Organoiridium-quinone conjugates for facile hydrogen peroxide generation

Article abstract of DOI:10.1039/d0cc04970k

An organoiridium complex bearing a quinone moiety was shown to significantly accelerate the rate of H2O2 formation in the presence of air and sodium formate at low catalyst concentrations. This reaction is proposed to operate through a synergistic mechanism involving transfer hydrogenation catalysis and radical chemistry. Our bifunctional iridium complex could potentially be used in anti-cancer chemotherapy or other applications requiring rapid generation of reactive oxygen species. This journal is

Full text of DOI:10.1039/d0cc04970k

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S. J. Connon, M. O. Senge et al.
Conformational control of nonplanar free base porphyrins:
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Organoiridium-Quinone Conjugates for Facile Hydrogen Peroxide
Generation
Received 00th January 20xx,
Accepted 00th January 20xx
Huong T. H. Nguyen, Loi H. Do*
DOI: 10.1039/x0xx00000x
An organoiridium complex bearing a quinone moiety was shown <50 µM), which is typically recommended for cell studies to
to significantly accelerate the rate of H formation in the minimize possible metal toxicity, the iridium and Q1 species
2 2
O
presence of air and sodium formate at low catalyst have a low probability of reacting with one another because
concentrations. This reaction is proposed to operate through a they could be distributed to different cellular locations. To
synergistic mechanism involving transfer hydrogenation catalysis circumvent this potential problem, we propose that the
and radical chemistry. Our bifunctional iridium complex could organoiridium complex be covalently tethered to a quinone
potentially be used in anti-cancer chemotherapy or other group to promote intramolecular reactivity. The benefits of
applications requiring rapid generation of reactive oxygen species. this bifunctional catalyst design are that both iridium-hydride
and hydroquinone units formed during reactions with NADH
Reactive oxygen species (ROS), such as peroxide, superoxide,
and hydroxyl radical, play critical roles in essential biochemical
functions as well as pathological processes. Strategies
2 2 2
are capable of reducing O to H O and oxidized quinone could
be continuously regenerated regardless of catalyst
concentration. This strategy of incorporating redox active
moieties into transition metal complexes has been shown to
1
exploiting ROS to selectively kill cancer cells have shown
2
clinical promise. They include the use of agents to increase
5,6
be highly effective for a variety of catalytic applications.
endogenous ROS, inhibit natural antioxidant enzymes, or
deplete glutathione concentrations. Although synthetic Scheme 1. Hydrogen peroxide formation achieved by transfer hydrogenation
catalysis.
compounds that induce ROS can operate by distinct
OH
mechanisms, achieving high efficiency and selectivity are still
major challenges. A recent advance in ROS generating agents is
the discovery by Sadler and co-workers that half-sandwich
OMe
OMe
O2
[Ir]
H O2
2
OH
Q2
organoiridium complexes could catalyse the formation of
NADH
O
+
2
hydrogen peroxide from O , H , and reduced nicotinamide
OMe
adenine dinucleotide (NADH) via a transfer hydrogenation
mechanism (Scheme 1). These Ir compounds were
OMe
H O
O /H
2
+
2
2
O
[Ir-H]
3
Q1
demonstrated to have more potent anti-cancer activity than
the well-known drug cisplatin in some cell lines. Later in 2016,
Suenobu, Fukuzumi, and co-worker showed that 2,3-
Suenobu/Fukuzumi, 2016
Sadler, 2014
To test the feasibility of our bifunctional catalyst concept,
we devised a novel molecular construct by attaching the
dimethoxy-6-methyl-1,4-benzoquinone
(Q1)
and
organoiridium compounds react with NADH and O
H O in a tandem catalytic process.
2 2
2
to produce
ubiquinone
mimic
Q1
to
(Ir1,
[Cp*Ir(N-
Cp*
4
phenylpyridinecarboxamidate)Cl]
pentamethylcyclopentadienyl anion). Complex Ir1 was found
in our previous work to be an active transfer hydrogenation
catalyst under biologically relevant conditions and inside
cells. The Q1 group was tethered to Ir1 using either an ether
or alkyl linker to give complexes Ir2 and Ir3a, respectively
=
The iridium/Q1 example above is particularly intriguing
because the coupling of transfer hydrogenation with
autocatalytic O
2
reduction could significantly boost H
2
O
2
7,8
formation.4 However, a possible concern with this dual
component system is that at low catalyst concentrations (e.g.,
9
(Chart 1). The detailed syntheses of these iridium-quinone
conjugates are provided in the Electronic Supplementary
Information (Schemes S1-S2). The final iridium complexes
were obtained in analytically pure form and characterized by
various spectroscopic and mass spectrometric methods. Single
Department of Chemistry, University of Houston, 4800 Calhoun Road, Houston, TX
7
7204
Electronic Supplementary Information (ESI) available: synthesis and
characterization, procedures, spectral data. See DOI: 10.1039/x0xx00000x
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Journal Name
crystals of Ir3a were grown from acetone/pentane and One possibility is that Ir3a coordinates to VieewacAhrticleoOtnhliener
analysed by X-ray diffraction. The molecular structure of Ir3a intermolecularly to give a mixture oDfOI:m10o.1n0o3m9/Det0aClClic049a7n0dK
showed the expected piano-stool motif, in which the iridium multimetallic species. However, further studies are needed to
centre was coordinated by a Cp* ring, two nitrogen donors determine the nuclearity of Ir3a in solution.
from ligand 8, and a chloride (Figure S38).
O
O
Ir Cl
N
OMe
OMe
Ir
H
OMe
OMe
O
O
NaHCOO
air
N
N
Ir Cl
N
Ir Cl
N
OMe
OMe
N
N
N
Ir1
Ir2
O
O
O
O
O
O
O
Ir3a
Ir3b
+
O
O
OMe
Ir Cl
N
OMe
OMe
N
Ir3a
R= H, Q1
Me, Q2
OH
OH
OH
OH
R
OMe
Ir
H
OMe NaHCOO
OMe
Ir Cl
N
OMe
OMe
O
N
N
O
O
N
Chart 1. Design of organoiridium-quinone conjugates.
O
O
Ir3c
Ir3d
Scheme 2. Reaction of Ir3a with NaHCOO in CD
3
OD studied by variable
temperature NMR spectroscopy.
Ir1
Q1
Ir3a (
methoxy
)
Ir3b (
)
Ir3c (
)
Ir3d (
methyl
(quinone)
)
methyl
(Cp*) hydride
methylene
Ir1/Q1
A) -35 °C, start
B) -20 °C
Ir3a
0.5 0.1 -0.3 -0.7 -1.1 -1.5
C) 0 °C
Potential (V, vs. NHE)
Figure 1. Cyclic voltammograms of iridium complexes (1.0 mM) and quinone (0.5
mM) recorded at 0.1 V/s in 0.1 M phosphate buffer saline (PBS). All potentials
are referenced to NHE.
D) 10 °C
E) 15 °C
The redox behaviour of the iridium complexes was
measured in phosphate buffered saline (PBS) by cyclic
voltammetry (Figure 1 and S1). Complex Ir1 displayed an
irreversible reduction wave at -0.96 V and oxidation waves at -
F) final + xs NaHCOO, RT
G) final + air, RT
0
.88 (weak) and 0.19 V vs. NHE, similar to those reported in
8
our previous work. Compound Q1 exhibited a reduction peak
at -0.13 V and oxidation peak at 0.22 V. The combined Ir1 and
Q1 (1:1) sample showed cathodic processes occurring at -0.86
and -0.15 V. Surprisingly, the former peak shifted from that of
4.0 3.8
2.9 2.7 2.5 2.3 2.1 1.9
1.5
-1 1.4
δ (ppm)
1
Ir1 by about +0.10 V. Studies by H NMR spectroscopy suggest
1
that this shift in reduction potential is not due to coordination Figure 2. H NMR spectra (CD
interaction between Q1 with the iridium complex (Figure S12). -35 °C (part A) and then allowed to warm up to -20 (B), 0 (C), 10 (D), and 15 (E)
3
OD, 600 MHz) of the reaction of Ir3a (5 mM) with
NaHCOO (10 mM) studied at variable temperature. The reactants were mixed at
°
C. The final sample was either treated with excess NaHCOO (F) or exposed to air
Even upon chloride abstraction by treating Ir1 with AgOTf in (G) overnight.
8
CD
3
OD/D
2
O (4:1), the resulting iridium-solvato species does
not appear to bind quinone. We hypothesize that perhaps
weak outer sphere interactions (e.g., halogen bonding )
To establish whether our iridium-quinone conjugates are
competent transfer hydrogenation catalysts, we first evaluated
1
0
between Ir1 and Q1 might be responsible for the Ir-centered their reactions with sodium formate. Because both NADH and
redox potential change.
NaHCOO hydride sources are compatible with organoiridium
7
1
The CV of Ir3a displayed reduction peaks at -1.10, -0.89, complexes, we used the latter because it does not have H
and -0.32 V and oxidation peaks at -0.87 (weak) and 0.25 V NMR peaks that overlap in the spectral regions of interest.
(
6
Figure 1 and S1). The cathodic process at -0.32 V was When a 5 mM solution of Ir2 in acetone-d was combined with
attributed to reduction of the quinone ring. This potential is 5.0 equiv. of NaHCOO in air, complete catalyst decomposition
similar to that observed in the CV of Q2 (Ered= -0.26 V, Figure was observed within 16 h, most likely due to oxidative
S2), which is expected given that Q2 has a 5-methyl group cleavage of its benzyl ether bond by the hydrogen peroxide
analogous to the alkyl chain attached to the quinone ring in generated (Figure S9). In contrast, no catalyst decomposition
Ir3a. We presume that the peaks at -1.10 and -0.89 V occurred using Ir3a under similar reaction conditions.
correspond to iridium-based reductions but are uncertain why
Because of its greater chemical stability, Ir3a was subjected
there are two peaks in this region since Ir1 showed only one. to more detailed reaction studies. At RT, reaction of Ir3a with
2
| J. Name., 2012, 00, 1-3
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excess NaHCOO led to quantitative conversion to the reduced
hydroquinone product within ~5 min (Scheme 2). To follow the sensitivity for our studies. Using this semi-quantitative
reaction in situ, variable temperature NMR spectroscopic detection method combined with ImageJ software analysis, we
measurements were performed (Figure 2). When Ir3a and measured the hydrogen peroxide concentration from
NaHCOO (1:2) were combined at -35 °C under nitrogen, only reactions of either Ir3a or Ir1/Q1 (1:1) with 20 equiv. of
COMMUNICATION
2 2
H O test strips provided fast response time and adequate
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DOI: 10.1039/D0CC04970K
3
2
peaks corresponding to the starting iridium complex and NaHCOO in H O/DMSO (99:1) under air (Figure S4 and S5). At
NaHCOO were present, suggesting no reaction had taken lower catalyst concentrations (Figure 3, top/middle), Ir3a gave
place. Upon warming to -20 °C, a distinct signal at more hydrogen peroxide and at a faster rate than Ir1/Q1. For
-
11.29 ppm appeared, which is characteristic of an iridium- example, after 5 h, Ir3a produced 2.4-fold (33 vs. 14 µM) and
7
,8
hydride species. This intermediate is proposed to be the 4.9-fold (78 vs. 16 µM) more H
iridium-hydride/quinone complex Ir3b formed from concentrations of 15 and 30 µM, respectively. Similar results
decarboxylation of NaHCOO by the Ir centre. When the were obtained when comparing the H forming ability of
2 2
O than Ir1/Q1 at catalyst
2 2
O
reaction mixture was increased to 0 °C, the formation of two Ir3a vs. Ir1/Q2 (Figure S6) at 30 µM catalyst concentration,
additional species was apparent. Their identities were suggesting that slight differences in the quinone redox
determined to be the iridium-chloride/hydroquinone (Ir3c) potential do not account for the faster rate observed in the
and iridium-hydride/hydroquinone (Ir3d) species based on former. Interestingly, when the amount of catalyst was
comparison with the NMR spectra obtained from increased to 50 µM, the opposite trend was observed (Figure
independently prepared samples (see ESI). Complex Ir3c can 3, bottom). After 1 h, Ir1/Q1 gave a 5.7-fold increase in H
be formed spontaneously from Ir3b as a result of either compared to that by Ir3a (85 vs. 15 µM, respectively). Reaction
intermolecular or intramolecular hydride transfer between Ir– of Ir1 with NaHCOO provided less H than that using either
Subsequent conversion to Ir3a or Ir1/Q1 (Figure S5), indicating that the presence of
Ir3d could then proceed by reaction of Ir3c with another quinone had a beneficial effect. As a control, combining Q1
equivalence of formate. Surprisingly, when the NMR sample with NaHCOO in the absence of iridium gave no H
was warmed from 10 to 15 °C, the amount of Ir3d decreased The catalytic efficiency of Ir3a was determined by
whereas the amount of Ir3c increased (cf. spectrum D vs. E in measuring its turnover number (TON). Because quantifying the
Figure 2). However, to establish that Ir3d is the most reduced total amount of H produced was problematic due to its
2 2
O
2 2
O
1
1,12
H and quinone functionalities.
2 2
O .
2 2
O
product, addition of excess NaHCOO to the 15 °C sample gave subsequent reactivity with Ir (vide infra), changes in NaHCOO
quantitative amounts of Ir3d (spectrum F). We found that ~4 concentration was monitored instead. We observed that
equiv. of NaHCOO is required for complete conversation of reaction of NaHCOO (20 µmol) with Ir3a (0.5 µmol) was
Ir3a to Ir3d (Figure S11). Since this reaction should only need complete after 21 h (Figure S14) and gave a TON = 40, which
two reducing equivalents rather than four, these results suggests that our iridium-quinone complex is indeed catalytic.
suggest that perhaps the Ir-H units could decay via reaction
NaHCOO NaCl/CO
2
O
O
Ir
N
H
1
3,14
Ir Cl
N
O
with solvent or other proton sources to produce H
2
.
Finally,
N
N
+
O /H
when the 15 °C sample was exposed to air overnight, the
2
2
H O2
O
O
O
starting Ir3a complex was regenerated (spectrum G, Figure 2).
Ir3a
H O2
Ir3b
2
2
H O
2 2
-
+
3
2
0
0
Ir3a (15 µM)
Ir1/Q1 (15 µM)
Cl /H
+
2
O /H
2
O2
10
OH
OH
OH
OH
Ir
H
Ir Cl
N
O
0
6
4
N
NaCl/CO2
NaHCOO
N
Ir3a (30 µM)
Ir1/Q1 (30 µM)
N
0
0
O
Ir3d
O /H
+
20
2
H O2
2
Ir3c
0
0
Ir3a (50 µM)
Ir1/Q1 (50 µM)
8
Scheme 3. Possible intramolecular pathways to produce H
of Ir3a with NaHCOO. Intermolecular reactions are also possible but less likely at
low catalyst concentrations. Reaction of hydroquinone with O could generate
hydrogen peroxide autocatalytically. Structures drawn in simplified form.
2 2
O from the reaction
40
2
0
0
5
10
15
20
25
Time (h)
2 2
The plots in Figure 3 revealed that H O growth was
accompanied by subsequent decay, which suggests that the
hydrogen peroxide produced may be reacting with one of the
reaction components. We observed that when excess H O
2 2
Figure 3. Formation of hydrogen peroxide from reaction of either Ir3a or Ir1/Q1
in O/DMSO (99:1) with 20 equiv. of NaHCOO at various catalyst
concentrations. The data shown are representative plots. The absolute H
concentrations can vary between repeat experiments due to limitations of the
image-based H quantification method but the relative trends are consistent.
H
2
2 2
O
2 2
O
was mixed with 30 µM of Ir1 or Ir3a, the hydrogen peroxide
concentration gradually decreased over time. In contrast,
Next, the hydrogen peroxide formation efficiency was
compared between the tethered vs. untethered iridium-
quinone catalysts. Although a variety of H O quantification
2 2
control solutions containing H
significant change in hydrogen peroxide levels over 22 h.
Characterization of the H -treated iridium complexes by
2 2 2 2
O only or Q1/H O showed no
2 2
O
methods have been reported, some used reagents that are not
readily available,1
have insufficient detection range. We found that commercial
5,16
17,18
both NMR (Figure S13) and UV-vis absorption spectroscopy
showed significant catalyst decomposition, suggesting that Ir1
incompatible with hydroquinone,
or
1
9
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Journal Name
and Ir3a are susceptible to oxidative damage in the presence iridium complexes23 with quinones could take aVdiewvaAnrtitcalegOenlionef
of excess hydrogen peroxide over an extended period. synergistic reactivity to maximize theirDOthI:e10ra.1p0e39u/tDic0CbCe0n4e97fi0tKs
Attempts to determine the identity of the decomposed Ir even in low-doses.
species were unsuccessful.
To confirm that H
This work was supported by the Welch Foundation (Grant
is responsible for catalyst decay, we No. E-1894) and NIH (Grant No. R01GM129276).
2
O
2
monitored the reaction of Ir3a with NaHCOO in the presence
of propyl sulfide as an antioxidant (Figure S15). After 18 h, our
Conflicts of interest
There are no conflicts to declare.
NMR spectra showed that the sample containing nPr
contained significant amounts of Ir3a whereas the sample
without nPr S had nearly no detectable amounts of Ir3a
present. We verified that nPr S did not inhibit the Ir catalyst
activity so its role was primarily an H scavenger.
2
S still
2
2
O
2 2
Notes and references
We propose that the iridium-quinone and NaHCOO
reactions operate by several competing pathways. In our
tethered Ir3a catalyst, H O could form from reaction of O
2 2 2
(
1
1) Nidhi, K.; Julia, C.; Ryan, J. M. Biol. Chem. 2017, 398, 1209-
227.
with Ir3b, Ir3c or Ir3d (Scheme 3). Because the iridium and (2) Trachootham, D.; Alexandre, J.; Huang, P. Nat. Rev. Drug
quinone units are covalently linked, the rate of intramolecular Discov. 2009, 8, 579-591.
hydride transfer to reactivate the quinone unit (i.e., Ir3b  (3)
Ir3c) is independent of catalyst concentration. Intermolecular
reactions between the Ir3a-Ir3d species are also possible but
Liu, Z.; Romero-Canelón, I.; Qamar, B.; Hearn, J. M.;
Habtemariam, A.; Barry, N. P.; Pizarro, A. M.; Clarkson, G. J.; Sadler,
P. J. Angew. Chem. Int. Ed. 2014, 53, 3941-3946.
4) Suenobu, T.; Shibata, S.; Fukuzumi, S. Inorg. Chem. 2016, 55,
747-7754.
(
less likely to occur at lower catalyst concentrations. In the
7
untethered Ir1/Q1 system, similar reaction pathways are
(
5) Kajetanowicz, A.; Milewski, M.; Rogińska, J.; Gajda, R.; Woźniak,
K. Eur. J. Org. Chem. 2017, 626-638.
potentially accessible. However, the key difference is that
hydride transfer from Ir1-hydride to Q1 is a bimolecular
(
6)
Kubanik, M.; Lam, N. Y. S.; Holtkamp, H. U.; Söhnel, T.;
1
1,12
reaction and thus, this step is concentration dependent.
high catalyst concentrations, we propose that the above
transfer hydrogenation process to generate H
important than the autocatalytic reaction between (8) Ngo, A. H.; Do, L. H. Inorg. Chem. Front. 2020, 7, 583-591.
hydroquinone and O
. In fact, studies by Suenobu/Fukuzumi (9) Bose, S.; Ngo, A. H.; Do, L. H. J. Am. Chem. Soc. 2017, 139,
792-8795.
At
Anderson, R. F.; Jamieson, S. M. F.; Hartinger, C. G. Chem. Commun.
2
018, 54, 992-995.
2 2
O
is less (7) Ngo, A. H.; Ibañez, M.; Do, L. H. ACS Catal. 2016, 6, 2637-2641.
2
8
and co-workers showed the rate of H
10) Mandal, K.; Bansal, D.; Kumar, Y.; Rustam; Shukla, J.;
Mukhopadhyay, P. Chem. Eur. J. 2020, 26, 10607-10619.
11) Liu, Z.; Deeth, R. J.; Butler, J. S.; Habtemariam, A.; Newton, M.
E.; Sadler, P. J. Angew. Chem. Int. Ed. 2013, 52, 4194-4197.
12) Komatsu, H.; Shindo, Y.; Oka, K.; Hill, J. P.; Ariga, K. Angew.
Chem. Int. Ed. 2014, 53, 3993-3995.
13) Maenaka, Y.; Suenobu, T.; Fukuzumi, S. J. Am. Chem. Soc.
012, 134, 9417-9427.
(14) Maenaka, Y.; Suenobu, T.; Fukuzumi, S. J. Am. Chem. Soc.
2 2
O formation was
(
dependent only on the concentrations of Q1 and O
iridium or NADH (when [Q1] > [Ir]). They established that
reaction of hydroquinone and O followed a sigmoidal curve,
2
2
and not
4
(
which is indicative of autocatalysis. Our observation that Ir3a is
more efficient at low concentration whereas Ir1/Q1 is more
efficient at high concentration is consistent with a switch in
major vs. minor reaction pathways. More detailed kinetic
studies, however, are needed to interrogate this hypothesis.
(
(
2
In summary, we showed for the first time that 2012, 134, 367-374.
organoiridium-quinone conjugates are more efficient H
(15) Matsubara, C.; Kawamoto, N.; Takamura, K. Analyst 1992,
17, 1781-1784.
16) Dickinson, B. C.; Huynh, C.; Chang, C. J. J. Am. Chem. Soc.
010, 132, 5906–5915.
17) Gay, C.; Collins, J.; Gebicki, J. M. Anal. Biochem. 1999, 273,
49-155.
18) Baga, A. N.; Johnson, G. R. A.; Nazhat, N. B.; Saadalla-Nazhat,
R. A. Anal. Chim. Acta. 1988, 204, 349-353.
19) Onoda, M.; Uchiyama, T.; Mawatari, K.-i.; Kaneko, K.;
2 2
O -
1
generating catalysts than iridium and quinone tandem
catalysts at low concentrations (<50 µM). We expect that
inside living cells, the hydrogen peroxide produced by Ir3a
would likely be scavenged by reactive biomolecules such as
glutathione before having the opportunity to degrade the
catalyst as observed in the reaction flask. Although we were
(
2
(
1
(
2 2
able to achieve up to ~4.9-fold increase in H O formation
(
using Ir3a, we anticipate that further optimization of the Nakagomi, K. Anal. Sci. 2006, 22, 815-817.
iridium-quinone construct could lead to even greater rate (20) Shibata, S.; Suenobu, T.; Fukuzumi, S. Angew. Chem. Int. Ed.
enhancements. Our results could have important biological 2013, 52, 12327-12331.
(
21) Hong, Y.; Sengupta, S.; Hur, W.; Sim, T. J. Med. Chem. 2015,
58, 3739-3750.
22) Zhang, X.; Li, X.; Li, Z.; Wu, X.; Wu, Y.; You, Q.; Zhang, X. Org.
Lett. 2018, 20, 3635-3638.
relevance because these studies were performed under
ambient3 rather than oxygen-enriched environments.
20
(
Because some of the most potent quinone-based anti-cancer
agents have 50% growth inhibition concentrations below 50
(
23) Liu, Z.; Sadler, P. J. Acc. Chem. Res. 2014, 47, 1174-1185.
2
1,22
µM,
allow them to fully exploit their autocatalytic H
capabilities. Thus, our strategy of combining half-sandwich
they are not typically used in amounts that would
2 2
O
forming
4
| J. Name., 2012, 00, 1-3
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Table of Content
Ir
Q
O
catalyst
OMe
Ir Cl
N
N
NaHCOO
O2
H
2
O
2
OMe
O
O
Ir-Q
O
Ir Cl
OMe
N
N
OMe
O
O
Tethered iridium-quinone catalyst in the presence of air and
sodium formate generates H more rapidly than iridium and
quinone mixtures at low catalyst concentration.
2 2
O
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