Solvent-dependent photophysics of a red-shifted, biocompatible coumarin photocage

Article abstract of DOI:10.1039/c9ob00632j

Controlling the activity of biomolecules with light-triggered photocages is an important research tool in the life sciences. We describe here a coumarin photocage that unusually combines the biocompatible optical properties of strong absorption at a long wavelength close to 500 nm and high photolysis quantum yields. The favourable properties are achieved by synthetically installing on the photocage scaffold a diethyl amino styryl moiety and a thionoester group rather than the lactone typical for coumarins. The photocage's photophysics are analysed with microsecond transient absorption spectroscopy to reveal the nature of the excited state in the photolysis pathway. The excited state is found to be strongly dependent on solvent polarity with a triplet state formed in DMSO and a charge-separated state in water that is likely due to aggregation. A long triplet lifetime is also correlated with a high photolysis quantum yield. Our study on the biocompatible photocage reveals fundamental insight for designing advanced photocages such as longer wavelengths in different solvent conditions tailored for applications in basic and applied research.

Full text of DOI:10.1039/c9ob00632j

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Biomolecular Chemistry
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Solvent-dependent photophysics of a red-shifted,
biocompatible coumarin photocage†
Cite this: DOI: 10.1039/c9ob00632j
c
Daniel Offenbartl-Stiegert,a Tracey M. Clarke, *b Hugo Bronstein,
a
Ha Phuong Nguyena and Stefan Howorka
*
Controlling the activity of biomolecules with light-triggered photocages is an important research tool in
the life sciences. We describe here a coumarin photocage that unusually combines the biocompatible
optical properties of strong absorption at a long wavelength close to 500 nm and high photolysis
quantum yields. The favourable properties are achieved by synthetically installing on the photocage
scaffold a diethyl amino styryl moiety and a thionoester group rather than the lactone typical for cou-
marins. The photocage’s photophysics are analysed with microsecond transient absorption spectroscopy
to reveal the nature of the excited state in the photolysis pathway. The excited state is found to be strongly
dependent on solvent polarity with a triplet state formed in DMSO and a charge-separated state in water
that is likely due to aggregation. A long triplet lifetime is also correlated with a high photolysis quantum
yield. Our study on the biocompatible photocage reveals fundamental insight for designing advanced
photocages such as longer wavelengths in different solvent conditions tailored for applications in basic
and applied research.
Received 18th March 2019,
Accepted 28th May 2019
DOI: 10.1039/c9ob00632j
rsc.li/obc
wavelength absorption and a high photolysis quantum yield
Introduction
within one photocage is usually difficult.11,13,15,16 Developing a
Photocaging is a powerful approach used in basic chemistry, photocage integrating both parameters is hence key for bio-
biology and biomedicine to control the activity of molecules logical applications.11
with the non-invasive trigger of light under high spatial and
A second demand is to understand the photocages’ funda-
temporal control.1–10 Photocages tune a molecule’s activity by mental photolytic process (Fig. 1). Insight is key to help design
(i) forming a covalent linkage to the molecule, (ii) thereby longer wavelength chromophores15 and may maximize yield of
blocking its activity, and (iii) absorbing light to photolyse the release.5 Yet, to establish design rules for efficient photocages
linkage in order to restore the molecule’s activity.1
several questions about fundamental steps after photo-
To be compatible with advanced biomedical research, induced excitation of photocages need to answered.17 For
efficient photocages should feature high-yielding photolysis, example, what is the detailed nature of the electronically
which implies high extinction coefficients and photolysis excited state that induces photolysis?15 Furthermore, what is
quantum yields. In addition, absorption wavelengths at the lifetime of the relevant excited state and how does this
500 nm or higher are increasingly demanded. Longer wave- affect the photolysis efficiency?18 In addition, to which extent
lengths are less mutagenic to biological cells,5 reach deeper do excited state and photolysis depend on the solvent in which
into biological tissues,11 and help create scope for using a the chromophore is dissolved? Organic solvents are often used
second orthologous photocage.11 Synthetic strategies to in photophysical studies18,19 but biological use requires under-
increase the absorption wavelength are to add auxochromes,12,20 standing from water-based data. A final question relates to the
extend the conjugated system,13 substitute oxygen in carbonyls photolysis product as the expected release of both uncaged mole-
or lactones,14 and combinations thereof.13 Yet, achieving long cule and reformed photocage can be experimentally confirmed,20
while sometimes only the uncaged molecule is traced.13
Here we pioneer a new coumarin photocage with long
aDepartment of Chemistry, Institute of Structural Molecular Biology,
University College London, London WC1H 0AJ, UK. E-mail: s.howorka@ucl.ac.uk
bDepartment of Chemistry, University College London, London WC1H 0AJ, UK.
E-mail: tracey.clarke@ucl.ac.uk
cDepartment of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob00632j
maximum wavelength of absorption and high photolysis
quantum yield. Our photophysical analysis also advances the
understanding of coumarin photocages (Fig. 1, 1a). Coumarins
were selected as they are
a
widely used class of
photocages2,11,13,14,21 that absorb at around 400 nm and
efficiently photodissociate; they are hence compatible with cell
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Fig. 1 Schematic representation of photolysis pathways of photocage
(1b) in DMSO (blue) and water (green). Note that the S1 and T1 energies
(black) are approximately the same in water and in DMSO. The charge
separated state (CS) is shown in blue for DMSO and green for water. The
charge separated state (CS) in water (green) is lowered below the triplet
state (shown by the grey arrow) and the photolysis thus proceeds via the
CS state. Bottom: chemical structure of the photocage developed and
investigated in this study.
Scheme 1 Synthesis of styryl thiocoumarin photocages (1a) and (1b). (i)
H2SO4, H2O; NaNO2, KI, 0 °C; 56% (ii) SeO2, reflux; NaBH4, EtOH/THF;
45% (iii) DMAP, DIPEA, TIPS·Cl, DMF; 58% (iv) PPH3CH3Br, KOtBu, THF;
66% (v) 6, Pd(OAc)2, TEA; dry DMF; 47% (vi) Lawesson’s reagent, dry
toluene, reflux; 33% (vii) Et3N·3HF, THF; 39% (viii) acetic acid, DMAP,
DCC, dry DCM; 76%.
biological research.11,13 Furthermore, they do not produce cyto-
toxic side-products observed for nitroaryl-based photocages that
are popular for non-cellular biomolecular applications.22,23 The
coumarin-based photocage presented in our study possesses an
absorption maximum at 479 nm in water – longer than any pre-
during the following synthetic steps. Using a ligand-free Heck-
coupling, protected iodinated coumarin (5) was furnished with
styrene (6) which had been prepared by a standard Wittig reac-
tion. The resulting styrene coumarin (7) was then thiated
using Lawesson’s reagent to yield TIPS-protected thionoester
(8). Following deprotection with triethylamine trihydrofluor-
ide, coumarin (1a) was obtained. Alternative deprotecting
routes such as TASF, TBAF and acyl chloride/methanol were
either too harsh or inefficient. Unprotected (1a) was used for
the spectroscopic analysis of the chromophore’s ground state.
However, (1a) was also modified with an acetyl group to
produce (1b) in order to characterize the excited state of the
photocage and to determine the rate of photolysis.15 Three
batches of (1a) and (1b) were synthesised over the course of
this study ensuring reproducible spectroscopic data.
vious coumarin scaffold11,13,14,24,25
– and high photolysis
quantum yield.
Our report also provides a step-change in characterizing the
identity of the photocage’s excited state and its kinetics in
organic solvent DMSO and water. We reveal that the nature of the
excited state is strongly solvent dependent. A triplet state is
formed in DMSO and a charge-separated state in water. The
nature of the excited state is important as it influences the photo-
lysis rate. The insight into key steps of the photolysis pathway can
help design further improved photocages to feature efficient
photodissociation at wavelength approaching the optical window.
UV-Vis spectroscopic analysis of photocage (1a) determined
the increase of absorption wavelength, λmax. Indeed, the
absorption spectrum for (1a) in water (Fig. 2) reveals absorp-
Results and discussion
To achieve long-wavelength absorption for (1a), coumarin was
equipped with two new moieties. A diethyl amino styryl
moiety,13 and a thionoester group rather than the lactone
typical for coumarins (Fig. 1).11 The synthetic route to styryl
thiocoumarin (1a) is shown in Scheme 1. Iodine-containing
analogue (3) was prepared via the initial diazotisation13 of
amine derivative (2) and halogen substitution. The methyl
group of (3) was then subjected to Riley oxidation and sodium
borohydride reduction to yield alcohol (4). The hydroxyl group
was subsequently protected with TIPS to give (5). TIPS was pre-
ferred over alternative protecting groups such as acetyl or tetra-
Fig. 2 UV-Vis absorption profile of styryl thiocoumarin (1a). 50 μM in
hydropyranyl which did not sufficiently ward off side reactions water.
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tion maximum λmax at 479 nm. This is longer than for styryl shown in Fig. 3A, the excited state of (1b) absorbs at 1090 nm
coumarin (λmax = 408 nm (ref. 13)) and all other coumarin and features vibronic structure with a shoulder at approxi-
photocages reported to date.11,13,14,24,25 The broad absorption mately 970 nm. The decay kinetics of the spectral response
peaks along with the low solubility in water potentially indi- were monoexponential, and the decay lifetime, τ, invariant of
cates the presence of aggregation which is investigated later in pump excitation density (Fig. 3B and ESI Fig. S4†): both key
the manuscript. The extinction coefficient ε of (1a) in water is characteristics of a triplet state. Fitting to a monoexponential
1.04 × 104 M−1 cm−1 (Table 1) which is in the range observed function yielded a lifetime of τ = 63 2 μs (n = 5). The presence
for coumarins.20 Furthermore, the absorption characteristics of solvated electrons can be discounted since they
of (1a) are strongly dependent on the solvent (ESI Fig. S1,† absorb above 1500 nm in DMSO and have a lifetime on the
Table 1).26 As an overall trend, increasing solvent polarity from order of a few nanoseconds.29,30 Our TAS analysis is the first to
hexane to water leads to a red-shift of absorption wavelength. experimentally confirm a triplet excited state in a coumarin
Acetonitrile is an exception indicating that factors other than photocage.
solvent polarity also play a role such as additional subtle
To further corroborate the presence of a triplet state, the
solvent–molecule interactions. The solvatochromism may be oxygen sensitivity of the transient species was investigated.
explained by the more polar nature of the excited state com- Triplet excited states are known to decay faster in oxygen due
pared to the ground state, and a stabilisation of the excited
state by polar solvents.
The detailed photophysical reason for the solvatochromism
was established with density functional theory (DFT) and time-
dependent (TD-DFT) calculations. The DFT calculations
(CAM-B3LYP/6-31G(d), ESI Tables S2–S5†) determined the
ground state geometries and molecular orbitals of (1a). The
HOMO and LUMO were found to be partially spatially separ-
ated which implies a partial charge transfer upon excitation to
the π–π* singlet state. To confirm stabilisation of the charge-
transfer state by a more polar solvent, the energy levels of the
excited state in different solvents were calculated with TD-DFT
using the SCRF/PCM model. The results supported the hypoth-
esis that the more polar solvent water stabilises the π–π*
excited singlet state more effectively, with a progressive
decrease in the energy of the π–π* state calculated with increas-
ing solvent polarity. Furthermore, these calculations indicate
that the lowest energy excited singlet state changes with
solvent: a π–π* state in water, but an n–π* state in the non-
polar solvent heptane.
After examining coumarin chromophore (1a), we investi-
gated the photocaged compound (1b). The spectroscopic pro-
perties, including solvatochromism, of (1b) are very similar to
(1a) (ESI Fig. S1 and S2†). The excited state of (1b) was experi-
mentally elucidated with microsecond transient absorption
spectroscopy (TAS).27,28 In this technique, the chromophore is
excited with a beam from a pulsed laser of wavelength λpump. A
probe beam with λprobe is then applied to determine the
change in absorption as a function of wavelength and time
delay between excitation and probing. The experimental set-up
for TAS is shown in ESI Fig. S3.†
The transient absorption spectrum of the excited state of
(1b) in DMSO was determined using λpump = 475 nm. As
Fig. 3 Characterisation of the excited state of (1b) with TAS. (A)
Table 1 Summary of spectroscopic properties of photocage (1a)
Absorption spectrum of the excited triplet state showing its decay over
obtained at 50 μM
time. Pump intensity = 37 μJ cm−2, 5 μM in DMSO, λpump = 475 nm.
(B) Change in optical density versus time at different pump intensities
Hexane
DCM
ACN
DMSO
Water
(μJ cm−2) in DMSO. (C) Quenching and successful recovery of the transi-
ent triplet state of (1b) in nitrogen and oxygen. λprobe = 1090 nm;
λpump = 475 nm, 5 μM in DMSO.
λmax (nm)
440
1.26
463
2.46
454
2.18
475
1.54
479
1.04
ε (×104 M−1 cm−1
)
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to quenching via triplet–triplet annihilation with triplet
oxygen.31,32 Oxygen addition should hence strongly reduce life-
time and signal amplitude of the excited state of (1b). Indeed,
both parameters were considerably lower in the presence of O2
and the triplet now decayed fully within 2 μs (Fig. 3C). In
further support, the absorption and lifetime of the triplet
could be fully recovered when the analysis solution was
degassed with N2 which is inert against triplet quenching.
Formation of a triplet state was corroborated by minimal
observation of the alternative pathway of fluorescence. As illus-
trated in a Jablonski diagram, an optically excited chromo-
phore in the S1 state can convert via intersystem crossing to a
triplet state, or decay via fluorescence to the ground state (ESI
Fig. S5†). In support of a strongly populated triplet state, the
fluorescence quantum yield, ϕf, of (1b) in DMSO was so low
that it could not be detected (ESI Fig. S6 and S7†); a minimal
ϕf of 1% was found in DCM. The proposed efficient intersys-
tem crossing to the triplet state is supported by this low fluo-
rescence quantum yield, even in polar solvents such as water
Fig. 4 Photolysis of (1b) in oxygen and argon using a concentration of
50 μM in DMSO. The solid lines are a fit to a monoexponential decay
function. The photocage is stable in the dark even after an extended
incubation time of 6 h.
After demonstrating the presence of a triplet state and its
link to photolysis in solvent DMSO, we analysed the excited
state in water, the biologically relevant solvent. In stark contrast
to our previous findings, the optical TAS analysis of (1b) could
not detect any long-lived triplet excited state in water (Fig. 5).
Instead, the excited state kinetics showed a power law behav-
iour, markedly different from the mono-exponential behaviour
in DMSO that is characteristic of triplets. As another striking
difference, TAS kinetics did not depend on the absence or pres-
ence of oxygen (Fig. 5). The power law kinetics and lack of
oxygen sensitivity in water are consistent with a charge-separ-
ated water-stabilized state rather than a long-lived triplet state.
The observation of triplets in DMSO but a charge-separated
state in water was investigated further using solvent-dependent
TD-DFT calculations. The aim was to identify any differences
in the energy levels of the singlet and triplet excited states that
could account for the different photophysics in water and
DMSO. However, these calculations (CAM-B3LYP/6-31G(d), ESI
Tables S6 and S7†) showed that the singlet and triplet excited
states had virtually identical energies and transition contri-
butions in both solvents. Consequently, an intrinsic energetic
origin to the differing behaviour is unlikely. An alternative
1
and DMSO where the π–π* state is stabilised below the non-
1
fluorescent n–π* state (Tables S3 and S5–S7†). π–π* states are
expected to be substantially more fluorescent than n–π*
excited states because their fluorescence back to the ground
state is symmetry-allowed. However, a contribution from
H-aggregate formation quenching the fluorescence is also a
possibility.33
After establishing the triplet nature of the excited state in
DMSO, we set out to determine whether the photolysis of (1b)
proceeds via the triplet state. Photolysis was investigated in O2
and in argon (O2-free) atmosphere to probe how a change in
triplet lifetime affects the photolysis rate in DMSO. Photolysis
was achieved using a quartz tungsten halogen lamp to irradi-
ate the sample. The beam was passed through a bandpass
filter with a centre wavelength of 475 nm. The power density at
475 nm was measured to be 6.7 mW cm−2 (ESI Fig. S8†). The
progress of photolysis was determined by tracking the residual
content of (1b) by HPLC, followed by normalization to the
amount of starting material.13 NMR spectra of the photolysis
products suggested formation of smaller fragments (ESI Fig. S9†).
As shown in Fig. 4, (1b) uncaging in O2 has a half-life of 54
6 min. This is similar to other coumarin photocages consid-
ering that a much lower light intensity of 6.7 mW cm−2 was
used for (1b) compared to high intensities of up to 28 mW cm−2
for other cages13 which can be damaging to cells.15 When the
photolysis reaction was studied in the absence of O2 – corres-
ponding to a longer triplet lifetime – faster photolysis was
observed (Fig. 4). The fast kinetics with a half-life of 10 2 min
correspond to
a higher photolysis quantum yield. The
strong influence of the presence or absence of oxygen on the
photolysis kinetics validate the proposed relationship between a
long-lived triplet state and high photolysis quantum yield.15 As
further insight into the photolysis mechanism, the continued
presence of photolysis under oxygen implies that photolysis
must proceed very quickly once the triplet state is generated.
Shortening the triplet lifetime therefore does not fully quench
photolysis.
Fig. 5 Characterization of the excited state kinetics of (1b) using TAS
in water and DMSO using different atmospheres. Pump intensity =
32 μJ cm−2, λpump = 475 nm, λprobe = 1090 nm. The concentration of
(1b) was 5 μM.
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explanation is that the energy levels of the excited state could in Table 2 20 and Table S8† indicating that our new dye com-
be altered by aggregate formation, which is not accounted for pares favourably to other coumarin11,13,14 as well as BODIPY
in our DFT calculations.
photocages.15
Aggregate formation was examined via concentration-depen-
dent steady-state absorption spectroscopy. A concentration
dependence of the absorption profile was indeed observed in Conclusions
water but not DMSO (ESI Fig. S10 and S11†). In particular,
This study has described a new coumarin-based photocage
increased absorption at the shorter-wavelength peak at higher
concentrations suggest H-aggregates in water.33 The absorp-
tion of these aggregates therefore coincides with higher-lying
electronic absorption bands of the compound. As further
characteristic of H-aggregates, both (1a) and (1b) showed large
Stoke’s shifts and low fluorescence quantum yields (ESI Fig. S6
and S7†). These observations imply that aggregation stabilises
the charge-separated state below that of the triplet in water,
presumably by allowing a lower energy intermolecular charge-
separated state to form.
To complement our analysis, we investigated the photolysis
of (1b) in water in both O2 and argon. The kinetics of photo-
lysis were in a similar time range as DMSO (Fig. 6). By contrast,
the difference between O2 and argon atmospheres, with half-
lives of 18 and 39 minutes, respectively, was much smaller
than in DMSO. This smaller difference is consistent with the
presence of charge-separated states, which relax back to the
ground state independently of the presence of oxygen. The
photolytic properties including quantum yield are summarised
that overcomes two pertinent hurdles in the field. In terms of
optical properties, the photocage favourably combines long
wavelength and a high photolysis quantum yield not pre-
viously attained. It is therefore highly suitable for applications
in biology such as to optically control the activity of
nucleotides3,10 and DNA nanostructures34–37 in cellular
tissues. In addition, the report has revealed the electronic
nature of the excited state active in the photolysis mechanism,
and its solvent dependency, something which has not been
done before. In new insight, photolysis in water was shown to
involve a charge-separated state while the pathway in organic
solvent proceeds via a triplet state. A long triplet lifetime was
correlated with higher photolysis quantum yields.
The new fundamental understanding can help guide the
future design of photocages with enhanced triplet population
and lifetime in organic solvents and water. Routes to increase
the triplet yield are to promote intersystem crossing to the
triplet state, e.g. by incorporating heavy atoms or by reducing
the S1 − T1 energy gap.15,38 However, these strategies do not
guarantee a long triplet lifetime. Longer triplet lifetimes could
be engineered by an energetically high T1 triplet state provided
it is not above any charged-separated state. Alternatively, there
should be no change in the orbital angular momentum
between the T1 and S0 states.39,40 The future design will also
have to consider the possible formation of the charge-separ-
ated state due to aggregation. The interaction may not occur
when the photocage is attached to the caged compound that is
large or polar enough to minimise dimerisation of photocage
moieties. Another simple strategy to avoid aggregation is to
improve the solubility of the photocage by introducing polar
moieties. In conclusion, our study has provided a photocage
with advanced bio-relevant optical properties and offers funda-
mental insight to establish design rules for efficient photocage
that promote basic and applied research.
Fig. 6 Photolysis of (1b) in oxygen and argon using a concentration of
50 μM in water, showing a much smaller difference in rate of consump-
tion between argon and oxygen atmosphere than in DMSO. The solid
lines are a fit to a monoexponential decay function.
Conflicts of interest
There are no conflicts to declare.
Table 2 Summary of photolytic properties of photocage (1b)
Water
(argon)
Water
(O2)
DMSO
(argon)
DMSO
(O2)
Acknowledgements
ka (×10−3 s−1
t1/2 (min)
)
17.8
39
0.034
337
37.9
18
0.071
712
71.4
54
0.133
2049
12.8
10
0.024
375
S. H. acknowledges support by the UK EPSRC grant EP/
N009282/1, BBSRC grants BB/M025373/1 and BB/N017331/1,
and the Leverhulme Trust RPG-2017-015. TMC would like to
acknowledge support from EPSRC project EP/N026411/1. We
thank Dr Abil Aliev and Helena Philpott for helping with NMR
analysis and Dr Kersti Karu for HRMS measurements.
b
Φ475
ε475 × Φ475 c (M−1 cm−1
)
a Photolysis rate constant for irradiation at 475 nm. b Quantum yield of
photolysis at λ = 475 nm. c Product of molar absorption coefficient and
quantum yield of photolysis at λ = 475 nm.
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and S. Howorka, Angew. Chem., Int. Ed., 2019, 58, 6620–
6624.
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