An Autocatalytic System of Photooxidation-Driven Substitution Reactions on a FeII4L6 Cage Framework

Article abstract of DOI:10.1002/anie.201507045

The functions of life are accomplished by systems exhibiting nonlinear kinetics: autocatalysis, in particular, is integral to the signal amplification that allows for biological information processing. Novel synthetic autocatalytic systems provide a foundation for the design of artificial chemical networks capable of carrying out complex functions. Here we report a set of Fe^II₄L₆ cages containing BODIPY chromophores having tuneable photosensitizing properties. Electron-rich anilines were observed to displace electron-deficient anilines at the dynamic-covalent imine bonds of these cages. When iodoaniline residues were incorporated, heavy-atom effects led to enhanced ¹O₂ production. The incorporation of (methylthio)aniline residues into a cage allowed for the design of an autocatalytic system: oxidation of the methylthio groups into sulfoxides make them electron-deficient and allows their displacement by iodoanilines, generating a better photocatalyst and accelerating the reaction.

Full text of DOI:10.1002/anie.201507045

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201507045
German Edition: DOI: 10.1002/ange.201507045
Metal–Organic Capsules
An Autocatalytic System of Photooxidation-Driven Substitution
II
4
Reactions on a Fe L Cage Framework
6
Prakash P. Neelakandan, Azucena JimØnez, John D. Thoburn, and Jonathan R. Nitschke*
Abstract: The functions of life are accomplished by systems
exhibiting nonlinear kinetics: autocatalysis, in particular, is
integral to the signal amplification that allows for biological
information processing. Novel synthetic autocatalytic systems
provide a foundation for the design of artificial chemical
networks capable of carrying out complex functions. Here we
mation of both dynamic covalent (C=N) and coordinative
(N!Metal) bonds for the synthesis of three-dimensional
[
6]
structures. Because both coordinative and covalent linkages
form reversibly under conditions of thermodynamic equili-
bration, structures formed using this technique offer more
pathways for reconfiguration than do structures held together
by a single kind of dynamic linkage. By employing this
methodology, we have demonstrated that a variety of metal–
organic cage systems can be synthesized and tailored for
diverse applications.
II
report a set of Fe L cages containing BODIPY chromo-
4
6
phores having tuneable photosensitizing properties. Electron-
rich anilines were observed to displace electron-deficient
anilines at the dynamic-covalent imine bonds of these cages.
II
4
When iodoaniline residues were incorporated, heavy-atom
We report here a series of Fe L cages 1–5 (Figure 1),
6
1
effects led to enhanced O production. The incorporation of
prepared through the reaction of bis(formylpyridyl) BODIPY
2
(
methylthio)aniline residues into a cage allowed for the design
L (where BODIPY is 4,4-difluoro-4-bora-3a,4a-diaza-s-inda-
1
5
of an autocatalytic system: oxidation of the methylthio groups
into sulfoxides make them electron-deficient and allows their
displacement by iodoanilines, generating a better photocatalyst
and accelerating the reaction.
cene) with the anilines A –A and iron(II). The identities of
II
the Fe L cages were established by one- and two-dimen-
4
6
sional NMR and ESI-MS (see Supporting Information,
T
he development of artificial supra-
molecular systems capable of com-
plex behavior is a vital strand of
[
1]
current enquiry.
Understanding
how complexity arises in synthetic
systems is helping to elucidate the
[
2]
origins and functioning of life.
Processes exhibiting nonlinear kinet-
ics, such as autocatalysis, are central
[
3]
to biological systems and may also
form the basis of adaptable materials
that respond to environmental stim-
1
5
Figure 1. Subcomponent self-assembly of the bis(formylpyridyl)BODIPY L with anilines A –A and
Fe (NTf ) to form Fe L cages 1–5. The structure of only one edge is shown for clarity.
2 2 4 6
[4]
II
II
uli in complex ways.
Metal-ion mediated self-assem-
bly is a fruitful method for the syn-
thesis of complex molecular assemblies. The technique of
subcomponent self-assembly utilizes the simultaneous for-
[5]
Figures S1–S10). The energy-minimized structures of these
cages (Figure S11) were analogous to previously-reported
II
Fe L cages derived from linear dialdehyde subcompo-
4
6
[
7]
[
*] Dr. P. P. Neelakandan, Dr. A. JimØnez, Prof. J. R. Nitschke
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge CB2 1EW (UK)
E-mail: jrn34@cam.ac.uk
nents. Their NMR spectra were consistent with T point
symmetry in solution.
As the BODIPY unit has been shown to be a competent
1
[8]
chromophore for the photogeneration of O , we set out to
2
Dr. P. P. Neelakandan
Current address: Institute of Nano Science and Technology, Habitat
Centre, Phase 10, Sector 64, Mohali 160062 (India)
investigate the effects of the substituents of the aniline
1
subcomponents upon O photogeneration. We thus moni-
2
tored the ability of cages to generate singlet oxygen by
Dr. A. JimØnez
1
tracking the rate of the reaction of photogenerated O with
2
Current address: Department of Chemistry, University of Oviedo
Julian Clavería 8, Oviedo 33006 (Spain)
1
,3-diphenylisobenzofuran (DPBF), which reacts rapidly with
1
[8d,f]
O (inset of Figure 2).
A solution containing both DPBF
2
Prof. J. D. Thoburn
and cage 5 was exposed to light and UV-Vis absorption
spectra were recorded. As shown in Figure 2 and S12, we
observed a regular decrease in the absorbance of DPBF as
a function of light exposure time, which we attribute to the
Department of Chemistry, Randolph-Macon College
Ashland, VA 23005 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507045.
1
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Figure 2. UV-vis spectrum of cage 5 (a) and the changes in the
absorption spectrum of a mixture of cage 5 (1 mm) and DPBF (6.1 mm)
in acetonitrile as a function of irradiation time. Inset shows the
reaction of singlet oxygen with 1,3-diphenylisobenzofuran (DPBF).
1
generation of O photosensitized by cages. At the same time,
2
the absorption bands corresponding to the cages remained
unaffected, suggesting the cages to be stable under these
conditions. The quantum yields of singlet oxygen generation
(
F ) were calculated by using methylene blue as a reference
D
[8d]
of known efficiency.
Cages 1–3, synthesized from non-
iodinated anilines, exhibited low F values (1–2%), whereas
D
5
cage 5, containing iodinated subcomponent A , exhibited
1
Figure 3. A) Partial H NMR spectra in CD CN of i) cage 1, ii) cage 5
3
[9]
5
5
a higher F = 4.5%. When a mixture of cage 2 and A was
obtained after addition of A to cage 1, and iii) cage 2 obtained after
addition of A to cage 5. The resonances corresponding to excess
subcomponents A , A and A are also labelled. B) Increase in the
quantum yield of singlet oxygen generation (F ) upon the conversion
of cage 1 into cage 5 after the addition of 4-iodoaniline (A ), followed
by the decrease in FD upon the conversion of cage 5 into cage 2 after
the addition of 4-methoxyaniline (A ).
D
2
used as photosensitizer, we observed a value of F ꢀ 2%,
D
1
5
2
which suggested that the covalent attachment of the iodine-
containing species to the BODIPY core is necessary for
higher FD.
D
5
Although these FD values are not competitive with
established photosensitizers such as methylene blue, the
frameworks of these cages are dynamic: electron-rich anilines
are capable of displacing electron-poor aniline residues in
2
a system would exhibit autocatalytic properties: Cage 3
contains 4-(methylthio)aniline (A , s = 0.0) residues, which
[10]
3
subcomponent assemblies.
We reasoned that the photo-
para
sensitization efficiency of cages could be tuned via subcom-
ponent exchange, ultimately allowing cages to act as both
could undergo photooxidation to become electron-deficient
4
4-(methylsulfinyl)aniline
(A ,
spara = 0.49)
residues
[14]
photosensitizers and substrates for reaction with photogen-
(Figure 4). If this reaction were to be carried out in the
1
erated O in an autocatalytic process. In order to verify this
2
hypothesis, we carried out a transformation in which cage
1
1
0
containing electron-poor aniline A (Hammett spara
=
[11]
1
.50 ) and having low O generation efficiency was trans-
formed into cage 5 by the addition of A (s = 0.18)
Figure 3). Cage 5 thus formed exhibited higher O gener-
2
5
para
1
(
2
ation efficiency than cage 1. This efficiency was subsequently
5
lowered following exchange of the A residues for more
2
electron-rich non-iodinated aniline
A
(spara = À0.27).
Although the singlet oxygen generation efficiency of these
cages is modest compared to well-established photosensitiz-
[
12,13]
ers,
the dynamic nature of the imine bonds in the cages
Figure 4. Schematic representation of the autocatalytic photooxidation
5
3
allows for tuning of the singlet oxygen generation efficiency
from an initial low rate to a higher rate, and subsequently
back to a lower rate, which would be challenging via
conventional methodologies.
We then investigated the consequences of a cage perform-
ing dual roles: as both photosensitizer, and as substrate for the
photogenerated singlet oxygen. We hypothesized that such
process that results in accelerating substitution of A for A residues
on the framework of 3. i) Equilibrium subcomponent substitution
3
occurs to a limited degree (K =0.084) in the dark. ii) O is converted
into O more efficiently by cages that contain progressively more A
residues as the reaction continues, accelerating it. iii) O reacts with
A residues, converting them into electron-poor A residues, which are
eq
2
1
5
2
1
2
3
4
5
5
then iv) displaced by A , increasing by one the number (n) of A
residues.
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5
4
presence of aniline A (s = 0.18), A would be displaced by
para
5
the more electron-rich A , leading to the generation of cage 5.
Crucially, as this transformation proceeds, the incorporation
5
of progressively more iodinated A residues will increase the
photosensitization efficiency of the system, thereby generat-
ing more singlet oxygen, which in turn increases the rate of
3
4
photooxidation of A to A . Progressive substitution will thus
3
increase the rate of the photooxidation of the A residues,
a behavior characteristic of an autocatalytic system, wherein
[
3]
the rate of reaction accelerates as it progresses.
1
Figure S13A shows the H NMR spectrum of cage 3 to
which A was added. The reaction medium was then saturated
5
with O and exposed to light. After 58 h of illumination, we
2
observed new multiple peaks (mp) overlapping with the Hj
Figure 5. Observed increase in the concentration of the displaced
and H doublets of cage 3 at d = 5.57 and 7.11 ppm (Fig-
3
k
aniline A as a function of time upon irradiating a mixture of cage 3
ure S13B–E). Concomitantly, new peaks were observed at
5
and A in acetonitrile under different reaction conditions. The arrow
5
.34 (mp), 6.65 (d) and 7.62 ppm (mp), whose intensity
indicates the point at which the reaction mixture followed in the lower
increased at the expense of peaks at 5.57 and 7.11 ppm as the
reaction continued. We also observed a small upfield shift
trace was exposed to O and light.
2
(
Dd = 0.03) of the signal at 6.65 ppm. As described below,
these observations are in accordance with the anticipated
photooxidation of cage 3.
We propose the following set of equations to describe the
autocatalytic cycle.
[16]
We attribute the appearance of multiple peaks during the
course of the reaction to the generation of a dynamic library
3
1
5
3
þ O ! 5 þ O
ð1Þ
ð2Þ
ð3Þ
2
2
[10b]
of cages.
As the photosensitized oxidation proceeds, three
1
þ O ! 4
2
3
kinds of aniline residues are present in the library: A from
4
5
4
cage 3, A from the product of photooxidation, and the added
4 þ A ! 5 þ A
5
A . Six potential bis(iminopyridyl)BODIPY ligands are thus
present: three homotopic and three heterotopic, which could
This system of equations describes an indirect autocatal-
ysis, one of the many types of autocatalysis. Oxygen and
[15]
[17]
form 91 constitutionally distinct cages,
leading to the
1
complexity of the observed H NMR spectra. Chemical shift
values of the new peaks at 5.34 and 7.62 ppm were compa-
light participate in the autocatalytic cycle by creating an
4
electron-deficient subcomponent (A ), the displacement of
rable to those of the H and Hk protons of cage 5 (Fig-
ure S13F), which is consistent with the incorporation of A
which becomes thermodynamically favorable during subcom-
ponent substitution. This proposed mechanism is consistent
with the kinetic data (See Supporting Information, Section S6
for a detailed analysis).
j
5
residues into the cage. Mass spectrometry also supported the
presence of a multitude of multiply substituted cage species,
containing all three kinds of aniline residues (Figure S14). A
complete transformation of the dynamic library into cage 5
was not observed even after prolonged exposure to light and
oxygen (13 days at 608C).
We carried out a control experiment to test our inter-
pretation of these events, wherein the same transformations
were carried out in the absence of light and oxygen (Fig-
3
ure S17). An initial exponential rise in the production of A
3
We tracked the concentration of the displaced aniline A
(Figure 5, lower trace (*)) was observed, with an observed
1
obs
À1
through H NMR integration as the reaction progressed. As
rate constant k1 = 0.018 Æ 0.002 h , continuing to equilib-
shown in Figure 5 (top trace (~)), the concentration was
observed to increase rapidly during the first ca. 75 h. An
intermediate stage was then observed (from ca. 75 h to 250 h),
where the rate of substitution was lower. Finally, the rate
increased in an exponential fashion after 250 h. We did not
observe a final sigmoidal plateau because the NMR peaks
rium (K = 0.084 Æ 0.002). However, we did not observe the
eq
second exponential rise in the absence of oxygen and light.
When the reaction medium was subsequently saturated with
oxygen and exposed to light, we observed the characteristic
induction period followed by a rapid increase in the rate of
obs
À1 À1
the reaction with k2 ꢀ 45m h . This control experiment
thus supports our hypothesis that photooxidation-driven
subcomponent exchange is responsible for autocatalysis.
Comparison of the two experiments of Figure 5 provides
further confirmation of autocatalysis: The more rapid initial
rise in the rate of substitution in the light reaction (top trace
(~)) as compared to the dark reaction (lower trace (*)) is
III
broadened, possibly due to a buildup of paramagnetic Fe
produced under oxidizing conditions over several hundred
hours.
3
We infer that the initial rapid release of A is due to an
imine exchange reaction that then slows as equilibrium,
3
mostly favoring A incorporation, is reached. The induction
3
4
5
period that follows involves photooxidation of A to A
inferred to be due to the greater degree of incorporation of A
4
followed by release of A , slowly at first, and then more
residues at earlier times, which engenders a progressively
faster substitution rate in the light reaction. If the substitution
observed in the light reaction were simply due to a pre-
equilibration (as in the dark reaction) followed by displace-
rapidly as autocatalysis sets in. The incorporation of iodoani-
5
1
line (A ) residues into the cage increases the O generation
2
efficiency, in turn increasing the rate of the oxidation step.
1
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4
ment of photogenerated A residues, where these residues
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the reaction rate with time would be expected. This observed
trend is consistent with a more effective catalyst being
5
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None of the bis(iminopyridyl)BODIPY cage ligands
[
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(
Figure 1) were observed to form in the absence of Fe
templates, in keeping with our previous observations that
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[
6,7]
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itself plays an integral role in the autocatalytic system, as any
5
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II
4
tization efficiency of metal–organic Fe L cages could be
6
tuned by subcomponent exchange, which allowed the possi-
bility of post-assembly modification of the cageꢀs structure
and reactivity. The ability of the cage to photosensitize singlet
oxygen formation can be tuned: substitution with iodoaniline
subcomponents enhances the photosensitization, whereas
methoxyaniline diminishes it. The singlet oxygen produced
was found to oxidize (methylthio)aniline residues, rendering
them more readily displaced by iodoaniline, which leads to
accelerated photosensitization and an autocatalytic cycle.
Because both a separate molecule (DPBF) and the cage
framework itself are able to serve as photooxidation sub-
strates, this cage system might be incorporated into more
complex systems. Signal molecules (such as anilines) could be
passed to the autocatalytic cycle, enabling the oxidation
reaction to be upregulated or downregulated, and the
oxidation products themselves could serve as signals to
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important future direction enabled by this work.
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Acknowledgements
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providing mass spectra.
Keywords: autocatalysis · metal–organic capsules ·
photosensitizers · self-assembly
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[
9] A further increase in quantum yield was observed for cages
synthesized from multi-iodinated anilines. Even though NMR
evidence suggested the formation of these cages, mass spec-
trometry evidence was inconclusive possibly because of frag-
mentation. Hence we see it inappropriate to include those cages
in the manuscript.
[14] L. Wang, J. Cao, J.-w. Wang, Q. Chen, A.-j. Cui, M.-y. He, RSC
Adv. 2014, 4, 14786.
[15] The number of cages that differ in mass was determined as 91 as
explained in Ref. [10b].
[16] Equations (1)–(3) are simplified in that 3, 4, and 5 are also taken
3
4
5
to comprise heteroleptic cages that contain A , A , and A ,
respectively.
[
10] a) D.-H. Ren, D. Qiu, C.-Y. Pang, Z. Li, Z.-G. Gu, Chem.
Commun. 2015, 51, 788; b) Y. R. Hristova, M. M. J. Smulders,
J. K. Clegg, B. Breiner, J. R. Nitschke, Chem. Sci. 2011, 2, 638;
c) D. Schultz, J. R. Nitschke, J. Am. Chem. Soc. 2006, 128, 9887.
11] C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91, 165.
12] Prior work suggests that the site of iodination is an important
factor that governs the efficiency of photosensitization proper-
ties of BODIPYs (see Ref. [13]). In cage 5, the iodine atoms are
[17] a) R. Plasson, A. Brandenburg, L. Jullien, H. Bersini, J. Phys.
Chem. A 2011, 115, 8073; b) R. Plasson, A. Brandenburg, L.
Jullien, H. Bersini, Artif. Life 2011, 17, 219.
[
[
Received: July 29, 2015
Revised: September 15, 2015
Published online: October 6, 2015
II
spatially separated from the BODIPY core, with an Fe center
1
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