Rewiring Chemical Networks Based on Dynamic Dithioacetal and Disulfide Bonds

Article abstract of DOI:10.1002/chem.201705654

The control of the connectivity between nodes of synthetic networks is still largely unexplored. To address this point we take advantage of a simple dynamic chemical system with two exchange levels that are mutually connected and can be activated simultan

Full text of DOI:10.1002/chem.201705654

A Journal of
Accepted Article
Title: Rewiring chemical networks based on dynamic dithioacetal and
disulfide bonds
Authors: Gaston Orrillo, Agustina La-Venia, Escalante Andrea, and
Ricardo L.E. Furlan
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Supported by

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Rewiring chemical networks based on dynamic dithioacetal and
disulfide bonds
[
a]
[b]
[a]
[a,c]
A. Gastón Orrillo, Agustina La-Venia, Andrea M. Escalante and Ricardo L. E. Furlan*
[a] Dr. A. G. Orrillo, Dr. A. M. Escalante, Prof. Dr. R. L. E. Furlan
Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (UNR-CONICET), Ocampo y
Esmeralda, 2000 Rosario (Argentina)
E-mail: rfurlan@fbioyf.unr.edu.ar
[b] Dr. A. La-Venia
Instituto de Química Rosario (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad
Nacional de Rosario, Suipacha 531, S2002LRK Rosario (Argentina)
c] Prof. Dr. R. L. E. Furlan
[
Farmacognosia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario,
S2002LRK Rosario (Argentina)
Supporting information for this article is given via a link at the end of the document.
Abstract
The control of the connectivity between nodes of synthetic networks is still largely unexplored. To
address this point we take advantage of a simple dynamic chemical system with two exchange levels
that are mutually connected and can be activated simultaneously or sequentially. Dithioacetals and
disulfides can be exchanged simultaneously under UV light in the presence of a sensitizer. Crossover
reactions between both exchange processes produce a fully connected chemical network. On the other
hand, the use of acid, base or UV light connects different nodes allowing network rewiring.
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Systems Chemistry aims to develop molecular systems of interacting and/or interconverting molecules
[
1]
that show emergent properties. The field is nowadays learnig the design rules, mastering the
[
1a]
underlying basic chemistry, and developing analytical tools to design new emergent behaviors.
The preparation of complex reaction networks constitutes an important part of systems chemistry.
One of the more successful methods to generate reaction networks is dynamic combinatorial
[2]
[
1c,3]
chemistry
wherein a few small building blocks react reversibly with each other, giving rise to
mixtures of library members or dynamic combinatorial libraries (Figure 1). In this context, appropriate
control of the reversible chemistry used to interconvert library members can rewire the network by
addition or removal of connections betweeen nodes, changing both, the structure of the molecular
[4]
network and the system adaptability towards environmental changes.
Covalent dynamic combinatorial chemistry usually utilizes one type of dynamic covalent bond to
generate molecular diversity. The combination of more than one type of reversible chemistry in the
[5]
same system adds complexity layers and offers additional handles to control it. However, exploitation
[6]
[7]
[8]
and exploration of dynamic chemical systems constructed by using two, three or more reversible
covalent chemistries are still scarce.
In terms of connectivity, combined reversible chemistries can be orthogonal, when each functional
group is involved in the formation of only one type of covalent bond, or they can communicate to each
other, which means that some of the functional groups can form more than one type of covalent bond.
In addition, orthogonal and communicating reversible reactions can be simultaneously or sequentially
activated. Combining simultaneous exchange chemistries that can communicate leads to the
generation of two exchange pools that share a building block type; consequently, any increase of the
amount of this building block type in one pool depletes it in the other one leading to antiparallel
[9]
chemistries.
[10]
Recently, we introduced the use of dithioacetals in dynamic covalent chemistry. Dithioacetals can
be exchanged under acidic conditions, are stable in neutral and basic conditions, and their
[11]
concentration can respond to templates. Dithioacetals share the thiol building block with disulfides,
[12]
one of the most popular dynamic covalent bonds, so both reactions can communicate. Interestingly,
each of these two exchange processes can be activated individually in organic solvents using
[10]
appropriate acid/base conditions.
When combined in one single dynamic system, these two
reactions allow the chemical communication between two diversity layers that can be sequentially
[13]
activated. In addition to nodes and edges used to describe “monolayer” molecular networks,
the
network of this system has two layers of complexity. Multilayer networks are networks of networks
[14]
equipped with intra- and inter-layer edges. As a consequence, each network is interconnected to
and interdependent with another network.
[12d]
Although dynamic disulfide bonds are normally activated under basic conditions,
they can also
[15]
[16]
[17]
be elicited in the presence of phosphine- or NHC-based catalysts as well as under ultrasound,
[18]
[19]
grinding
and photoirradiation.
The photochemical exchange of dithioacetals has not been
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explored, however the photoactivation of their C-S bond has been exploited for addition of dithioacetals
[20]
[21]
to alkenes
and for deprotection of dithioacetals.
Here we report that: (a) dithioacetals can be
exchanged under UV light in the presence of a sensitizer, (b) disulfides can be exchanged under the
same conditions, (c) crossover reactions occur under photochemical conditions when disulfides and
dithioacetals coexist in the same system, and (d) the use of acid, base or UV ligth changes nodes
connectivity. In this way the network can be rewired to selectively access the disulfides or the
dithioacetals layer, or to access the whole chemical network (Figure 1).
The exchange of dithioacetals 1A1 and 2A2 (Figure 2a,b) was initially attempted under a series of
photochemical conditions varying the amount of photosensitizer, atmosphere, solvent, volume, mode
of stirring and dithioacetal concentration (see Section 4.1.1. in Supplementary Information). The best
results were obtained in an oxygen-saturated acetonitrile-d solution containing the two starting
3
dithioacetals (30 mM) in the presence of 9,10-dicyanoanthracene (DCA, 0.3 mM) as a photosensitizer.
Light exposure (λ = 365 nm) of the stirred solution led to a constant concentration of the
heterodithioacetal product 1A2 (Figure 2c) after 5 h of reaction. At this moment, the mixture was
equilibrated (Figure 2d). When the reaction was carried out starting from dithioacetals derived from
different thiols and aldehydes, a statistical distribution of dithioacetals is achieved in around ten hours
(
Figure S1).
It has been reported that dithioacetals can form radical species under irradiation in similar
[20,21b,21d,22]
conditions.
Therefore, the time evolution of the reaction was monitored by HPLC in the
presence of TEMPO. Mixtures of 1A1 and 2A2 were exposed to UV light, and TEMPO was added at
different times (Figure 3). Inhibition of the exchange reaction suggests that the photosensitized
dithioacetal exchange requires radical intermediary species.
Then the simultaneous activation of disulfide and dithioacetal exchanges was studied. With this aim,
the exchange of disulfides was attempted under the photochemical conditions previously used for the
exchange of dithioacetals. A solution of disulfides 11 and 22 (Figure 4a,b) was exposed to UV
light/DCA giving place to the exchange product 12 (Figure 4c), which reached a steady concentration
[23]
after 3 h of reaction (Figure 4d).
The existence of crossover between disulfides and dithioacetals exchanges under photochemical
conditions was analyzed next. Exposure of disulfide 11 and dithioacetal 2A2 to UV-light led to the
expected disulfides, 12 and 22, and dithioacetals, 1A1 and 1A2 (Figure 5a-c). Formation of the
[23]
disulfide product 12 was the fastest, reaching a constant concentration in 4 h (Figure 5d,e). This
crossover experiment shows that the formation of heteroproducts 12 and 1A2 (Figure 5d,e) is slower
than in the experiments based on isolated dithioacetals or disulfides exchanges (Figures 2d and 4d,
respectively), indicating that building block transference between two dithioacetals or between two
disulfides is faster than the crossed transference between one dithioacetal and one disulfide. This
could be the result of limited building block availability, which is regulated by a decreased reactivity of
one particular functional group. For instance, the slower formation of disulfide 12 in this experiment
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could be due to a decreased reactivity of dithioacetals 1A2 and 2A2, who are the only source of
building block 2 able to produce 12. Alternatively, the two exchange processes could affect their
[24]
kinetics by sharing one common reagent or intermediate that can act as a hub of the network.
In order to explore further the disulfide/dithioacetal crossover, a system was studied in which
building blocks 1 and 2 are available independently of the other co-existing exchange process.
Exposure of dithioacetals 1A1 and 2A2 and disulfides 11 and 22 to UV-light led to a constant
concentration of the disulfide product 12 after 3 h of reaction, an almost identical behaviour to that of
the isolated disulfide equilibrium (Figure 6a). This gives further support to dithioacetal controlled
building block shortage as one cause for the delay observed in the previous experiment (shown in
Figure 5). On the contrary, formation of dithioacetal 1A2 in the presence of disulfides was slower than
in the isolated dithioacetal equilibrium, demanding about 40 h to reach a nearly constant dithioacetal
ratio (Figure 6b). This result suggests that the observed differences are most likely due to different
kinetics of the reactions between the formed radicals and the disulfides or the dithioacetals. In this
case radical species would react faster with disulfides than with dithioacetals, so the disulfides
exchange at more or less the same rate as in the isolated system, whereas the dithioacetals exchange
slower than in the isolated system.
[25]
The study of reaction kinetics on dynamic chemical systems is gaining increasing attention.
Differences in reactivity between isolated and networked reversible reactions have been previously
[
2a]
described by the group of Lehn for imine formation and exchange, showing that competition between
different amino compounds may lead to out-of-equilibrium states where a slow formation step leads
towards the equilibrium with a nonlinear kinetics. In other example, some simultaneous-communicating
reactions have been showed to have a very slow velocity, impeding to exactly determine whether the
[7a]
equilibrium point has been reached.
Selective or dual activation of disulfide and dithioacetal exchange under acid/base/photochemical
conditions can be used to network rewiring (Figure 1). Treatment of a static mixture of 11 and 2A2 with
TEA and the thiol 2 selectively activates the disulfide layer of the network whereas the dithioacetal
layer stays disconnected (Figure 7a). Addition of TFA disconnects the disulfide layer and activates the
dithioacetal layer (Figure 7b). Sequential activation of exchanges results in a multilayer molecular
network in which the layers are separated in activation time but connected through thiol nodes (Figure
7c). The two layers can be activated in the opposite sequence by adding first the corresponding thiol 1
and the acid and then the base (Figure 7d–f). The differences observed in the final compositions of
these mixtures are the result of the systems history. In parallel, simultaneous photochemical activation
of the disulfide and dithioacetal layers (Figure 7g) connects all the nodes sharing the same type of
building block, leading to a fully wired network (Figure 7h).
Controlling relationships between nodes leads to an assortment of network structures. A change in
network structure can have a significant effect on the responsiveness of the system. It represents an
interesting entry point to analyze the effect of network structure on the function of fully reversible
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covalent systems. Since each layer of the multilayer molecular network is dynamic, multiple responses
can be expected for a given selective pressure. Given that different layers are not independent of each
other, adaptation reached in the first level of exchange could, in theory, be transmitted to the next layer
even when the selection pressure has disappeared. The connection of reversible processes to
[
2c,5d,26]
[8,24,27]
[28]
irreversible processes has been studied by the groups of Ramstrꢀm,
Miljaniꢁ,
Herrmann
[29]
and Philp,
giving access to a variety of systems with interesting properties. The connection of
reversible processes to other reversible processes that can be sequentially or simultaneously activated
opens interesting possibilities, in particular in line with the antiparallel chemistry concept recently
[9]
proposed by the group of Otto. In this work, rewiring is introduced to engineer novel synthetic
multi/monolayer networks in complex chemical systems.
Experimental Section
In a typical experiment, dithioacetals and/or disulfides (15 µmol of each one) were dissolved in
acetonitrile (0.5 mL) containing DCA (0.03 mg, 0.15 µmol). The resulting solution was poured in a 5 mL
test tube and oxygen was bubbled for 3 min before closing the system. The test tube was placed close
1
to a UV desk lamp (4W, λ = 365 nm) and the solution was magnetically stirred (speed = 350 rpm). H-
NMR or HPLC-UV monitoring involved transferring the solution to a NMR tube or HPLC vial, make the
measurement and then pour the solution back to the test tube or vial to extend the time of light
exposure. For more details, see the Supporting Information.
Acknowledgements
This work was supported by FONCYT (PICT2015-3574), CONICET (PIP 695) and Universidad
Nacional de Rosario.
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Figure 1. Network rewiring in dynamic combinatorial libraries (DCLs).
Figure 2. (a) Photochemical exchange (λ = 365 nm) of dithioacetals 1A1 and 2A2 (30 mM of each
one) in an oxygen-saturated acetonitrile-d solution in the presence of DCA (0.3 mM). Signals of the
3
1
dithioacetal groups protons in the H-NMR spectra (CD CN, 600 MHz, 298°K) recorded (b) before or
3
(
c) after 4 h of photoreaction. (d) Kinetic profile of the reaction. Y-axis shows the proportion of
1
dithioacetals calculated from the integration of dithioacetal proton signal in the H-NMR spectra
expressed as percentage of the total integration for dithioacetal proton signals.
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Figure 3. Effect of the addition of TEMPO on the dithioacetal exchange between 1A1 and 2A2 (30 mM
of each one) in an acetonitrile solution saturated with O and in the presence of DCA (0.3 mM). Y-axis
2
shows the HPLC-UV peak area for dithioacetal 1A2 (λ = 250 nm).
Figure 4. (a) Photochemical exchange (λ = 365 nm) of disulfides 11 and 22 (30 mM of each one) in an
oxygen-saturated acetonitrile solution in the presence of DCA (0.3 mM). HPLC-UV chromatograms (λ =
250 nm) as obtained (b) before and (c) after 2 h of photoreaction. (d) Kinetic profile of the reaction. Y-
axis shows the HPLC-UV peak area for disulfides 11, 12 and 22 (λ = 250 nm) expressed as
percentage of the total disulfide peaks area.
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Chemistry - A European Journal
10.1002/chem.201705654
COMMUNICATION
Figure 5. HPLC-UV chromatograms (λ = 250 nm) of the mixtures formed from 11 and 2A2 (30 mM of
each one) in an oxygen-saturated acetonitrile solution with DCA (0.3 mM) as obtained (a) before or
after (b) 8 h or (c) 14 h of photoreaction. Kinetics of the equilibration of (d) dithioacetals and (e)
disulfides. Y-axis in (d) shows the HPLC-UV peak area for dithioacetals 1A1, 1A2 and 2A2 expressed
as percentage of the total dithioacetal peaks area. Y-axis in (e) shows the HPLC-UV peak area for
disulfides 11, 12 and 22 expressed as percentage of the total disulfide peaks area.
Figure 6. Comparison of the kinetic profiles of formation of 12 and 1A2 through isolated and networked
disulꢉide and ditꢈioacetal pꢈotocꢈemical excꢈanges. In tꢈe “network” experiment (a and bꢅ product
formation results from the photochemical exchange (λ = 365 nm) of disulfides 11 and 22 (30 mM of
each one) and dithioacetals 1A1 and 2A2 (30 mM of each one) in an oxygen-saturated acetonitrile
solution in the presence of DCA (0.3 mM). Tꢈe “isolated” disulꢉide experiment (aꢅ is carried under tꢈe
same conditions but in absence of dithioacetals. Tꢈe “isolated” ditꢈioacetal experiment (bꢅ is carried
out under the same conditions but in absence of disulfides. Y-axis shows the HPLC-UV peak area (λ =
250 nm) for disulfide 12 expressed as percentage of the total area of disulfide peaks (a), or for
dithioacetal 1A2 expressed as percentage of the total area of dithioacetal peaks (b).
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Chemistry - A European Journal
10.1002/chem.201705654
COMMUNICATION
Figure 7. HPLC chromatograms obtained when the exchange of disulfide 11 and dithioacetal 2A2 was
sequentially activated (a-b and d-e), leading to multilayer networks (c and f), or simultaneously
activated (g) leading to a fully connected monolayer network (h). Chromatogram labels: components
involved (green) or not involved (red) in a dynamic exchange process. Components that are formed
under some of the other conditions used, but not under the conditions depicted (dotted). Network graph
labels: disulfides (black), dithioacetals (blue). Grey nodes represent thiols under base and acid
conditions (c and f) or radical species under UV light (h).
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