groups were then stud-
(
1 mM) in buffered water (pH 10.1, NaHCO =10 mM,
3
ied at this position in order to improve further the
catalytic activity of the resulting biaryls (see Figure 2,
in blue).
Na CO =16 mM) at 258C.
2
3
The derivatives with chlorine (15) or phenyl (16) particular, the methoxyhydroquinone-orcinol biaryl
substituents on the resorcinol part have lower turn- 23 is able to reduce almost all the dissolved dioxygen
over and reaction rates compared with the methyl (7), at concentration as low as 1 mM (Figure 3, red curve).
but are still much better than the resorcinol derivative Therefore, to allow the comparison of the catalysts,
(
11). When the phenyl group is fused to the resorcinol the concentration has been decreased to 0.1 mM
part (naphthalene core, 17), the turnover dramatically (Table 1 and Figure 4).
drops. However, when the two moities are separated
The reduction of dioxygen is not first-order depen-
by a conjugated double bond like for the biaryl con- dent in catalyst as shown by the maximum reaction
stituted with resveratrol (19), the catalytic activity is rates and the percentages of reduced dioxygen which
À1
still good, although lower than 16.
respectively decrease from 14.5 to 4.4 mMmin and
As expected, in the case of the lactonized product from 85 to 36% only when the concentration of the
(
18), the initial reaction rate is zero since the hydro- catalyst 7 decreases by ten-fold from 1 to 0.1 mM. It is
quinone part is masked. However, in basic medium, noteworthy that the turnover of the catalyst, i.e.,
the lactone slowly saponifies leading to a decrease of ([O2]initialÀ[O2]final])/[catalyst], is much higher at low
dioxygen over two hours (see the Supporting Infor- concentration, meaning that some degradation path-
mation). This can be useful to delay or trigger deoxy- ways occur when two molecules of catalyst meet each
genation through pH change.
other.
Addition of a methyl substituent on the hydroqui-
Since no noticeable improvement of the catalytic
activity was obtained by grafting different substituents none part in 7 (catalyst 20) increases by around two-
at the meta-position of the resorcinol moiety, modifi- fold the maximum reaction rate and 1.5-fold the con-
cations on the hydroquinone part were then investi- version of dioxygen. On the contrary, a phenyl sub-
gated, keeping the orcinol part. In addition to elec- stituent (21) slows down the reaction rate compared
tronic effects on the redox potential of hydroquinone,
steric effects should also play an important role re-
garding the robustness of the catalyst towards nucleo-
philic attack of the generated hydrogen peroxide. It buffered water (pH 10.1, NaHCO =10 mM, Na CO =
Table 1. Turnover and reaction rate of various catalysts for
the reduction of dissolved dioxygen by DEHA (0.84 mM) in
3
2
3
should be noted that several substituents on hydroqui- 16 mM) at 258C.
none have already been tested in a previous work and
À1
Catalysts
[Cat] (mM)
Vmax (mMmin )
Turnover
none of them was found to work better than hydro-
quinone itself, except chloro- and methoxyquinones
which exhibited higher reaction rates, counterbal-
7
7
1
14.5
4.4
7.0
5.6
5.8
0.9
20.3
7.2
0.5
213
810
0.1
0.1
0.1
0.1
0.1
0.1
1
anced however by a more rapid degradation leading 20
1250
1700
1750
1670
1990
143
[
19]
to a turnover similar to that of hydroquinone. It is 21
2
2
2
2
2
4
2
3
5
6
noteworthy that the additional orcinol core could in-
crease the reaction rate as well as the robustness of
the substituted catalysts in different ways.
Indeed, several catalysts were found to be more ef-
ficient than the hydroquinone-orcinol-based biaryl. In
1
16
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Figure 4. Consumption of dissolved dioxygen (ꢀ275 mM) by
DEHA (840 mM) in the presence of different catalysts
Scheme 13. Possible pathways for the oxidation of the semi-
quinone radical anion of a hydroquinone-resorcinol based
biaryl.
(
0.1 mM) in buffered water (pH 10.1, NaHCO =10 mM,
3
Na CO =16 mM) at 258C. Compounds 20, 21, 22 are mix-
2
3
tures of regioisomers (see Scheme 5).
the hydroquinone moiety (Scheme 13, route a) or
through the resorcinol core (Scheme 13, routes b or
to the methyl group (20) while the final conversion is c). However, the fact the reaction runs well with the
better, as well as for the catalyst having two methyl biaryl based on 3,5-dimethylphenol (33) would disfa-
substituents (24). Increasing the steric bulkiness with vour pathways b and c.
a tert-butyl substituent (22) dramatically reduces the
The kinetics of hydroquinone regeneration from
reaction rate but still maintains a very good turnover. benzoquinone by DEHA was investigated by UV
The best catalyst is finally the one with a methoxy spectroscopy comparing phenylbenzoquinone (from
substituent (23) which provides an increase of around 8) and the p-quinone corresponding to compound 7,
five-fold for the reaction rate and 2.5-fold for the con- in methanol at 258C. This latter compound is less re-
version of dioxygen compared to the hydroquinone- active than the former (see the Supporting Informa-
orcinol-based reference 7. On the contrary, a chlorine tion, S54) showing that the electron-rich substituent
substituent (25) is deleterious and the replacement of of the orcinol part impedes the reduction compared
the hydroquinone moiety by a naphthoquinone (26) to a simple phenyl ring. At this stage, this does not
almost depletes the catalytic activity.
rule out the formation of the quinone during the
The reaction of hydroquinone with dioxygen fol- mechanism of dioxygen reduction since this reaction
lows a second order kinetics in hydroxide anion at does not necessary correspond to the rate-determin-
neutral pH, meaning that the reactive form of hydro- ing step of the catalytic cycle. However, assuming that
[
33]
quinone is its dianion as shown in previous work.
the kinetics is first order in both reagents, i.e., v=
The first pK of substituted hydroquinone is between k·[Q]·[DEHA], the reaction rate constant was deter-
a
9
and 11 depending on the susbtituents, and the mined with a pseudo-first order kinetics considering
second pK is about 2 units higher. Hence, electron- that the DEHA concentration is constant at the be-
a
withdrawing groups should favour the reactivity of hy- ginning of the reaction (see Supporting Information,
droquinone towards oxidation, as shown for chlor- S54–55). The p-quinone derived from 7 is 1.6-fold less
[
34]
À1
À1
ides.
However, the stability of the resulting semi- reactive than phenylbenzoquinone (k=30M min
À1
À1
quinone should also be considered. Indeed, while the and k=46M min , respectively). In the conditions
semiquinone of the hydroquinone/quinone redox used for the dioxygen reduction with maximum 1 mM
couple does not react with dioxygen,
nating substituents should enhance its reducing power tion rates would be 0.025 and 0.041 mMmin respec-
towards dioxygen to give the quinone, or the direct tively, which are much slower than the kinetics.
abstraction of the hydrogen atom of DEHA to regen- Therefore, it is unlikely that the mechanism involves
erate the hydroquinone anion. Increasing the stability the quinone.
[
35]
electron-do- of the quinone and 840 mM of DEHA, the initial reac-
À1
of the corresponding quinone should also favour the
On the other hand, the reaction kinetics of hydro-
disproportionation of the semiquinone into quinone quinones 7 and 23 with dioxygen were compared in
and hydroquinone. Considering the structure of the the absence of DEHA. Since the reaction is very fast,
heterodimers, the stabilization of the quinone induced the reaction medium has to be cooled down to 2.58C
by the second aromatic ring can increase the oxidiza- to be monitored (see the Supporting Information,
bility of the semiquinone radical anion either through S56). Comparing the initial reaction rates, the reac-
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tion runs 3.7-fold faster with compound 23 compared toward dioxygen of 23 compared to 7, the same rea-
to 7. This kinetic ratio is a bit lower than the one ob- soning cannot be applied between 7 and phenylhydro-
served in the presence of DEHA at 258C (4.6 vs. 3.7, quinone. Such an absence of correlation between re-
see Table 1), meaning that the rate-limiting step activity toward dioxygen and oxidation potential has
[
11]
would rather imply DEHA, probably for the reduc- already been discussed in the literature.
tion of the generated semiquinone anion. Actually, the chemical reduction of dioxygen does
The impact of both the orcinol moiety and a me- not proceed like the transfer of an electron to an elec-
[37]
thoxy substituent on the oxidizability of the hydroqui- trode surface. Valgimigli, Pratt and co-workers cal-
none core was investigated using cyclic voltammetry culated that under neutral conditions, dioxygen would
[
36]
in DMF under neutral conditions (Figure 5).
The react on the semiquinone radical through an addi-
catalyst 7 was first compared to phenylhydroquinone tion–elimination mechanism (Scheme 14) rather than
which presents a closer structure than hydroquinone, a direct hydrogen atom transfer. Intramolecular hy-
then to the more active catalyst 23.
drogen bond would in this case prevent the rupture of
the CÀO bond. Another mechanism was proposed by
Tatikolov between dioxygen complexed to an anthra-
semiquinone radical through a cyclic transition state
[
38]
(
Scheme 14).
Figure 5. Cyclic voltammetries in DMF with tetrabutylam-
À1
monium tetrafluoroborate (100 mM), 100 mVs , without
compounds (black), and with phenylhydroquinone
8
(
green), 7 (blue), 23 (red) at 1 mM. Working electrode:
glassy carbon, auxiliary electrode: platinum electrode, refer-
ence electrode: saturated calomel, under argon, at 258C,
five cycles.
Scheme 14. Proposed mechanisms for the dioxygen reduc-
[37,38]
tion by semiquinone radicals in the literature.
Under these conditions, phenylhydroquinone
(
green curve) presents one oxidation wave which can
be reduced in a reversible way. When the phenyl
Since the pK of the semiquinone anion is estimat-
a
group is replaced by orcinol (7), a second oxidation ed around 4.1 and the reactions were performed in
wave appears around 1.3 V (red curve) which is at- buffered solution at pH 10.1, the reactivity of the
tributed to the oxidation of the electron-rich orcinol semiquinone radical anion has to be considered. It
part. Indeed, at higher concentration (10 mM) and can be expected that the phenol at the ortho-position
À1
slower scan (50 mVs ) the system becomes irreversi- would form intramolecular hydrogen bonds on the hy-
ble as shown by the decreasing of the oxidation sig- droquinone radical anion generated after a first re-
nals as the number of cycle increases (see the Sup- duction of the dioxygen (Scheme 15, product A).
porting Information, S57). In this case, if the oxida- Then, several pathways are conceivable. The semiqui-
tion is stopped at 1.2 V after the first oxidation wave, none can react with dioxygen (path a) to give the
a thin layer having a red colouration appeared on the adduct B according to Valgimigli et al. However, in
working electrode, showing the formation of the cor- this case, the intramolecular hydrogen bond would
responding quinone, and the system becomes reversi- impede the elimination of the superoxide anion (path
ble again.
b), making the formation of the quinone unlikely, in
Catalyst 23 exhibits a similar voltamperogram as 7, agreement to the kinetic experiments discussed
except that the oxidation of the hydroquinone part above. The regeneration of the semiquinone anion
occurs earlier (Vox(max)/calomel =0.64 mV vs. 0.77). may then rather be done by the reaction of B with
Whereas this would explain the higher reactivity DEHA through the fragmentation of the intermedi-
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have received little attention until now. In this work,
several such structures have been synthesized in
a single step by addition of phenol or resorcinol on
benzoquinone under basic or acidic conditions. A
structure–activity relationship study was performed to
determine the minimal active structure causing the
dramatic effect on the catalytic reduction of dioxygen
by diethylhydroxylamine observed with the biaryl
consisting of hydroquinone-orcinol. The presence of
a phenol function at the ortho-position of the biarylic
linkage dramatically increases the catalytic activity
compared to that of hydroquinone, only when
a second substituent is present at the other ortho-posi-
tion. On the contrary, when the two aromatic cores
are separated by an alkyl chain, the catalytic activity
considerably decreases. The increase of the reactivity
cannot be correlated to the oxidation potential since
the same anodic waves are observed for phenylhydro-
quinone and the biaryl consisting of the hydroqui-
none-orcinol couple. This is rather ascribed to the re-
activity of the semiquinone anion generated after
a first electron transfer to dioxygen. The intramolecu-
lar hydrogen bond would stabilize the semiquinone
anion to favour either its reduction with DEHA, or
the direct addition of dioxygen which would be fur-
ther reduced by DEHA then eliminate.
Among these structures, the biaryl constituted by
a methoxyhydroquinone and orcinol core was found
as a highly active dioxygen scavenger. In complement
to these redox properties, the antioxidant activity of
this polyphenol series as radical chain reaction inhibi-
tors will be reported in due course.
Scheme 15. Proposed mechanism for dioxygen reduction by
a semiquinone radical anion in case of ortho-hydroxy sub-
stituent on hydroquinone-based biaryls.
ary E. Alternatively, the direct reduction of A by
DEHA (path d) would generate the hydroquinone for Experimental Section
further reaction with dioxygen.
The higher catalytic activity observed when All the synthesis and data characterizations of the com-
pounds are detailed in the Supporting Information, with the
curves of the catalytic consumption of dioxygen in their
presence.
a second substituent is present at the ortho’-position
may be explained by conformational considerations.
Indeed, the atropoisomerism would be more pro-
nounced to favour the intramolecular hydrogen bond
Kinetics of the Catalytic Reduction of Dioxygen by
DEHA
and also to prevent the nucleophilic attack on the hy-
droquinone to avoid the degradation of the catalyst,
maintaining a good turnover. On the other hand,
larger substituents would slow down the dioxygen
Dioxygen concentration was monitored by luminescence ex-
tinction using an LDO-Hach HQ30 apparatus. Water was
attack for steric reasons. The presence of the methoxy purified by Milliporeꢄ Simplicity 185 and collected at the
substituent on the hydroquinone core would rather resistivity of 18.2 MW·cm.
favour the path d, that would explain the higher cata-
lytic activity of the corresponding product.
A 250-mL Erlenmeyer flask equipped with a magnetic
stirrer was filled with 285 mL of a buffered solution of
sodium hydrogen carbonate (10 mM) and sodium carbonate
(
16 mM) and thermostatted at 258C using a water bath. The
probe going through a septum closed the Erlenmeyer such
a manner that a minimum of air was remaining. The amount
of dissolved dioxygen was adjusted to nearly 0.28 mM by
bubbling dioxygen or argon, then diethylhydroxylamine
Conclusions
In spite of extensive research on polyphenols and
biarylic structures through organometallic cross-cou-
(
23 mL, 0.84 mM) was introduced. After a few minutes of
À1
pling catalysis, the simple structures constituted by hy- stirring, the catalyst diluted in ethanol (1 mgmL for 1 mM
droquinone and another phenolic or resorcinolic core concentrations) was added.
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Acknowledgements
M. A. T. Rogers, G. Trappe, J. Chem. Soc. 1956, 1093–
103.
1
Chevreul Institute (FR 2638), Ministꢀre de l’Enseignement
Supꢁrieur et de la Recherche, Rꢁgion Hauts-de-France and
FEDER are acknowledged for supporting and partially fund-
ing this work. Mike Howsam and Mostafa Kouach are kindly
acknowledged for the mass analysis.
[18] a) R. Lebeuf, Y. Zhu, V. Nardello-Rataj, J.-P. Lallier, J.-
M. Aubry, Green Chem. 2012, 14, 825–831; b) R.
Lebeuf, V. Nardello-Rataj, J.-M. Aubry, Top. Catal.
2013, 56, 933–938.
[19] R. Lebeuf, V. Nardello-Rataj, J.-M. Aubry, Chem.
Commun. 2014, 50, 866–868.
[
20] R. Pummerer, G. Huppmann, Ber. Dtsch. Chem. Ges. B
927, 60, 1442–1451.
1
References
[
[
21] N. E. Stjernstrom, Ark. Kemi 1963, 6, 57–63.
22] P. Kuser, M. Inderbitzin, J. Brauchli, C. H. Eugster,
Helv. Chim. Acta 1971, 54, 980–995.
[1] S. Patai, Chemistry of the Quinonoid Compounds,
Wiley, 2010.
[
[
23] H. Musso, U. v. Gizycki, U. I. Zahorszky, D. Bormann,
[2] a) A. Brunmark, E. Cadenas, Free Radical Biol. Med.
Justus Liebigs Ann. Chem. 1964, 676, 10–20.
1
989, 7, 435–477; b) H. Nohl, W. Jordan, R. J. Young-
24] M. V. Gomez, A. Moreno, E. Vazquez, A. de La Hoz,
A. I. Aranda, A. Diaz-Ortiz, ARKIVOC (Gainesville,
FL, U.S.) 2010, 264–273.
man, Adv. Free Radical Biol. Med. 1986, 2, 211–279.
3] P. J. OꢅBrien, Chem.-Biol. Interact. 1991, 80, 1–41.
4] V. Roginsky, T. Barsukova, D. Loshadkin, E. Pliss,
Chem. Phys. Lipids 2003, 125, 49–58.
[
[
[
25] a) S.-L. Zhang, Z.-S. Huang, Y.-D. Shen, Y.-M. Li, J.-H.
Yao, M. Huang, A. S. C. Chan, L.-Q. Gu, Tetrahedron
Lett. 2006, 47, 6757–6760; b) U. M. Wagh, R. N. Us-
gaonkar, Indian J. Chem. Sect. B 1976, 14B, 861–863;
c) T. J. King, C. E. Newall, J. Chem. Soc. 1965, 974–977;
d) J. H. Wood, C. S. Colburn Jr, L. Cox, H. C. Garland,
J. Am. Chem. Soc. 1944, 66, 1540–1542.
[5] D. Loshadkin, V. Roginsky, E. Pliss, Int. J. Chem. Kinet.
2
002, 34, 162–171.
[
6] a) A. Niesbach, J. Daniels, B. Schrçter, P. Lutze, A.
Gꢃrak, Chem. Eng. Sci. 2013, 88, 95–107; b) N. N. Poz-
deeva, E. T. Denisov, Kinet. Catal. 2011, 52, 506–512;
c) H. Becker, H. Vogel, Chem. Eng. Technol. 2004, 27,
[
[
[
26] A. G. Osborne, S. J. Andrews, R. Mower, J. Chem. Res.
1
122–1126.
2
003, 114–115.
[
[
[
7] T. Nishimi, T. Kamachi, K. Kato, T. Kato, K. Yoshiza-
wa, Eur. J. Org. Chem. 2011, 4113–4120.
8] N. Decharin, S. S. Stahl, J. Am. Chem. Soc. 2011, 133,
27] H. Dressler, Resorcinol: Its Uses and Derivatives,
Springer, USA, 2013.
28] a) P. Brassard, P. L’Ecuyer, Can. J. Chem. 1958, 36,
5
732–5735.
9] a) X. Xie, E. Bakker, J. Am. Chem. Soc. 2014, 136,
857–7860; b) W. Huang, Z. Zhu, L. Wang, S. Wang, H.
Li, Z. Tao, J. Shi, L. Guan, J. Chen, Angew. Chem.
7
00–708; b) A. A. Matnishyan, ꢆ. V. Prut, G. V. Fomin,
7
B. I. Liogon’kii, A. A. Berlin, Russ. Chem. Bull.
(Transl. of Izv. Akad. Nauk, Ser. Khim.) 1972, 21,
1961–1965.
2
9
013, 125, 9332–9336; Angew. Chem. Int. Ed. 2013, 52,
162–9166; c) B. Rausch, M. D. Symes, L. Cronin, J.
[29] N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishikawa, M.
Sato, A. Suzuki, J. Am. Chem. Soc. 1989, 111, 314–321.
[30] J. F. Corbett, J. Chem. Soc. C 1966, 24, 2308–2311.
[31] S. Fukuzumi, T. Yorisue, J. Am. Chem. Soc. 1991, 113,
7764–7765.
Am. Chem. Soc. 2013, 135, 13656–13659; d) B. Huskin-
son, S. Nawar, M. R. Gerhardt, M. Aziz, ECS Trans.
2
013, 53, 101–105.
[
10] a) S. Renault, S. Gottis, A.-L. Barres, M. Courty, O.
Chauvet, F. Dolhem, P. Poizot, Energy Environ. Sci.
[32] I. Richter, J. Minari, P. Axe, J. P. Lowe, T. D. James, K.
Sakurai, S. D. Bull, J. S. Fossey, Chem. Commun. 2008,
1082–1084.
[33] A. Weissberger, D. S. Thomas Jr, J. E. Lu Valle, J. Am.
Chem. Soc. 1943, 65, 1489–1495.
[34] Y. Song, B. A. Wagner, J. R. Witmer, H.-J. Lehmier,
G. R. Buettner, Proc. Natl. Acad. Sci. USA 2009, 106,
9725–9730.
2
013, 6, 2124–2133; b) S. Wang, L. Wang, K. Zhang, Z.
Zhu, Z. Tao, J. Chen, Nano Lett. 2013, 13, 4404–4409.
11] a) V. Roginsky, T. Barsukova, J. Chem. Soc. Perkin
Trans. 2 2000, 1575–1582; b) Y. Song, G. R. Buettner,
Free Radical Biol. Med. 2010, 49, 919–962.
12] Oxygen Scavengers in Steam Generating Systems and in
Oil Production, NACE International – The Corrosion
Society, 1994.
13] T. Friedrich, J. Bioenerg. Biomembr. 2014, 46, 255–268.
14] a) P. P. Pande, Asian J. Chem. 2010, 22, 2549–2553;
b) A. F. Barrero, E. J. Alvarez-Manzaneda, R. Chah-
boun, R. Meneses, Synlett 1999, 1663–1666.
[
[
[35] K. B. Patel, R. L. Willson, J. Chem. Soc. Faraday Trans.
[
[
1 1973, 69, 814–825.
[36] a) R. C. Prince, P. L. Dutton, J. M. Bruce, FEBS Lett.
1983, 160, 273–276; b) I. Gonzalez, C. Frontana, M.
Gomez, M. Aguilar, J. A. Bautista, N. A. Macias, M.
Salas, P. D. Astudillo, F. J. Gonzalez, ECS Trans. 2007,
3, 25–36.
[
15] a) J. E. LuValle, J. Am. Chem. Soc. 1952, 74, 2970–
2
977; b) P. A. Clapp, D. F. Evans, WO Patent
WO9302961, 1993.
16] S. Fujita, K. Sano, J. Org. Chem. 1979, 44, 2647–2651.
17] a) D. Shaffer, J. Heicklen, J. Phys. Chem. 1986, 90,
[37] L. Valgimigli, R. Amorati, M. G. Fumo, G. A. DiLabio,
G. F. Pedulli, K. U. Ingold, D. A. Pratt, J. Org. Chem.
2008, 73, 1830–1841.
[
[
4
408–4413; b) T. Caceres, E. A. Lissi, E. Sanhueza, Int.
[38] A. S. Tatikolov, Russ. Chem. Bull. (Transl. of Izv. Akad.
J. Chem. Kinet. 1978, 10, 1167–1182; c) D. H. Johnson,
Nauk, Ser. Khim.) 1997, 46, 1082–1088.
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2 Hydroquinone-Based Biarylic Polyphenols as Redox
Organocatalysts for Dioxygen Reduction: Dramatic Effect
of Orcinol Substituent on the Catalytic Activity
Adv. Synth. Catal. 2017, 359, 1 – 12
Raphaꢀl Lebeuf, Vꢁronique Nardello-Rataj,
Jean-Marie Aubry*
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