New unsymmetrical alkyl-s-tetrazines: Original syntheses, fluorescence and electrochemical behaviour

Article abstract of DOI:10.1039/c3ra46893c

Despite previous report of failure of this reaction, a series of new monoalkyltetrazines and a dialkyltetrazine have been prepared by nucleophilic aromatic substitution, albeit sometimes in moderate yields. In addition to the original synthetic procedure, the fluorescence and electrochemical behaviour of these new compounds have been reported. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3ra46893c

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New unsymmetrical alkyl-s-tetrazines: original
syntheses, fluorescence and electrochemical
behaviour†
Cite this: RSC Adv., 2014, 4, 7193
ab
Qing Zhou,ab Pierre Audebert,
Gilles Clavier,a Fabien Miomandrea and Jie Tangb
Received 21st November 2013
Accepted 6th January 2014
*
DOI: 10.1039/c3ra46893c
www.rsc.org/advances
Despite previous report of failure of this reaction, a series of new Kotschy et al. tried to rationalise this within the framework of
monoalkyltetrazines and a dialkyltetrazine have been prepared by the Hard So Acid Base (HSAB) theory10 in the case of carbon
nucleophilic aromatic substitution, albeit sometimes in moderate nucleophiles, the situation is likely more complicated, since
yields. In addition to the original synthetic procedure, the fluorescence both hard (alkoxides or amines) and so (thiols) heteroatomic
and electrochemical behaviour of these new compounds have been nucleophiles readily react with chlorotetrazines. On the other
reported.
hand, one may notice that the application eld of the HSAB
theory has been recently seriously questioned, especially in the
case of bidentate nucleophiles.11
Introduction
In this article, we demonstrate that indeed, the conditions
for nucleophilic attack on tetrazines are probably not deter-
mined by the hard/so character of the nucleophiles, but rather
depend on different considerations like the relative kinetics of
competing reactions, among which the oen neglected electron
transfer. We have found that the SNAr reaction on the tetrazine
ring is strongly dependant on temperature, and, under carefully
controlled conditions, the selectivity of the substitution reac-
tion could be reversed, taking place on the carbon atom instead
of the nitrogen. We report here several example of SNAr
substitution on chlorotetrazines with alkyl lithium reagents,
leading to various new alkyl tetrazines. In addition, we also
studied their photophysical and electrochemical properties. It
is worth noticing that, while we were performing this work, an
interesting extension of the classical Pinner method using
Lewis acids appeared and provided a concurrent useful way of
elaboration of dialkyltetrazines.12
s-Tetrazines chemistry has been known for more than a
century,1 and their photophysical2 and electrochemical3 prop-
erties have been briey reported in the past. However regarding
the recent interest in conjugated molecules and materials,4 the
s-tetrazine building block is more and more recognised as a very
promising and fascinating one. s-Tetrazines are electroactive
heterocycles, having a very high electron affinity, and in addi-
tion, they have a low lying p* orbital, inducing a low energy n–
p* transition in the visible range, which makes them highly
coloured, and sometimes uorescent. The chemistry of s-tetra-
zines has been recently reviewed by us and others.5
From our previous work,6 and other reports,3,7 it is known
that direct substitution on the carbon atom of the tetrazine ring
is possible essentially with nucleophiles where the nucleophilic
pair is centered on an heteroatom. With carbon-centered
nucleophiles, the situation is more complicated. Some work
reported that so carbanions could lead to nucleophilic
substitution.8 On the other hand Kotschy et al. have shown that
an azaphilic attack occurred with harder carbon-centered
nucleophiles (like Grignard reagents or alkyllithium) leading
oen to non-aromatic and unstable adducts,9 which was
apparently a lock to the access of useful alkyl tetrazines. While
Results and discussion
We have tested the reaction of butyllithium with various chlor-
otetrazines, both at low temperature (ꢀ78 ꢁC), and at 0 ꢁC. The
results were striking in the fact that at low T, the main observa-
tion was degradation of the tetrazines, along with a small
amount of C-substitution products. On the other hand, when the
aPPSM, ENS Cachan, CNRS UMR 8531, 61 Avenue President Wilson, F-94230 Cachan,
France. E-mail: audebert@ppsm.ens-cachan.fr; Fax: +33 1 47 40 24 54; Tel: +33 1 47
ꢁ
reaction was performed at 0 C, moderate yields of C-substitu-
40 53 39
tion were obtained exclusively on the C–Cl position, without any
aza-addition products or SNAr on the other carbon (Table 1).
The reactivity of tetrazines towards organometallic reagents,
is not trivial at all. These very reactive nucleophiles, which can
bEast China Normal University, Department of Chemistry, Shanghai, 200062, P. R.
China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra46893c
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Table 1 Reaction yields of n-butyl-s-tetrazinea
Reactant
Product
Yield/%
35
Scheme 2 Possible addition sites of a radical on a stable s-tetrazine
anion-radical.
16b
substitution products when the initially produced anion-radical
can quickly expell a leaving anionic group, on the other hand
the production of a relatively stable anion-radical always leads
to aza-addition products (Scheme 2) as demonstrated in the
case of uorenone.14 We have shown in the past15 that tetrazines
anion-radicals are always stable, even in the case of dichloro-
tetrazine, a very unusual situation triggered by the very high
electron affinity of this peculiar heterocycle.
52
30
Altogether, the aza-addition can proceed, as shown on
Scheme 1, both by direct attack on the nitrogen atom of the
tetrazine, or on the other hand through a rst electron transfer
step, followed by coupling between the anion-radical and the
radical created aer the electron transfer step. Since, according
to Kotschy,9 aza-addition products are obtained at low T, it is
likely that they are obtained through an electron transfer-radi-
cals coupling reaction instead of a direct attack on a nitrogen
18
45
Reaction conditions: n-BuLi (1.2 eq.) in THF at 0 ꢁC. b 2.4 equivalents of
a
n-BuLi were used.
ꢁ
atom. As can be seen from Table 1, at 0 C, the C-substitution
tolerates several other different groups on the remaining carbon
of the tetrazine ring with reasonable yields. Only the dis-
ubstitution by butyl carbanions occurs with a low yield, while
the reason for this is not obvious.
We have investigated the physicochemical characteristics of
the new tetrazines obtained, namely their absorption, uores-
cence and reduction potential. Since alkyl groups do not exhibit
a mesomeric donor character, which could raise the p-orbital of
the tetrazine ring close to the LUMO, all tetrazines substituted
by an alkyl group and an alkoxide or two alkyl groups are uo-
rescent. Typical uorescence spectra are given in Fig. 1 and
show that the inductive effect of the n-butyl induces a slight
bathochromic effect.
attack on both reactive places on the tetrazine ring, are also
good electron donors. This opens the possibility of electron
transfer which is likely to be a pathway of consideration with
tetrazines since they are strongly electron-decient rings.
Hence, a competition between three possible reactional path-
ways (Scheme 1) could occur depending on the temperature.
This was an obvious reasoning regarding competition
between nucleophilic attack and electron transfer, since it has
long been remarked that in analogous cases in heterocyclic
chemistry electron transfer was strongly favoured at low
temperatures, while nucleophilic attack became dominant
upon rising T. This has been thoroughly discussed, especially in
the case of SNAr reactions on activated benzenoid aromatics
within several articles from the Lund's group past work.13 In
addition, while an initial electron transfer usually leads to
All spectroscopic and electrochemical data of the new tet-
razines are reported in the Table 2. In order to get rid of any
perturbation due to the “antenna” effect in compounds 1d and
2d, the excitation was made in the visible absorption band. It
can be observed that in some occasions very high uorescence
Scheme 1 Possible reaction pathways between s-tetrazine and a Fig. 1 Fluorescence spectra for compounds 2a (purple), 3a (red), 2b
nucleophile.
(green), 2c (blue) and 2d (light blue) in dichloromethane; lex ¼ 520 nm.
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Table 2 Spectroscopic characteristics of butyl-s-tetrazines and their
chloro counterparts recorded in dichloromethane (C z 10ꢀ6 M)
Notes and references
1 R. Katritzky, Handbook of Heterocyclic Chemistry, Pergamon
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Compound labs/nm 3/L molꢀ1 cmꢀ1 lem/nm fF
sF/nsa Eꢁ/Vb
1ac
1bc
2a
515
520
520
528
526
518
525
517
526
460
1900
730
660
520
822
540
400
180
551; 567 0.14 58
ꢀ0.68
ꢀ0.99
ꢀ0.87
ꢀ1.19
ꢀ1.19
ꢀ0.63
ꢀ0.92
ꢀ0.86
ꢀ1.63
ꢀ1.21
567
563d
576e
576f
566
572h
562
572f
—
0.38 160
0.52 159
0.14 39
0.21 45
3a
2b
1cg
2c
0.09
—
0.37 112
0.32 158
0.18 59
1di
2d
2e
425; 529 720; 320
—
—
a
lex ¼ 520 nm. b vs. Ag/10ꢀ1 M Ag+. c Data taken from ref. 15. d lex ¼ 520
nm. e lex ¼ 528 nm. f lex ¼ 526 nm. g Data taken from ref. 6b. h lex ¼ 525
nm. i Data taken from ref. 16.
5 (a) G. Clavier and P. Audebert, Chem. Rev., 2010, 110, 3299;
(b) N. Saracoglu, Tetrahedron, 2007, 63, 4199.
6 (a) Y.-H. Gong, P. Audebert, J. Tang, F. Miomandre,
yields are obtained from dissymmetrical alkyl tetrazines; for
example tetrazine 2a has the highest uorescence yield known to
date. Similarly to previously observed, the symmetrical tetrazines
displayloweryieldsinthe15%range, whichtendstodemonstrate
an inuence of the dipole moment on the uorescence yield.
As previously observed,15,16 all the new tetrazines can be
reversibly reduced to their stable anion radical, which does not
show any tendancy to expel a chloride anion, when this is
possible, even in the case where a donor alkyl group is present
on the other side of the molecule. The redox potentials are
shied to more negative values when an alkyl chain replaces an
electron withdrawing group, as it could be expected.
´
´
G. Clavier, S. Badre, R. Meallet-Renault and J. Marrot,
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´
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14 T. Lund, M. L. Pedersen and L. A. Frandsen, Tetrahedron
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Conclusions
We have described a new way of preparing dissymmetrical alkyl
tetrazines starting from chlorotetrazines, through a general
nucleophilic substitution method with organolithium reagents.
We have shown that control of the reaction temperature around
0 ꢁC was essential to the success of the reaction, which tends in
addition to show that the previously observed azaphilic addition
is likely to proceed through a two-step mechanism involving a
rst electron transfer followed by a coupling step between the
radical and the anion-radical initially formed. Some of the new
tetrazines formed display in addition among the highest uo-
rescence yields observed in this family of compounds.
`
15 P. Audebert, F. Miomandre, G. Clavier, M.-C. Vernieres,
´
´
S. Badre and R. Meallet-Renault, Chem. – Eur. J., 2005, 11,
5667.
´
16 Q. Zhou, P. Audebert, G. Clavier, R. Meallet-Renault,
F. Miomandre and J. Tang, New J. Chem., 2011, 35,
1678.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 7193–7195 | 7195