Chloromethyl-modified Ru(ii) complexes enabling large pH jumps at low concentrations through photoinduced hydrolysis

Article abstract of DOI:10.1039/c9sc03957k

Photoacid generators (PAGs) are finding increasing applications in spatial and temporal modulation of biological events in vitro and in vivo. In these applications, large pH jumps at low PAG concentrations are of great importance to achieve maximal expected manipulation but minimal unwanted interference. To this end, both high photoacid quantum yield and capacity are essential, where the capacity refers to the proton number that a PAG molecule can release. Up to now, most PAGs only produce one proton for each molecule. In this work, the hydrolysis reaction of benzyl chlorides was successfully leveraged to develop a novel type of PAG. Upon visible light irradiation, Ru(ii) polypyridyl complexes modified with chloromethyl groups can undergo full hydrolysis with photoacid quantum yield as high as 0.6. Depending on the number of the chloromethyl groups, the examined Ru(ii) complexes can release multiple protons per molecule, leading to large pH jumps at very low PAG concentrations, a feature particularly favorable for bio-related applications.

Full text of DOI:10.1039/c9sc03957k

Showcasing research from Professor Xuesong Wang’s and
Qianxiong Zhou’s laboratory, Technical Institute of Physics and
Chemistry, Chinese Academy of Sciences, Beijing, China.
As featured in:
Chloromethyl-modified Ru(II) complexes enabling large pH
jumps at low concentrations through photoinduced hydrolysis
Photoinduced hydrolysis of benzyl chlorides was first utilized to
fabricate novel photoacid generators. Upon green light (520 nm)
irradiation, 4,4'-bis(chloromethyl)-2,2'-bipyridine coordinated
Ru(II) complexes 1-3 can undergo efficient hydrolysis and release
HCl quantitatively, with photoacid quantum yields of as high as
about 0.6. Complex 3 with three bcm-bpy ligands can release six
protons per molecule, thus large pH jumps can be achieved at
low concentrations (10 μM).
See Xuesong Wang,
Qianxiong Zhou et al.,
Chem. Sci., 2019, 10, 9949.
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Chloromethyl-modified Ru(II) complexes enabling
large pH jumps at low concentrations through
photoinduced hydrolysis†
Cite this: Chem. Sci., 2019, 10, 9949
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
ab
ab
ab
ab
ab
a
Na Tian, Weize Sun, Yang Feng, Xusheng Guo, Jian Lu, Chao Li,
a
ab
a
Yuanjun Hou, Xuesong Wang
*
and Qianxiong Zhou
*
Photoacid generators (PAGs) are finding increasing applications in spatial and temporal modulation of
biological events in vitro and in vivo. In these applications, large pH jumps at low PAG concentrations are
of great importance to achieve maximal expected manipulation but minimal unwanted interference. To
this end, both high photoacid quantum yield and capacity are essential, where the capacity refers to the
proton number that a PAG molecule can release. Up to now, most PAGs only produce one proton for
each molecule. In this work, the hydrolysis reaction of benzyl chlorides was successfully leveraged to
develop a novel type of PAG. Upon visible light irradiation, Ru(II) polypyridyl complexes modified with
chloromethyl groups can undergo full hydrolysis with photoacid quantum yield as high as 0.6.
Depending on the number of the chloromethyl groups, the examined Ru(II) complexes can release
multiple protons per molecule, leading to large pH jumps at very low PAG concentrations, a feature
particularly favorable for bio-related applications.
Received 8th August 2019
Accepted 15th October 2019
DOI: 10.1039/c9sc03957k
rsc.li/chemical-science
concentrations not easy to realize under in vitro and in vivo
Introduction
conditions, were usually needed because each PAG molecule
4a,5–7
Photoacid generators (PAGs) are molecules which can generate can theoretically generate one proton only.
High concen-
1
acids under light irradiation, and have been widely used as trations of PAGs and their corresponding photoproducts may
photo-initiators of cationic polymerization in photolithography, also interfere with the examined biological processes,
photocuring, and three-dimensional (3D) printing. The great hampering their application severely. Though efforts have been
2
success that PAGs have achieved in the elds of the micro- made to address this issue by integrating two PAG moieties into
electronic industry and microfabrication relies on their spatial a single molecule, the resultant PAGs showed poor photoacid
1
c,3
and temporal control of proton concentrations. Protons also quantum yields.
New strategies that can endow PAGs with
play pivotal roles in a variety of biological events. As a result, both high photoacid capacity (i.e. the proton number a PAG
PAGs have found ever-increasing applications in biochemical, molecule can release) and high photoacid quantum yield are in
biological, and biomedical areas in recent years, such as urgent demand to boost their bio-related utilization.
3
4
photodynamic therapy, drug delivery, adenosine triphosphate
(
Thermal hydrolysis of haloalkanes may release HX (X ¼ Cl,
ATP) biosynthesis, photocontrol of enzyme activity, and Br, I) and the acid capacity depends strictly on their halogena-
5
6
7
11
protein conformations, as well as proton transfer in biomole- tion levels. To the best of our knowledge, such a classic reac-
8
cules. For these bio-related applications, PAGs may have some tion has not been capitalized on in PAGs. What attracts our
specic characters, including proper solubility in aqueous attention is the hydrolysis of benzyl chloride, the kinetics of
9
solutions, light response in the visible or near-infrared region which can be effectively modulated by electron donating/
12
for deep tissue penetration and minimal damage to biomole- withdrawing groups. Electron donating groups will accel-
10
cules, and large pH jumps to get remarkable bio-effects. To erate the process while an opposite effect may be observed for
reach instant large pH jumps, high photoacid quantum yields electron withdrawing groups. As reported by A. Fry and S.
were vigorously pursued. However, mM levels of PAGs, Yamabe, para-methoxy benzyl chloride has a hydrolysis rate of 4
orders of magnitude higher than that of the para-NO
2
coun-
12
terpart. Inspired by these facts, we herein synthesized a series
a
0
0
Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical
of 4,4 -bis(chloromethyl)-2,2 -bipyridine (bcm–bpy) coordinated
Ru(II) complexes (1–3, Scheme 1) to explore their PAG capability.
The rationale behind our design is as follows. (1) The bcm–bpy
ligand is expected to be inactive in thermal hydrolysis due to the
electron-decient feature of the pyridine ring, which may be
Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R.
China. E-mail: xswang@mail.ipc.ac.cn; zhouqianxiong@mail.ipc.ac.cn
b
University of Chinese Academy of Sciences, Beijing 100049, P. R. China
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c9sc03957k
1
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ligand, which will greatly enhance the electron density of bcm–
bpy. Such an expectation is further convinced by comparison of
Mulliken charges of the ground state (GS) and T1 state. Taking
complex 1 as an example (Table S1†), the selected Mulliken
charges of the atoms on the bcm–bpy ligand in the T1 state are
all negatively shied compared with that in the GS. In addition,
˚
˚
the length of C–Cl bonds stretches from 1.83 A (GS) to 1.85 A
T1) (Fig. S3–S5†). All these results are favorable for photoin-
(
Scheme 1 Chemical structures of complexes 1–3.
duced hydrolysis of the chloromethyl groups.
13
consolidated further upon coordination to the Ru(II) center.
A
Synthesis and characterization
good stability in the dark is a prerequisite for a desired PAG. (2)
The highest occupied molecular orbital (HOMO) of Ru(II) poly-
The synthesis and characterization of complexes 1–3 were re-
13
14
ported in our previous work. The aqueous solutions of all the
complexes are quite stable in the dark, as evidenced by the
negligible changes in absorption spectra, emission spectra, and
pyridyl complexes is generally Ru(II) centered, while the lowest
unoccupied molecular orbital (LUMO) of complexes 1–3 should
localize on the bcm–bpy ligand due to the electronegativity of Cl
1
15
H NMR (nuclear magnetic resonance) spectra, as well as pH
atoms. Thus, the bcm–bpy related metal-to-ligand charge
transfer (MLCT) state will be accessed preferentially upon light
irradiation, from which an efficient hydrolysis of the chlor-
omethyl groups is also anticipated due to the greatly enhanced
electron density on the bcm–bpy ligand. This is indeed what we
observed in our experiments. Complexes 1–3 can undergo effi-
cient hydrolysis upon visible light irradiation in aqueous solu-
tions, and release 2, 4, and 6 equivalents of HCl, respectively,
with photoacid quantum yields as high as 0.6. Both high pho-
toacid capacity and high photoacid quantum yield of complex 3
make large pH jumps feasible at low concentrations. Complex 3
is not only the rst PAG which can release six protons per
molecule, but also the rst type of PAG that makes use of
hydrolysis reaction of benzyl chloride groups. As a conceptual
demonstration, complex 3 was successfully used to switch on
the activity of acid phosphatase upon visible light irradiation at
values of the solutions (Fig. S7†). Upon irradiation at 520 nm,
rapid changes in these spectra were observed. Taking complex 3
as an example, the absorbance in the regions of 315–375 nm
and 425–500 nm decreased gradually, along with a slight blue-
shi of the ligand-based transition peak centered at 291 nm
(Fig. 2). The emission intensity also increased quickly upon
irradiation (Fig. 2). The absorption and emission spectra did
not change any more aer irradiation for only 3 min. At that
time, the solution exhibited nearly the same absorption and
2
+
0
emission as that of [Ru(bhm-bpy) ] (20 mM, bhm-bpy ¼ 4,4 -
3
0
bis(hydroxymethyl)-2,2 -bipyridine), suggesting full hydrolysis
of the six chloromethyl groups. The excited [Ru(bhm-bpy)3]
2
+
without competing photolysis decay should have a longer exci-
tation lifetime and also a higher luminescence quantum yield
compared with complex 3, and thus a turn-on luminescence was
observed. The known PAGs usually show absorption changes
upon light irradiation. Our complexes represent the rst class of
PAGs that exhibit remarkable luminescence turn-on along with
proton release. By virtue of the higher sensitivity of uorescence
detection as well as the wide application of uorescence
confocal microscopy, this feature may facilitate biological
6
a concentration as low as 10 mM.
Results and discussion
Theoretical calculations
Theoretical calculations based on the Gaussian 09 program studies. In addition, the transformation of 3 into [Ru(bhm-
1
6
2+
package (see ESI†) were carried out before experiments to bpy)
3
]
is also conrmed by high resolution electron spray
1
examine our ideas. As expected, the calculated HOMO and ionization mass spectra (HR ESI-MS) (Fig. S16†) and H NMR
LUMO of 1–3 are mainly Ru(II) and bcm–bpy based, respectively spectra (Fig. 3). Only an m/z peak of 375.0861 which can be
(
Fig. 1 and S1–S2†). Thus MLCTRu/bcm–bpy excitation means ascribed to the product with six hydroxymethyl groups was
pumping one electron from the Ru(II) center to the bcm–bpy observed aer irradiation in H O. A similar result was obtained
2
Fig. 2 Absorption (left) and emission (right) spectral changes of 3 (20
mM) in H O upon irradiation (520 nm), compared with that of [Ru(bhm-
2
2+
Fig. 1 HOMO (left) and LUMO (right) of complex 1.
3
bpy) ]
2
(20 mM in H O).
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ethanethiol decreased quickly (Fig. S22–S24†), showing their
desirable anti-interference ability.
Photoacid quantum yields
The photoacid quantum yields of 1–3 (50 mM) in H
2
O were
measured using potassium ferrioxalate as a chemical actinom-
20
eter (ESI). The light of 520 nm was not suitable for potassium
ferrioxalate due to its quite small extinction coefficient at
520 nm, and thus a 470 nm LED was selected. The obtained
quantum yields at 470 nm are 0.62 ꢁ 0.01 for complex 1, 0.65 ꢁ
0
.02 for complex 2 and 0.61 ꢁ 0.01 for complex 3, which are
1c,d,2a,b
among the highest reported for PAGs.
1
Fig. 3 H NMR spectra of 3 in D
2
O before (1, peaks were marked with Photoacid mechanism
the red triangles) and after irradiation at 520 nm for 5 min (2) and
1
2+
The high photoacid quantum yields and photoacid capacities of
–3, along with their good dark stability, make the hydrolysis
2
0 min (3), and H NMR spectrum of [Ru(bhm-bpy)
3
]
(4, peaks were
1
marked with the purple dots).
mechanism of the chloromethyl groups anchored on these
complexes particularly interesting. Generally, a thermal hydro-
lysis of a haloalkane may undergo through either an S 1
N
1
8
18
in H
2
O (Fig. S19†), and the O labeled Ru product was
12
(
unimolecular) or an S 2 (bimolecular) pathway. For benzyl
N
1
observed. The H NMR signals of 3 displayed a slight shi to
higher eld upon irradiation, and nally overlapped with that of
Ru(bhm-bpy) ] . Similar results were also obtained for
N N
chlorides, the mechanism may change from S 1 to S 2
depending on the electron donating/withdrawing abilities of
substituents. According to the reports of A. Fry and S. Yamabe,
the hydrolysis of para-methoxy benzyl chloride proceeds
2
+
[
3
complexes 1 and 2 (Fig. S8–S15, S17 and S18†).
N N 2
through an S 1 way, while S 2 is found for the para-NO
compound. For complexes 1–3, MLCT excitation enhances the
electron density of the bcm–bpy ligand, which is favorable for
pH changes
The pH changes of the aqueous solutions of complexes 1–3 (10
S 1 rather than S 2 Based on the theoretical and experimental
N N
mM) were monitored with a pH meter (Fig. 4). The initial pH results, a possible photoacid mechanism is schematically
values of the solutions were about 6.6. The weak acidity may be illustrated in Scheme 2, taking complex 1 as an example.
1
7
attributable to the dissolved CO
2
absorbed from ambient air.
Furthermore, we also examined the photolysis of the bcm–bpy
O. The absorption of the free bcm–bpy ligand
4 h (Fig. S7†). Upon LED (light-emitting diode) irradiation at appears below 310 nm. Under direct UV light (254 nm) irradi-
20 nm, the pH values decreased quickly to 4.9 for 1, 4.6 for 2 ation, HCl was also generated, most probably through
The pH values of the solutions kept unchanged in the dark for ligand in H
2
2
5
and 4.3 for 3 in 3 min (the theoretically calculated results are a different mechanism involving homolysis of a carbon–chorine
4
.7, 4.4 and 4.2 for complexes 1–3, respectively). A large pH bond as reported by R. Sinta et al. in the studying of photoacid
21
jump of 2.3 units was obtained for complex 3 at a concentration properties
of
4,6-bis(trichloromethyl)-1,3,5-triazines.
as low as 10 mM, which obviously prots from its ability to Compared with the clean transformation of 1–3 into their cor-
generate 6 protons for each molecule. To reach a similar pH responding hydroxymethyl products, the photolysis of bcm–bpy
jump, much larger concentrations, usually several hundreds of
micromolar, were generally needed for the reported
6,17,18
systems,
unfavorable for biological applications.
In bio-related applications, bioactive molecules, such as
glutathione (GSH), may serve as strong nucleophilic agents to
impair the dark stability of these chloromethyl-modied Ru
19
complexes. Thus, the effect of GSH was also studied. The
initial pH value of a GSH (1 mM) aqueous solution was
measured to be 3.4. Addition of 1–3 (10 mM) did not cause any
pH changes in 24 h without irradiation (Fig. S20†). The negli-
gible pH changes may also be the result of the strong buffering
ability of GSH. To rule out this possibility, ethanethiol (1 mM)
was used instead of GSH. Similar results were obtained again at
ꢀ
either room temperature or 37 C (Fig. S21 and S24†), con-

rming the good dark stability of complexes 1–3 even in the
presence of strong nucleophilic agents. Upon 520 nm irradia-
2
Fig. 4 pH changes of 1–3 (10 mM) in H O upon 520 nm LED
tion, the pH values of 1–3 (10 mM) solutions containing irradiation.
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Scheme 2 A proposed photoacid mechanism for 1.
is very complicated. The absorption spectra changed in an
irregular way (Fig. S25†), and complex photoproducts were ob-
tained as evidenced by the mass spectrum (Fig. S26†), in line (0.08 mg mL ) in the presence of 3 (10 mM) before (dark line) and after
with a homolysis-based radical mechanism. As a result, only 0.8 520 nm irradiation (4 mW cm , red line).
Fig. 5 Hydrolytic conversion of MUP to MU by acid phosphatase
ꢂ1
ꢂ2
unit of pH change was observed at 10 mM of bcm–bpy
(Fig. S25†), in sharp contrast to complex 1, which led to 1.6 units
of pH jump at the concentration of 10 mM upon visible light mM was implemented in their experiments. Light irradiation in
irradiation.
the control experiment without the enzyme caused no effects on
To the best of our knowledge, this is the rst time that the MUP (Fig. S28†).
hydrolysis reaction was applied to develop a novel type of PAG.
Since their discovery four decades ago, PAGs have been domi-
nated by iodonium and sulfonium salts. Only over the past
Conclusions
decade, new structures along with their unique properties have In conclusion, we designed and synthesized three bcm–bpy
emerged in the PAG arsenal, such as photochromic triangle based Ru(II) complexes as novel PAGs, which can work in
1
e,2a
17,18
terarylenes,
the open form of spiropyrans,
and N-oxy- aqueous solution and be excited by green light with photoacid
22
imidesulfonates. Bearing in mind that the benzyl chloride quantum yields of about 0.6. Complex 3 can release six protons
groups are easy to integrate into a variety of photosensitizers, per molecule, leading to large pH jumps at low concentrations.
such as porphyrins, phthalocyanines, and boron dipyrrome- Theoretically, more protons may be released provided more
thene (BODIPY) dyes, more diverse PAG structures and their chloromethyl groups are anchored on the ligand. Our results
broader applications are expected.
may open new avenues for developing novel PAGs with both
high photoacid quantum yield and capacity to meet more
challenging demands particularly in bio-related areas.
Biological applications
As a conceptual demonstration of its possible biological appli-
Conflicts of interest
cations, complex 3 at 10 mM was used to modulate the activity of
6
acid phosphatase (ACP). ACPs are widely distributed in the There are no conicts to declare.
human body. An abnormal activity of ACPs is related to many
diseases, including prostate cancer, kidney disease, multiple
myeloma, Gaucher disease, etc. Therefore, controlling the ACP
Acknowledgements
23
activity may nd potential applications in disease treatment This work was nancially supported by the National Key R&D
and drug development. S. Kohse and co-workers successfully Program of China (2018YFC1602204), the NSFC (21390400,
utilized a photoacid (2-nitrobenzaldehyde) to realize efficient 21571181 and 21773277) and the Strategic Priority Research
6
tuning of the ACP activity. Similarly, 4-methylumbelliferyl Program of Chinese Academy of Sciences (XDB17000000). We
phosphate (MUP) was selected as the substrate of ACP. The also appreciate the funding and technical support from the
transformation of MUP into 4-methylumbelliferone (MU) was Shanghai Supercomputer Center in theoretical calculations.
monitored by absorption spectra. The initial pH of the solution
of MUP and acid phosphatase was kept at 8.0, where the activity
of the enzyme was faint as negligible spectral changes were
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