Preorganization in bistriazolyl anion receptors

Article abstract of DOI:10.1016/j.tetlet.2013.05.133

A series of 4,6-bis-(1,2,3-triazolyl)-pyrimidine and 4,6-bis-(1,2,3- triazolyl)-pyridine anion receptors were synthesized and the effect of the pyrimidine and pyridine moieties on their binding properties was examined. We found that intramolecular interactions preorganize the 4,6-bis-(1,2,3-triazolyl) -pyridine receptors resulting in higher anion binding constants in comparison with the nonpreorganized 4,6-bis-(1,2,3-triazolyl)-pyrimidine receptor.

Full text of DOI:10.1016/j.tetlet.2013.05.133

Accepted Manuscript
Preorganisation in bistriazolyl anion receptors
Tamara Merckx, Peter Verwilst, Wim Dehaen
PII:
S0040-4039(13)00924-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.133
TETL 43033
Reference:
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
4 April 2013
24 May 2013
29 May 2013
Please cite this article as: Merckx, T., Verwilst, P., Dehaen, W., Preorganisation in bistriazolyl anion receptors,
Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.05.133
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Preorganisation in bistriazolyl anion
receptors
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Tamara Merckx, Peter Verwilst, Wim Dehaen
Molecular Design and Synthesis, Department of Chemistry, KULeuven, Celestijnenlaan 200F, 3001 Leuven

1
Tetrahedron
journal homepage: www.elsevier.com
Preorganisation in bistriazolyl anion receptors
Tamara Merckxa , Peter Verwilsta and Wim Dehaena, 
aMolecular Design and Synthesis, Department of Chemistry, KULeuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of 4,6-bis-(1,2,3-triazolyl)-pyrimidine and 4,6-bis-(1,2,3-triazolyl)-pyridine anion
receptors were synthesized and the effect of the pyrimidine and pyridine moieties on their
binding properties was examined. We found that intramolecular interactions preorganize the
4,6-bis-(1,2,3-triazolyl)-pyridine receptors resulting in higher anion binding constants in
comparison with the non-preorganized 4,6-bis-(1,2,3-triazolyl)-pyrimidine receptor.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Anion receptor
Click reaction
Preorganisation
Anions play an important role in chemical and biological
processes1. In the last two decades, increasing attention has been
devoted to the synthesis of receptors for these anions2. The
majority of anion binding motifs make use of strong hydrogen
bond donor groups like NH and OH. Only a few years ago it has
been discovered that CH hydrogen bonds can also play a
determining role in receptor-anion binding3. Recently, the use of
1,4-disubstituted-1,2,3-triazoles in anion recognition gained
interest because of their large polarity (dipole moment ~5D) with
the positive end of the dipole situated at the CH group4. This
reduces the electron density in the CH bond, making it suitable
for hydrogen bonding. The practical utility of 1,4-disubstituted
1,2,3-triazoles as functional species in intra- and intermolecular
interactions is enhanced by the fact that they are readily
accessible through the Cu(I)-catalyzed coupling of azides and
alkynes5. Triazolophanes for example have unexpectedly large
halide binding constants, which take advantage of macrocyclic
preorganisation to direct four triazole CH donors and four
phenylene CH donors into the central cavity6. Moreover,
preorganized aryl-triazole pentads are shown to be good
receptors for chloride anions.7
In the design of a receptor, preorganizing the conformation is
crucial to obtain high binging affinities. Intramolecular hydrogen
bonds have already been used to preorganize acyclic receptors7,8.
Herein we demonstrate the effect of pyridine and pyrimidine
moieties on the preorganisation of 4,6-bis-(1,2,3-triazolyl)-
pyrimidine and 4,6-bis-(1,2,3-triazolyl)-pyridine anion.
Fig 1: Reagents and conditions: a) 1-bromopropane, Et3N, MeOH, reflux,
20h, 90%; b) POCl3, reflux, 18h, 58%; c) 1. NaN3, Bu4NBr, THF, 50°C, 3h;
2. N-boc-propargylamine, CuSO4, NaAsc, tert-butanol/H2O, 50°C, 2h, 71%;
d) 1. HCl in dioxane (4N), rt, 30 min; 2. butylisothiocyanate, Et3N, CH2Cl2,
rt, 18h, 67%
Thiobarbituric acid was first alkylated with 1-bromopropane in
the presence of triethylamine yielding the desired derivative 6,
which was then chlorinated with POCl3 to afford 7. Compound 8
The 4,6-bis-(1,2,3-triazolyl)-pyrimidine receptor
s—yn—the—sized from thiobarbituric acid as shown in fig 1.
1
was
 Corresponding author. Tel.: +32 16 327439; fax: +32 16 327990; e-mail: wim.dehaen@chem.kuleuven.be

2
Tetrahedron
Fig 2: Reagents and conditions: a) NaN3, DMF, 70°C, 48h, 27%; b) methyl propiolate, [(CH3CN)4Cu]PF6, THF, 50°C, 2h, 51%; c) NaOH, MeOH/H2O, rt, 16h,
88%; d) n-butylamine, HOBt, HBTU, DMF, rt, 20h, 49%; e) N-boc propargylamine, [(CH3CN)4Cu]PF6, THF, 2h, 50°C, 85%; f) 1. HCl in dioxane (4N), rt, 1h, 2.
butyl isothiocyanate, CH2Cl2, rt, 16h, 43%; g) 1. HCl in dioxane (4N), rt, 1h, 2. 4-(tert-butyl)benzoyl chloride, CH2Cl2, DIPEA, rt, 16h, 59%; h) 1. HCl in
dioxane (4N), rt, 1h, 2. tert-pentyl isocyanate, Et3N, CH2Cl2, rt, 16h, 54%
was then obtained in an one pot procedure by a substitution
reaction with NaN3, followed by a click reaction with N-Boc-
propargylamine9. Finally the the desired receptor 1 was obtained
after removal of the Boc-group10 and subsequent treatment of the
resulting product with butyl isothiocyanate. The synthetic details
and structural analysis data are described in Electronic
Supplementary Information (ESI).
anions in acetonitrile. The data was fitted to a 1:1 binding model
as confirmed by Job plot analysis (Fig S1 in the ESI) and the
anion binding constants were calculated with HypNMR11. The
binding constants are shown in Table 1 and reveal that, for all
the receptors, the binding with the chloride anion is stronger than
with bromide. For the 4,6-bis-(1,2,3-triazolyl)-pyridine receptors
1
2-5, a downfield shift of the H NMR resonances of the triazole
CH protons and NH protons was observed upon addition of the
tetra-n-butylammonium salts of chloride and bromide, clearly
indicating the formation of hydrogen bonds to the anion (Fig 3).
Table 1: Stability constants (log(Ka)) determined by 1H NMR titrations with
the tetra-n-butylammonium salts of the anions in acetonitrile.
The 4,6-bis-(1,2,3-triazolyl)-pyridine receptors 2-5 were
synthesized from 2,6-difluoropyridine as shown in fig 2. In a first
step, 2,6-diazidopyridine 9 was synthesized by a reaction of 2,6-
difluoropyridine with NaN3 in DMF. Compound 10 was then
obtained by a click reaction between molecule 9 and methyl
propiolate. A saponification reaction of 10 with NaOH and a
subsequent amide coupling reaction with n-butylamine yielded
the desired receptor 2. Molecule 12 was synthesized by a click
Receptor
Cl-
Br-
1
2
3
4
5
2.24±0.07
1.36± 0.01
3.4±0.1
1.91± 0.01
0.95±0.2
2.62±0.05
2.69±0.02
1.01±0.02
reaction between 2,6-diazidopyridine
9
and N-Boc-
propargylamine. Finally, receptors 3-5 were synthesized by a
Boc-deprotection reaction of 12 and subsequent reaction of the
resulting product with respectively butyl isothiocyanate, tert-
pentyl isocyanate and 4-tert-butylbenzoyl chloride. The R-groups
of the receptors 1-5 were chosen for the purpose of solubility in
acetonitrile, which was the solvent chosen for the 1H NMR-
titrations.
3.02±0.03
1.34±0.01
The highest binding affinities were obtained for receptor 3
with log(Ka) of 3.4 for chloride and 2.62 for bromide. Receptor 4
has comparable binding constants with log(Ka) of 3.02 for
chloride and 2.69 for bromide. The binding constants of the two
receptors 2 and 5 on the other hand were significantly lower with
The binding constants of all the receptors were determined by
1H NMR titrations with the tetra-n-butylammonium salts of the

3
a
c
b
a
b
c
a
b
c
PPM 10.0
9.6
9.2
8.8
8.4
8.0
7.6
7.2
6.8
6.4
6.0
Fig 3: 1H NMR spectra (aromatic region) of 3 upon titration with
tetra-n-butylammonium chloride
log(Ka) of respectively 1.356 and 1.34 for chloride and 0.95 and
1.01 for bromide.
Fig 5: Anion binding of a) 4,6-bis-(1,2,3-triazolyl)-pyrimidine receptor 1 and
and b) 4,6-bis-(1,2,3-triazolyl)-pyridine receptors 3
The anion binding strength of 3 was then compared with 1.
With a log(Ka) of 2.24 for chloride and 1.91 for bromide, the
binding constants of receptor 1 are approximately a tenfold lower
in comparison with the analogous pyrimidine-based receptor 3.
The amide receptors 2 and 5 possess two less NH binding sites
then the (thio)urea receptors 3 and 4, resulting in lower binding
affinities. Moreover, intramoleculair hydrogen bonding of the
amide groups to the N3 nitrogen atom of the triazoles can further
disfavour anion binding. This effect apparently does not occur for
the less acidic (thio)urea receptors 3 and 4.
1
The stack plot of receptor 1 shows a downfield shift of the H
NMR resonances of the triazole CH protons and NH protons,
indicating the formation of hydrogen bonds to the anion (Fig 4).
The pyrimidine CH proton on the other hand show only a small
upfield shift up to the addition of approximately one equivalent
By comparing the receptors 2 and 5, we could also evaluate
the effect of terminal preorganisation. The NH-groups of receptor
2 will most likely prefer to point out of the cavity because of
repulsion between the carbonyl group and the N3 nitrogen atom
of the triazole, unlike receptor 5 which doesn’t suffer from such
an effect. However the binding constants of 2 and 5 are almost
the same, indicating that the terminal preorganisation doesn’t
influence much of the binding affinity.
of tetra-n-butylammonium chloride, followed by
a small
downfield shift upon addition of more tetra-n-butylammonium
chloride. This might indicate that the pyrimidine CH proton is
not involved in the anion binding. Comparing the structure of
both receptors reveals that, for the pyrimidine receptor 1, the
triazole CH protons can form electrostatically attractive hydrogen
bond-like interactions with the nitrogen atoms of the pyrimidine,
yielding a more linear conformation. This implicates that the
receptor might need to undergo a flip conformational change
upon anion binding (Fig 5). Moreover, repulsive interactions
between the nitrogen atoms of the pyrimidine and the triazoles
further destabilize the complex. For the pyridine receptor 3 on the
other hand, intramolecular hydrogen binding between the triazole
CH atoms and the nitrogen atom of the pyridine does preorganize
the receptor for anion binding.
In summary, a series of 4,6-bis-(1,2,3-triazolyl)-pyrimidine
and 4,6-bis-(1,2,3-triazolyl)-pyridine anion receptors were
synthesized and their binding properties were examined.
Intramolecular hydrogen bonding between the triazole CH atoms
and the nitrogen of the pyridine preorganize the 4,6-bis-(1,2,3-
triazolyl)-pyridine receptors 2-5 for anion binding. This results in
higher anion binding constants in comparison with the receptor 1,
where intramolecular CH-N interactions can stabilize
a
conformation which is less suited for anion binding. On the other
hand, terminal preorganisation doesn’t have a great influence on
the binding affinity.
b
Acknowledgments
a
The authors are grateful to the FWO-Vlaanderen, IWT,
KULeuven and the Ministerie voor wetenschapsbeleid for
continuing financial support.
c
d
References and notes
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c
d
2
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c
d
3
(a) The Weak Hydrogen Bond in Structural Chemistry and Biology;
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PPM 10.0
9.6
9.2
8.8
8.4
8.0
7.6
7.2
6.8
6.4
6.0
Fig 4: 1H NMR spectra (aromatic region) of 1 upon titration with
tetra-n-butylammonium chloride

4
Tetrahedron
J. M.; Pham, D. M.; Craig, S. L. Angew. Chem. Int. Ed. 2008, 47, 3740-
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Angew. Chem., Int. Ed. 2002, 41, 2596−2599; (b) Tornøe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057−3064.
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(a) Bianca, S. R.; Antonisse, M.; Engbersen, J.; Timmerman, P.;
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fig1.tif

fig 2.tif

Fig 3.doc
a
c
b
4 eq
a
b
c
0.7 eq
a
b
c
Blanco
PPM 10.0
9.6
9.2
8.8
8.4
8.0
7.6
7.2
6.8
6.4
6.0
Fig 3: 1H NMR spectra (aromatic region) of 3 upon titration with
tetra-n-butylammonium chloride

Fig 4.doc
b
a
c
d
c
d
c
d
PPM 10.0
9.6
9.2
8.8
8.4
8.0
7.6
7.2
6.8
6.4
6.0
Fig 4: 1H NMR spectra (aromatic region) of 1 upon titration with
tetra-n-butylammonium chloride
4 eq
0.7 eq
Blanco

fig 5.tif

graphical abstract def.tif