Solid-phase synthesis as a platform for the discovery of new ruthenium complexes for efficient release of photocaged ligands with visible light

Article abstract of DOI:10.1021/ic502791y

Ruthenium-based photocaging groups have important applications as biological tools and show great potential as therapeutics. A method was developed to rapidly synthesize, screen, and identify ruthenium-based caging groups that release nitriles upon irradiation with visible light. A diverse library of tetra- and pentadentate ligands was synthesized on polystyrene resin. Ruthenium complexes of the general formula [Ru(L)(MeCN)_n]^m+ (n = 1-3, m = 1-2) were generated from these ligands on solid phase and then cleaved from resin for photochemical analysis. Data indicate a wide range of spectral tuning and reactivity with visible light. Three complexes that showed strong absorbance in the visible range were synthesized by solution phase for comparison. Photochemical behavior of solution- and solid-phase complexes was in good agreement, confirming that the library approach is useful in identifying candidates with desired photoreactivity in short order, avoiding time-consuming chromatography and compound purification.

Full text of DOI:10.1021/ic502791y

Article
pubs.acs.org/IC
Solid-Phase Synthesis as a Platform for the Discovery of New
Ruthenium Complexes for Efficient Release of Photocaged Ligands
with Visible Light
Rajgopal Sharma,† Jessica D. Knoll,‡ Nicholas Ancona,† Phillip D. Martin,† Claudia Turro,*,‡
and Jeremy J. Kodanko*,†,§
†Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
‡Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
§Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201, United States
S
* Supporting Information
ABSTRACT: Ruthenium-based photocaging groups have
important applications as biological tools and show great
potential as therapeutics. A method was developed to rapidly
synthesize, screen, and identify ruthenium-based caging groups
that release nitriles upon irradiation with visible light. A diverse
library of tetra- and pentadentate ligands was synthesized on
polystyrene resin. Ruthenium complexes of the general
formula [Ru(L)(MeCN)n]m+ (n = 1−3, m = 1−2) were
generated from these ligands on solid phase and then cleaved
from resin for photochemical analysis. Data indicate a wide
range of spectral tuning and reactivity with visible light. Three complexes that showed strong absorbance in the visible range were
synthesized by solution phase for comparison. Photochemical behavior of solution- and solid-phase complexes was in good
agreement, confirming that the library approach is useful in identifying candidates with desired photoreactivity in short order,
avoiding time-consuming chromatography and compound purification.
routinely in biological research. However, a major drawback
of organic cages is that they usually require UV light, which is
absorbed by nearly all species in vivo.25 Metal complexes have
emerged more recently as an important class of photocaging
groups.24,27−43 They are attractive because they bind to a
variety of different functional groups, including those that
cannot be protected with organic-based cages such as
nitriles,44−49 nitrogen-containing heteroaromatics,50 or thio-
ethers.51 Thus, metal complexes offer an orthogonal approach
to organic caging methods. Metal-based caging groups also
carry the advantage of being labile with visible light under
single-photon excitation,52 which is rare for organic photolabile
protecting groups that are usually cleaved with UV light.53,54
Of the various classes of metal-based photocaging groups,
ruthenium complexes based on planar, heteroaromatic ligands
have been particularly successful (Figure 1). Pioneering work in
the neuroscience area proved that the Ru(bpy)2 group (bpy =
2,2′-bipyridine) can be used to achieve high spatial and
temporal control over receptor activity in live neuronal
cells.50,52,55−62 Importantly, no toxic effects were observed
from the caged neurotransmitters, or their metal-based
byproducts. Later work proved that the Ru(bpy)2 caging
moiety of other Ru(II) complexes with related bidentate
INTRODUCTION
■
Metal complexes are actively being developed as therapeutics
and tools for chemical biology.1−14 Despite their success in
multiple arenas, our ability to rapidly synthesize, screen, and
identify metal complexes with desired properties has not
evolved at the same pace as organic molecules, which are
synthesized routinely in large libraries and screened in high
throughput assays.15 Notwithstanding a few notable excep-
tions,16−19 metal complexes are usually synthesized and
evaluated one molecule at a time when being developed for
biological applications. This approach is less than ideal if
inorganic compounds are to compete with their organic
counterparts as tool compounds and therapeutics. Given that
structure−activity relationships of metal complexes vary widely
and are notoriously difficult to predict,20−22 more rapid
methods are clearly needed to identify optimal candidates for
biological applications.
One area of biology where metal complexes have made an
important impact is photocaging.23−25 Photocaging has
revolutionized our ability to study living systems, by allowing
researchers to control spatial and temporal aspects of biological
activity through selective deprotection or “uncaging” of active
compounds.26 Current photocaging methods take advantage of
a variety of different protecting groups.23 Organic-based
photocages have now advanced to the point where many
caged compounds are commercially available and used
Received: November 24, 2014
© XXXX American Chemical Society
A
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tuning and reactivity with light, demonstrating the utility of this
screening technology, as well as the power it has to identify lead
caging groups.
RESULTS
■
Synthesis of Ligand Library. Our strategy for the
synthesis of the ligand library was based on previous work
from the Kodanko laboratory, where a single pyridine precursor
bound to resin was functionalized with two components (R1
and R2) to create a library of polypyridyl ligands.63,64 The
pyridine precursor chosen for the present study was derived
from commercially available dimethylpyridine-2,5-dicarboxylate
(1, Scheme 1). Following a literature protocol,65 selective
Scheme 1. Synthesis of Pyridine Precursor 3
reduction of the ester in the 2-position furnished alcohol 2.
Amidation of 2 with excess 1,3-propanediamine by heating in
MeOH at 80 °C provided amine 3 in quantitative yield, where
excess 1,3-propanediamine could be removed simply by
azeotropic distillation from toluene.
To begin our studies with solid phase, Fmoc-protected Rink
amide MBHA resin derived from polystyrene (4, Scheme 2)
Figure 1. Planar heteroaromatic ligands found in ruthenium-based
caging groups and ligands derived from trialkylamines.
ligands can also be used to cage cytotoxic agents45,47 and
protease inhibitors46 for cell-based assays.48 In an effort to
identify other photolabile protecting groups distinct from this
class, we showed recently that ruthenium tri(2-pyridylmethyl)-
amine, Ru(TPA), is an effective cage for bioactive nitriles (see
Figure 1 for ligand).49 Although complexes of the general
formula [Ru(TPA)(RCN)2]2+ (RCN = bioactive nitrile)
showed promising activity, including excellent stability in the
dark and high levels of selectivity for enzyme inhibition under
dark vs light conditions, the potential for improvement
remained. Most notably, UV light is required for efficient
release of nitriles because singlet metal-to-ligand charge transfer
(1MLCT) bands for these complexes occur at λ < 400 nm. In
addition, only one of the two potentially labile nitrile molecules
was released upon irradiation. Therefore, we sought to develop
a streamlined approach to evaluate other ligands of this class in
ruthenium complexes for optimizing properties of the caging
group.
Scheme 2. Solid Phase Synthesis of the Polypyridyl Ligand
Library (8a−j)
Herein, we report a library approach for accessing ruthenium
complexes by solid phase synthesis that provides rapid access to
new derivatives for screening photochemical behavior. Ligands
designed to tune spectral properties of the ruthenium-based
photocaging group were synthesized in a parallel fashion on
solid phase. This library was processed to form caged
ruthenium complexes bound to resin, and then subsequently
they were cleaved and analyzed for photochemical reactivity.
Three compounds identified from this screen were synthesized
by solution phase and characterized photochemically. The data
from the latter were in good agreement with compounds from
solid phase, thus validating the predictive power of our library
approach. Data indicate a surprisingly wide range of spectral
was chosen for attachment of the pyridine precursor 3.
Deprotection of the Fmoc group from 4 using 1:1
piperidine/DMF, followed by treatment with succinic anhy-
dride in DMF furnished acid 5. Acid 5 was coupled to amine 3
using HBTU in DMF, giving pyridylmethyl alcohol 6,
containing a 10-atom spacer between the pyridine group and
B
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Figure 2. Structures of polypyridyl ligand library bound to resin (8a−j) and cleaved for analysis (9a−j).
the amide nitrogen bound to resin. Activation of alcohol 6 was
accomplished by either mesylation or chlorination using
conditions shown in Scheme 2. Mesylation with MsCl and
Et3N proceeded smoothly at RT with 100 mg or less of resin to
furnish 7 (X = OMs). However, upon further scale up, it was
difficult to observe full consumption of alcohol 6, as judged by
1H NMR and ESMS analysis of product cleaved from resin.
Optimal conditions developed later involved heating resin to 50
°C in the presence of excess TsCl, LiCl, iPr2EtN, and MeCN,
which worked routinely on scales of up to 1 g of resin,
providing 7 (X = Cl).
A library of 10 polypyridyl derivatives (8a−j) was accessed in
1−2 steps from monopyridine 7 (X = Cl or OMs) using
straightforward alkylation chemistry (Scheme 2). Full structures
of the ligands prepared by this method are shown in Figure 2.
Individual schemes for syntheses of 8a−h are presented in the
Supporting Information (Figure S3). In some cases, the
delivery of the appropriate secondary amine resulted in
nucleophilic displacement of the leaving group (X = Cl or
OMs), providing derivatives of 8 in one step (Strategy A).
Alternatively, the reaction with a primary amine (R1NH2) was
used to attach one group to the ligand (R1), with a second
alkylation reaction using R2Cl to complete synthesis of the
tertiary amine ligand (Strategy B).
purities for the 10 derivatives ranged from 52 to 99%, with
seven of the 10 compounds in >88% purity. Initially, compound
9g, a derivative of the known ligand N4Py, was produced in
<20% purity, with the remainder being unreacted 7 (X = Cl). In
this case, the secondary amine used to synthesize 9g, 1,1-
di(pyridin-2-yl)-N-(pyridin-2-ylmethyl)methanamine, is a hin-
dered nucleophile.63,66 Optimized reaction conditions were
developed using NaI as a catalyst, MeCN as solvent, and
iPr2EtN, which raised the level of purity of 9g to 88%. Synthesis
of compound 9e proceeded smoothly in the first alkylation of 7
(X = Cl) with 2-pyridylmethylamine (Scheme S3, Supporting
Information). Subsequent alkylation with 2,6-bis-
(bromomethyl)pyridine followed by aniline proved challenging,
resulting in lower conversion to product 9e (52% purity) under
a variety of conditions and was not optimized further.
Synthesis of Ruthenium Complex Library by Solid
Phase. With a library of resin-bound polypyridyl ligands 8a−j
in hand, conditions were developed to generate ruthenium
complexes with bound MeCN groups to be released photo-
chemically. Ligands 8a−c and 8j contain four donor atoms and
were expected to furnish complexes of the general formula
[Ru(L)(MeCN)2]n+ (n = 1, 2) with two molecules of MeCN
coordinated to the metal. Ligands 8d−i each carry five potential
donor atoms and were expected to result in complexes of the
general formula [Ru(L)(MeCN)]n+ (n = 1, 2) with only one
bound nitrile. A mixture of neutral and anionic ligands were
incorporated that were expected to furnish ruthenium(II)
complexes as mono- or dicationic species.
After the ligand syntheses were completed, the library was
evaluated by cleaving a small amount of each derivative from
the resin using 95% TFA in H2O (Figure 2), providing terminal
amides 9a−j that were characterized by LCMS (Figures S1−10,
1
Supporting Information) and H NMR spectroscopy (Figures
Optimization efforts began by surveying a number of
S12−21, Supporting Information). LCMS analysis indicated
conditions and ruthenium(II) precursors for metalation of the
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resin-bound ligands (Scheme 3, Table 1). Compound 8a, a
derivative of TPA, was used to develop the protocol because
solvent (DMF, EtOH, or MeCN) and heat (50−80 °C) led to
metalation, as judged by UV−vis spectroscopic and ESMS
analysis of products cleaved from resin using 95% TFA in H2O.
Relative yields were approximated by absorbance using
extinction coefficients of the species [Ru(9a)(DMSO)Cl]+
and [Ru(9a)(MeCN)2]2+. Importantly, both species were
shown to be stable for >24 h in the TFA cleavage cocktail in
the absence of irradiation, indicating decomposition does not
occur to a measurable extent during 15 min cleavage from resin.
Data indicated a wide range of yields for metalation
conditions surveyed. Relative to cis-[Ru(DMSO)4Cl2] (Table
1, entries 1−3), [Ru(COD)(MeCN)4](OTf)2 is a sluggish
ruthenium(II) starting material, giving <5% yield after 18 h at
50 °C in MeCN. The choice of solvent was also important.
DMF, which shows superior swelling of polystyrene resin
compared to MeCN, MeOH, or EtOH, actually showed much
lower yields for metalation (entries 1, 2, and 7). We considered
at this stage that swelling properties could play a key role in
optimizing formation of the ruthenium complex bound to resin,
so compound 8a was also prepared bound to Tenta-Gel resin,
which shows better swelling properties than polystyrene in
protic solvents, where yields for binding to Ru(II) were higher.
However, use of Tenta-Gel resin did not enhance yields for
metalation with EtOH (entry 8). Optimal conditions using
conventional heating methods were identified using polystyr-
ene-based 8a, 4 equiv of cis-[Ru(DMSO)4Cl2], EtOH as the
solvent, and heating at 80 °C for 18 h (entry 6). Time scales
were reduced significantly using microwave heating, cutting
reaction time scales down from 18 h to 30 min (entry 7).
Raising the amount of Ru(II) source to 10 equiv and heating at
120 °C for 1 h in the microwave reactor did not enhance the
yield relative to 4 equiv and 80 °C (entry 9). Thus, cis-
[Ru(DMSO)4Cl2] (4 equiv), EtOH as the solvent and heating
at 80 °C for 30 min with microwave irradiation were deemed
optimal for formation of the intermediate [Ru(8a)(DMSO)-
Cl]+.
A number of conditions were also surveyed for conversion of
the resin-bound [Ru(8a)(DMSO)Cl]+ to the caged nitrile
species [Ru(8a)(MeCN)2]2+. Heating the resin in MeCN
solvent lead to poor conversion to [Ru(8a)(MeCN)2]2+ as
judged by UV−vis spectroscopic and ESMS analysis of product
cleaved from resin. Addition of H2O to the MeCN medium did
enhance conversion to [Ru(8a)(MeCN)2]2+; however, full
conversion was still not observed. We hypothesized at this stage
that it could be difficult to obtain higher yields of [Ru(8a)-
(MeCN)2]2+ because of the chloride counteranions, which are
highly polar, show limited ability to solubilize dications in
organic media and may not be favorable for association of the
dicationic complex with the polystyrene polymer. Therefore,
additives were explored that could potentially exchange with
chloride, including NaBF4, NaOAc, NaOTf, and NH4PF6.
However, significant levels of decomposition with little to no
formation of product were observed. Considering these facts,
an additional ruthenium(II) source was explored that already
contained a less polar anion than chloride. Gratifyingly, heating
resin 8a in the presence of fac-[Ru(DMSO)3(O2CCF3)2-
(H2O)]70 (4 equiv) in EtOH at 80 °C for 30 min under
microwave irradiation, followed by microwave irradiation in
MeCN/H2O (1:1) for 30 min at 80 °C and cleavage from resin,
resulted in good conversion and provided [Ru(9a)(MeCN)2]-
(O2CCF3)2 (11a) in 81% yield (Table 1, entry 10).
Scheme 3. Three Methods (A−C) Explored for Synthesis of
Ru(II) Complexes [Ru(9a)(DMSO)Cl]Cl (10a) and
a
[Ru(9a)(MeCN)2]X2 (11a, X = OTf, O2CCF3)
a
See Table 1 for more details.
Table 1. Conditions and Ru(II) Sources Examined for
Conversion of Resin-Bound Ligand 8a to Ru(II) Complexes
[Ru(9a)(DMSO)Cl]Cl (10a) and [Ru(9a)(MeCN)2]X2 (11a,
X = OTf, O2CCF3)
Ru(II)
source
temperature
de
,
ab
,
c
fg
time (h) % yield ,
condition
(equiv)
solvent
DMF
(° C)
a
d
f
1
A (2)
A (2)
B (2)
B (4)
B (4)
A (4)
A (4)
A (4)
50
18
24
35
a
d
f
2
MeOH
MeCN
MeCN
EtOH
EtOH
EtOH
EtOH
50
18
a
d
g
g
g
3
50
18
<5
<5
<5
a
e
4
80
0.5
0.5
18
a
e
5
80
a
d
f
6
80
70
57
68
51
81
a
e
f
7
80
0.5
0.5
1
b
e
f
8
80
a
e
f
9
A (10) EtOH
120
a
e
g
10
C (4)
EtOH,
then
80
0.5 × 2
MeCN/
H2O
a
b
8a derived from polystyrene resin (0.75 mmol/g). 8a derived from
c
Tenta-Gel resin (0.23 mmol/g). Ruthenium(II) sources are cis-
[Ru(DMSO)4Cl2] (A), [Ru(COD)(MeCN)4](OTf)2 (B), and fac-
d
e
[Ru(DMSO)3(O2CCF3)2(H2O)] (C). Conventional heating. Mi-
f
crowave heating (50 W); % yield of [Ru(9a)(DMSO)Cl]+ as
determined by absorbance at λmax = 345 nm (ε = 10 500 M−1 cm−1)
g
after cleavage from resin with 95% TFA in H2O. % yield of
[Ru(9a)(MeCN)2]2+ as determined by absorbance at λmax = 348 nm
(ε = 9040 M−1 cm−1) after cleavage from resin with 95% TFA in H2O.
data for ruthenium(II)-TPA complexes were available to use as
benchmarks.49,67,68 Two ruthenium(II) starting materials were
surveyed initially, cis-[Ru(DMSO)4Cl2], which was expected to
give a mixture of complexes of the general formula [Ru(8a)-
(DMSO)Cl]+ that could later be converted into [Ru(8a)-
(MeCN)2]2+, and [Ru(COD)(MeCN)4](OTf)2,69 which could
potentially give access to the desired complex [Ru(8a)-
(MeCN)2]2+ directly in one step. Combining resin-bound 8a
with 2−10 equiv of these ruthenium salts in the presence of
With optimal conditions developed, the library of resin-
bound ligands 8a−j was processed to Ru(II)-MeCN complexes
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(Scheme 4). Conditions for metalation employed fac-[Ru-
(DMSO)3(O2CCF3)2(H2O)] (4.0 equiv) in EtOH with
Scheme 4. Synthesis of Ru(II)-MeCN Complex Library
microwave heating at 80 °C for 30 min, followed by
replacement of the solvent with MeCN/H2O and microwave
heating at 80 °C for an additional 30 min. In the case of
compounds 8b, 8c, 8d, and 8i, 2,6-lutidine (10 equiv) was
added during step 1 for deprotonation of acidic protons. Each
member of the library was cleaved from resin and screened by
UV−vis spectroscopy for reactivity with visible light (30 min
irradiation, λirr ≥ 395 nm) in H2O, with the goal of identifying
complexes that exchanged MeCN for H2O upon irradiation
(Figure 3a−j).
Data from the photochemical screening indicate a range of
spectral tuning, as well as reactivity with visible light. All of the
complexes absorb strongly below 400 nm, with select examples
showing significant absorbance from 400 to 500 nm (e.g., 11f−
g and 11i−j). As expected, most of the complexes are slow to
1
react with visible light because their corresponding MLCT
bands lie below 400 nm (11a−e, 11h). However, strong
absorbance above 400 nm did not guarantee reactivity with
visible light. Complex 11f, which absorbs strongly to almost
500 nm, did not react with visible light. The N4Py derivative
14g did react slowly with visible light, but did not demonstrate
the expected bathochromic shift for substitution of H2O for
MeCN. Complexes 11i and 11j did show the desired shift to
longer wavelengths, with 11j showing the most rapid spectral
change upon irradiation with visible light.
In addition to photochemical screening, each of the library
members was analyzed by ESMS (Table 2). Major peaks were
observed for each species, along with suitable isotope patterns,
corresponding to calculated m/z values for dications.
Compounds 11a, 11c−e, and 11j all showed m/z values
consistent with two bound MeCN groups. Data for 11b were
consistent with three bound nitriles, suggesting that the
carboxylic acid group of ligand 9b was not bound to ruthenium.
Complexes derived from the pentadentate ligands 11f−h all
showed major species corresponding to one bound MeCN
group.
Synthesis and Characterization of Complexes by
Solution Phase. On the basis of results from our screening,
three ligands were chosen for further evaluation of their
corresponding Ru(II)-MeCN complexes. Ligand 8f, a derivative
of the known ligand DPAbpy, was chosen because its Ru(II)-
MeCN complex showed significant absorption in the visible
spectral range, yet no photoreactivity was detected with visible
light, a surprising observation that needed to be verified by
solution phase. Ligand 8g, a derivative of the known ligand
N4Py, was chosen because it also showed significant absorption
at λ ≥ 400 nm. Unlike 11f, complex 11g did exhibit
photoreactivity with visible light irradiation, but data were not
consistent with substitution of H2O for MeCN, because a
bathochromic shift was not observed. Therefore, a follow up
study was warranted. Finally, ligand 8j, which contains two
Figure 3. (a−j) Changes in the electronic absorption spectra upon
irradiation with visible light (λirr ≥ 395 nm) in H2O of complexes
11a−j for 0 (black), 5 (red), 15 (green), and 30 (blue) min.
isoquinoline moieties, was identified as the lead ligand from this
study. There is a significant bathochromic shift in the
absorption maximum of 11j relative to that of 11a, and spectral
changes were observed with a low photon flux of visible light
and short irradiation times that were consistent with
substitution of H2O for MeCN. However, instead of 9j, we
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Table 2. ESMS Data for Compounds 11a−j Showing Major
m/z Values Observed and Molecular Formulas for Dications
a
Consistent with the Data
compound
m/z (obs)
formula (calcd)
11a
11b
11c
11d
11e
11f
11g
11h
11i
337
340
344
351
389
355
355
382
[Ru(11a)(MeCN)2]2+
[Ru(11b)(MeCN)3]2+
[Ru(11c)(MeCN)2]2+
[Ru(11d)(MeCN)2]2+
[Ru(11e)(MeCN)2]2+
[Ru(11f)(MeCN)]2+
[Ru(11g)(MeCN)]2+
[Ru(11h)(MeCN)]2+
a
a
nd
nd
11j
387
[Ru(11j)(MeCN)2]2+
a
Ruthenium complex with suitable isotope pattern was not detected
by ESMS.
chose to examine the C3 symmetric ligand TQA,71 which
replaces the pyridine donor of 9j with an isoquinolone. This
substitution was expected to simplify our analysis, because only
one isomer can be formed from TQA, unlike 9j, where
isoquinoline donors could adopt either a cis or trans
configuration and lead to formation of two isomers.
Three Ru(II) complexes were synthesized by solution phase
for evaluation against compounds from our library screen
(Scheme 5). The ligands DPAbpy,72 N4Py,73 and TQA71 were
Scheme 5. Synthesis of Ru(II)-MeCN Complexes 12−14 by
Solution Phase Methods
Figure 4. Perspective view of the dications [Ru(DPAbpy)(MeCN)]2+
(A) and [Ru(TQA)(MeCN)2]2+ (B) derived from 12 and 14,
respectively. Thermal ellipsoids are shown at 50% probability.
Hydrogen atoms are omitted for clarity. Select bond lengths (Å)
and angles (deg) for [Ru(DPAbpy)(MeCN)]2+ (A); Ru−N1,
2.052(11); Ru−N2, 2.060(12); Ru−N3, 2.085(12); Ru−N4,
1.986(14); Ru−N5, 1.954(11); Ru−N6, 2.052(11); N1−Ru−N6,
97.6(4). Select bond lengths (Å) and angles (deg) for [Ru(TQA)-
(MeCN)2]2+ (B); Ru−N1, 2.032(1); Ru−N2, 2.067(1); Ru−N3,
2.052(1); Ru−N4, 2.061(1); Ru−N5, 2.042(1); Ru−N6, 2.042(1);
N1−Ru−N6, 87.50(4).
to the single nitrile of 12, 2.052(11) Å for Ru−N1, is
considerably longer than those measured for related complexes,
such as [Ru(TPA)(MeCN)2 ]2 + or [Ru(bpy)2 -
(MeCN)2]2+.49,68,75−78 Metal−nitrogen bond distances to
nitrile for 14 are 2.032(1) and 2.042(1) Å for Ru−N1 and
Ru−N6, respectively, which are similar to [Ru(TPA)-
(MeCN)2]2+, with bond distances of 2.031(5) and 2.037(5)
for Ru−N1 and Ru−N6, respectively.49 In the case of 14, Ru−
N1 and Ru−N6 distances are outside the range of error, with
the longer bond positioned cis to the basic nitrogen atom N5
(Figure 4B).
The changes to the electronic absorption spectra of 12, 13,
and 14 in H2O at room temperature were monitored as a
function of irradiation time to detect generation of any
photochemical products. No change in the absorption spectrum
of 12 was observed following irradiation (λ ≥ 395 nm) for 1 h
synthesized using literature procedures. Treating each ligand
with one equiv of cis-[Ru(DMSO)4Cl2] in MeOH at 80 °C led
to rapid formation of the corresponding metal complex.
Concentration and heating in MeCN/H2O (1:1), followed by
precipitation with NH4PF6 produced [Ru(DPAbpy)(MeCN)]-
(PF6)2 (12), [Ru(N4Py)(MeCN)](PF6)2 (13), and [Ru-
(TQA)(MeCN)2](PF6)2 (14) in yields of 47−75%. Complexes
1
12−14 were characterized by H NMR and IR spectroscopies
and ESMS. X-ray crystallographic data were collected for
complexes 12 and 14 only, and data for 13 were described
previously in the literature.74
Diffusion of Et2O into acetone solutions provided crystals of
12 and 14 suitable for X-ray crystallographic analysis. Select
data for 12 and 14 are presented in Figure 4. The bond distance
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Figure 5. Electronic absorption spectra of 13 irradiated for 0, 0.5, 1, 4, 7, and 15 min (A) and 15, 40, and 85 min (B) and 14 irradiated for 0, 0.5, 1,
and 2 min (C) and 2, 5, 20, and 60 min (D), in H2O upon irradiation with λ ≥ 395 nm.
(Figure S38, Supporting Information). The irradiation of 13 in
H2O with λ ≥ 395 nm results in a shift in the absorption
maximum from 348 to 361 nm, whereas the peak at 420 nm
blue shifts to 408 nm with clear isosbestic points at 368 and 412
nm (Figure 5A). This process, occurring with Φ400 = 0.019(3),
is not consistent with substitution of CH3CN with H2O
because a shift of the MLCT band at 420 nm to lower energy is
expected. Further irradiation causes a red shift of the 420 nm
peak (Figure 5B), suggesting that substitution of CH3CN may
occur as a secondary process following the first photoinduced
event. The first event is presumed to correspond to the
substitution of one of the coordinated pyridyl substituents from
the N4Py ligand with H2O, a point that is explored by 1H NMR
spectroscopy with the results described below. Irradiation of 14
with λ ≥ 395 nm, Figure 5C, causes a red shift of the
absorption maximum from 418 to 425 nm with an isosbestic
point at 420 nm and Φ400 = 0.027(1). This red shift of the
MLCT band is consistent with formation of the corresponding
monoaqua complex upon substitution of one CH3CN. Further
irradiation results in a further red shift to 460 nm (Figure 5D),
consistent with substitution of the second CH3CN ligand with
H2O. Indeed, a second isosbestic point is apparent at 398 nm in
Figure 5D for the changes to the absorption spectrum at longer
irradiation time.
irradiation time in D2O with λ ≥ 395 nm. In D2O in the dark,
no changes were observed (Figures S39 and S40, Supporting
Information), confirming that the complexes are stable in
solution in the absence of light. Figure 6A depicts the changes
in the NMR spectrum of 14 upon irradiation in D2O. In 180
min, a clean progression to a single photoproduct is observed,
assigned to the monoaqua species, labeled M in Figure 6A.
Most notably, the loss of the singlet at 2.32 ppm concurrent
with the evolution of a singlet at 2.06 ppm (free CH3CN)
indicates substitution of bound CH3CN with D2O. By
comparison with the previously reported [Ru(TPA)-
(CH3CN)2]2+ analogue,49 the photosubstituted CH3CN is
assigned as the ligand trans to the quinoline group (N6, Figure
4B), as this CH3CN chemical shift is more shielded than the
CH3CN trans to the amine (2.92 ppm). A schematic
representation of this ligand exchange is shown in Figure 6B.
This experiment confirms the ability of 14 to release a nitrile
ligand and coordinate a solvent molecule when irradiated with
visible light at early irradiation times. It should be noted that
after 180 min of irradiation, the integration of the peak
corresponding to remaining bound CH3CN ligand begins to
decrease, together with a continued increase in free CH3CN. At
360 min of irradiation, peaks corresponding to the bis-aqua
1
product are discerned in the H NMR spectrum, labeled B in
To confirm the nature of the photoproducts formed during
Figure 6A. This finding, together with the presence of an
isosbestic point a longer irradiation times in the absorption
spectra (Figure 5B), is indicative that the first step shown in
1
the photolysis of 13 and 14, the changes to the H NMR
spectrum of each complex was monitored as a function of
G
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Figure 6. 1H NMR spectra following irradiation of 14 in D2O with λirr ≥ 395 nm for 0, 15, 45, 90, and 180 min; the label M indicates a signal from
the monoaqua intermediate and B from the bis-aqua product formed upon irradiation with selected integrations shown parentheses (A) and
schematic representation of the first ligand exchange process of the complex (B).
Figure 7. 1H NMR spectra following irradiation of 13 in D2O with λirr ≥ 395 nm for 0, 30, 60, and 120 min. Stars indicate new signals evolved upon
irradiation.
Figure 6B is followed by the exchange of the second CH3CN
ligand with prolonged photolysis.
The photoproduct(s) formed upon irradiation of 13 in D2O
were also studied by 1H NMR spectroscopy, and the results are
shown in Figure 7. Unlike 14, the bound CH3CN singlet at
2.81 ppm does not show a clear decrease concurrent with only
free CH3CN evolution; instead, as the singlet at 2.81 ppm
decreases, a new peak at 2.86 ppm increases as well as a small
increase of free CH3CN at 2.06 ppm. Additionally, the singlet at
6.62 ppm, assigned as the methine proton, decreases, and two
new additional singlets at 6.08 and 6.35 ppm appear with
irradiation. The aromatic region becomes more complicated
H
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Article
with new peaks arising at 6.98, 7.80, 8.25, and 8.84 ppm. The
shift is consistent with a small change in the environment
around the CH3CN protons upon exchange of one coordinated
The library members from this study displayed a wide range
of reactivity with visible light. Many of the examples showed
little, if any, photochemical activity, an observation easily
explained by the fact that most compounds did not absorb
strongly in the visible region. Indeed, photochemistry is
observed for many of the compounds surveyed when irradiated
in the MLCT bands with UV light.106 However, several of the
compounds prepared absorb well in the visible range, and either
do react when irradiated with visible light to follow a
nondesired pathway, such as the pyridine release observed
with complex 13, or are not photoactive with visible light at all
(e.g., 12). Thus, absorbing in the visible range did not
guarantee nitrile release with visible light, an observation that
has been reported with other caging strategies.40 The lead
compound established from this study was complex 14, which
acts much like its congener [Ru(TPA)(MeCN)2]2+,49 with the
selective release of the nitrile ligand positioned trans to
quinoline upon irradiation with short irradiation times.
Complex 14, however, does provide numerous advantages
over [Ru(TPA)(MeCN)2]2+, including efficient release of
1
pyridyl ring for a solvent molecule. The H NMR results are
consistent with the presence of multiple photoprocesses upon
visible light irradiation, where the dominant pathway is the
dissociation of a coordinated N4Py pyridyl ring from the
ruthenium center, but with CH3CN exchange for a solvent
molecule also operative to a smaller extent, the methine proton
singlet upfield is consistent with one of the pyridyl rings being
released and replaced by solvent.
DISCUSSION
■
Combinatorial chemistry, diversity-oriented synthesis, and
other compound library approaches have made a major impact
in chemical biology and drug discovery.79−85 Methods for
synthesizing large libraries of organic compounds have
advanced to the point where a single researcher can synthesize
hundreds of thousands of compounds in a week.15 In
comparison to organic compounds, methods to synthesize
libraries of inorganic compounds are grossly underdeveloped.
Most attention has focused on the discovery of metal-based
catalysts for organic reactions,86−88 selective metal-binding
agents,89−91 and new photosensitizers.92 Peptide- and oligonu-
cleotide conjugates of metal complexes have been synthesized
by solid phase for biological applications, and these compounds
have enjoyed great success as biologically active agents and tool
compounds.93−102 However, their synthesis often involves late-
stage attachment of the complex (or ligand) to the biomolecule,
where the coordination environment of the complex is preset.
Surprisingly, even though there is an enormous amount of
chemical space that remains unexplored, studies that apply
combinatorial chemistry to vary and tune the coordination
sphere of biologically active inorganic compounds are rare.16−19
To the best of our knowledge, library approaches had not been
applied yet toward discovery of new metal-based caging groups,
a class of inorganic compounds with many important biological
applications.30,32−40,46,48−50,52,55,57−62,103−105
MeCN with visible light and larger quantum yield, Φ400
=
0.027(1) for 14 vs Φ350 = 0.012(1) for [Ru(TPA)(MeCN)2]2+.
In order to explain the wide range of reactivity with light,
computations were carried out with compounds 12−14 and
other examples.107 Time-dependent density functional theory
(TD-DFT) calculations, the focus of a separate manuscript,
have provided significant insight into the disparity of reactivity
for these complexes, which are all derived from very similar
ligands. These data have allowed us to assign many of the
optical bands observed in the absorption spectra of the
1
complexes as MLCT transitions, which fall in the UV to
visible range. Preliminary assessment of the data indicates that
the barrier for internal conversion between the lowest energy
3MLCT state and the dissociative triplet metal centered (3MC)
states is a key factor that controls the outcome and selectivity of
nitrile release with these complexes. Results of these studies will
be published elsewhere.
The solid phase synthesis and screening platform described
in this manuscript allowed us to rapidly identify complexes that
release their ligands with visible light. Three examples with
varied reactivity were synthesized and fully characterized, and
the photochemical behavior of the complexes was in good
agreement between solid- and solution-phase compounds
(Figures S41−43, Supporting Information). Thus, our library
approach was validated as a method for identifying lead caging
groups. Solid-phase synthesis carries numerous advantages over
its solution-phase counterpart, including the ability to perform
reactions on a small scale, and isolate compounds by simple
filtration, thereby avoiding time-consuming and often tedious
purifications of ligand precursors, ligands, and metal complexes,
which all can be challenging. Removing the need for compound
isolation and chromatography is a major advantage, especially
for researchers who do not carry a strong experimental skill set
in synthesis. Key to this study is that only 1−2 compounds out
of the 10 surveyed actually reacted with visible light in the
desired manner to release bound nitriles. Synthesizing and
characterizing the photochemistry of each of these 10
complexes would have taken considerable effort. The synthesis
and screening approach we adopted allowed us to direct our
efforts in synthesis and full characterization toward the most
promising compounds only.
CONCLUSIONS
■
In conclusion, we have described a new platform for
discovering metal-based caging groups that provides rapid
access to new derivatives for screening photochemical behavior.
A representative library of 10 compounds was produced that
contained a range of different donors, denticities, and
coordination geometries. Absorption and photoreactivity with
visible light were screened, resulting in the identification of
several compounds that demonstrated interesting behavior
worthy of further investigation. Three new analogues were
synthesized by solution phase, and data for compounds were in
good agreement with the corresponding complexes from solid
phase, thus validating the predictive power of the library
approach. The wide range of reactivity with visible light among
the library of compounds illustrated the need to prescreen
compounds for their photochemical behavior, before efforts
were directed toward solution phase synthesis and full
characterization, an inherently tedious but necessary process.
In general terms, this study represents an important example of
why combinatorial, library-based approaches should be applied
toward the development of inorganic complexes for biological
applications. Such studies are currently underway in our
laboratory.
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Article
(27) Rimmer, R. D.; Richter, H.; Ford, P. C. Inorg. Chem. 2010, 49,
1180.
ASSOCIATED CONTENT
* Supporting Information
General considerations, experimental procedures for prepara-
■
S
(28) Ford, P. C. Acc. Chem. Res. 2008, 41, 190.
(29) Ford, P. C.; Bourassa, J.; Lee, B.; Lorkovic, I.; Miranda, K.;
Laverman, L. Coord. Chem. Rev. 1998, 171, 185.
(30) Patra, A. K.; Mascharak, P. K. Inorg. Chem. 2003, 42, 7363.
(31) Ghosh, K.; Eroy-Reveles, A. A.; Avila, B.; Holman, T. R.;
Olmstead, M. M.; Mascharak, P. K. Inorg. Chem. 2004, 43, 2988.
(32) Afshar, R. K.; Patra, A. K.; Mascharak, P. K. J. Inorg. Biochem.
2005, 99, 1458.
1
tion of 3, 5−7, 8a−j, 9a−j, 11a−j, 12−14, H NMR spectra,
and LCMS characterization data for 9a−j, X-ray crystallo-
graphic data for 12 and 14, 1H NMR spectra and time-resolved
UV−vis data for 12−14, including dark controls. This material
is available free of charge via the Internet at http://pubs.acs.org.
(33) Eroy-Reveles, A. A.; Leung, Y.; Mascharak, P. K. J. Am. Chem.
Soc. 2006, 128, 7166.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: jkodanko@chem.wayne.edu (J.J.K.).
*E-mail: turro@chemistry.ohio-state.edu (C.T.).
Notes
■
(34) Madhani, M.; Patra, A. K.; Miller, T. W.; Eroy-Reveles, A. A.;
Hobbs, A. J.; Fukuto, J. M.; Mascharak, P. K. J. Med. Chem. 2006, 49,
7325.
(35) Eroy-Reveles, A. A.; Leung, Y.; Beavers, C. M.; Olmstead, M.
M.; Mascharak, P. K. J. Am. Chem. Soc. 2008, 130, 6650.
(36) Rose, M. J.; Mascharak, P. K. Curr. Opin. Chem. Biol. 2008, 12,
238.
(37) Rose, M. J.; Mascharak, P. K. Coord. Chem. Rev. 2008, 252, 2093.
(38) Halpenny, G. M.; Mascharak, P. K. Inorg. Chem. 2009, 48, 1490.
(39) Halpenny, G. M.; Gandhi, K. R.; Mascharak, P. K. ACS Med.
Chem. Lett. 2010, 1, 180.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Institutes of Health
(EB 016072) and Wayne State University (Rumble Fellowship
to R.S.) for their generous support of this research.
(40) Chakraborty, I.; Carrington, S. J.; Mascharak, P. K.
ChemMedChem. 2014, 9, 1266.
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DOI: 10.1021/ic502791y
Inorg. Chem. XXXX, XXX, XXX−XXX