Direct Observation of Photoinduced Ultrafast Generation of Singlet and Triplet Quinone Methides in Aqueous Solutions and Insight into the Roles of Acidic and Basic Sites in Quinone Methide Formation

Article abstract of DOI:10.1021/jacs.7b10387

Femtosecond time-resolved transient absorption spectroscopy experiments and density functional theory computations were done for a mechanistic investigation of 3-(1-phenylvinyl)phenol (1) and 3-hydroxybenzophenone (2) in selected solvents. Both compounds went through an intersystem crossing (ISC) to form the triplet excited states T? and Tn? in acetonitrile but behave differently in neutral aqueous solutions, in which a triplet excited state proton transfer (ESPT) induced by the ISC process is also proposed for 2 but a singlet ESPT without ISC is proposed for 1, leading to the production of the triplet quinone methide (QM) and the singlet excited QM species respectively in these two systems. The triplet QM then underwent an ISC process to form an unstable ground state intermediate which soon returned to its starting material 2. However, the singlet excited state QM went through an internal conversion process to the ground state QM followed by the formation of its final product in an irreversible manner. These differences are thought to be derived from the slow vinyl C-C rotation and the moderate basicity of the vinyl C atom in 1 as compared with the fast C-O rotation and the greater basicity of the carbonyl O atom of 2 after photoexcitation. This can account for the experimental results in the literature that the aromatic vinyl compounds undergo efficient singlet excited state photochemical reactions while the aromatic carbonyl compounds prefer triplet photochemical reactions under aqueous conditions. These results have fundamental and significant implications for understanding of the ESPT reactivity in general, as well as for the design of molecules for efficient QM formation in aqueous media with potential applications in cancer phototherapy.

Full text of DOI:10.1021/jacs.7b10387

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Article
Direct Observation of Photoinduced Ultrafast Generation of Singlet
and Triplet Quinone Methides in Aqueous Solutions and Insight into
the Roles of Acidic and Basic Sites in Quinone Methide Formation
Jia ni Ma, Xiting Zhang, Nikola Basaric, and David Lee Phillips
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b10387 • Publication Date (Web): 28 Nov 2017
Downloaded from http://pubs.acs.org on November 28, 2017
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Direct Observation of Photoinduced Ultrafast Generation of Singlet
and Triplet Quinone Methides in Aqueous Solutions and Insight into
the Roles of Acidic and Basic Sites in Quinone Methide Formation
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*,1‡
*,2‡
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*,2
Jiani Ma , Xiting Zhang , Nikola Basarić and David Lee Phillips
1
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry
and Materials Science, Northwest University, Xi’an, P. R. China
2 Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. China
3
Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, 10 000 Zagreb, Croatia
KEYWORDS ESPT, Quinone methide, Ultrafast transient absorption, DFT calculations
ABSTRACT: Femtosecond time-resolved transient absorption spectroscopy (fs-TA) experiments and density functional theory
(DFT) computations were done for a mechanistic investigation of 3-(1-phenylvinyl)phenol (1) and 3-hydroxybenzophenone (2) in
selected solvents. Both compounds went through an intersystem crossing (ISC) to form the triplet excited states T* and Tn* in
acetonitrile (ACN) but behave differently in neutral aqueous solutions, in which a triplet excited state proton transfer (ESPT) pro-
cess induced by the ISC process is also proposed for 2 but a singlet ESPT process without ISC is proposed for 1, leading to the
production of the triplet quinone methide (QM) and the singlet excited QM species respectively in these two systems. The triplet
QM then underwent an ISC process to form an unstable ground state intermediate which soon returned to its starting material 2. On
the other hand, the singlet excited state QM went through an internal conversion (IC) process to the ground state QM followed by
the formation of its final product in an irreversible manner. These differences are thought to be derived from the slow vinyl C-C
rotation and the moderate basicity of the vinyl C atom in 1 as compared with the fast C-O rotation and the more basicity of the
carbonyl O atom of 2 after photoexcitation. This can account for the experimental results in the literature that the aromatic vinyl
compounds undergo efficient singlet excited state photochemical reactions while the aromatic carbonyl compounds prefer triplet
photochemical reactions under aqueous conditions. These results have fundamental and significant implications for the understand-
ing of the ESPT reactivity in general, as well as for the design of molecules for efficient QM formation in aqueous media with
potential applications in cancer phototherapy.
INTRODUCTION
systems to achieve high quantum yields of QM formation. On
the other hand, a number of investigations have been done to
examine the photochemical reaction mechanisms of these
systems which are important to elucidate how QMs are pro-
duced and which processes determine the yields and products
made. The accurate identification of the intermediates gener-
ated upon irradiation is also necessary to know when these
systems are to be used in biological applications.
Excited state proton transfer (ESPT) is an essential biological
and chemical process that has been investigated by a large
number of researchers. An aromatic molecule containing both
acidic and basic positions will typically display greater acidity
and basicity upon excitation, respectively and thus afford
opportunities for the excited state proton transfer (ESPT) to
occur. ESPT reactions can results in the production of tauto-
mers which may be hard to make by thermal methods.
Quinone methides (QMs) are reactive intermediates of general
interest in different areas of chemistry. QMs have been shown
to undergo reactions with amino acids and DNA, and QMs
can also alkylate and crosslink DNA which enables them to
1
14
2
In some of the molecular systems that are of interest to be
used in biological applications, ESPT is sometimes thought to
be involved in the reaction mechanisms for QM production.
For ESPT reactions previously examined, a typical acidic
location may be a phenolic proton, and a typical basic location
3
4
5
67
15
may be a heteroatom on a heterocyclic ring, or a carbonyl
become powerful agents in cancer therapy. Although QMs
may be formed in thermal reactions,
reactions of some phenols [like photodehydroxylation of hy-
16
8 9 10
moiety. Remarkably, the carbon atom was recently found to
the photochemical
be able to act as a basic group.2 Wan and coworkers reported
that the ESPT in3-(1-phenylvinyl)phenol (1) gives the QM
species (1QM), which is trapped by water forming a diaryl
11
12
droxybenzylphenols, photoelimination of acetic acid or
13
amines ] have appeal due to the milder reaction conditions
1
718
ethanol product. The protonation of carbon atoms has been
considered to take place slower than the protonation of het-
needed to generate them. Photoinduced QM formation also
has potential uses in photodynamic therapy applications.
Much effort has gone into the development of new molecular
1
9
eroatoms, and therefore, it was not usually taken into ac-
count as a competing excited state pathway with ESPT to H O
2
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or ESPT to heteroatoms. However, theoretical and experi-
mental investigations provided pieces of evidence that pro-
tonation of carbon atoms can be fast and compete with ESPT.
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Scheme 1. The proposed QM formation mechanisms of 1 and
2
in neural aqueous solutions include a concerted pathway and
17-18
a stepwise pathway as illustrated below.
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Although a lot of effort has been out toward the study of 1 and
useful information has been obtained, several questions are
still left to be answered. First, only the decay of the QM was
observed by nanosecond transient absorption (ns-TA) spectra
due to the apparent ultrafast formation of the QM species of
1
7-18
1. Hence, how the QM species is formed is still uncertain.
It could be accomplished by a concerted water-relay ESPT
with the phenolic proton transfer to the alkene α-carbon, or by
a stepwise ESPT with the phenolic proton ionized first to the
solvent and then a fast reprotonation at the alkene α-carbon
Figure 1.The fs-TA spectra of 1 in ACN at (a) early, (b) late
times after 267-nm excitation, and (c) the comparison of the
calculated UV-vis spectra of likely intermediate species with
the experimental fs-TA spectra. The calculated UV-vis spectra
were calculated at the TD-M062X/6-311+G** (ACN) level of
theory using a scale factor of 1.05 and a half-width of 1800
(Scheme 1). Second, as mentioned above, the carbonyl group
is a typical basic site for the ESPT while the carbon atom is
viewed as an unusual group to be protonated. However, the
fast overall rates and high quantum efficiencies of 1 to gener-
ate the QM intermediate observed are surprising. Furthermore,
it is reported that the transfer of the proton to a carbonyl group
is easily reversible reaction, while the ESPT to a carbon atom
is in many cases irreversible that can lead to subsequent reac-
-1
cm .
Figure 1 presents the fs-TA spectra of 1 in neat ACN. Upon
2
67-nm excitation, 1 is excited to a high excited state S as
3
suggested by results from TD-DFT calculations. Then, S3
proceeds to the lowest singlet excited state 1(S ) with a 333
2
1222324
1
tion to form a reactive QM.
Third, the generation of the
nm absorption band via an internal conversion (IC) from 0 to 1
ps, as shown in Figure 1a. The clear isobestic feature at 342
nm in Figure 1b indicates a dynamical transformation from
QM intermediate of 1 was reported to take place via a singlet
excited state as in many other cases of QM formation. Differ-
ently, a facile intersystem crossing (ISC) to the triplet state in
benzophenone containing compounds that have a carbonyl
1
(S ) to another species that appears at 376, 480 and 615 nm
1
during the time range from 1.5 ps to 8.4 ps. The new species
denoted as X) is likely the triplet produced via ISC in view of
2
5
group is also well known to occur. To clarify the above
questions and to unravel the reasons for the efficient QM
generation of 1 as well as to illuminate how the carbon atom
(
the transformation time scale. From 8.4 ps the species X de-
cayed as the absorbance features at 376, 480 and 615 nm
diminished in intensity while the band at 333 nm increased up
to the time delay of 2.96 ns, suggesting the generation of
another species (denoted as Y). The species Y has prominent
absorption bands at 333 and 376 nm. Simulated UV-vis spec-
of the vinyl CH moiety in 1 affects the ESPT process, we
2
have chosen to conduct the ultrafast spectroscopic study for 1,
as well as for 3-hydroxybenzophenone (2) (Scheme 1) which
contains a more electron-withdrawing oxygen part of the
carbonyl moiety and also has the same acidic site of the phe-
nolic proton as found in 1. Our main finding is that water-
assisted ESPT takes place in both molecules giving zwitterion-
ic QMs in the excited state, singlet for 1 and triplet for2. How-
ever, the ground state zwitterionic structure is only possible in
the case of 1, leading to the efficient hydration, and the lack of
hydration for 2.
tra by TD-M062X for 1(S ), 1(Tn*) and 1(T*) (Figure 1c)
1
respectively resemble the corresponding experimental spectra
of 1(S ), X and Y. That is, the species generated in ACN at
1
7
05 fs, 2.51 ps and 2.96 ns can be attributed to the
1
(S ),1(T*) and 1(Tn*) species, respectively. The assign-
1
ment agrees with Wan and coworkers’ work using nanosecond
transient absorption spectra that no transients were observed in
pure ACN and the formation of QM was excluded under this
RESULTS AND DISCUSSION
A. fs-TA and DFT Study of1
17,18
solution condition.
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at very early time (Figure 3a) is similar to that found in ACN,
indicating that the 1(S ) →1(S *) process also takes place in
1
2
3
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6
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3
1
neutral aqueous solution. After 3.44 ps the absence of the
absorption bands at 376, 480 and 615 nm implies that the
1(T*) and 1(Tn*) species detected in ACN were not gen-
erated in the neutral aqueous solution. Instead, a new intense
band was formed at 405 nm and the initial absorbance at 330
nm was also not decreased significantly from 3.44 ps to 32.4
ps, indicating that the new species (denoted as IM1 hereafter)
observed should have two comparable characteristic absorp-
tions at both 330 and 405 nm. As the delay time increased,
IM1 transformed soon into another transient species (denoted
as IM2) with its absorbance band red shifted from 405 nm to
8
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Figure 2.The structural parameters (Å) and the corresponding
spin distributions of 1(S ),1(Tn*) and 1(T*) are shown.
1
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To deeper understand the photophysical pathway(s) for1 in
ACN, the structural parameters for 1(S )and 1(Tn*) were
1
examined and these results are depicted in Figure 2. It is re-
vealed that the C-C bond distances in the two phenyl rings in
4
25 nm, accompanied with the absorbance at 330 nm decreas-
ing in intensity significantly (Figure 3c). Once the species IM2
was fully generated, it then decayed without a new species
being observed (Figure 3d) over the time scale accessible to
the fs-TA experiment (up to about 3 ns).
1
(Tn*) are almost the same in the range of 1.39~1.41 Å,
which agrees well with there being no spin distributed on the
two phenyl rings. Only the * transition can occur for the
singlet excited state because of there being no n orbital for the
Since the ns-TA and final product analysis show the formation
ground state 1.Furthermore, the species 1(S ) displays phenyl
1
15-16
of ground state QM(S ) for 1 in neutral aqueous solutions,
0
C-C bonds with more different values of 1.38~1.43 Å which is
induced by some spin being distributed onto these two phenyl
TD-M062X calculations were performed for the transient
species related with QM formation (see Figure 4a) to help in
the assignment of the species IM1 and IM2. It can be found
that the experimental spectrum of the species IM1 at 32.4 ps
shows reasonable similarity with the calculated UV-vis spec-
groups (see spin populations for 1(S ) with a * electronic
1
configuration shown in Figure 2). The two radicals are distrib-
uted parallel as a * molecular type on the vinyl group for
1
(T*), whose energy is 8.1kcal/mol lower than that of 1(S1).
trum of the singlet excited state of 1QM(S ) possessing two
1
Accompanied with the C-C rotation, 1(T*) is transferred to
become 1(Tn*) via an IC process and releasing an energy of
comparable bands at 305 and 405 nm, while this is obviously
different from the calculated spectrum of the triplet excited
state of 1QM(T ) species. The ground state of 1QM(S ) ab-
3
1.4 kcal/mol to the solvent. The photophysical process for 1
1
0
in ACN can be summarized as 1(S ) →1(S ) →1(T*)
3
1
sorbs at 305 nm and 395 nm while the intensity of the band at
305 nm is much weaker than that at 395 nm, which is similar
with the experimental IM2 spectrum at 1.48 ns. The assign-
→1(Tn*).
ment of IM2 to 1QM(S ) is consistent with ns-TA and final
0
1
7-18
product analysis study results.
It is noted that the position
of the computed absorption band of 1QM(S ) shows some
1
difference from the experimental spectrum of IM1, which
could be due to theM062X/TD-M062X calculation not being
highly accurate for this species.
Figure 3.The fs-TA spectra of 1 in ACN-H O (pH 7, 1:1)
2
under 267-nm irradiation are shown.
After characterizing the photophysics of 1 in ACN, we started
to explore the photochemical pathways of 1 in aqueous solu-
tions, especially for how QM is generated in aqueous envi-
ronments which have yet to be determined in the systems of
interest here. The fs-TA results for 1 in near neutral aqueous
solution are given in Figure 3. The transformation that occurs
3
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Figure 4. Comparison of the calculated UV-vis spectra of
likely intermediate species (indicated by the red and blue
colored lines) with the fs-TA spectra recorded in (a) ACN-
H O (pH 7, 1:1) and (b) ACN-H O (pH 2, 1:1) after 267-nm
the delocalized two radicals on 1QM(S ). This is consistent
1
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with the experimental result that 1QM(S ) was probed for 1 in
1
both neutral and acidic aqueous solutions. On the other hand,
the species IM3 was fully formed with the hydrogen atom
being bonded to the meta-oxygen (bond distance: 0.97 Å) and
exhibited a different fs-TA spectra profile from that of
2
2
irradiation. The calculated UV-vis spectra were obtained using
TD-M062X/6-311+G** (ACN) with a scale factor of 1.08 and
-
1
a half-width of 1800 cm .
1QM(S ). This indicates 1 undergoes a protonation reaction
0
with the formation of the carbocation IM3 in an acidic aque-
The QM of 1was thoroughly quenched by water to produce
ous solution after 1QM(S ). Close examination of the spectral
1
the diaryl ethanol product, that may possibly equilibrate with
profile of IM3 indicates it has some weak but recognizable
absorbance around 525 nm (see Figure 4b), which was not
seen in the neutral aqueous solution. Therefore, this indicates
that the transformation from QM to the carbocation species is
negligible for 1 in a neutral aqueous solution.
17,18
the carbocation species via protonation.
On the other hand,
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only the carbocation was formed via the acid-catalyzed photo-
protonation of the double bond at low pH, as have been ob-
17-18
served for other aryl alkenes.
To probe the formation of
the carbocation species and to compare with the photochemi-
cal reaction of 1 in neutral aqueous conditions, fs-TA spectra
were also acquired for 1 in a pH 2 aqueous solution (see Fig-
ures 1S and4b).It was found that the first two processes of 1 in
acidic aqueous solution (Figure 1Sa and Figure 1Sb) are es-
sentially identical with that detected in the neutral aqueous
condition, suggesting the sequential transformation of 1(S3)
One may consider the parallel occurrence of the stepwise
and concerted reaction of 1 in neutral aqueous solution. To
gain more information, fs-TA experiments were performed in
alkaline aqueous solutions (see Figure 2S), where QM was
1
5-16
also formed based on previously reported studies.
The
absorption spectra of 1 in an alkaline solution found a sequen-
tial appearance of absorption bands at 333 nm within 197~333
fs, 405 nm within 809 fs~8.75 ps and 425 nm within341
ps~2.62 ns (Figure 2S), which can be respectively assigned to
1(S ), 1QM(S ) and 1QM(S ). The exception from a neutral
→
1(S ) and 1(S ) →1QM(S ). However, the decay of 1QM(S )
1
1
1
1
with the generation of a species IM3 absorbing at 418 nm
Figure 1Sc) indicated that 1QM(S )was not produced for 1 in
(
0
1
1
0
the acidic aqueous solution examined. The experimental spec-
trum for the species IM3 recorded at 2.27 ns (330, 418 and
aqueous condition is the detection of a signal at 355 nm within
763~809 fs, indicating a new species (denoted as IM4) that
appeared between 1(S ) and 1QM(S ). One can expect that an
5
15 nm) shows a reasonable spectra profile resemblance with
1
1
the calculated spectrum of the S carbocation species of 1 with
alkaline aqueous solution may facilitate the deprotonation of
the phenol group so the experimental spectrum of IM4 was
1
characteristic absorption bands at 310, 390 and 485 nm (see
Figure 4b).In summary, 1QM(S ) undergoes protonation with
compared to the calculated spectrum for the anion S species
1
1
the formation of the S state of the carbocation species in
(Figure 3S) and the good resemblance between the experi-
mental and calculated spectra strongly supports the above
assignment. From another point of view, the absence of the
absorbance at 355 nm in neutral aqueous solution implies that
the primary generation reaction mechanism for QM of 1 in a
neutral aqueous solution is the concerted water-relay ESPT
without participation of the step-wise reaction mechanism.
1
acidic aqueous solution. Protonation of QM to carbocation in
acidic solutions has been reported, however, taking place in
2
6
the ground state.
1
14.9
1
08.2
1ts2(S )
1
1(S3)
103.5
1
ts1(S1)
E(G)
kcal/mol
9
1.3
1PCS1
8
7.1
(90.7)
1ts2(T )
(
81.6)
94.9
1
1
ts1(T1)
1(S1)
7
8.5
1QMS1
1
(T*
68.2
79.0
77.6)
(
4
5.0
43.5)
1ts1(S0)
42.9
1PCT1
(
(38.9)
3
6.1
5
6.8
1QMT1
(37.4)
(
53.2)
1ts2(S0)
1
(Tn*)
3
2.5
31.9)
1QMS0
Figure 5.The calculated structures for (a) 1QM(S ) and (b)
1
(
1QM(S ) detected in ACN-H O (pH 7, 1:1) solution and (c)
0
2
H
HO
H
OH
H
1QM(S ) and (d) IM3 detected in ACN-H O (pH 2, 1:1) solu-
OH
H
1
2
H
HO
tions at the M062X/6-311+G** (ACN) level of theory. The
numbers refer to the bond distance (Å) between the hydrogen
and the meta-oxygen atoms.
0.0
0.0)
1(S0)
CH2
CH3
OH
(
OH
-6.6
H
(-2.2)
H
O
1ts1
1PCS0
O
1ts2
H
H
HO
H
To explain the different pathways of 1QM(S ) in neutral and
OH
HO
OH
1
OH
H
H
HO
acidic aqueous solutions, the structural parameters for
H
OH
CH3
H
OH
CH2
CH3
+
OH
H
1
QM(S ) and 1QM(S ) observed in neutral water solutions,
1
0
H
H
and the two species 1QM(S ) and IM3 (the carbocation)
O
O-
1QM
O
1
1
1PC
probed in acidic solutions were investigated (see Figure 5). It
appears that no hydrogen is bonded to the meta-oxygen for
both 1QM(S ) and 1QM(S ) in neutral water solution. Some-
Figure 6.The potential energy surface profiles for 1 in ACN-
0
1
H O at the M062X/6-311+G** (ACN) level of theory are
2
what unexpectedly, the hydrogen atom is also not fully con-
depicted. The blue line shows the triplet reaction pathway, the
red line shows the singlet reaction pathway and the black line
shows the ground state reaction pathway.
nected to the meta-oxygen for 1QM(S ) with the atom distance
1
being 1.05 Å in acidic solutions, which should be stabilized by
4
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The potential energy surface profiles of 1 in neutral aqueous
solution were mapped employing M062X/6-311+G** (ACN)
calculations (see Figure 6). A Stern-Volmer analysis of fluo-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
rescence extinguishing of 1 displayed a cubic dependence the
17-18
concentration of water for the formation of QM.
Three
H O molecules were introduced into the calculation system.
2
The species 1 was induced by 267-nm irradiation to take place
via the electronic transition from 1(S ) to 1(S ). Then the
0
3
singlet excited route is feasible to overcome a moderate 13.3
Figure 8.The structural parameters (Å) and the corresponding
*
kcal/mol energy barrier from 1(S ) to a transition state 1ts1(S ),
spin distributions of 2(S ), 2(T ) and 2(Tn*) are given.
1
1
1
and then it goes downhill to 1QM(S ) by a significantly exo-
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
thermic process (39.6 kcal/mol). 1QM(S ) goes through the IC
1
To compare and contrast with the photoexcited processes of 1,
the counterpart 2 was also monitored using similar experi-
mental and calculation methods, and these results are briefly
discussed here. Figure 7 presents the fs-TA spectra of 2 in
ACN and Figure 8 displays the structural parameters (espe-
process to the ground state species 1QM(S ), which is difficult
0
to be produced directly according to the ground state pathway
(activation energy: 43.5 kcal/mol). It is interesting the final
product cannot realistically be produced by the singlet excited
route since it needs a 46.7 kcal/mol activation energy from
1QM(S ) to 1ts2(S ). The final product should be formed
cially the phenyl C-C bond distances of 1.39~1.41 Å in 2(S ))
1
1
1
and the corresponding spin distributions of 2(S ) with n*
1
irreversibly by the significantly exothermic pathway which
molecular orbital type, 2(T*) and 2(Tn*). Upon 267-nm
starts from 1QM(S ) that goes through 1ts2(S )overcoming a
0
0
irradiation, 2went to a high excited state 2(S ). Then, 2(S )
3
3
5.5 kcal/mol activation energy, that agrees well with the final
product analysis that QM is totally quenched by water to pro-
relaxes to the lowest singlet excited state 2(S ) with an absorp-
1
1
7-18
tion band at 333 nm via an IC process within 1.5 ps (see Fig-
duce the diaryl ethanol product.
The photochemical pro-
ure 7a). The species 2(S ) decayed as the absorbance at 333
1
cess induced by the triplet species 1(Tn*) seems difficult
because of its high energy barrier of 28.4 kcal/mol is required
nm decreased while the absorbance features at 418, 518 and
578 nm increased in intensity up to 53.7 ps (see Figure 7b),
and then decayed without a new species being observed (Fig-
ure 7c). Both the calculated UV-vis spectra of2(Tn*)and
2(T*)contribute to the absorbance in the fs-TA spectra at
53.7 ps, which suggests a mixture of 2(Tn*)and 2(T*) in
ACN. This assignment is consistent with DFT calculations
that 2(Tn*)and 2(T*) are energetically very close to each
other (△G: 0.2 kcal/mol) and supported by recent publica-
to reach 1ts1(T )compared with the singlet excited pathway.
1
B. Ultrafast Study of 2
2
7-28
tions. 2(S ) goes through the ISC process to 2(T*) with a
1
10.6 kcal/mol energy gap because the 2(T*) appeared at
578 nm after 1.6 ps, equilibrated with 2(Tn*) after 3.6 ps. It
is noted that there is some species generated with an absorb-
ance at 578 nm (see the line recorded at 1.7 ps) between 2(S1)
and the mixture of the triplet state species. Based on the calcu-
lated energy results, this species should be the 2(T*) pro-
duced via an ISC process. The absence of the 418 nm band at
1
.7 ps could be caused by a competing pathway from 2(S ) to
1
the ground state via fluorescence which bleached the absorb-
ance of 2(T*) at this wavelength region. The fluorescence
of 2 in ACN is depicted in Figure 8S. To sum up, the photo-
physical process for 2 in ACN can be depicted as 2(S3)
→
2(S ) →2(T*) ↔2(Tn*)
1
.
Figure 7.The fs-TA spectra of 2 in ACN after 267-nm irradia-
tion are shown. A comparison of the calculated UV-vis spectra
of likely intermediates with the fs-TA spectra recorded in
ACN after 267-nm irradiation is also shown. The calculated
UV-vis spectra were determined at the TD-M062X/6-
311+G** (ACN) level of theory using a scale factor of 1.13
-
1
and a half-width of 1800 cm .
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2
(S ) decayed as the absorption band at 333 nm decreased in
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
intensity whereas that at 578 nm emerged (Figure 9b), which
indicates an ISC process from 2(S ) →2(T*). Thereafter,
1
the spectra profile varies greatly from that observed in ACN,
especially with the band at 392 nm generated and the one at
418 nm disappearing (Figure 9c). The species with strong
absorbance features at 333, 392 and 515 nm is denoted as IM5,
which decays after 110 ps. The potential energy surface pro-
file of 2 in neutral aqueous solution (see Figure 10) also sup-
ports an ISC process from 2(S ) to 2(T*). Then the triplet
reaction route goes forward to produce the triplet quinone
methide 2QM(T ) with a barrier-free and exothermic process.
We compare the experimental fs-TA spectrum of the species
IM5 which was produced from 2(T*) with the simulated
one of 2QM(T ) (Figure 9d). The excellent correlation shown
in Figure 9d suggested that IM5 can be attributed to 2QM(T1).
The appearance of the species 2QM(T ) at early time (18.8 ps)
is also consistent with the calculated results about the fast
consumption of 2(T*) so that its characteristic band at 418
nm is not easy to detect. Due to the high energy barrier of 53.3
kcal/mol, the species 2QM(T ) is difficult to overcome the
second transition state 2ts (T ), while it is more feasible to
transfer to the ground state IM6 via an ISC process. The calcu-
lation result indicates that IM6 is not 2QM(S ) because the
protonation of the carbonyl O atom still did not completely
transfer from meta-OH for IM6 (Figure 4S). This indicates
that IM6 is unstable and will soon go back to the ground state
2(S ). It is indicated from the ground state energy profile (the
black line in Figure 10) that a concerted pathway is proposed
for 2 without an intermediate, where the photohydration can
be accomplished by the H O molecule being split into H and
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
1
1
2
1
Figure 9.The fs-TA spectra of 2 in ACN-H O (pH 7, 1:1)
2
subsequent to 267-nm excitation are presented. A comparison
of the calculated UV-vis spectra of likely intermediate species
with the fs-TA spectra recorded in ACN after 267-nm irradia-
tion is also shown. The calculated UV-vis spectra were deter-
mined at the TD-M062X/6-311+G** (ACN) level of theory
0
0
-
1
using a scale factor of 1.13 and a half-width of 1800 cm .
H
H
H2
O
HO
+
OH
H
126.5
2
H
O
HO
2ts2(S )
-
1
H
OH which respectively transfer to the carbonyl O and the C
O
115.1
PCS1
OH
OH
atom without the involvement of the meta-OH. Therefore, no
photohydration product can be detected after photoexcitation
for 2 in neutral aqueous solutions. It should be noted that
photohydration products are unstable, so even if they were
formed, they would revert to the starting material.
2
H
H
2(S3)
O
O
IM
2ts(S0)
1
03.0
(102.3)
8
6.1
91.4
2ts1(S1)
91.0
7
8.8
73.8)
(Tn*)
2QMS1
2
ts2(T1)
2(S1)
(90.5)
(
73.6
2
2PCT1
The above results provide evidence that 1 and 2 go through
different ISC processes in pure ACN. That is, the ISC process
involves S *↔ T* for 1 while S n*↔ T* for 2. The
6
9.0
6
6.1
63.7)
(T*)
49.9
(
2
63.0)
(
2
(
49.0)
ts1(T )
1
2
QMT1
33.9
(34.3)
1
1
2
5.7
IC process of Tπ*→ Tn* is the same which respectively
involves the vinyl C-C rotation for 1 and the carbonyl C-O
rotation for 2. However, fs-TA results indicate there is a sig-
nificant difference for the bond rotation. It seems that the
carbonyl C-O rotation is much faster (from 1.5 ps to 4.2 ps,
see Figure 7) than the vinyl C-C rotation (from 1.5 ps to 2.96
ns, see Figure 1). Actually, 2(Tn*) mixes with 2(Tπ*) and
can transfer to each other with a fast equilibrium as shown by
fs-TA results and their degenerate free energy. However,
1(Tn*) is lower by 31.4 kcal/mol in energy than 1(T*),
which in turn accounts for the slow vinyl C-C rotation so that
the second triplet state 1(T*) also can be stabilized (energy
(
24.3)
E(G) kcal/mol
2ts(S0)
IM
H
OH
H
HO
6
.1
OH
H
0
.0
HO
OH
(9.7)
OH
H
(0.0)
2PCS0
H
H
2
(S0)
O
2ts2
O
OH
H
OH
H
H
H
H
H
HO
OH
O
OH
H
HO
HO
OH
2ts1
H
OH
OH
OH
O
+
OH
H
H
O
H
O
O-
QM
2PC
2
29
2
gap law ) during 1.5 ps to 2.96 ns in ACN. Inspection of the
spin distribution for 1(T*) and 2(T*) provides more
insight: two radicals localize on the vinyl group for 1(T*)
while they delocalize to the substituted phenyl ring for
Figure 10.The potential energy surface profiles for 2 in ACN-
H O at the M062X/6-311+G** (ACN) level of theory are
2
shown. The blue line shows the singlet reaction pathway, the
red line shows the triplet reaction pathway and the black line
shows the ground state reaction pathway.
2
(T*). The electronic configuration with the spin delocali-
zation to the substituted phenyl ring is also located for 1 by the
TD-M062X method (Figure 5S). However, it is the third tri-
plet excited state, that is higher by 1.7 kcal/mol in energy than
1
(T*). These results are explicitly derived from the essen-
Figure 9 shows the fs-TA results of 2 in neutral aqueous
solution. The change in the very early time region (Figure 9a)
shows the occurrence of the 2(S ) →2(S ) process. After2.1 ps
tial fact that the electron-withdrawing carbonyl O atom can
lower the lowest unoccupied molecular orbital (LUMO) of the
3
1
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CH2
phenyl ring so that the electron transfer is also favored from
the carbonyl group to the phenyl as compared with the car-
OH
OH
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
bonyl C-O rotation after the carbonyl photoexcitation. Instead,
the poor electron-withdrawing vinyl C atom cannot lower the
LUMO of the phenyl group, which induces the vinyl C-C
rotation to be much more favorable than spin delocalization to
the phenyl ring. It should be emphasized that the polar ACN is
an inert solvent that only allows for the photophysical process
for 1 and 2. However, the protic solvent water opens the door
to photochemical reactions besides only the photophysical
process seen in ACN. In neutral aqueous solution, the 1QM(S1)
H2O hv
1
1
*
-
CH2
OH -H O
2
stepwise
ESIPT
concerted
ESIPT
1
(S1):330nm
1
CH2
*
H O
2
-
O
concerted
H2O
ESIPT
CH3
CH3
*
1
-
IM4:355nm
O
*
+
-
stepwise
ESIPT
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
H O
2
formation promoted by the 1(S ) is fast enough (energy barrier:
+
1
-
1QM(S1)
-OH
1
3.3 kcal/mol, see Figure 6) to compete with the vinyl C-C
1
QM(S1):330, 405nm
IC
1
CH3
*
rotation between 1(T*) and 1(Tn*) (from 1.5 ps to 2.96 ns,
-
IC H+
O
+
see Figure 1). As a result, the 1QM(S ) formation but not ISC
1
is the main process for 1(S ). In contrast, the transient ISC
1QM(S1)
1
CH3
-
+
process (see Figure 7) and the reactive species 2(T*) (see
Figure 10) are favored for the subsequent triplet ESPT process
rather than singlet one, which is further corroborated by other
CH3
O
OH
IC
+
1QM(S0):425nm
CH3
3
0
IM3: 418, 515nm
-
O
aromatic carbonyl compounds reported in aqueous solutions.
+
H2O Hydration
H2O
-H
It is wondered why the QM formation for 1 is so efficient
while that is not the case for 2. The hydration reaction is very
difficult to occur without photoexcitation according to the
ground state energy profile for both 1 and 2 (see the black line
in Figures 6 and 10), which however, indicate a stepwise
pathway for 1 and a concerted pathway for 2. Considering that
the excited species must go through the IC process back to the
ground state in the halfway or terminal point on the energy
profile after photoexcitation, the QM intermediate located by
the ground state energy profile is crucial upon irradiation as
compared with 2 without a ground state QM species. This
difference is obviously correlated with vinyl and carbonyl
moieties. The electron rich carbonyl O atom can directly split
+
O
H2
Hydrat
dratio
1QM(S0)
n
H C OH
3
io
n
OH Hy
Figure 11. The proposed photophysical and photochemical
pathways of 1 in neutral, acidic and alkaline aqueous solutions
based on the combined fs-TA study and DFT calculations
reported here is shown. The letters and numerical values next
to the structures are the notations presented in the main text.
The absorbance bands of the transient fs-TA detected species
are also given.
Although the carbon atom of the vinyl group in 1 is more
difficult to be protonated than the oxygen atom of the carbonyl
group in 2, the formal ESPT for 1 with efficient generation of
the QM species revealed a particularly fascinating aspect of
these photochemical reactions. The results here can aid re-
searchers in the design of new precursors for the efficient
photogeneration of QM intermediates. For instance, the great-
H O to undergo the hydration reaction by one step while the
2
poor vinyl group requires the assistance from the better proton
donor of the meta-OH group to achieve the vinyl C protona-
tion, and then the protonated vinyl group enhances hydroxide
-
abstracted from H O and the leaving proton returns to meta-O .
2
That is why the ground state energy profile can locate a
er acidity of the phenol group in S in these kinds of molecules
is viewed to be required for QM formation as previously de-
1
1
QM(S ) intermediate. It is reasonable to predict that a less
0
3
1323334
basic group than the vinyl group is also disfavored for the
photohydration because the proton transfer from meta-OH will
become difficult in the singlet excited state, which might turn
to the ISC process and the formation of unreactive triplet state
scribed.
Our work here clearly points out that the basic
site is of equal importance for the design of QM precursors.
Besides, the comparison between 1 and 2 applies fundamental
and essential information for a deep understanding of the
photophysical and photochemical behaviors of aromatic com-
pounds, like, a small change of the skeleton with one atom
leads to distantly different destinations for the reaction. It
should be noted that, these two compounds are meta substitut-
ed and the intermediates via the photohydration reaction only
have “non-Kekulé” structures, which may be of interest to
computational chemists. Furthermore, the distinct characteri-
zations and assignments of all the key intermediates and tran-
sients in the pathways of the QM formation furnish important
knowledge for further insight and future work into the pho-
toinduced QM reactions with DNA and amino acids in cancer
therapy. We also note that phototoxicity is an important aspect
when evaluating the biological and clinical use of a cancer
agent. The totally different behaviors of 1 in water containing
solutions or not containing water (eg. the ACN solution results)
conditions may potentially be exploited as a new and useful
tool to study the dynamics of solvent-assisted reactions in
biological systems.
(
Figure 6). Therefore, the moderate basic character of the
vinyl group is crucial for the efficient QM formation of 1.
CONCLUSION
In this contribution we report an ultrafast transient absorption
spectroscopic experimental study combined with a computa-
tional investigation for 1 in different solvents and directly
characterize the excited-states and intermediates involved in
the formation of the QM species. The predominant photophys-
ical and photochemical pathway for 1 in neutral, acidic and
alkaline aqueous solutions can be depicted in Figure 11 below.
The letters and numbers shown next to the chemical structures
in Figure 11 are those for the key intermediates also presented
in the text. Mechanistic investigations utilizing ultrafast time-
resolved spectroscopy and DFT calculation studies can help
unravel two distinct pathways for 1 and 2, leading to the for-
mation of 1QM(S ) but not 2QM(S ), respectively.
0
0
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EXPERIMENTAL AND COMPUTATIONAL
METHODS
-(1-phenylvinyl)phenol was prepared using literature meth-
lator strengths from TD-DFT (M062X /6-311G**) calculations
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
for the transient species, and Cartesian coordinates, total energies,
and vibrational zero point energies for the optimized geometry
from the M062X /6-311G** calculations for the compounds and
intermediates considered in this paper. This material is available
free of charge via the Internet at http://pubs.acs.org.
3
1
13
ods (see the supporting information with the H NMR and
NMR spectra shown as Figure 6S and Figure 7S, respective-
C
1
7,18
ly).
Its pKa is determined to be 9.56 ± 0.03 (see the details
in Figure 9S, Figure 10S and Figure 11S). 3-
hydroxybenzophenone was commercially acquired and used
as-is. Deionized water and spectroscopic grade acetonitrile
were employed to make samples with. perchloric acid and
sodium hydroxide used as needed to adjust the pH of the sol-
vent (before addition of the sample compound). Taking the
AUTHOR INFORMATION
Corresponding Authors
*majiani@nwu.edu.cn, *zhangxitinghk@gmail.com and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
*phillips@hku.hk
alkaline sample solution for instance, the solvent, ACN-H O
2
Author Contributions
(1:1, v:v), was brought to pH 10.0 by addition of sodium hy-
The manuscript was written through contributions of all authors. /
All authors have given approval to the final version of the manu-
script. / ‡These authors contributed equally.
droxide. Then, a certain amount of compound 1 was added
until the absorbance reached 1 at 266 nm. After the addition of
the compound 1 the pH of the solution was around 8.0 which
is below the pKa (9.5) of 1 (see the details given in Table 1S).
That is, the species existing in the alkaline aqueous solution
for the fs-TA experiments is the ground state of the neutral
form of 1, rather than the phenolate form. Fs-TA experiments
were done with a femtosecond regenerative amplified
Ti:Sapphire laser apparatus. The 120 fs oscillator output seed-
ed the amplifier. About 5% of the amplified 800 nm produc-
tion was employed to make the probe pulse320 nm to 700 nm
ACKNOWLEDGMENT
We acknowledge B. Trinajstic, L. Wang and P. Wan at the Uni-
versity of Victoria for a sample of 1. The research was sponsored
in part by grants from the Research Grants Council of Hong Kong
(HKU17301815) to D.L.P. and the National Science Fund of
China (21503167), China Postdoctoral Science Foundation
(2017M613184) and “Top-rated Discipline” construction scheme
of Shaanxi higher education to J.M. and partial support from the
Areas of Excellence Scheme (Grant AoE/P-03/08), the UGC
Special Equipment Grant (SEG-HKU-07) and the University of
Hong Kong Development Fund 2013-2014 project “New Ultrafast
Spectroscopy Experiments for Shared Facilities”.
white-light continuum via a CaF crystal. Two portions of the
2
probe beam were used in the experiments with one directed to
a reference spectrometer and the other going through the sam-
ple. 40 ml sample solutions were passed through a cuvette
with a 2 mm path-length that a 267 nm pump beam excited.
The experiments used sample solutions made so that they had
an absorbance of 1 at 267-nm.
M062X method DFT calculations were performed for the
ground state and triplet state with a 6-311+G** basis set. The
MO62X method is thought to be reasonably reliable to predict
the chemical behavior of main groups by several other
REFERENCES
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3
5
groups. Frequency calculations using the identical method
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at local minima (with all-real frequencies) or at transition
states (containing one imaginary frequency only). The transi-
tion state character was found by examining the movement by
the eigenvector connected with the imaginary frequency.
Wiley-VCH, Weinheim, 2007; (b) Kwon, J. I.; Park, S. Y. Adv. Ma-
ter., 2011, 23, 3615; (c) Tolbert, L. M.; Solntsev, K. M., Acc. Chem.
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36
Intrinsic reaction coordinates were calculated to determine
that the pertinent transition state structures connected the two
pertinent minima. TD-M062X/6-311+G** computations were
used to compute the singlet excited state and the UV-vis spec-
tra. The second and the third triplet state for compound 1 in
ACN solvent were also optimized by TD-M062X. The effect
of solvent polarity on the stability of the relevant species was
examined with structural optimization calculations done using
the integral equation formalism polarizable continuum model
(IEFPCM) in ACN ( = 35.688) on the gas-phase structures in
which the nonelectrostatic terms and the radii used the univer-
sal solvation model (SMD) developed by Truhlar and co-
2
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workers. The Gibbs free energy Gsolv. was used in the discus-
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ASSOCIATED CONTENT
Supporting Information. Figures and tables giving the fs-TA
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