Dynamic Nucleophilic Aromatic Substitution of Tetrazines

Article abstract of DOI:10.1002/anie.202106230

A dynamic nucleophilic aromatic substitution of tetrazines (S_NTz) is presented herein. It combines all the advantages of dynamic covalent chemistry with the versatility of the tetrazine moiety. Indeed, libraries of compounds or sophisticated molecular structures can be easily obtained, which are susceptible to post-functionalization by inverse electron demand Diels–Alder (IEDDA) reaction, which also locks the exchange. Additionally, the structures obtained can be disassembled upon the application of the right stimulus, either UV irradiation or a suitable chemical reagent. Moreover, S_NTz is compatible with the imine chemistry of anilines. The high potential of this methodology has been proved by building two responsive supramolecular systems: A macrocycle that displays a light-induced release of acetylcholine; and a truncated [4+6] tetrahedral shape-persistent fluorescent cage, which is disassembled by thiols unless it is post-stabilized by IEDDA.

Full text of DOI:10.1002/anie.202106230

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Dynamic Nucleophilic Aromatic Substitution of Tetrazines
Authors: Romen Carrillo, Tanausú Santos, David S. Rivero, Yaiza
Pérez-Pérez, Endika Martín-Encinas, Jorge Pasán, and
Antonio Hernández Daranas
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202106230
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10.1002/anie.202106230
Angewandte Chemie International Edition
RESEARCH ARTICLE
Dynamic Nucleophilic Aromatic Substitution of Tetrazines
Tanausú Santos, [a] David S. Rivero, [a] Yaiza Pérez-Pérez, [a] Endika Martín-Encinas, [a] Jorge Pasán, [b]
Antonio Hernández Daranas [a] and Romen Carrillo*[a]
[a]
Mr. T. Santos, Mr. D. S. Rivero, Ms. Y. Pérez-Pérez, Dr. E. Martín-Encinas, Dr. A. H. Daranas and Dr. R. Carrilllo
Structure, Design and Molecular Function Group
Instituto de Productos Naturales y Agrobiología (IPNA-CSIC)
Avda. Astrofísico Fco. Sánchez 3, 38206, La Laguna, Spain
E-mail: rcarrillo@ipna.csic.es
[b]
Dr. J. Pasán
Laboratorio de Materiales para Análisis Químicos (MAT4LL), Departamento de Física, Universidad de La Laguna (ULL), La Laguna, Tenerife, 38206,
Spain.
Supporting information for this article is given via a link at the end of the document.
Abstract: A dynamic nucleophilic aromatic substitution of tetrazines
(SNTz) is presented herein. It combines all the advantages of
dynamic covalent chemistry with the versatility of the tetrazine ring.
Indeed, libraries of compounds or sophisticated molecular structures
can be easily obtained, which are susceptible to post-
functionalization by Inverse Electron Demand Diels-Alder (IEDDA)
reaction, which also locks the exchange. Additionally, the structures
obtained can be disassembled upon the application of the right
stimulus, either UV-irradiation or a suitable chemical reagent.
Moreover, SNTz is compatible with the imine chemistry of anilines.
The high potential of this methodology has been proved by building
two responsive supramolecular systems: A macrocycle that displays
a light-induced release of acetylcholine; and a truncated [4+6]
tetrahedral shape-persistent fluorescent cage which is disassembled
by thiols unless it is post-stabilized by IEDDA.
overlooked almost completely.[37][38] Obviously, SNAr requires an
electron-poor aromatic ring to be involved. But this requirement
offers the chance to explore tetrazines as a potentially optimal
moiety for an extremely versatile dynamic process. Indeed,
tetrazines are not only electron-poor aromatic rings amenable to
SNAr, but they are also a very useful moiety.[39] Thus, they have
been profusely used as a way to attach different compounds and
moieties by Inverse Electron Demand Diels-Alder (IEDDA)
reaction,[40] which has found many applications in biology,[41-46]
and materials science.[47-51] Tetrazine is a valuable scaffold to
build stimulating architectures such as corona[n]arenes.[52-57]
They also show an interesting redox performance,[58-60] and
some of them display fluorescence.[61-64] Even when it is known
that some tetrazines, such as 3,6-dichloro-1,2,4,5-tetrazine (Cl-
Tz-Cl) can undergo SNAr,[65][66] the reversibility of the substitution
is completely unexplored. In this regard, phenols or thiols may
act both as good nucleophiles and as efficient leaving groups,
and therefore it seems reasonable to focus on them as optimal
candidates as substituents of tetrazine in order to achieve a
reversible SNAr.
Introduction
Dynamic Covalent Chemistry (DCC) has become a powerful tool
in supramolecular chemistry and materials science. This is
probably due to the ability of DCC to "error-checking" and “proof-
reading”, as it is based on reversible covalent reactions under
thermodynamic control. This allows to correct synthetic dead-
ends as it happens in non-covalent chemistry, although with
much more robust molecular systems.[1-4] The relevance of DCC
on current chemistry is clearly reflected by the number of
reported application in the synthesis of sophisticated molecular
architectures,[5-9] in polymer chemistry,[10][11] in finding novel
porous materials,[12] or bioactive compounds,[13-17] and in
systems chemistry.[18-20]
Even when there are well-established reversible reactions such
as imine chemistry,[21][22] disulfide exchange,[23][24] boronic
linkages,[25][26] olefin metathesis,[27][28] and some other interesting
examples,[29-35] there is still a limited set of reactions amenable
to dynamic covalent chemistry. Therefore, scope and
functionality of the molecular structures synthesized could be
improved by new additions to the toolkit of DCC. Particularly
interesting would be to envision a novel dynamic process which
inherently displays relevant physico-chemical properties and
which allows for further functionalization.
Figure 1. (a) Tetrazine is a very versatile moiety with interesting properties. (b)
This work combines the intrinsic advantages of dynamic covalent reactions
with the chemical versatility of the tetrazine ring.
In this regard, we thought that a good choice for a robust and
versatile DCC reaction could be the nucleophilic aromatic
substitutions (SNAr) of tetrazines. In fact, SNAr is known to be
reversible in some cases,[36] yet its dynamic nature has been
Having all that in mind, a novel tool for DCC is herein
introduced: The nucleophilic aromatic substitution of tetrazines
(SNTz) with phenols and alkyl thiols. This fast exchange reaction
1
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10.1002/anie.202106230
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RESEARCH ARTICLE
combines the intrinsic advantages of dynamic covalent
chemistry with the chemical versatility of the tetrazine moiety. In
fact, it allows not only to obtain dynamic libraries of compounds,
or complex molecular structures in an easier way, but it also
takes advantage of the tetrazine moiety itself, and its interesting
physico-chemical properties.
The dynamic nature of SNTz has been successfully confirmed by
obtaining the same distribution of compounds in a series of
reactions conducted in both forward and reverse directions.
Activation and deactivation of the exchange was observed by
the presence or absence of a base respectively. Additionally,
other exciting features of this dynamic reaction were also
proved: Post-functionalization by IEDDA, which also inhibits the
exchange process; photolysis by UV irradiation; and finally this
exchange reaction successfully proved its potential in some
supramolecular systems. Indeed, light induced guest-release
and responsive covalent cages were also achieved by SNTz.
On the other hand both phenols and thiols give good yields of di-
substituted tetrazines at room temperature and thus we focused
on them for this work. [67]
We took the reaction between cresol (1) and the disubstituted
tetrazine with 4-methoxyphenol (2-Tz-2) as the reference
process, which was compared with the reverse reaction,
between 4-methoxyphenol (2) and the cresol disubstituted
tetrazine (1-Tz-1), to test reversibility and exchange ability in
SNTz (Figure 2b). One equivalent of the disubstituted tetrazine
and two equivalents of the corresponding phenol were solved in
different deuterated solvents, and finally 3 equivalents of
triethylamine were added. Fortunately, the experimentally
indistinguishable NMR spectra obtained for reactions conducted
in both forward and reverse directions demonstrate that
equilibrium was achieved (Figure 2c and 2d).
As expected, polar aprotic solvents accelerate the reaction.
Indeed, in CDCl3 reaction was very slow at room temperature,
although progression was evident at 50°C, and after 15 hours at
that temperature, equilibrium was reached. On the other hand, in
deuterated DMSO at room temperature, reaction equilibrated so
fast that it was impossible to be followed by NMR, while in
acetonitrile it was complete in less than two hours at room
temperature or in 30 minutes heating at 50°C. The choice of the
base also affects the kinetics of the exchange. Triethylamine
(TEA) and di-isopropylethylamine (DIPEA) yield the fastest
exchange, while less basic compounds such as N-
methylmorpholine (NMM) take longer times to completion, and
pyridine was not even able to induce the exchange. Inorganic
bases such as Cs2CO3 in DMSO were detrimental to the
reaction. [67]
Results and Discussion
3,6-di-substituted tetrazines were prepared starting from the
corresponding nucleophile and 3,6-dichloro-1,2,4,5-tetrazine (Cl-
Tz-Cl) (Figure 2a), which can be synthesized in five steps in
gram scale.[67] Amines and aliphatic alcohols were discarded
from this work because previous studies,[39][66][68] and several
experiments in our lab showed that di-substituted tetrazines are
frequently hard to obtain with that kind of nucleophiles: Harsh
conditions are required and usually only low yields are obtained.
Forward
Neutral
Reverse
a)
b)
CD3CN or DMSO-d6 or CDCl3 Et3N, r.t., time (see table 1)
Same product distribution
Quantification by q-13C NMR
d)
c)
1-Tz-2
2-Tz-2
1-Tz-1
Forward
Reverse
triethylamine
Figure 2. (a) Synthesis of the disubstituted tetrazines was carried out from Cl-Tz-Cl and the corresponding thiol or phenol. (b) Reactions performed on both
directions (forward and reverse) and also starting directly from Cl-Tz-Cl (neutral), led to identical product distribution. (c) 1H NMR of the forward and reverse
reactions in CD3CN. Unfortunately the peaks of 1-Tz-2 and those of the homodimers overlap, so no quantification of all the compounds of the reaction
mixture can be performed by 1H NMR. (d) The 13C NMR shows slight differences between homo and hetero dimers of tetrazine, and therefore a quantitative
experiment can be carried out to obtain the ratios of all the compounds in equilibrium.
2
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10.1002/anie.202106230
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RESEARCH ARTICLE
NMR that 2 is almost completely detached from the tetrazine
ring. [67]
Table 1. Equilibration time observed for the reverse reference reaction.
Solvent
Base
Time (min)
In order to examine the scope of this dynamic process and the
effect of the nature of the nucleophile in the outcome of the
equilibrium, a series of different reactions were set up in
deuterated solvents at room temperature (Table 2). Both the
forward and the reverse reactions were followed until no further
changes were observed. Then, quantification of all the
compound in the reaction mixture was performed by quantitative
13C NMR, [67] except for the reaction with 4-bromophenol 3 (entry
CDCl3
TEA
1000[a]
90 (30)[a]
<5[b]
CD3CN
TEA
1
2), that could be quantified by H NMR. Moreover, as in most of
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
TEA
the cases a complete quantification of the species in equilibrium
could be achieved, then calculation of the corresponding
equilibrium constants was trivial (Table 2). Curiously, there are
scarce papers about dynamic covalent reactions where the
equilibrium constants of the exchanges are calculated,[71][72] even
when it is a key physico-chemical property for a reversible
process and it provides a great deal of information.
DIPEA
NMM
Pyridine
Cs2CO3
<5
600
n.r. [c]
[d]
-
From Table 2, it is clear that electron rich phenols tend to remain
attached to the tetrazine ring (smaller constants) while electron
poor ones are more prone to be released (larger constants)
(entries 1-4). Actually, 4-bromophenol 3 (entry 2) is mostly found
free in the equilibrium, and when the extremely electron poor
pentafluorophenol 4 is compared to cresol 1 (entry 3), the
equilibrium is completely shifted towards the release of 4.
It is worth mentioning that phenols with substituents in ortho
position also reached the equilibrium, although much more
slowly. Indeed, 5 and 6 only equilibrated after 24 hours in
acetonitrile (entry 5). Thiols on the other hand might be
problematic in this reaction. Many of them, such as N-acetyl-L-
cysteine, 2-mercaptoethanol or all the thiophenols tested led to a
competitive redox process: Reduction of the tetrazine ring to 1,4-
dihydro-s-tetrazine, with the concomitant oxidation of the thiol to
the corresponding disulfide.[67][73] Only some aliphatic thiols such
as dodecanethiol and benzylmercaptan display an efficient
exchange reaching equilibrium so fast that it cannot be followed
by NMR (entry 7). Interestingly, alkyl thiols tend to displace
phenols from the tetrazine very efficiently. Indeed dodecanethiol
7 completely displaces cresol from the tetrazine in 5 hours (entry
6),[67] while in the other direction of the reaction, cresol 1 is not
able to substitute the thiol attached to the tetrazine core.
[a] Heating at 50°C. [b] Equilibrium reached already in the first NMR spectrum
acquired. [c] No progress of the reaction was observed after 5 days. [d]
Decomposition of the reagents.
It was also shown that a base is required for a successful
exchange of phenols. In fact, when trifluoroacetic acid was
added after 10 minutes to the reaction in acetonitrile, the
progress of the reaction was stopped. After additional 10
minutes, a new addition of triethylamine allows to reinitiate the
exchange to finally reach equilibrium. Therefore, SNTz can be
stopped and activated by the proper addition of an acid or a
base respectively, and reminds in this sense to the imine
exchange,
but
with
the
opposite
scheme
of
activation/deactivation.[67]
Obviously, an important part of this work was to quantify all the
1
species coexisting in the equilibrium. However, in the H NMR
spectra, the peaks corresponding to the heterodimer 1-Tz-2
overlap with those of the homodimers 1-Tz-1 and 2-Tz-2, and
therefore it is not possible to distinguish each compound in the
mixture and as a consequence, the ratio of all the species of the
reaction cannot be calculated by 1H NMR (Figure 2b).
Conversely, some of the peaks in the 13C NMR spectrum can be
unambiguously assigned to the heterodimer, and therefore a
quantitative 13C NMR could be used to quantify each and every
chemical species in the reaction mixture. (Figure 2d and Table 2,
entry 1). Interestingly, when reaction was set up directly from Cl-
Tz-Cl and two equivalents of phenols 1 and 2 and triethylamine
in acetonitrile (neutral in Figure 2b), exactly the same distribution
of products than the forward and reverse reaction was found.[69]
It is clear from Table 2 (entry 1) that the equilibrium is shifted
towards the release of cresol 1 while phenol 2 tends to bind the
tetrazine (roughly 60% of cresol ends up free and 60% of p-
methoxyphenol ends up attached to the tetrazine). This result is
reasonable considering the respective Hammett sigma of both
substituents on the phenol, being 1 the best leaving group (σp=-
0.268 for methoxy, σp=-0.170 for methyl group). Reversibility of
this process was further proved by shifting the equilibrium
backwards, i. e. towards the unfavorable direction by increasing
the concentration of one of the chemical species in solution.[70]
Specifically, once the equilibrium was reached in the reaction
between 2 and 1-Tz-1, which implies that most of 2 is attached
to the tetrazine ring, we added 10 more equivalents of cresol 1,
in order to force the release of phenol 2. It is clearly seen by
Dynamic covalent chemistry in aqueous environments is
challenging for some reactions such as imines and boronic
esters exchanges due to their labile nature.[74-76] However the
bonds involved in SNTz are more robust. Thus we tested one
exchange between 1-Tz-1 and sodium 2-mercaptoethane-
sulfonate 9 in a mixture of deuterated water and acetonitrile (8:2).
We found that 0.1 M sodium carbonate is enough to promote a
successful exchange (Figure 3).
Figure 3. SNTz in aqueous environments
The initial suspension of 1-Tz-1 slowly reacts, and while the
mixture slowly homogenizes, the solution progressively gets
colored. The final result is
a mixture of water soluble
compounds: cresol 1, 9-Tz-9 and 1-Tz-9, which are stable for
days in those conditions.
3
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RESEARCH ARTICLE
Considering
the
basic
Table 2. Quantification of different equilibria and their corresponding constants.
conditions required for SNTz,
we thought that it might be
possible to combine it with
imine chemistry that it is usually
[a]
performed
under
acidic
conditions. Combination of two
or more dynamic covalent
reactions in an orthogonal way
[b]
is
increasingly
interesting
Entry
because it eases the synthesis
of multifunctional molecular
architectures.[77-82]
1
Consequently, dialdehyde 10-
Tz-10 was synthesized and
[c]
Solvent: CD3CN
exposed
acetonitrile (Figure 4). The
corresponding imine
to
toluidine
in
precipitated from the reaction
mixture, it was filtrated and
solved in deuterated DMSO.
2
1
Solvent: CD3CN
The H NMR clearly shows the
formation of 11-Tz-11 and
therefore confirms that SNTz is
compatible with the mine
chemistry of anilines.
[d]
[d]
3
Solvent: DMSO-d6
Obviously, one of the strengths
of this novel dynamic reaction
is
the
ability
of
post-
functionalization by IEDDA.
Additionally, it is interesting to
check if, once the Diels-Alder
4
reaction
transforms
the
Solvent: CD3CN
tetrazine into an electron-richer
1,2-diazine, the exchange is
interrupted. Thus, the IEDDA
reaction between 2-Tz-2 and a
5
slight
excess
of
bicyclic
compound 12 was examined
(Figure 5a). We thought that 12
was an optimal dienophile to
follow the reaction by NMR,
because it displays only three
singlet peaks, and once the
initial cycloaddition finishes and
one molecule of N2 is released,
Solvent: CD3CN
6
[d]
[d]
Solvent: CDCl3
then
a retro Diels-Alder is
expected to occur, giving the
diazine 2-Dz-2 and the furan 13
which displays just two singlets
in the 1H NMR. Fortunately,
IEDDA reaction was carried out
in high yield as it can be told by
the stacked NMR spectra
displayed in Figure 5b.
After 48 hours heating at 50°C
in CDCl3 the 1H NMR only
showed peaks corresponding to
the expected final products and
the remaining 12. The isolated
7
Solvent: CD3CN/CDCl3
(1:1)
[a] Nucleophiles employed. [b] Schematic equilibria and their corresponding constants. [c] All reactions
were carried out in 0.5 ml of the specified solvent (chosen due to solubility and kinetic reasons), and 0.02
mmol of the corresponding phenol or thiol, which were adjusted to the correct stoichiometry, prior to the
addition of 5 µL of triethylamine. Reactions were followed by 1H NMR until no further changes were
observed. Equilibration times range from less than 5 minutes to 24 hours. [d] Only the peaks
corresponding to the compounds displayed at one of the ends of the equilibria can be seen by 1H NMR,
and we assumed that less than 1% of the rest of the compounds is present in the mixture, so we could
estimate a constant. n. d.: not determined.
4
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10.1002/anie.202106230
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yield of such post-functionalization was 94%. Interestingly the
exchange reaction was inhibited after the functionalization
(Figure 5c). Indeed, heating 2-Dz-2, and triethylamine in the
presence of cresol 1 or dodecanethiol 7 led to no reaction at all,
even after 5 days, neither in DMSO at room temperature, nor
heating at 50°C in CDCl3. Therefore, post-functionalization by
IEDDA is not only an efficient way to attach different molecules
to the dynamic libraries of compounds obtained, but it is also a
complementary way to cancel the exchange. Interestingly, when
an intramolecular IEDDA reaction is possible, such as in
compound 6-Tz-6, then heating the mixture gives the
corresponding diazine (6-Dz) in 96% yield, which concomitantly
implies that an irreversible self-inhibition of the exchange can be
triggered by high temperatures. This property might be used for
the kinetic control of the dynamic libraries of compounds
obtained.[83-88]
There are alternative ways to manipulate some of the tetrazine
compounds obtained by SNTz. Inspired by the work by Amos B.
Smith III and Robin M. Hochstrasser,[89][90] it is possible to break
down the S,S-tetrazine derivatives by photolysis which gives two
molecules of the corresponding thiocyanate and one molecule of
nitrogen. Indeed, by UV irradiation with a medium pressure Hg
lamp (450W) complete transformation of 7-Tz-7 into n-dodecyl
thiocyanate 14 was achieved in two hours (Figure 6a). It is worth
mentioning, that an O,O-tetrazine such as 1-Tz-1 or an O,S-
tetrazines such as 1-Tz-7 are not degraded by UV light.
Therefore, all the S,S-tetrazine derivatives obtained by SNTz are
potentially photo-cleavable.
Controlling the behavior of molecular structures is essential to
develop functional systems. As it has been proved, SNTz allows
for a precise chemical control of the compounds obtained, either
by photodegradation under UV-light or by the complete
substitution of phenols by thiols. Those properties together with
its dynamic nature make SNTz a potentially valuable tool for the
synthesis of functional systems. With all this in mind, we decided
to test some of its possible applications through two examples.
On one hand, we decided to prove that SNTz allows for the easy
synthesis of photo cleavable receptors. Controlled release of
guest by light is very attractive because it is a clean and
switchable process which has been reported in several
supramolecular systems.[91-95]
Figure 4. Combination of SNTz and imine chemistry.
a)
T1
T2
T3
R3
R2
R1
D1
D4
F2
D2
D3
F1
b)
R3
R1
R1
R2
R2
D1
D2
D3
F1
F2
D4
48h
24h
0h
R3
T3
T1
T2
c)
Figure 6. (a) Photolysis of 7-Tz-7 by UV-irradiation. (b) Release of
acetylcholine after macrocycle 15 is photo-cleaved.
d)
Due to the abovementioned intrinsical properties of S,S-
tetrazines, they could be employed to create receptors with the
ability to release their guest after disassembly triggered by light.
Actually, tetrazine-bearing crown ether 15 was synthesized in
two steps in 44% yield, and it displays an association constant of
1.1
·102
M-1
with
neurotransmitter
acetylcholine
hexafluorophosphate (ACh PF6) in acetonitrile (Figure 6b).[96-99]
However, UV irradiation causes the macrocycle to break down
into two molecules of dithiocyanate podand 16, which shows no
binding with acetylcholine. Therefore, SNTz is not only an
efficient way to click molecular fragments into a functional
structure, but it confers macrocycle 15 the ability to release
Figure 5. (a) Inverse Electron Demand Diels Alder (IEDDA) reaction on 2-Tz-2
with bicyclic dienophile 12. (b) 1H NMR of the reaction mixture before and after
heating for 24h and 48 h. (c) Diazines do not undergo SNTz. (d) Heating
converts the exchangeable 6-Tz-6 into unreactive 6-Dz by an intramolecular
IEDDA reaction.
5
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acetylcholine triggered by UV irradiation, although it seems
difficult to apply this results to biological systems for the time
being, considering the potent irradiation required for hours for a
successful release.
The compound 17 crystallized in the non-centrosymmetric Pna21
space group and a single cage and two acetone solvent
molecules form its asymmetric unit.[67] Each tetrahedral cage is
formed by four phloroglucinol groups located in the vertices and
six tetrazine groups on the edges. They form an almost perfect
tetrahedron able to accommodate a sphere of 7 Å of diameter
inside.[67]
In spite of the reported good anion binding abilities of i-
corona[6]arenes, [111] cage 17 shows no remarkable association
constant with any anion tested. This fact is probably due to
rigidity of the cage compared with i-corona[6]arenes: Indeed, in
the macrocycle the aromatic proton can be accommodated
towards the cavity and plays a key role on the binding event,
which is obviously not possible with the cage.
Interestingly, 17 is able to respond to a chemical stimulus such
as the presence of a thiol. Indeed dodecanethiol 7 in the
presence of triethylamine is able to rapidly disassemble the cage
into phloroglucinol and 7-Tz-7 (Figure 7d). Such reaction can be
followed by 1H NMR where the singlet peak of cage 17
disappears completely in less than 30 minutes, and an up field
singlet corresponding to phloroglucinol shows up (Figure 7e).
Notably, the fluorescence of the reaction mixture is lost as none
of the final products is fluorescent. As expected, once cage 17 is
conveniently functionalized by IEDDA, the resulting diazine cage
18 becomes unresponsive to the effect of thiols. To the best of
our knowledge, there are only a couple of precedents of such
post-stabilization by Diels-Alder reaction and in both cases, only
for DCC products based on imines.[112][113]
On the other hand, SNTz allows clicking phenols together and
declicking them with thiols.[100] Such ability could be used to
synthesize responsive molecular architectures, that would be
disassembled upon the presence of the right chemical
environment. We decided to test it on a shape persistent cage,
as it is one of the traditional uses of dynamic
methodologies.[27][101-110] We reasoned that pholoroglucinol and
Cl-Tz-Cl should lead to a truncated [4+6] tetrahedral cage,
where each of the four faces is actually an i-corona[6]arene
(Figure 7a).[111] As expected, cage 17 was successfully
synthesized in one step in 43% yield.
Conclusion
We have proved that nucleophilic substitution of tetrazines
(SNTz) with phenols and alkyl thiols is a truly dynamic covalent
reaction. The examples reported herein may serve as glimpse of
the numerous applications that SNTz can find. All those
possibilities are related not only to the dynamic nature of the
process itself, but also to the inherent chemical properties of the
tetrazine. Indeed, it has been shown that post-functionalization
by IEDDA of the compounds obtained allows for the attachment
of molecular fragments while at the same time it inhibits the
exchange. Moreover the thiol derivatives can be photolized by
UV irradiation as an efficient and clean way to break down
irreversibly those compounds. Functional supramolecular
systems such as a tetrahedral responsive fluorescent cage and
a macrocycle that releases acetylcholine upon irradiation were
also studied.
SNTz is a robust and versatile dynamic covalent reaction an
therefore it unleashes a huge potential of applications in the
synthesis of porous organic cages, interlocked structures,
covalent adaptable networks and COFs, all of which could be
post-functionalized, and, in some cases they could also respond
to the right stimulus, either UV-irradiation or a specific chemical
reagent. Moreover, modulation of the compounds obtained
through IEDDA or many other chemical reactions,[114-117] will
ease the access to numerous functional systems. Other well-
known properties of tetrazines such as fluorescence or an
interesting redox behavior, foresee also a bright future to SNTz in
the fields of molecular sensors and electronics. There are
Figure 7. (a) Synthesis of cage 17. (b) Yellow-orange fluorescence of cage 17
under UV light. (c) Single-crystal X-ray molecular structure of 17. One
molecule of acetone lies inside the cavity while other is outside. (d) Cage 17
is disassembled by thiol 7 in the presence of triethylamine, however post-
stabilization can be achieved by IEDDA. (e) Stacked plot of the 1H NMR of
pure 17, the crude of the disassembling reaction mixture after 30 minutes and
phloroglucinol all in CD3CN.
This covalent molecular capsule displays an orange
fluorescence with a maximum emission wavelength in acetone
of 532nm (Figure 7b). A suitable single crystal was obtained by
slow diffusion of hexane into acetone/dichloromethane (1:1).
6
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[23] S. P. Black, J. K. M. Sanders, A. R. Stefankiewicz, Chem. Soc. Rev.
2014, 43, 1861–1872.
undoubtedly plenty of possibilities for this novel dynamic
covalent reaction awaiting to be explored.
[24] M. Dumartin, J. Septavaux, M. Donnier-Maréchal, E. Jeamet, E.
Dumont, F. Perret, L. Vial, J. Leclaire, Chem. Sci. 2020, 11, 8151–8156.
[25] S. D. Bull, M. G. Davidson, J. M. H. van den Elsen, J. S. Fossey, A. T.
A. Jenkins, Y.-B. Jiang, Y. Kubo, F. Marken, K. Sakurai, J. Zhao, T. D.
James, Acc. Chem. Res. 2013, 46, 312–326.
Acknowledgements
[26] R. Nishiyabu, Y. Kubo, D. James, J. S. Fossey, Chem. Commun. 2011,
47, 1124–1150.
This work was financially supported by Ministerio de Ciencia e
Innovación (PGC2018-094503-B-C21 and MAT2017-89207) and
by Agencia Canaria de Investigación, Innovación y Sociedad de
la Información (ACIISI) (ProID2020010089). J.P. thanks Cabildo
de Tenerife for the Agustín de Betancourt research position at
the University of La Laguna and also Nanotec, INTech, Cabildo
de Tenerife and ULL for laboratory facilities. D.S.R. thanks
Ministerio de Ciencia, Innovación y Universidades for his FPU
fellowship. E.M.-E. acknowledges his current contract financed
by Cabildo de Tenerife, Program TF INNOVA 2016‐21 (with
MEDI & FDCAN Funds). All the authors thank SEGAI-ULL, and
SDS-IPNA, and they are particularly grateful with Nieves M.
Rodríguez and Manuel Cabrera for their technical support in this
research.
[27] Y. Jin, Q. Wang, P. Taynton, W. Zhang, Acc. Chem. Res. 2014, 47,
1575–1586.
[28] M. J. Marsella, H. D. Maynard, R. H. Grubbs, Angew. Chem. 1997, 109,
1147–1150; Angew. Chemie - Int. Ed. 1997, 36, 1101–1103.
[29] R. C. Brachvogel, M. Von Delius, Chem. Sci. 2015, 6, 1399–1403.
[30] J. M. Hoerter, K. M. Otte, S. H. Gellman, Q. Cui, S. S. Stahl, J. Am.
Chem. Soc. 2008, 130, 647–654.
[31] N. A. Stephenson, J. Zhu, S. H. Gellman, S. S. Stahl, J. Am. Chem.
Soc. 2009, 131, 10003–10008.
[32]
S. E. Eldred, D. A. Stone, S. H. Gellman, S. S. Stahl, J. Am. Chem.
Soc. 2003, 125, 3422–3423.
[33] B. Zhang, P. Chakma, M. P. Shulman, J. Ke, Z. A. Digby, D.
Konkolewicz, Org. Biomol. Chem. 2018, 16, 2725–2734.
[34] D. P. Nair, M. Podgórski, S. Chatani, T. Gong, W. Xi, C. R. Fenoli, C. N.
Bowman, Chem. Mater. 2014, 26, 724–744.
Keywords: Cage compounds • Dynamic Covalent Chemistry •
Inverse-electron-demand Diels–Alder reaction • Photolysis •
Tetrazine
[35] S. Lee, A. Yang, T. P. Moneypenny, J. S. Moore, J. Am. Chem. Soc.
2016, 138, 2182–2185.
[36] Modern Nucleophilic Aromatic Substitution (F. Terrier), Wiley-VCH
Verlag GmbH & Co., 2013.
[1]
S. J. Rowan, S. J. Cantrill, G. R. L. Cousins, J. K. M. Sanders, J. F.
Stoddart, Angew. Chem. 2002, 114, 938–993; Angew. Chem. Int. Ed.
2002, 41, 898–952.
[37] W. J. Ong, T. M. Swager, Nat. Chem. 2018, 10, 1023–1030.
[38] X. Li, H. Wang, H. Chen, Q. Zheng, Q. Zhang, H. Mao, Y. Liu, S. Cai, B.
Sun, C. Dun, M. P. Gordon, H. Zheng, J. A. Reimer, J. J. Urban, J.
Ciston, T. Tan, E. M. Chan, J. Zhang, Y. Liu, Chem 2020, 6, 933–944.
[39] G. Clavier, P. Audebert, Chem. Rev. 2010, 110, 3299–3314.
[40] Z. M. Png, H. Zeng, Q. Ye, J. Xu, Chem. - An Asian J. 2017, 12, 2142–
2159.
[2]
[3]
[4]
[5]
[6]
P. T. Corbett, J. Leclaire, L. Vial, K. R. West, J. L. Wietor, J. K. M.
Sanders, S. Otto, Chem. Rev. 2006, 106, 3652–3711.
Y. Jin, C. Yu, R. J. Denman, W. Zhang, Chem. Soc. Rev. 2013, 42,
6634–6654.
Dynamic Covalent Chemistry: Principles, Reactions, and Applications
(Eds.: W. Zhang, Y. Jin), John Wiley & Sons Ltd, 2018.
R. C. Brachvogel, F. Hampel, M. Von Delius, Nat. Commun. 2015, 6,
1–7.
[41] B. L. Oliveira, Z. Guo, G. J. L. Bernardes, Chem. Soc. Rev. 2017, 46,
4895–4950.
O. Shyshov, R. C. Brachvogel, T. Bachmann, R. Srikantharajah, D.
Segets, F. Hampel, R. Puchta, M. von Delius, Angew. Chem. 2017, 130,
794–799; Angew. Chemie - Int. Ed. 2017, 57, 776–781.
K. S. Chichak, S. J. Cantrill, A. R. Pease, S. H. Chiu, G. W. V. Cave, J.
L. Atwood, J. F. Stoddart, Science 2004, 304, 1308–1312.
J. F. Ayme, J. E. Beves, D. A. Leigh, R. T. McBurney, K. Rissanen, D.
Schultz, Nat. Chem. 2012, 4, 15–20.
[42] M. Pagel, J. Pept. Sci. 2019, 25, 1–9.
[43] M. L. Blackman, M. Royzen, J. M. Fox, J. Am. Chem. Soc. 2008, 130,
13518–13519.
[7]
[8]
[9]
[44] E. Ros, M. Bellido, X. Verdaguer, L. R. de Pouplana, A. Riera,
Bioconjugate Chem. 2020, 31, 933–938.
F. Beuerle, B. Gole, Angew. Chem. 2017, 130, 4942–4972; Angew.
Chemie - Int. Ed. 2017, 57, 4850–4878.
[45] C. Canovas, M. Moreau, C. Bernhard, A. Oudot, M. Guillemin, F. Denat,
V. Goncalves, Angew. Chem. 2018, 130, 10806-10810; Angew.
Chemie - Int. Ed. 2018, 57, 10646-10650.
[10] W. Zou, J. Dong, Y. Luo, Q. Zhao, T. Xie, Adv. Mater. 2017, 29, DOI
10.1002/adma.201606100.
[11] S. Billiet, K. De Bruycker, F. Driessen, H. Goossens, V. Van
Speybroeck, J. M. Winne, F. E. Du Prez, Nat. Chem. 2014, 6, 815–821.
[12] J. Hu, S. K. Gupta, J. Ozdemir, M. H. Beyzavi, 2020, DOI
10.1021/acsanm.0c01327.
[46] C. Canovas, M. Moreau, J.-M. Vrigneaud, P.-S. Bellaye, B. Collin, F.
Denat, V. Goncalves, Bioconjugate Chem. 2019, 30, 888–897.
[47] V. Kardelis, M. M. Denk, A. Adronov, Angew. Chem. 2021, 133, 3017–
3023; Angew. Chemie - Int. Ed. 2021, 60, 2980–2986.
[48] A. C. Knall, S. Kovaćić, M. Hollauf, D. Reishofer, R. Saf, C. Slugovc,
Chem. Commun. 2013, 49, 7325–7327.
[13] D. Carbajo, Y. Pérez, J. Bujons, I. Alfonso, Angew. Chem. 2020, 132,
17355–17359; Angew. Chemie - Int. Ed. 2020, 59, 17202–17206.
[14] M. Lafuente, J. Solà, I. Alfonso, Angew. Chem. 2018, 130, 8557–8560;
Angew. Chemie - Int. Ed. 2018, 57, 8421–8424.
[49] A. C. Knall, C. Slugovc, Chem. Soc. Rev. 2013, 42, 5131–5142.
[50] C. Chen, C. A. Allen, S. M. Cohen, Inorg. Chem. 2011, 50, 10534–
10536.
[15] A. Herrmann, Chem. Soc. Rev. 2014, 43, 1899–1933.
[16] S. Ulrich, Acc. Chem. Res. 2019, 52, 510–519.
[17] O. Ramström, J. Lehn, Nat. Rev. Drug Discov. 2002, 1, 26–36.
[18] R. F. Ludlow, S. Otto, Chem. Soc. Rev. 2008, 37, 101–108.
[19] M. Kindermann, I. Stahl, M. Reimold, W. M. Pankau, G. Von Kiedrowski,
Angew. Chem. 2005, 117, 6908–6913; Angew. Chemie - Int. Ed. 2005,
44, 6750–6755.
[51] C. F. Hansell, P. Espeel, M. M. Stamenović, I. A. Barker, A. P. Dove, F.
E. Du Prez, R. K. Oreilly, J. Am. Chem. Soc. 2011, 133, 13828–13831.
[52] Z. Da Fu, Q. H. Guo, L. Zhao, D. X. Wang, M. X. Wang, Org. Lett. 2016,
18, 2668–2671.
[20] O. Š. Miljanić, Chem 2017, 2, 502–524.
[53] Q. H. Guo, L. Zhao, M. X. Wang, Angew. Chem. 2015, 127, 8506–
8509; Angew. Chemie - Int. Ed. 2015, 54, 8386–8389.
[21] M. E. Belowich, J. F. Stoddart, Chem. Soc. Rev. 2012, 41, 2003–2024.
[22] H. Vardhan, A. Mehta, F. Verpoort, RSC Adv. 2015, 5, 67011–67030.
7
This article is protected by copyright. All rights reserved.

10.1002/anie.202106230
Angewandte Chemie International Edition
RESEARCH ARTICLE
[85] K. Osowska, O. Š. Miljanić, Angew. Chem. 2011, 123, 8495–8499;
Angew. Chemie - Int. Ed. 2011, 50, 8345–8349.
[54] Q. H. Guo, Z. Da Fu, L. Zhao, M. X. Wang, Angew. Chem. 2014, 126,
13766–13770; Angew. Chemie - Int. Ed. 2014, 53, 13548–13552.
[55] H.-B. Liu, Q. Zhang, M. X. Wang, Angew. Chem. 2018, 130, 6646–
6650; Angew. Chemie - Int. Ed. 2018, 57, 6536–6540.
[86] Q. Ji, O. Š. Miljanić, J. Org. Chem. 2013, 78, 12710–12716.
[87] C.-W. Hsu, O. Š. Miljanić, Angew. Chem. 2014, 127, 2247–2250;
Angew. Chemie - Int. Ed. 2014, 54, 2219–2222.
[56] S. Y. Guo, Q. H. Guo, S. Tong, M. X. Wang, Angew. Chem. 2020, 132,
8155–8160; Angew. Chemie - Int. Ed. 2020, 59, 8078–8083.
[57] Z. C. Wu, Q. H. Guo, M. X. Wang, Angew. Chem. 2017, 129, 7257–
7261; Angew. Chemie - Int. Ed. 2017, 56, 7151–7155.
[88] C.-W. Hsu, O. Š. Miljanić, Chem. Commun. 2016, 52, 12357–12359.
[89] M. J. Tucker, J. R. Courter, J. Chen, O. Atasoylu, A. B. Smith, R. M.
Hochstrasser, Angew. Chem. 2010, 122, 3694–3698; Angew. Chemie -
Int. Ed. 2010, 49, 3612–3616.
[90] S. P. Brown, A. B. Smith, J. Am. Chem. Soc. 2015, 137, 4034–4037.
[91] D.-H. Qu, Q.-C. Wang, Q.-W. Zhang, X. Ma, H. Tian, Chem. Rev. 2015,
115, 7543–7588.
[58] Q. Zhou, P. Audebert, G. Clavier, R. Méallet-Renault, F. Miomandre, Z.
Shaukat, T. T. Vu, J. Tang, J. Phys. Chem. C 2011, 115, 21899–21906.
[59] Y. H. Gong, P. Audebert, J. Tang, F. Miomandre, G. Clavier, S. Badré,
R. Méallet-Renault, J. Marrot, J. Electroanal. Chem. 2006, 592, 147–
152.
[92] Y. Liu, H. Wang, P. Liu, H. Zhu, B. Shi, X. Hong, F. Huang, Angew.
Chem. 2021, 133, 5830–5834; Angew. Chemie Int. Ed. 2021, 60,
5766–5770.
[93] F. A. Arroyave, P. Ballester, J. Org. Chem. 2015, 80, 10866–10873.
[94] N. Basílio, U. Pischel, Chem. - A Eur. J. 2016, 22, 15208–15211.
[95] A. Díaz-Moscoso, P. Ballester, Chem. Commun. 2017, 53, 4635–4652.
[96] http://supramolecular.org/
[60] P. Audebert, S. Sadki, F. Miomandre, G. Clavier, M. C. Vernières, M.
Saoud, P. Hapiot, New J. Chem. 2004, 28, 387–392.
[61] P. Audebert, F. Miomandre, G. Clavier, M. C. Verniéres, S. Badré, R.
Méallet-Renault, Chem. - A Eur. J. 2005, 11, 5667–5673
[97] P. Thordarson, Chem. Soc. Rev. 2011, 40, 1305–1323
[98] D. Brynn Hibbert, Pall Thordarson, Chem. Commun. 2016, 52, 12792–
12805
[62] Y. H. Gong, F. Miomandre, R. Méallet-Renault, S. Badré, L. Galmiche,
J. Tang, P. Audebert, G. Clavier, European J. Org. Chem. 2009, 6121–
6128.
[99] Synthesis of macrocycle 14 does not show any remarkable
improvement by adding ACh PF6 probably due to the low association
constant.
[63] Z. Qing, P. Audebert, G. Clavier, F. Miomandre, J. Tang, T. T. Vu, R.
Méallet-Renault, J. Electroanal. Chem. 2009, 632, 39–44.
[64] W. Mao, J. Tang, L. Dai, X. He, J. Li, L. Cai, P. Liao, R. Jiang, J. Zhou,
H. Wu, Angew. Chem. 2021, 133, 2423–2427; Angew. Chemie - Int. Ed.
[100] K. L. Diehl, I. V. Kolesnichenko, S. A. Robotham, J. L. Bachman, Y.
Zhong, J. S. Brodbelt, E. V. Anslyn, Nat. Chem. 2016, 8, 968–973.
[101] M. Mastalerz, Acc. Chem. Res. 2018, 51, 2411–2422.
[102] K. Ono, K. Johmoto, N. Yasuda, H. Uekusa, S. Fujii, M. Kiguchi, N.
Iwasawa, J. Am. Chem. Soc. 2015, 137, 7015–7018.
2021, 60, 2393–2397.
[65] N. Saracoglu, Tetrahedron 2007, 63, 4199–4236.
[66] Z. Novák, B. Bostai, M. Csékei, K. Lőrincz, A. Kotschy, Heterocycles
2003, 60, 2653–2668.
[103] S. Klotzbach, F. Beuerle, Angew. Chem. 2015, 127, 10497-10502;
Angew. Chemie - Int. Ed. 2015, 54, 10356-10360.
[104] T. Tozawa, J. T. A. Jones, S. I. Swamy, S. Jiang, D. J. Adams, S.
Shakespeare, R. Clowes, D. Bradshaw, T. Hasell, S. Y. Chong, C.
Tang, S. Thompson, J. Parker, A. Trewin, J. Bacsa, A. M. Z. Slawin, A.
Steiner,A. I. Cooper, Nature Mater. 2009, 8, 973–978.
[67] See the Supporting Information.
[68] L. Pellegatti, E. Vedrenne, J. M. Leger, C. Jarry, S. Routier,
Tetrahedron 2010, 66, 4383–4389.
[69] Reaction of phenols and Cl-Tz-Cl with base in DMSO does not work,
probably due to solubility issue of the very apolar dichlorotetrazine.
[70] T. H. G. Schick, F. Rominger, M. Mastalerz, J. Org. Chem. 2020, 85,
13757–13771.
[105] J. R. Holst, A. Trewin, A. I. Cooper, Nature Chem. 2010, 2, 915–920
[106] K. E. Jelfs, X. Wu, M. Schmidtmann, J. T. A. Jones, J. E. Warren, D. J.
Adams and A. I. Cooper, Angew. Chem. 2011, 123, 10841–10844;
Angew. Chem., Int. Ed. 2011, 50, 10653–10656.
[71] P. J. Boul, P. Reutenauer, J.-M. Lehn, Org. Lett. 2005, 7, 15–18. I
[72] C. Bravin, C. A. Hunter, Chem. Sci. 2020, 11, 9122-9125.
[73] t is well-known the ability as reducing agent of many thiols, such as N-
acetyl-L-cysteine, or many thiophenols, particularly those bearing
electron donating substituents. Additionally, some tetrazines have been
used as oxidants to obtain disulfides. See: (a) S. Samanta, S. Ray, A.
B. Ghosha, P. Biswas, RSC Adv. 2016, 6, 39356–39363. (b) A. G.
Larsen, A. H. Holm, M. Roberson, K. Daasbjerg, J. Am. Chem. Soc.
2001, 123, 1723–1729.
[107] M. Mastalerz, M. W. Schneider, I. M. Oppel, O. Presly, Angew.
Chem. 2011, 123, 1078–1083; Angew. Chem. Int. Ed. 2011, 50, 1046–
1051.
[108] G. Zhang, O. Presly, F. White, I. M. Oppel, M. Mastalerz, Angew. Chem.
2014, 126, 1542–1546; Angew. Chem. Int. Ed. 2014, 53, 1516–1520.
[109] G. Zhang, O. Presly, F. White, I. M. Oppel, M. Mastalerz, Angew. Chem.
2014, 126, 5226–5230; Angew. Chem. Int. Ed. 2014, 53, 5126–5130.
[110] J. L. Katz, K. J. Selby, R. R. Conry, Org. Lett. 2005, 7, 3505–3507.
[111] S. Y. Zhuang, Y. Cheng, Q. Zhang, S. Tong, M. X. Wang, Angew.
Chem. 2020, 132, 23924–23931; Angew. Chemie - Int. Ed. 2020, 59,
23716–23723.
[74] Y. Lei, Q. Chen, P. Liu, L. Wang, H. Wang, B. Li, X. Lu, Z. Chen, Y.
Pan, F. Huang, H. Li, Angew. Chem. 2021, 133, 4755–4761; Angew.
Chem. Int. Ed. 2021, 60, 4705–4711.
[112] X. Li, C. Zhang, S. Cai, X. Lei, V. Altoe, F. Hong, J. J. Urban, J. Ciston,
E. M. Chan, Y. Liu, Nat. Commun. 2018, 9, 2998.
[75] T. Hasell, M. Schmidtmann, C. A. Stone, M. W. Smith, A. I. Cooper,
Chem. Commun., 2012, 48, 4689-4691.
[113] P.‐E. Alexandre, W.‐S. Zhang, F. Rominger, S. M. Elbert, R. R.
Schröder, M. Mastalerz, Angew. Chem. 2020, 132, 19843–19847;
Angew. Chem. Int. Ed. 2020, 59, 19675–19679.
[76] F. Klepel, B. J. Ravoo, Org. Biomol. Chem., 2017, 15, 3840–3842.
[77] A. Wilson, G. Gasparini, S. Matile, Chem. Soc. Rev. 2014, 43, 1948–
1962.
[114] J. Tu, M. Xu, S. Parvez, R. T. Peterson, R. M. Franzini, J. Am. Chem.
Soc. 2018, 140, 8410–8414.
[78] S. Lascano, K. Da Zhang, R. Wehlauch, K. Gademann, N. Sakai, S.
Matile, Chem. Sci. 2016, 7, 4720–4724.
[115] J. Tu, D. Svatunek, S. Parvez, H. J. Eckvahl, M. Xu, R. T. Peterson, K.
N. Houk, R. M. Franzini, Chem. Sci. 2020, 11, 169–179.
[79] N. Christinat, R. Scopelliti, K. Severin, Angew. Chem. 2008, 120, 1874–
1878; Angew. Chemie - Int. Ed. 2008, 47, 1848–1852.
[116] J. Zhang, V. Shukla, D. L. Boger, J. Org. Chem. 2019, 84, 9397–9445.
[117] R. M. Versteegen, R. Rossin, W. ten Hoeve, H. M. Janssen, M. S.
Robillard, Angew. Chem. 2013, 125, 14362–14366; Angew. Chemie -
Int. Ed. 2013, 52, 14112–14116.
[80] B. Içli, N. Christinat, J. Tönnemann, C. Schüttler, R. Scopelliti, K.
Severin, J. Am. Chem. Soc. 2009, 131, 3154–3155.
[81] K. D. Okochi, G. S. Han, I. M. Aldridge, Y. Liu, W. Zhang, Org. Lett.
2013, 15, 4296–4299.
[82] J. F. Reuther, S. D. Dahlhauser, E. V Anslyn, Angew. Chem. 2019, 131,
76–88; Angew. Chemie - Int. Ed. 2019, 58, 74–85.
[83] Q. Ji, R. C. Lirag, O. Š. Miljanić, Chem. Soc. Rev. 2014, 43, 1873–1884.
[84] K. Osowska, O. Š. Miljanić, J. Am. Chem. Soc. 2011, 133, 724–727.
8
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Entry for the Table of Contents
SNTz: DCC with tetrazines
Synthetic advantages
Post-stabilization by IEDDA
All the advantages of Dynamic Covalent Chemistry and the versatility of the tetrazine ring have been combined in a novel exchange
reaction: The nucleophilic aromatic substitution of tetrazines (SNTz) with phenols and alkyl thiols. Not only sophisticated structures
can be easily synthesized, but they can also be disassembled upon the application of the right chemical stimulus or UV-irradiation.
Importantly, all the compounds obtained can be further functionalized by Inverse Electron Demand Diels Alder (IEDDA) reaction,
which also locks the exchange. There is no doubt that SNTz unleashes a huge potential of applications.
Institute and/or researcher Twitter usernames: @CarrilloGroup @IPNA_CSIC
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