Phototriggered release of a leaving group in Ketoprofen derivatives via a benzylic carbanion pathway, but not via a biradical pathway

Article abstract of DOI:10.1002/chem.201300285

2-Acetoxymethyl-2-(3-benzoylphenyl)propionic acid (KP-OAc) was used as a model to elucidate the solvent-mediated photochemistry mechanism of Ketoprofen (KP). In solutions with a low concentration of water, KP-OAc exhibits a benzophenone-like photochemistry, reacting with water molecules through some reaction to form a ketyl radical intermediate. In neutral solutions with a high concentration of water or acidic solutions, KP-OAc undergoes a photodecarboxylation reaction with the assistance of water molecules or with the catalysis of perchloric acid to directly generate a biradical intermediate that cannot induce the phototrigger reaction to release the AcO^- group. Therefore, the lifetime of the biradical intermediate of KP-OAc is almost same as that of the biradical intermediate formed from KP in the same kinds of solutions. However, the photodecarboxylation of KP-OAc in phosphate buffer solution directly produces the benzylic carbanion intermediate, which can induce the phototrigger reaction to release the AcO^- group. Therefore, the lifetime of the biradical intermediate of KP-OAc is significantly shorter than the lifetime of the biradical intermediate of KP in phosphate buffer solution. Interestingly, the investigation of the photochemistry of KP-OAc not only verifies the solvent-mediated photochemistry mechanism of KP but also provides some new insight into the potential of using this kind of platform for phototrigger applications. The biradical intermediate is not the key species leading to the phototrigger reaction but the benzylic carbanion species is the key reactive intermediate that can mediate the phototrigger reaction of KP-OAc. Therefore, a change in the pH of the solutions can be utilized to switch on and switch off the photorelease reactions of KP derivative phototrigger compounds. Copyright

Full text of DOI:10.1002/chem.201300285

FULL PAPER
Reaction Mechanisms
M.-D. Li, T. Su, J. Ma, M. Liu, H. Liu,
X. Li, D. L. Phillips* ........ &&&& — &&&&
Phototriggered Release of a Leaving
Group in Ketoprofen Derivatives via a
Benzylic Carbanion Pathway, But not
via a Biradical Pathway
The right path! Photodecarboxylation
of the 2-acetoxymethyl-2-(3-benzoyl-
phenyl)propionic anion (KP-OAcꢀ) in
a phosphate buffer solution leads to
the direct formation of the benzylic
carbanion intermediate, which under-
goes a phototrigger reaction to release
the AcOꢀ group. However, in neutral
solutions with a high concentration of
water or acidic solutions, the photode-
carboxylation reaction with the assis-
tance of water or acid directly gener-
ates a biradical intermediate, which
does not trigger the release of the
AcOꢀ group (see scheme).
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DOI: 10.1002/chem.201300285
Phototriggered Release of a Leaving Group in Ketoprofen Derivatives via a
Benzylic Carbanion Pathway, But not via a Biradical Pathway
Ming-De Li,[a] Tao Su,[b] Jiani Ma,[b] Mingyue Liu,[b] Han Liu,[b] Xuechen Li,[b] and
David Lee Phillips*[b]
Abstract: 2-Acetoxymethyl-2-(3-ben-
zoylphenyl)propionic acid (KP-OAc)
was used as a model to elucidate the
lifetime of the biradical intermediate of
KP-OAc is almost same as that of the
biradical intermediate formed from KP
in the same kinds of solutions. Howev-
er, the photodecarboxylation of KP-
OAc in phosphate buffer solution di-
rectly produces the benzylic carbanion
intermediate, which can induce the
phototrigger reaction to release the
AcOꢀ group. Therefore, the lifetime of
the biradical intermediate of KP-OAc
is significantly shorter than the lifetime
of the biradical intermediate of KP in
phosphate buffer solution. Interesting-
ly, the investigation of the photochem-
istry of KP-OAc not only verifies the
solvent-mediated
mech nism of Ketoprofen (KP). In so-
lutions with a low concentration of
photochemistry
solvent-mediated
photochemistry
A
U
mech nism of KP but also provides
ACTHUNGTRENNUNaG ACHTUNGTRENNNUG
A
U
some new insight into the potential of
using this kind of platform for photo-
trigger applications. The biradical inter-
mediate is not the key species leading
to the phototrigger reaction but the
benzylic carbanion species is the key
reactive intermediate that can mediate
the phototrigger reaction of KP-OAc.
Therefore, a change in the pH of the
solutions can be utilized to switch on
and switch off the photorelease reac-
tions of KP derivative phototrigger
compounds.
water, KP-OAc exhibits a benzophe-
none-like photochemistry, reacting with
water molecules through some reaction
to form a ketyl radical intermediate. In
neutral solutions with a high concentra-
tion of water or acidic solutions, KP-
OAc undergoes a photodecarboxyla-
tion reaction with the assistance of
water molecules or with the catalysis of
perchloric acid to directly generate a
biradical intermediate that cannot
induce the phototrigger reaction to re-
lease the AcOꢀ group. Therefore, the
Keywords: carbanions · decar
ylation · density functional calcula-
tions photochemistry radical
ions · time-resolved spectroscopy
ACHTUNGTNERbNUNG ox-
A
A
·
·
Introduction
50%).[12–16] However, the dissociated form of KP tends to
undergo a prompt photodecarboxylation reaction to gener-
ate a benzylic carbanion intermediate in phosphate buffered
(PB) solutions (pH 7.4) and in basic solutions.[12–16] Recently,
Scaiano and co-workers reported a new phototrigger based
on the photochemistry of KP.[17] KP exhibits interesting fea-
tures of rapid and efficient photodecarboxylation (F=0.75)
to give a benzylic carbanion after electronic excitation of
After irradiation, Ketoprofen (KP) is known to induce pho-
totoxicity, which hinders its applications as a nonsteroidal
anti-inflammatory drug (NSAID).[1–2] To understand further
the phototoxicity of KP, much research has focused on the
photochemistry of KP and its derivatives.[3–11] Laser flash
photolysis (LFP) and nanosecond time-resolved resonance
Raman spectroscopy (ns-TR3) studies on KP established
that the neutral form of KP exhibits a benzophenone-like
photochemistry to give rise to the triplet state of KP (3KP),
KP in PB solution. Subsequently, the benzylic carbACHTUNGTRENNUNGanion is
rapidly protonated by the solvent (kꢁ4.9ꢁ106 sꢀ1) to give 3-
ethylbenzophenone.[17] Derivatives of KP that include an ap-
propriate leaving group sited on the photogenerated carban-
ion intermediate can release the leaving group in its active
form, along with the final product 3-(2’-allyl)benzophe-
none.[17] Among these types of derivatives, 2-acetoxymethyl-
2-(3-benzoylphenyl)propionic acid (KP-OAc) has a higher
efficiency for photorelease that significantly competes with
the protonation of the carbanion intermediate. Therefore,
the lifetime of the benzylic carbanion of KP-OAc becomes
significantly shorter compared with that of the benzylic car-
banion formed from KP. Recent ns-TR3 studies on the pho-
tochemistry of KP revealed that water molecules or acid can
assist the excited triplet state intramolecular proton transfer
(ESIPT) from the carboxyl group to the carbonyl group; the
neutral form of KP can then also undergo a photodecarbox-
which, in turn, produces a ketyl radical species in non
ACHTUNGTRENNUNGous solvents such as neat acetonitrile or isopropanol, and in
aqueous solutions with a low concentration of water (below
ACHTUNGTNERaNUNG que-
[a] Dr. M.-D. Li
Department of Chemistry, University of California
Berkeley, California, 94720 (USA)
[b] T. Su, J. Ma, M. Liu, Dr. H. Liu, Prof. Dr. X. Li,
Prof. Dr. D. L. Phillips
Department of Chemistry, The University of Hong Kong
Pokfulam Road, Hong Kong (P.R. China)
E-mail: phillips@hku.hk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300285. It contains details of
the DFT calculations and the procedure used to synthesize KP-OAc.
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Photochemistry of a Ketoprofen Derivative
FULL PAPER
ylation reaction in neutral solutions with a high concentra-
tion of water (more than 70%) or strongly acidic solutions.
3
The photodecarboxylation reaction causes the KP to trans-
form into a biradical intermediate.[18] Although we proposed
that the benzylic carbanion of KP was not involved in the
photodecarboxylation reaction of the neutral form of KP in
neutral solutions with a high concentration of water or
acidic solutions, compared with a predominant benzylic car-
banion intermediate generated from KP in PB solution,
there is no unambiguous evidence to support this proposed
mechanism. Here, KP-OAc was used as a model to study
the highly efficient photogenerated carbanion induced pho-
totrigger reaction in PB solution as well as water- or acid-as-
sisted photodecarboxylation reactions to generate the birad-
ical intermediate directly in neutral solutions with a high
concentration of water or strongly acidic solutions. In PB
solution, the negative charge located on the benzylic carban-
ion is the driving force that initiates photorelease of the
AcOꢀ group and this leads to fast decay of the carbanion in-
termediate. Solvent-mediated ESIPT may shuttle a proton
from the carboxyl group to the carbonyl group, which will
induce the photodecarboxylation reaction and generate a
KP-OAc biradical intermediate. The KP-OAc biradical spe-
cies is very stable in neutral solutions with a high concentra-
tion of water or strongly acidic solutions. The phototrigger
reaction to release the AcOꢀ group is not likely to occur
from the KP-OAc biradical intermediate, so the lifetime of
the KP-OAc biradical may last for several hundreds of
nanoseconds.
Results and Discussions
Ns-TR3 spectra of KP-OAc in neutral solutions with a low
concentration of water —formation of a ketyl radical inter-
mediate: Figure 1 A shows the ns-TR3 spectra of KP-OAc
obtained in pure acetonitrile (CH3CN) solvent. At early
delay times, one species with its main resonance Raman
bands at 966, 1173, 1221, and 1538 cmꢀ1 was observed. This
first species, seen in the ns-TR3 spectra, is assigned to the
triplet state of KP-OAc (3KP-OAc) for the following rea-
sons. The spectrum of KP-OAc obtained at 0 ns in CH3CN
solvent was in good agreement with that of KP obtained at
5 ns in CH3CN solvent.[15] Because CH3CN is a relatively
inert solvent, the intermediate of KP observed on the nano-
second time-scale in pure CH3CN has previously been as-
Figure 1. A) Ns-TR3 spectra of KP-OAc in pure CH3CN and B) in H2O/
CH3CN 1:1 obtained by using 266 nm pump excitation wavelength and
319.9 nm probe wavelength at various time delays indicated next to the
spectra. The asterisk (*) marks regions affected by solvent subtraction
artifacts and/or stray light.
3
signed as a KP on the basis of femtosecond transient ab-
sorption (fs-TA) and ns-TR3 studies.[19] Thus, the first species
of KP-OAc at 0 ns observed in pure CH3CN can readily be
acteristic Raman band at 1538 cmꢀ1 of KP-OAc indicates
3
3
that KP-OAc is the precursor of the second intermediate.
3
3
assigned to the KP-OAc intermediate. At later delay times
As the KP-OAc species decays, a new intermediate emerg-
(180 ns), a very weak band appears at 1582 cmꢀ1, which can
be attributed to the formation of a ketyl radical, possibly
generated from intramolecular hydrogen abstraction on the
side chain in KP-OAc.[15] Figure 1 B displays the ns-TR3
spectra of KP-OAc obtained in a H2O/CH3CN 1:1 mixture.
At 0 ns, the band in the Raman spectrum at 1538 cmꢀ1 has a
shoulder at 1582 cmꢀ1. Initially, the observation of the char-
es with main Raman bands at 987, 1177, and 1582 cmꢀ1. The
latter band is characteristic of the ketyl radical of KP, which
indicates that the new species observed following decay of
3
3KP-OAc is a ketyl radical produced when the KP-OAc in-
termediate reacts with the surrounding water molecules,
similar to previously observed spectra for KP in analogous
solutions.[16] Subsequently, the KP-OAc ketyl radical may
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D. L. Phillips et al.
decay either by a self-coupling reaction or by a cross-cou-
pling reaction with water molecules to form a metastable
light absorption transient (LAT) intermediate that can sur-
vive hundreds of microseconds.[1] Therefore, at delay times
of more than 1 microsecond the Raman signal at 1592 cmꢀ1
and 1648 cmꢀ1 is due to the long-lived LAT species.
The triplet state of benzophenone (BP; the parent chro-
mophore of KP-OAc) does not easily abstract hydrogen
from CH3CN, and no Raman signal for the ketyl radical was
observed in pure CH3CN solvent. Only the Raman signal of
the triplet state of BP was observed in pure CH3CN sol-
vent.[9,20] For BP and KP, Raman spectra apparently due to a
ketyl radical-like species can be observed in aqueous solu-
tions on the nanosecond time-scale. Furthermore, for KP,
the intensity of the Raman signal of the apparent ketyl radi-
cal-like species gradually becomes stronger as the water
concentration increases from 10 to 50%.[9] This suggests that
water molecules may play some role in the generation of
the ketyl radical-like species after photolysis of KP in aque-
ous environments. These results indicate that the triplet
state of BP and KP neither abstract hydrogen from CH3CN
solvent nor significantly abstract hydrogen from the ground
state of BP and KP, even though a higher concentration of
samples were used in the ns-TR3 experiments in pure
CH3CN solvent. The observation of the Raman signal of the
ketyl radical-like intermediate implies that the triplet state
of BP and KP may react with water through some reaction
to generate a ketyl radical-like intermediate; however,
mechanistic details for its formation are still not clear. Thus,
for KP-OAc, the source of the ketyl radical-like species in
solutions with a low concentration of water is not clearly un-
derstood and further work is required to better understand
how it is formed in these kinds of aqueous environments.
KP-OAc exhibits a benzophenone-like photochemical be-
havior in CH3CN solvent or neutral solutions with a low
concentration of water, which is similar to that of KP under
corresponding conditions. For the photochemical reaction of
KP-OAc in neutral solutions with a low concentration of
water, Scheme 1 shows that the singlet excited state of KP-
3
OAc will transform into the KP-OAc intermediate by an
3
ISC process, then the KP-OAc intermediate will undergo
some reaction to generate a ketyl radical species.
Figure 2. A) Ns-TR3 spectra of KP-OAc in H2O/CH3CN 8:2 and B) in
perchloric acid (H2O/CH3CN 1:1, pH 0) solutions obtained by using
266 nm pump excitation wavelength and 319.9 nm probe wavelength at
various time delays indicated next to the spectra. The asterisk (*) marks
regions affected by solvent subtraction artifacts and/or stray light.
Ns-TR3 spectra of KP-OAc in neutral solutions with a high
concentration of water or acidic solutions—direct formation
of the biradical intermediate: Figure 2 A shows the ns-TR3
spectra obtained in neutral solutions with a high concentra-
tion of water. A new Raman band at 1519 cmꢀ1 can be ob-
served in the 80% water solution compared with the Raman
spectra obtained in the 50% water solution. Previous studies
pointed out that the 1519 and 1579 cmꢀ1 Raman bands are
characteristic of the biradical
intermediate of KP and this in-
dicates that some portion of
KP-OAc molecules will under-
go a photodecarboxylation re-
action to generate a biradical
intermediate in solutions with a
Scheme 1. The proposed photochemistry mechanism of KP-OAc in neutral solutions with a low concentration high concentration of water.[16]
of water.
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Photochemistry of a Ketoprofen Derivative
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In Figure 2A, the intensity of the 1519 cmꢀ1 Raman band is
weaker than that of the 1582 cmꢀ1 band. In the CH3CN/H2O
2:8 solution, the photodecarboxylation reaction generating
the KP-OAc biradical and the reaction with water, generat-
ing the ketyl radical, occur on a similar time-scale so that
these two reactions compete. The KP-OAc biradical has a
characteristic Raman band at 1579 cmꢀ1 and the ketyl radi-
cal has a characteristic Raman band at 1582 cmꢀ1, thus these
two Raman bands overlap and make it difficult to complete-
ly separate them and study their kinetics with this Raman
feature. Nevertheless, it appears that the decay times of the
1519 and 1579 cmꢀ1 bands are different in the CH3CN/H2O
2:8 solution. It should be noted that DFT calculations pre-
dicted the Raman spectra of the KP-OAc biradical and indi-
cated that the 1519 and 1579 cmꢀ1 Raman bands correspond
to the KP-OAc biradical. Further increasing the water con-
centration will make the photodecarboxylation reaction
become the predominant process due to the increasing ef-
fectiveness of the water-mediated proton transfer from the
went a solvent-assisted ESIPT process and then the photo-
decarboxylation reaction was initiated to generate a biradi-
cal intermediate directly in neutral solutions with a high
concentration of water or acidic solutions, whereas the KP
anion tended to undergo its photodecarboxylation reaction
to directly produce the benzylic carbanion of KP with triplet
state character in PB solution. In an attempt to verify this
proposed mechanism, we chose to use KP-OAc as a model
molecule to test the mechanism. Previous studies by Scaiano
and co-workers found that KP-OAc was a clear and efficient
phototrigger that initiated photorelease of an AcOꢀ group,
and a benzylic carbanion intermediate was formed to medi-
ate the photorelease of the leaving group in PB solution.[17]
Figure 3 A displays the ns-TR3 spectra of KP-OAc obtained
3
in 50% PB solution. The KP-OAc intermediate is barely
observable in PB solution. A new species is observed at the
early delay times of ns-TR3 spectra and this species has its
main Raman bands at 989, 1178, 1519, and 1579 cmꢀ1. Due
to the observation of the characteristic Raman bands of the
biradical intermediate of KP at 1519 and 1579 cmꢀ1, this spe-
cies is assigned to the KP-OAc biradical intermediate gener-
ated by the photodecarboxylation reaction; this intermedi-
ate completely disappears after 100 ns. For KP in PB solu-
tion, Figure 3 B shows that the Raman intensity of the bi-
carboxyl group to the carbonyl group, which significantly in-
[18]
ꢀ
duces cleavage of the C C bond and the release of CO2.
Previous studies concluded that acid can also catalyze a sim-
ilar photodecarboxylation reaction of KP for which two
steps were involved when perchloric acid was used to induce
the photodecarboxylation reaction of KP in highly acidic
solutions.[18] For the acid-induced photodecarboxylation, the
carbonyl group is first protonated and then the proton of
the carboxyl group is transferred to the perchloric anion and
AHCTUNGTREGrNNUN adical intermediate is relatively strong and its lifetime is
clearly longer than that of the KP-OAc biradical species ob-
served in PB solution.[16,18]
Interestingly, the results obtained with KP-OAc in the ns-
TR3 study coincidentally confirm our initial hypothesis for
the reaction mechanism proposed for the decarboxylation of
KP under the different aqueous conditions. As expected, the
lifetime of the KP-OAc biradical is significantly shortened
in PB solution, whereas the lifetime of the KP-OAc biradi-
cal intermediate is not affected in neutral solutions with a
high concentration of water or acidic solutions. In solutions
with a high concentration of water or acidic solution (pH 0),
the dynamics of the KP-OAc biradical intermediate is
almost the same as that of KP obtained under the same con-
ditions.[18] For example, the time dependence of the integrat-
ed areas of the 1579 cmꢀ1 Raman band for the KP-OAc bir-
adical intermediate (closed squares) in a water/CH3CN 1:1
perchloric acid (pH 0) solution could be fit by a two-expo-
nential function with a ca. 13 ns growth time constant and a
ca. 240 ns decay time constant (see Figure 4). The KP-OAc
biradical intermediate could survive with a long lifetime
(240 ns decay time constant) that is very close to the lifetime
(ca 280 ns) of KP in the same solution.[18] This implies that a
KP-OAc biradical intermediate is directly generated by the
photodecarboxylation reaction with the assistance of water
or acid. The benzylic carbanion species is not involved in
the photochemistry of KP-OAc and KP in solutions with a
high concentration of water or acidic solutions. However,
the lifetime of the biradical intermediate of KP-OAc and
KP exhibits a salient difference in PB solution. Figure 5
presents a comparison of the kinetics of the biradical inter-
mediate for KP-OAc and KP obtained in 50% PB solution.
The decay time constant of the KP-OAc biradical intermedi-
ꢀ
simultaneous cleavage of C C leads to release of CO2.
Figure 2B presents the ns-TR3 spectra of KP-OAc ob-
tained in pH 0 aqueous solution. The main Raman bands
(966, 989, 1024, 1178, 1284, 1519, and 1579 cmꢀ1) of KP-
OAc are essentially the same as those observed for the KP
intermediates obtained in an analogous acidic aqueous solu-
tion, and this implies that a biradical intermediate is also
generated for the KP-OAc molecule. Therefore, KP-OAc
can also decarboxylate through catalysis by perchloric acid.
In acidic aqueous solution and phosphate buffer solutions,
the photodecarboxylation reaction is the predominant reac-
tion. Therefore, the biradical intermediate is the major tran-
sient detected, and the 1519 and 1579 cmꢀ1 Raman bands
have the same decay time because both correspond to the
biradical intermediate. As mentioned earlier, the Raman
band at 1582 cmꢀ1 is assigned to the ketyl radical. The
1519 cmꢀ1 Raman band is saliently enhanced compared with
that obtained in 80% water solution, which is consistent
with the activation energy barrier calculated for the acid-
mediated photodecarboxylation reaction of KP being lower
than that of the water-molecule-assisted photodecarboxyla-
tion reaction of KP.[18]
Ns-TR3 spectra of KP-OAc in PB solution—direct forma-
tion of the benzylic carbanion intermediate: Based on the
ns-TR3 and nanosecond transient absorption studies of KP
in neutral solutions with a high concentration of water or
acidic solutions and DFT calculations simulating the sol-
vent-assisted ESIPT process, we proposed that KP under-
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D. L. Phillips et al.
Figure 4. Time dependence of the integrated areas of the 1579 cmꢀ1
Raman band of the biradical intermediate for KP-OAc (closed squares)
in perchloric acid/(H2O/CH3CN 1:1) pH 0 were fit by a two-exponential
function with a ca. 13 ns growth time constant and a ca. 240 ns decay
time constant.
Figure 5. Time dependence of the integrated areas of the 1579 cmꢀ1
Raman band for the biradical intermediate of KP-OAc (open circles) in
PB/CH3CN 1:1 were fit by a two-exponential function with a ca. 30 ns
decay time constant. Time dependence of the integrated areas of the
1579 cmꢀ1 Raman band for the biradical intermediate of KP (open
squares) in PB/CH3CN 1:1 were fit by a two-exponential function with a
ca. 37 ns growth time constant and a ca. 780 ns decay time constant.
Figure 3. A) Ns-TR3 spectra of KP-OAc in PB/CH3CN 1:1 and B) ns-TR3
spectra of KP in PB/CH3CN 1:1 obtained by using 266 nm pump excita-
tion wavelength and 319.9 nm probe wavelength at various time delays
indicated next to the spectra. The asterisk (*) marks regions affected by
solvent subtraction artifacts and/or stray light.
(see Scheme 3). Therefore, the predominant competitive
phototrigger reaction will significantly shorten the lifetime
of the KP-OAc biradical intermediate. As for KP, the ben-
ate in PB solution is only 30 ns, which is dramatically shorter
than the time constant of the biradical intermediate for KP
in PB solution (780 ns). For KP, the formation process of the
biradical intermediate is still readily observed in 50% PB
solution, whereas only the decay process of the KP-OAc bi-
zylic carbACTHNUTRGENUGaN nion is resonant with the biradical intermediate,
which may last for a long lifetime, and then finally the birad-
ical intermediate will undergo a hydrogen shift and intersys-
tem crossing (ISC) to generate the final product.[8]
ACHTUNGTRENNUNG
Benzylic carbanion switches on and biradical intermediate
A
switches off the photoreleasing reaction of KP-OAc: To
obtain direct evidence to confirm that the photodecarboxACHTUNGTRENNUNGyl-
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Scheme 2. The proposed photodecarboxylation mechanism of KP-OAc in solutions with a high concentration of water (water-rich) or acidic solutions.
3
ation reaction is initiated from the KP-OAc, femtosecond
generates a biradical intermediate. Although 3KP-OAc al-
ready decays to some extent within 3 ns, the triplet state is
still observed at the beginning of the nanosecond time
delays, and a shoulder Raman band of the 1538 cmꢀ1 main
Raman band can be observed. In PB solution, with the dra-
matic decay of the band intensity at 523 nm, a new band ap-
pears around 600 nm that is assigned to the benzylic carban-
transient absorption (fs-TA) experiments were conducted
for KP-OAc in pure CH3CN solution, in high water content
solution, in acidic aqueous solution, and in PB aqueous solu-
tion. In pure CH3CN solvent, a sharp band (maximum at
334 nm) was first observed, which gradually increased in in-
tensity on the early picosecond time-scale (see Figure 1S in
the Supporting Information); this transient was assigned to
the singlet state of KP-OAc.[12,19] Subsequently, the sharp
band around 334 nm gradually reduced in intensity and
shifted to 325 nm; at the same time, a broad band (maxi-
mum at 523 nm) appeared and gradually increased in inten-
sity within 50 ps (see Figure 1S). This process can be as-
signed to the singlet state undergoing an intersystem cross-
ing (ISC) process to form 3KP-OAc.[12,19] The 3KP-OAc is
relatively stable in this solvent and does not decay within
3 ns, so that the Raman band at
3
ion species.[12,19] Therefore, in PB solution, KP-OAc cannot
be observed in the ns-TR3 experiment. The observation of
3
the ISC process and KP-OAc in higher water content solu-
tion, acidic aqueous solution, and PB solution by the fs-TA
experiments suggests that the KP-OAc biradical and carban-
ion species are formed in the triplet state.
Schemes 2 and 3 display the proposed photochemistry
mechanisms of KP-OAc in neutral solutions with a high con-
centration of water, acidic, and PB solutions. After 266 nm
1538 cmꢀ1, which was assigned
3
to KP-OAc, can be clearly ob-
served in the ns-TR3 experi-
ments performed in pure
CH3CN solvent. In solutions
with
a low concentration of
water, 3KP-OAc slightly re-
duces in intensity within 3 ns,
but can still be observed within
100 ns in this solvent system. In
higher water content solution
and in acidic solution, a photo-
Scheme 3. The proposed photodecarboxylation mechanism of KP-OAc in PB solution.
chemical process similar to that
observed in pure CH3CN solvent and in solutions with a low
concentration of water is also observed. First, a sharp band
around 334 nm increases in intensity within about 1 ps (see
Figure 2S in the Supporting Information); this transient can
be assigned to the S1!Sn transition absorption from the S1
(np*) singlet state. Then the band at 334 nm decreases in in-
tensity and a broad band at 523 nm increases in intensity
(see Figure 6 a and b) in a process that corresponds to the
photoexcitation in neutral solutions with a high concentra-
tion of water or acidic solutions, the singlet excited state un-
dergoes intersystem crossing (ISC) to transform into the
3
triplet excited state so that the KP-OAc species is the inter-
mediate first observed by the ns-TR3 experiments, and then
the excited triplet state proton transfer from the carboxyl to
carbonyl group occurs with the assistance of water mole-
cules or perchloric acid to produce a very short-lived zwit-
terion intermediate that subsequently undergoes a fast com-
petitive intramolecular charge transfer to evolve into the
KP-OAc biradical intermediate, which has a relatively long
lifetime. Previous studies showed that acid can also catalyze
the photodecarboxylation reaction of KP, for which two
steps were involved when perchloric acid was used to induce
the photodecarboxylation reaction of KP in the strong
acidic solutions.[18]
3
singlet state undergoing ISC to form the KP-OAc with high
efficiency. The band at 523 nm begins to decrease in intensi-
ty with an increase of the delay times in solutions with a
high concentration of water and in acidic aqueous solution,
3
which indicates that KP-OAc partly decays through decar-
boxylation reaction in these types of solutions. With the
decay of the band at 523 nm at later times (several ns), a
band at 325 nm begins to increase in intensity again, the
new band around 325 nm is assigned to the biradical spe-
For the acid-induced photodecarboxylation, DFT calcula-
tions showed that the carbonyl group is protonated first and
3
cies[19] and demonstrates that the decay of KP-OAc directly
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D. L. Phillips et al.
Figure 6. Transient absorption spectra of KP-OAc obtained in a) H2O/CH3CN 8:2, b) in acidic H2O/CH3CN 1:1, pH 0, and c) in CH3CN/PB 1:1, pH 7.4.
then the proton of the carboxyl group is transferred to the
acid KP in the S0 is 4.7[1] and the pKa of triplet state of BP is
1.5,[21–24] the low activation reaction barriers make it possible
that KP-OAc can decarboxylate through catalysis by
perchloric acid. However, in PB solution, the deprotonated
form initiates the photochemistry of KP-OAc. When KP-
OAc is excited at 266 nm, ISC will lead to the generation of
ꢀ
perchloric anion and, simultaneously, cleavage of C C leads
to release of CO2. The activation energy barriers for
perchloric acid assisted proton transfer from the hydroxyl
group to the carbonyl group are ꢀ0.21 and ꢀ1.32 kcalmolꢀ1,
respectively. For those systems with negative reaction barri-
ers, these reactions usually need to overcome the low activa-
tion reaction barriers.[20] Therefore, although the pKa of the
the
carboxylation reaction on the sub-nanosecond time-scale to
3[KP-OAc]ꢀ anion, which will undergo a fast photode-
ACHTUNGTRENNUNG
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Photochemistry of a Ketoprofen Derivative
FULL PAPER
generate a benzylic carbanion species that will induce the
phototrigger reaction to release the leaving group AcOꢀ and
subsequently form the final product 3-(2’-allyl)benzophe-
none. The KP-OAc biradical anion is a resonant structure of
the benzylic carbanion, and such a KP-OAc biradical inter-
mediate is also observed in PB solution by the ns-TR3 ex-
periments. Although the zwitterion has a negative charge lo-
cated at the sidechain of KP-OAc, it must be noted that the
zwitterion intermediate does not easily undergo the photo-
trigger reaction because the lifetime of the KP-OAc biradi-
cal is almost the same as that of the KP biradical under
analogous conditions. A possible reason for this is that the
intramolecular charge transfer is a very fast process, mean-
ing that the phototrigger reaction cannot compete with the
intramolecular charge transfer.
Figure 8. Relative energy profiles (in kcalmolꢀ1
) obtained from the
UB3LYP/6-311G** calculations for the phototrigger reactions of the ben-
zylic carbanion and the KP-OAc biradical intermediate.
DFT computational study on the mechanism of the benzylic
carbanion and biradical intermediates mediating the photo-
trigger reaction of KP-OAc: To gain more insight into the
phototrigger reaction mechanism of KP-OAc, DFT calcula-
tions were carried out to simulate the benzylic carbanion
and KP-OAc biradical intermediates mediating the photore-
lease reaction. Figure 7 shows the optimized geometries
(bond lengths in ꢂ) of reactive complexes (RC), transition
energy profiles (in kcalmolꢀ1) obtained from the UB3LYP/
6-311G** calculations for the phototrigger reactions of the
benzylic carbanion and the KP-OAc biradical intermediate.
The free energy barrier for the phototrigger reaction of the
benzylic carbanion only needs
to
overcome
9 kcalmolꢀ1,
whereas it is 15.5 kcalmolꢀ1 for
the biradical intermediate pho-
totrigger reaction. Therefore,
the negative charge located on
the C(1) atom will greatly pro-
mote release of the AcOꢀ
anion. The phototrigger reac-
tion can be expected to easily
consume the benzylic carban-
ion, which provides a basic ex-
planation that is consistent with
the experimental observation
that the lifetime of the KP-OAc
biradical intermediate is very
short in PB solution.
Figure 7. Optimized geometries (bond lengths in ꢂ) of the reactive complex (RC), the transition state (TS)
and the product complex (PC) found from the UB3LPY/6-311G** calculations for the phototrigger reactions
of the benzylic carbanion and the KP-OAc biradical intermediate.
states (TS), and product complexes (PC) found from the
UB3LPY/6-311G** calculations for the phototrigger reac-
tions of the benzylic carbanion and the KP-OAc biradical
intermediates. The bond distance between C(2) and O(3)
(labeled in Figure 7) is 1.470 ꢂ for the benzylic carbanion,
which is somewhat longer than that for the KP-OAc biradi-
cal intermediate (1.452 ꢂ). This reveals that cleavage be-
tween C(2) and O(3) is more facile for the benzylic carban-
ion. Additionally, the bond distance between C(2) and O(3)
is 2.185 ꢂ in the TS of the benzylic carbanion whereas it is
2.243 ꢂ in the TS of the KP-OAc biradical intermediate.
The energy barrier to scan from 1.470 to 2.185 ꢂ for the
benzylic carbanion can be expected to be smaller than the
energy barrier upon going from 1.452 to 2.243 ꢂ for the KP-
OAc biradical intermediate. Figure 8 shows the relative
Conclusion
This study investigated the photochemical reaction mecha-
nisms of KP-OAc in solutions with a low and a high concen-
tration of water, acidic, and PB solutions. In neutral solu-
tions with a low concentration of water, ns-TR3 spectra re-
vealed that a 3KP-OAc intermediate was first observed,
which then transformed into a ketyl radical intermediate by
some reaction with the sidechain of KP-OAc or surrounding
water molecules. In neutral solutions with a high concentra-
tion of water, KP-OAc underwent a photodecarboxylation
reaction with the assistance of water molecules or perchloric
acid to directly generate a KP-OAc biradical intermediate
that cannot easily induce the phototrigger reaction. In PB
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D. L. Phillips et al.
resonance Raman spectrum. The TR3 spectra presented here were ob-
tained by subtracting the resonance Raman spectrum with a negative
time delay of ꢀ100 ns (probe-before-pump spectrum) from the resonance
Raman spectrum with a positive time delay (pump-probe spectrum). The
TR3 spectra in this work were calibrated by using the known Raman
bands of CH3CN solvent with an estimated accuracy of ꢂ5 cmꢀ1. In the
ns-TR3 experiments, a micropump was employed to push the sample sol-
ution, and a 1 mm concentration of KP was used in the ns-TR3 experi-
ments.
solution, the deprotonated KP-OAc anion underwent a pho-
todecarboxylation reaction to directly produce a benzylic
carbanion intermediate that can easily induce a phototrigger
reaction to release the leaving group AcOꢀ. Therefore, the
KP-OAc system is a good model molecule with which to ex-
amine the proposed photochemistry mechanisms of KP and
its derivatives. Water or acid can mediate ESIPT processes
that will induce photodecarboxylation reactions of KP in
neutral and acidic aqueous solutions. It should be noted that
the new insight into the intermediates that more easily un-
dergo phototrigger reactions in the photochemistry mecha-
nisms of KP-based derivatives makes it possible to under-
stand how to modulate the phototrigger reactions of KP de-
rivative compounds and, potentially, other aromatic carbon-
yl based systems by varying the pH values of the solutions
as well as modulating the properties of the key reactive in-
termediates. When the pH value is increased to a slightly
basic solution, the phototrigger reaction will occur mostly
from the anionic form of the derivative, in the case of KP-
OAc, the phototrigger reaction is switched on, whereas de-
creasing the pH value in an acidic solution will switch off
the phototrigger reaction in the case of KP-OAc. As a con-
sequence, this makes KP-based phototrigger compounds
very promising platforms with which to develop new types
of phototriggers for utilization in the biological and medical
fields.
Fs-TA experiments: The fs-TA experiments were performed by using ap-
paratus and methods discussed in detail previously.[19, 26] The fs-TA meas-
urements were performed based on a femtosecond Ti:Sapphire regenera-
tive amplified Ti:sapphire laser system and an automated data acquisition
system. At each temporal delay, data were averaged for 2 s. For the pres-
ent experiments, the sample solution was excited by a 267 nm pump
beam (the third harmonic of the fundamental 800 nm from the regenera-
tive amplifier). The 50 mL solutions were studied in a flowing 2 mm
path-length cuvette with the intensity of absorption 1.0 at 267 nm
throughout the data acquisition. The raw spectra obtained for KP-OAc in
water solutions contain an overlapping contribution from the sample ab-
sorption and solvated electrons produced by the two-photo ionization of
the water when 267 nm was used as pump laser. The hydrated electron
has a very strong absorption at approximately 600 nm. Therefore, sub-
traction of the solvent signal should be performed to compensate for the
influence of the solvent signal as soon as possible; under these conditions,
most of the contribution of the hydrated electron signal will be eliminat-
ed. Details of the methods used for this were described previously.[27]
DFT calculations: Density functional theory (DFT) was used to investi-
gate the phototrigger reaction of the benzylic carbanion and the biradical
intermediates for KP-OAc. The optimized geometries, vibrational modes,
and the vibrational frequencies for the different species were obtained
from (U)B3LYP DFT calculations employing a 6-311G** basis set. No
imaginary frequency modes were observed at the stationary states of the
optimized structures shown here and only one imaginary frequency was
observed for the saddle point transition state structures. All of the reac-
tions have been explored by optimizing the structures of the reactant
(RC), transition states (TS), and product complexes (PC). Transition
states were located by using the Berny algorithm. Frequency calculations
at the same level of theory have also been performed to identify all of
the stationary points as minima for transition states (one imaginary fre-
quency). Intrinsic reaction coordinates (IRC)[28] were calculated for the
transition states to confirm that the relevant structures connect the two
relevant minima. All of the calculations were performed using the Gaus-
sian 03 program suite.[29]
Experimental and Computational Methods
Materials: 2-Acetoxymethyl-2-(3-benzoylphenyl)propionic acid was pre-
pared by following literature procedures with minor modification. Com-
mercially available 2-(3-benzoylphenyl)-2-methyl propionic acid (Keto-
profen) and other reagents were used without further purification. 1H
and 13C NMR spectra were recorded with a Bruker AVANCE 400 spec-
trometer at 400 MHz and 100 MHz, respectively. All NMR data were in
accordance with reported data.[17] Details of the synthetic procedures are
presented in the Supporting Information.
Perchloric acid (reagent grade from Aldrich) was used to vary the pH
value of the aqueous solutions used in all of the experiments reported
here. Spectroscopic grade CH3CN and deionized water were used as sol-
vents for the experiments presented in this work. In the ns-TR3 experi-
ments, the concentration of the experimental sample of KP-OAc was
1 mm. Unless specified, all of the mixed solvent ratios were of volume
ratio.
Ns-TR3 experiments: The nanosecond time-resolved resonance Raman
(ns-TR3) experiments were performed with an apparatus and methods
discussed in detail previously[25] and only a brief description will be given
here. The 266 nm pump laser pulse generated from the fourth harmonic
of a Nd:YAG nanosecond pulsed laser and a 319.9 nm probe laser pulse
produced from the third anti-Stokes hydrogen Raman shifted laser line
from the second harmonic were used in the TR3 experiments. The two
Nd:YAG lasers were synchronized electronically by a pulse delay genera-
tor (DG535) to control the time delay of pump and probe lasers, and this
time delay between the laser pulses was monitored by a fast photodiode
and a 500 MHz oscilloscope. The time resolution for the TR3 experiments
was approximately 10 ns. The pump and probe laser beams were lightly
focused onto the sampling system and the Raman light was collected
using reflective optics into a spectrometer the grating of which dispersed
the light onto a liquid nitrogen cooled CCD detector. The Raman signal
was acquired for 30 s by the CCD before reading out in the interfaced
PC computer and 10 scans of the signal were accumulated to produce a
Acknowledgements
This work was supported by a grant from the Research Grants Council
of Hong Kong (HKU 7035/08P and HKU 7048/11P) to D.L.P. and partial
support from the Areas of Excellence Scheme (AoE/P-03/08) and the
Special Equipment Grant (SEG HKU/07) are also gratefully acknowl-
edged.
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Received: January 25, 2013
Published online: && &&, 0000
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