Role of Distance in Singlet Oxygen Applications: A Model System

Article abstract of DOI:10.1021/jacs.6b01555

Herein, we present a model system that allows the investigation of a directed intramolecular singlet oxygen (¹O₂) transfer. Furthermore, we show the influence of singlet oxygen lifetime and diffusion coefficient (D) on the preference

Full text of DOI:10.1021/jacs.6b01555

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Article
The Role of Distance in Singlet Oxygen Applications: A Model System
Matthias Klaper, Werner Fudickar, and Torsten Linker
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01555 • Publication Date (Web): 17 May 2016
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The Role of Distance in Singlet Oxygen Applications:
A Model System
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Matthias Klaper, Werner Fudickar, and Torsten Linker*
Department of Chemistry, University of Potsdam, KarlꢀLiebknechtꢀStr. 24ꢀ25, 14476 Golm, Germany
Singlet oxygen, intramolecular transfer, distance dependence, quenching and competition experiments
ABSTRACT: Herein, we present a model system which allows the investigation of a directed intramolecular singlet oxygen (1O2)
transfer. Furthermore, we show the influence of singlet oxygen lifetime and diffusion coefficient (D) on the preference of the intraꢀ
over the intermolecular reaction in competition experiments. Finally, we demonstrate the distance dependence in quenching experꢀ
iments, which enables us to draw conclusions about the role of singlet oxygen and 1O2 carriers in PDT.
1
time τ limits the range d where O2 can exist, which correlates
Introduction
with its diffusion coefficient D (d=√2τD). Using literature data
this gives a value of d=125 nm in water at ambient temperaꢀ
ture.12 The inhomogeneity of a cell is distorting the picture of a
uniform diffusion of 1O2 and the efficiency of a transfer of this
reactive species depends on the localization of the sensitizer,
being either close (direct transfer) or remote (indirect transfer)
from the target (Figure 1).
Singlet oxygen (1O2)1 is a very convenient oxidant in organꢀ
ic chemistry and can undergo different reactions such as
SchenckꢀEne reactions,2 [2+2]3ꢀ and [4+2]ꢀcycloadditions.4 It
can be generated from its ground state by photosensitization
using sensitizers like tetraphenylporphyrin (TPP),5 from inorꢀ
ganic sources (H2O2),6 or with O2 donors like naphthalene
1
endoperoxides.7
It has also become very important for the treatment of canꢀ
cer,8 where it is used in photodynamic therapy (PDT).9 This
technique relies on the precise localization of a sensitizer close
to the tumor cells, which are selectively destroyed by light
induced formation of reactive oxygen species (ROS) including
1O2. One major drawback of PDT is its lack in selectivity
1
towards the target.10 Owing to its high reactivity, O2 destroys
healthy domains when it is either generated or has traveled
1
into these domains.11 Fortunately, the short lifetime of O2
prevents it from travelling larger distances. The lifetime τ is
inversely related to rates of deactivation processes arising
from physical and chemical interactions with the environment
(Scheme 1).
Figure 1. Transfer of 1O2 from a sensitizer to a target within
Scheme 1. Modes of Deactivation of 1O2
a cell.
1
In cells, chemical reactions of O2 with amino acids of proꢀ
kd
3O2
3O2
1O2
1O2
+
+
solvent
teins, unsaturated lipids, or nucleic acids are effectively reducꢀ
ing its lifetime.13 In addition, diffusion coefficients are varying
strongly inside the cell. Several strategies where performed in
order to determine the effective range d in cells: The group of
kq
kr
M
M
1O2
+
MO2
1
Ogilby tackles the question by spatially resolving O2 in cells
τ = (kd + kT[M] )ꢀ1
1
kT=kq+kr
based on the microscopic imaging of the O2 phosphoresꢀ
cence.14 Surprisingly, the lifetimes measured inside the cell
were long, suggesting that chemical quenching processes are
negligible. On the other hand, different subcellular domains
The physical quenching by the solvent (kd) is an unimolecuꢀ
lar reaction whereas chemical reactions (kr) and the physical
deactivation (kq) with substrates M are bimolecular. The lifeꢀ
1
restrict traveling of O2, possibly due to different viscosities
1
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inside the cell.14b Other strategies were followed by Moan and
mers.22 Compared to the donor/acceptor systems, used in our
previous work,18 these photooxygenations can run to full conꢀ
1
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7
8
Berg, who studied intracellular photoꢀdegradation processes of
two dyes which could be excited selectively at different waveꢀ
lengths.15 Their results revealed that singlet oxygen causes
damage rather at the dye where it is generated than at the dye
which is not sensitizing. They estimated a travel distance of
only 10ꢀ20 nm.
1
version since O2 is generated continuously. In addition to the
synthesis of SAS, it is necessary to have a reference system
(RS) which carries only the acceptor unit and the spacer with a
phenyl terminus without the sensitizing unit. To avoid differꢀ
1
ent O2 quantum yields, we carried out all photooxygenations
A third strategy comprises the investigation of model sysꢀ
of RS with a 1:1 mixture of the corresponding RS/SAS, where
1O2 is always generated by the porphyrin unit of SAS linked to
an alkyl chain.23 The RS would resemble the typical situation
of an intermolecular reaction while SAS combines both, interꢀ
and intramolecular reactions. Our aim in this study is to conꢀ
trol and estimate the contributions of these two reactions in
SAS.
1
tems where O2 is transferred within one molecule or within a
molecular assembly (intramolecular reaction). Such systems
would constitute both, the photosensitizer and the 1O2 target in
one entity and would principally resemble modern PDT delivꢀ
ery vehicles, which convey the sensitizer close to the tumor
tissue.9a
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A single molecule atomic force microscopy study of a sysꢀ
1
tem was performed, where a sensitizer and O2 cleavable linkꢀ
Scheme 2. Syntheses of SASꢀ and Reference Systems (RS)
and Subsequent SchenckꢀEne Reactions to Hydroperoxꢀ
ides
ers were located on a 2D DNA origami.16 The sensitizer genꢀ
1
erated O2 which caused chain scission at different positions.
For the first time, it was possible to monitor the behavior of
1O2 in the nanometer range. It was shown that the closer linker
was stronger affected than the further remote one under irradiꢀ
ation of the sensitizer.
Shu, To and Fadul developed an imaging technology, where
large protein complexes were inserted between a singlet oxyꢀ
gen sensor and generator.17 Their method allowed confirming
the topology of protein complexes owing to a distance deꢀ
pendent 1O2 transfer.
Very recently, our group investigated such a transfer by usꢀ
ing a chemical donor of 1O2 connected to an acceptor unit.18 In
1
this study, only one molecule O2 could be donated from the
carrier to the acceptor. In competition experiments with a
second nonꢀbound acceptor molecule it was found that the
intramolecular transfer prevails depending on the molecular
conformation, the temperature and the solvent depended lifeꢀ
1
time of O2. However, the scope of these experiments was
limited by the fact that a maximum of only one equivalent of
1O2 is available from the donor.
Herein we demonstrate how an intramolecular reaction is
controlled in a sensitizerꢀacceptor system (SAS), where the
reactive species can be generated continuously. We will adꢀ
dress both, the questions of dependence on the distance and on
the surrounding environment which will reveal important
insights to PDT (Figure 1).
Results and discussion
We decided to employ a sensitizerꢀacceptor system (SAS),
At first, we paid our attention to RS. During irradiation in
the presence of ambient atmospheric oxygen of 5ꢁ10ꢀ5 M soluꢀ
tions of both, RS and the corresponding sensitizer,23 in aceꢀ
tonitrile (MeCN) the consumption of starting material was
followed by HPLC. The semiꢀlogarithmic plot of the concenꢀ
tration versus time gives a straight line which is in accordance
with a pseudo first order reaction (Figures SI). The slope
equals the observed rate constant kobs which can be expressed
by the following equation.24
1
which carries a porphyrin functioning as the O2ꢀsensitizing
1
unit and an alkene functioning as the O2 acceptor. Both units
are connected by alkyl spacers at various chain lengths
(SAS0‒6) for n=0‒6 separating the site where 1O2 is generated
from the site where it is trapped at varying distances.
For the sensitizing part, we used a hydroxyꢀsubstituted
1
tetraphenylporphyrin (TPP), since it has a high O2 quantum
yield and is easily accessible.19 The acceptor is a trimethylꢀ
substituted alkene bound to the termini of spacer units with
varying chain lengths (n=0–6). Therefore, porphyrin 120 and
the bromo compounds 221 were synthesized according to litꢀ
erature procedures and linked together via a Williamson ether
synthesis (Scheme 2, Supporting Information). The alkene
ln[A]t=ln[A]0‒(νFkr/kd)ꢀt=ln[A]0‒kobsꢀt
(1)
Here, [A] is the concentration of the substrate (RS) and νF is
1
undergoes a SchenckꢀEne reaction with O2 to give hydroperꢀ
1
the production of O2 (its determination is described in detail
oxides SASO2a and SASO2b as a mixture of two regioisoꢀ
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in the SI, giving a value of 3.6ꢁ10– Msꢀ1 for all following
experiments). Note that any other quenching process as menꢀ
tioned in Scheme 1 is neglected since kd>>kT[A]. The bimoꢀ
lecular constants kr of the seven RS0‒6 in MeCN (kd=1.5ꢁ104
sꢀ1)25 were calculated from equation 1 and are summarized in
Table 1. With exception of the more slowly reacting sterically
hindered RS0, the values alternate between 1ꢀ1.7ꢁ105 M‒1s‒1.
Compounds RS1, 3 and 5 with an even number of methylene
groups between the oxygen atom and the olefinic unit are
reacting faster than compounds RS2, 4 and 6 with an odd
number. Oddꢀeven effects are known to affect molecular propꢀ
erties such as packing, solubility and phase transitions as
well.26
5
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Table 1. Bimolecular Rate Constants kr of the SchenckꢀEne
Reactions of RS in Acetonitrile and Ethanol
kr
entry
RS
n
kr (MeCN)/
(EtOH)/
‒
‒
‒
‒
1
1
1 1
104 M s
104 M s
1
2
3
4
5
6
7
RS0
RS1
RS2
RS3
RS4
RS5
RS6
0
1
2
3
4
5
6
1.5±0.1
1.5±0.1
15.3±0.1
9.97±0.1
17.3±0.2
9.64±0.1
16.1±0.1
10.1±0.1
13.9±0.2
10.4±0.3
16.1±0.2
8.3±0.2
11.3±0.3
7.4±0.2
Figure 2. Observed rates of the photooxygenation depicted as
semi logarithmic plots: a) RS2 (blue) and SAS2 (red) in MeCN;
b) RS2 (green) and SAS2 (black) in EtOH.
Table 2. Observed Rate Constants kobs of RS and SAS in
Acetonitrile and Ethanol
RS
RS
SAS EtOH
kobs
SAS
MeCN
Next, photooxygenations were carried out under the same
conditions with SAS. The slopes of the semiꢀlogarithmic plots
of SAS0‒6 are indeed steeper as for the corresponding RS0‒6
(Figure 2a, S2‒8, Table 2). For SAS the oddꢀeven effects are
preserved at the same degree as for RS. It is important to note
that the comparison between RS and SAS assumes essentially
identical values for kr, since the reactive centers are identical.
To support this postulate, the geometries of SAS0‒6 were
optimized by DFT calculations (see SI). In such calculations
all SAS are linearly stretched, depicting the reacting olefinic
moiety isolated from the pendant macrocycle. Although in
solution the alkyl chain should be more flexible, the above
described oddꢀeven effect speaks for a stretched and not bendꢀ
ed chain. We can therefore conclude that electronic and steric
influences on these centers are nearly identical. Thus, the
observed rate constants kobs for a photooxygenation with a
partial contribution of an intramolecular 1O2 transfer are slightꢀ
ly increased for SAS. This change is the result of the smaller
degree of solvent quenching since kd reduces the overall rate
kobs.
/
MeCN
EtOH
kSAS
/kRS
n
‒
‒
5
1
kobs
/
kobs
/
kobs
/
10 s
kSAS
kRS
/
‒
‒
5
1
‒
‒
1
‒
‒
1
5
5
10 s
10 s
10 s
1.36
1.33
1.69
1.35
1.30
1.27
1.22
1.98
2.80
2.31
1.83
1.50
1.50
1.48
0
1
2
3
4
5
6
3.74±0.1
37.3±0.1
24.4±0.1
42.3±0.5
23.6±0.7
39.3±0.4
25.4±0.3
5.11±0.1
49.8±0.1
41.3±0.1
57.8±0.8
31.1±0.5
49.9±0.2
36.8±0.3
0.37±0.01
2.48±0.01
2.24±0.01
4.17±0.07
2.78±0.47
3.77±0.02
2.48±0.04
0.74±0.01
6.96±0.03
5.16±0.01
7.75±0.06
4.18±0.02
5.68±0.03
3.69±0.02
Consequently, the impact of an intramolecular reaction
should become more pronounced when solvent quenching is
stronger and kd is increased. We therefore switched the solvent
system to ethanol (kd=7.2ꢁ104 s‒1).25 As expected, the observed
rates are strongly reduced as compared to the solvent MeCN
but the differences in the slopes between RS and SAS are
increased (Figure 2b, Table 2). Quantitatively, the effect of an
intramolecular reaction can be expressed by the ratio of the
observed rate constants kSAS/kRS. From Table 2 it becomes
clear that this effect is becoming stronger with increasing
solvent quenching.
The biasing of an intramolecular reaction reaches a limit
with water as the most quenching solvent (kd=3.2ꢁ105 s‒1).25
However, the solvent water is incompatible with our systems.
The domination of the intramolecular reaction of SAS should
become further increased, when the intermolecular reaction of
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SAS has to compete with another intermolecular reaction
arising from a second substrate which reacts with O2 at a
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8
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higher rate. Thus, we chose tetramethylethylene (TME), an
1
extremely reactive substrate towards O2 (kr=5.6ꢁ107 M–1s‒1).24
1
Accordingly, the lifetime of O2 is reduced to 1.7 µs which is
less than its lifetime in water (3ꢀ5 µs).24 Photooxygenation of
TME leads to one single hydroperoxide which does not underꢀ
go further transformations under the present conditions.27
Thus, although organic hydroperoxides are associated with
oxidative damages in biologic systems,28 they suit well for our
model systems.
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As described before, irradiation was now carried out in the
2
presence of TME at a concentration of 10– M. The results of
these competition experiments are summarized in Table 3.
Here, the intermolecular reaction is suppressed by magnitudes
as reflected by the high values of kSAS/kRS.
The alternation pattern of reactivities found in the two forꢀ
mer cases with no TME is reduced but still present. More
importantly, the ratio of intraꢀ versus intermolecular reactions
(kSAS/kRS) decreases remarkably with increasing n (Figure 3,
Table 3). Thus, we can give evidence for a relationship beꢀ
tween the prevalence of intramolecular reaction and the disꢀ
tance. By means of the calculated structures (see SI), the disꢀ
tances between sensitizer and acceptor increase from 12 Å to
19.5 Å from SAS1 to SAS6. According to Figure 3 the domiꢀ
nance of intramolecular transfer would drop to kSAS/kRS=1 at 7ꢀ
Figure 3. Preference of intraꢀ over intermolecular reaction
(kSAS/kRS) in the presence of TME as a function of n.
In addition to the revelation of the chain length dependence,
we focused on a quantification of the influence of quenchers
on biasing an intramolecular reaction in a system such as SAS
as well. Therefore, we first evoke equation (2), which expressꢀ
es an intermolecular oxygenation of a substrate A in the presꢀ
ence of a second competing substrate A’ in excess. This forꢀ
mula should be suitable to calculate the rate constants of the
photooxygenations by knowledge of kr, kd and k’r.24
1
8 methylene groups (≥2 nm). The travel distance of a O2
molecule before quenching under the given conditions is
1
d=√(2k– D), where k includes all quenching processes and
9
1
D=9.2ꢁ10– m2s– . This gives a value of d=176 nm. Therefore,
the travel distance of 1O2 is still by magnitudes higher than the
molecular dimensions of SAS.
ln[A]t=ln[A]0–(νFkr/(kd+k’[A‘]))ꢁt=ln[A]0–kobsꢀt
r
(2)
Considering the concentration of [A’] as constant (0.01 M)
Table 3. Observed Rate Constants kobs of RS and SAS in
the Presence of TME (200eq) in Acetonitrile
1
1
1
and using 1.5ꢁ104 s– for kd, 5.6ꢁ107 M– s– for k’r (TME) and
the kr values for RS from Table 1, we obtain kobs ranging beꢀ
6
6
1
RS
SAS
kobs
tween 6.3ꢁ10– and 10.7ꢁ10– s– . Thus, the expected theoretical
values for kobs are higher than the measured values ranging
kobs
/
/
factor
entry
n
6
6
1
only between 1.2ꢁ10– and 2.6ꢁ10– s– (see Table 3). This can
be a result from underestimated chemical quenching of TME
at this high concentration and from the products generated
from the oxygenation of TME. In contrast, if assuming a genuꢀ
ine intramolecular reaction which is essentially free from any
competing reactions and from solvent quenching, the simple
equation (3) should become valid.
10–5s–1a
10–5s–1
kSAS/kRS
0.04
0.24
0.24
0.26
0.15
0.23
0.12
119
118
113
103
91
1
2
3
4
5
6
7
0
1
2
3
4
5
6
4.92±0.01
28.51±0.01
27.53±0.02
26.86±0.4
13.81±0.02
16.51±0.01
4.64±0.05
ln[A]t=ln[A]0–νFkrꢀt=ln[A]0–kobsꢀt
(3)
70
38
The expected theoretical values for kobs would therefore
1
range between 3.6 and 6.1 s– as compared to the observed
aError=±0.01
4
1
rates of SAS of 0.4 to 2.8ꢁ10– s– . This strong deviation (factor
≈104) shows that quenching processes still occur for the intraꢀ
molecular reaction under our experimental conditions. Note
that kobs calculated from equation (3) deviates of course much
stronger for RS (factor ≈106). Even at the shortest distance,
SAS1 reacts far too slow. This may be explained by picturing
the environment around a new born 1O2 molecule from a SAS.
We can consider a hypothetical sphere with the radius d (176
1
nm as calculated above), centered at the point where O2 was
1
generated. From this point O2 can travel into any direction
and can either hit the reactive site or abandon the sphere to be
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deactivated. However, the reactive site covers only a small
Conclusion
1
2
sector within the sphere and all other deviating travel direcꢀ
1
In summary, we synthesized several sensitizerꢀacceptor sysꢀ
tems with different intramolecular distances. The observed
rates of their photooxygenations in acetonitrile under continuꢀ
ous irradiation are moderately higher than rates of analogous
intermolecular reactions. By using ethanol as solvent, with
tions would cause the loss of O2 (Figure 4). Therefore, geꢀ
3
4
5
6
7
8
9
ometry depending factors become effective, which are also
used for example, for expressing the Förster critical distance.29
It becomes clear, that a quantitative intramolecular process
would be realized only when the sensitizer is connected with
multiple acceptors in a 3D dendrimeric structure, covering the
entire inner part of the sphere. Thus, the reactions of SAS
proceed slower as expressed in equation (3). This model exꢀ
plains also why the intramolecular prevalence fades out at
considerably smaller chain lengths: We may therefore considꢀ
er spheres with radii r corresponding to the diameters of SAS.
SAS0, for example, would give V≈7nm3, and SAS6 would
give V≈32nm3. Importantly, the volume covered by the reacꢀ
tive centers is the same. Thus, the ratio between the space
covered by the reactive space and the total volume drops with
r3.
1
higher O2 quenching rate, the ratio of intraꢀ versus intermoꢀ
lecular oxidation increases. The most dramatic increase of this
ratio by a factor of ≈120, however, is achieved by using an
additional chemical 1O2 quencher. We have presented a quantiꢀ
tative relation of kintra/kinter to chemical rate constants, concenꢀ
trations and solvent parameters.
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In addition, we have shown a strong impact of the distance
on this preference in the highly quenching solvent system. For
the design of such a sensitizerꢀacceptor molecule, the distance
should not exceed 2 nm. These experimental findings are not
conflicting with the much higher predictable travel distance of
1
1O2 derived from its lifetime and diffusion coefficient: A O2
From these observations we can draw the following concluꢀ
1
molecule generated in the proximity of a reactive site is not
inevitably causing a reaction but can travel in other directions.
Thus, the sole intramolecular process would require a special
sions: An oxygenation reaction where one molecule O2 is
attacking exclusively at a site where its generated (either from
the same molecule or intermoleculary but within the vicinity
of the sensitizer) can be realized only by the use of strong
competing quenchers, requiring kquencher[Aquencher]>>kr and a
1
3D molecular architecture, where any travel direction of O2
would lead to a successful encounter. This insight helps to
understand the relations between diffusion, lifetime and chemꢀ
ical efficiency of 1O2 in PDT.
distance between sensitizer and reactive site <<√(2kquencher 1D)
–
(see Scheme 1). Fulfillment of these requirements would inꢀ
deed reduce intermolecular reactions below 1%. On the other
hand, the time required for a complete oxidation is increased
which can be predicted using equation (3). For PDT applicaꢀ
tions benign quenchers might be available, which protect
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and
characterization data, sample preparation, determination of kꢀ
values including plots of c/c0 versus t, NMR spectra, and
quantum chemical calculations. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
healthy regions from damage by O2. As the main challenge
remains the accomplishment of the required proximity beꢀ
tween sensitizer and target for a true intramolecular process.
The distance dependence found in this work reveals that this
proximity is by magnitudes smaller than expected.
AUTHOR INFORMATION
Corresponding Author
*linker@uniꢀpotsdam.de
ACKNOWLEDGMENT
We thank the University of Potsdam for generous financial supꢀ
port. We thank Dr. Heidenreich for assistance in NMR analysis
and Dr. Starke for measurement of mass spectra.
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