Triazole-based chromogenic and non-chromogenic receptors for halides

Article abstract of DOI:10.1016/j.tetlet.2011.10.066

We designed and synthesized a series of triazole-based receptors for anion recognition. Our studies demonstrated that an amide-linked triazole unit is a promising moiety for anion recognition. We synthesized various chromogenic and non-chromogenic recepto

Full text of DOI:10.1016/j.tetlet.2011.10.066

Tetrahedron Letters 52 (2011) 6930–6934
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Triazole-based chromogenic and non-chromogenic receptors for halides
⇑
V. Haridas , Srikanta Sahu, P. P. Praveen Kumar
Department of Chemistry, Indian Institute of Technology (IIT), New Delhi 110016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We designed and synthesized a series of triazole-based receptors for anion recognition. Our studies dem-
onstrated that an amide-linked triazole unit is a promising moiety for anion recognition. We synthesized
various chromogenic and non-chromogenic receptors based on this moiety. Receptor 11 binds very
strongly (K = 102,750 MÀ1) to fluoride. Receptor 18 changes color from faint yellow to orange upon bind-
ing to fluoride.
Received 19 August 2011
Revised 8 October 2011
Accepted 12 October 2011
Available online 18 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Anion binding
Click reaction
Triazole
Recognition
Receptors
The design of anion receptors is an area of intense research
interest, owing to their biological, medical, and chemical applica-
tions. Anions and cations are important players in living systems
and therefore their transport across the cell membrane has high
therapeutic significance.1 Synthetic ligands with cation-binding
properties are common, but less effort has been devoted to the de-
sign and synthesis of anion receptors, in spite of their significance
and potential applications.2 For example, a defect in chloride ion
transport leads to cystic fibrosis; synthesized anion receptors could
contribute to a cure for this disease.3 Fluoride ions are commer-
cially used in toothpaste industries; excess fluoride in the body
can lead to fluorosis.4 Chemists are interested in the design of an-
ion receptors and have produced novel receptors with many intri-
cate structures.5 These receptor molecules display good binding
ability and selectivity for anions.6
hydrogen bonding is an additional attractive interaction that
chemists can employ in isolation or with other attractive interac-
tions in the design of receptors.
O
HN
N
NH
NH
NH
O
O
H
N
N
(a)
(b)
(c)
Figure 1. Comparison of anion binding motifs (a) amide; (b) urea and; (c) amide-
linked triazole unit. The colored protons are the potential hydrogen bond donors.
There are several positively charged synthetic anion receptors.
Their binding efficacy is mainly due to Coulomb interactions that
contribute to the attractive force.7 Neutral receptors bind anions
through interactions weaker than Coulomb interactions. Therefore,
preorganization and the introduction of several binding sites are
the salient features of neutral anion receptor design. The use of
non-conventional H-bonding moieties is an additional advantage
in the design of anion receptors. The crystallographic evidence of
CHÁ Á ÁX (X = N, O) hydrogen bonds was first proposed by Taylor
and Kennard in 1982.8 A number of studies later demonstrated
their existence, after notable developments in crystal engineering.9
In recent years, the design of receptors that use non-conventional
hydrogen bonding interactions has gained importance. CHÁ Á ÁX
O
O
O
O
N
N
HN
H
H
HN
O
H
H
N
N
N
H
NH
N
N
N
N
N
N
R
R
(a)
(b)
(c)
Figure 2. Comparison of two peptide linkages with an amide-linked triazole. The
trans arrangement of hydrogen bond donors (a and b). Co-facially oriented amide-
linked triazole on a scaffold (c).
⇑
Corresponding author.
E-mail address: h_haridas@hotmail.com (V. Haridas).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.066

V. Haridas et al. / Tetrahedron Letters 52 (2011) 6930–6934
6931
N3
N3
Herein, we report the design and synthesis of anion receptors
with remarkable selectivity and binding affinity. Receptors with
selectivity for spherical anions like halides are mainly based on
cavity size. A cavity decorated with a variety of H-bond donors
may show selectivity. Conventional hydrogen bond donors (e.g.,
amide NHs and urea NHs) are used in typical receptor designs.10
Urea moieties bind anions, but in most cases fluoride binding
involves proton transfer.11 The use of triazole in the design intro-
duced rigid geometry, as well as an acidic CH capable of H-bond-
ing.12 Triazole is an excellent amide bond mimic; therefore, we
hypothesized that a triazole-amide link would be similar to two
consecutive peptide linkages (Fig. 1). Co-facially oriented amide-
linked triazole places the H-bond donors on one face and thus is
ideal for anion binding (Fig. 1c). A scaffold that can arrange two
co-facially orientated amide-linked triazole moieties so that they
face each other will favor better binding (Fig. 2).
N3
N3
N3
OH
OH
OH
1
2
3
4
5
N3
N3
N3
N3
OH
OH
NO2
OH
8
6
7
9
Figure 3. Structure of various azides.
O
O
O
O
HN
N
NH
N3
N3
HN
N
NH
N
HO
OH
N
N
N
N
N
N
N
N
N
CuI
CuI
HO
OH
HO
OH
12
15
16
O
O
O
O
N3
HN
NH
N3
HN
N
NH
N
N
N
N
O
N
O
N
N
N
N
HO
N
N
OH
HN
NH
CuI
CuI
HO
OH
HO
10
OH
13
14
N3
N3
N3
O
O
O
O
CuI
HN
HN
N
NH
NH
N
N
N
OH
CuI
OH
CuI
N
N
N
N
N
N
N
N
O
O
HO
HN
N
OH
NH
OH
17
HO
N
N3
N
N
N3
N
N
O
O
O
O
HN
N
NH
HN
NH
N
NO2
CuI
11
N
N
N
N
CuI
N
N
N
N
N
N
O2N
NO2
19
18
Scheme 1. Synthesis of triazole-based receptors 11–19.

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V. Haridas et al. / Tetrahedron Letters 52 (2011) 6930–6934
Table 1
We envisioned that a rigid phenyl ring with a 1,3-substitution
Binding constant of various receptors determined using 1H NMR
could accommodate spherical anions. The cavity generated as a
result of functionalization at the 1,3-positions could be further
decorated with H-bond donors. The amide-linked triazole moiety
on the 1,3-positions of the phenyl ring could thus serve as an ideal
motif for anion recognition.
The dialkyne 10 was synthesized by reacting isophthaloyl chlo-
ride and propargyl amine. It was further reacted with a series of
azides 1–9 (Fig. 3) to provide the amide-linked triazole receptors
11–19 (Scheme 1). Azides 6–8 were synthesized by reacting the
corresponding benzyl alcohol with triphenyl phosphine and so-
dium azide.13 The aryl azides 1–4 and 9 were synthesized from
the corresponding amino compound by reacting with NaNO2/HCl,
by the formation of diazonium salt as the intermediate. The diazo-
nium group was displaced with an azide nucleophile by the reac-
tion with sodium azide.14 This was completed in a single step
and the yields were ꢀ75–90%. These azides were reacted with dial-
Anion
salts
Ka (MÀ1
(11)
)
Ka (MÀ1
(12)
)
Ka (MÀ1
(15)
)
Ka (MÀ1
(17)
)
Ka (MÀ1
(18)
)
FÀ
102,750
56,515
2124
1285
492
6568
502
223
31
742
1616
798
ClÀ
BrÀ
IÀ
5001
1203
595
177
257
a
a
60
a
Indicating very low binding constant value.
kyne 10 to provide good yields (ꢀ80–90%) of the final triazole-
based receptors 11–19.
We performed systematic experiments to determine the bind-
ing abilities of these receptors 11–18 toward tetrabutylammonium
halides. The binding studies of halide ions were conducted using
1H NMR studies (Figs. 4 and 5). Tetrabutylammonium halide
(TBAX) was added to the receptor; amide NHs, triazole CHs, and
Ar-C2Hs were monitored for the 1H NMR chemical shifts. The affin-
ity of the receptor toward anions was analyzed by NMR titration,
followed by WinEQ NMR analysis.15 To quantify the complexation
between halides and the receptor, a Job’s plot was done using 1H
NMR by varying the concentrations of both TBAX and the receptor.
The maximum point appears at the mole fraction of 0.5, consistent
with a 1:1 stoichiometry (Fig. 6).
A comparison of binding constants showed that phenyl-substi-
tuted triazole 11 is superior to the benzyl-substituted receptor 19
(Table 1, Fig. 7). Receptor 11 showed an exceptionally high binding
constant (K ꢀ 105 MÀ1) for fluoride. This is attributed to the ÀI ef-
fect of the phenyl group. We envisioned that placing a hydroxyl
group on the phenyl ring would further enhance binding via addi-
tional hydrogen bonds with the guest molecule. Moreover, the two
hydroxyl groups in the receptors 12–17 can make intramolecular
hydrogen bonds and thus can preorganize the receptors. However,
another aspect of the hydroxyl groups is that the activation of the
benzene ring decreases the hydrogen bond donor ability of the tri-
azole CH.
Figure 4. Chemical shift changes of the aromatic proton in the 1H NMR spectrum
(300 MHz, DMSO-d6 + CDCl3) of 18 as a result of addition of TBAX.
Analysis of the 1H NMR binding studies showed that the initial
addition of TBAF to phenolic receptors 12–17 resulted in the disap-
pearance of hydroxyl protons in the 1H NMR spectrum, indicating a
deprotonation event. Subsequent addition of TBAF showed binding
to amide NHs and aromatic C2H. This sequence of events indicates
the possibility that the initial step might be the proton exchange
between the fluoride and –OH. In the next step; the fluoride binds
to the amide-linked triazole moiety. To unconditionally prove such
an unusual binding mechanism, requires a detailed structural anal-
ysis using X-ray crystallography. In order to investigate the role of
the position of the hydroxyl group in anion binding, we placed the
–OH group on a different position on the terminal phenyl ring. The
1H NMR titration studies indicated that, in all cases, the hydrogen
of phenolic –OH disappeared instantly upon the addition of TBAF.
This observation suggests that the phenolic –OH as such is not aug-
menting the binding of fluoride to the amide-linked triazole moi-
ety; instead the fluoride independently removes the hydroxyl
proton. This finding is supported by a control experiment in which
phenolic azides 2–4, 6–8 treated with TBAF displayed an instanta-
neous exchange of –OH protons. Of all the phenolic receptors 12–
17, hydroxylated ortho-receptors 12, 15 have the higher binding
constant (1285, 6568 MÀ1) for fluoride. Interestingly, the ortho
hydroxybenzyl substituted receptor 15 showed higher binding to-
ward fluoride than the unsubstituted receptor 19. The higher bind-
ing of the fluoride to the amide-linked triazole moiety of 15
compared to 19 might be due to the presence of two ortho-pheno-
late groups. These ortho-phenolates might arrange in such a way
that repulsion is minimized, resulting in higher binding. The order
of binding of receptor 17 toward halide is: ClÀ > FÀ > BrÀ > IÀ.
Figure 5. Chemical shift changes of the aromatic proton in the 1H NMR spectrum
(300 MHz, acetone-d6) of 11 as a result of addition of TBAX.
Figure 6. Job’s plot for 11 with TBAF.

V. Haridas et al. / Tetrahedron Letters 52 (2011) 6930–6934
6933
Figure 7. Changes in the 1H NMR spectrum (300 MHz, acetone-d6) of receptor 11 with the addition of varying amounts of TBACl.
DMSO-d6 in CDCl3). Receptor 18 binds the anion in the order: Cl
À > BrÀ > FÀ > IÀ. The p-nitro substituted receptor 18 changes color
from faint yellow to orange on binding to fluoride ions (Fig. 8) and
thus is an excellent chromogenic receptor for fluoride detection.
Addition of TBAF to 18 showed changes in the chemical shift of tri-
azole CHs, amide NHs, and aromatic C2H (gradual down field shift
of triazole CHs, amide NHs, and aromatic C2H. See supplementary
data, page S-17). This indicates a co-operative binding phenome-
non, wherein all hydrogen bond donors of the receptor take part
at the same time for binding to fluoride.16 The addition of other ha-
lides did not result in a visible color change even after adding
30 equiv. Receptor 18 is therefore useful for detecting fluoride in
the presence of other halides. The addition of water changes the
color from orange to colorless. Since water binds strongly to an-
ions, thereby releasing them from the receptor, this indicates that
the orange color is caused by the fluoride complex of 18. This also
indicates the complex formation between the receptor and the an-
ion is reversible.
Figure 8. Photograph of (a) (4.3 mM) solution of receptor 18 in (2% DMSO in
CHCl3); (b) after addition of 0.5 equiv of FÀ; (c) 30 equiv of ClÀ; (d) 30 equiv of BrÀ;
(e) 30 equiv of IÀ.
The fine-tuning of the pKa value of triazole CH enhances the
binding, as evidenced by the change of the benzyl to phenyl ring.
Activating groups such as –OH decreases the binding affinity.
Therefore, to further test this hypothesis, we used a p-nitrophenyl
unit on the N-1 position of the triazole unit. The receptor 18, with a
nitro group on the terminal phenyl ring, was synthesized. This
receptor showed insolubility in acetone-d6 and CDCl3; therefore,
the binding studies were performed in (2% DMSO-d6 in CDCl3). It
should be noted that DMSO, being a very polar solvent, will result
in reduced receptor binding. The binding constant of 18 for chlo-
ride, bromide, and iodide was higher than that of 11 in (2%
In this communication, we demonstrated a design strategy for
anion binding that illustrated the use of amide-linked triazole on
an aromatic scaffold. The substituent at the N1 position on the tri-
azole has a profound influence on anion binding. By fine-tuning the
electronic nature of the substituent at N1, we can influence the
acidity of triazole CH to ensure enhanced binding to guest mole-
cules. This is primarily due to the enhanced hydrogen bonding nat-
ure of triazole CH. In conclusion, we have demonstrated that the
amide-linked triazole is an excellent motif for anion recognition.
It can be considered a mimic of constrained dipeptide linkage
and could be used efficiently for binding guest molecules. We also

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V. Haridas et al. / Tetrahedron Letters 52 (2011) 6930–6934
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Acknowledgments
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Supplementary data
Supplementary data (synthetic procedure and data for all new
compounds. All the spectral details and the details of binding stud-
ies) associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2011.10.066.
14. Bakunov, S. A.; Bakunova, S. M.; Wenzler, T.; Ghebru, M.; Werbovetz, K. A.;
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