Aramidocalix[4]arenes as new anion receptors

Article abstract of DOI:10.1016/j.tetlet.2007.09.046

Calix[4]arenes bearing aromatic amide (aramid) moieties at the upper rim display interesting recognition properties toward anions and in particular versus planar trigonal nitrate and Y-shaped benzoate. Molecular modeling and DFT calculations indicate that the high affinity displayed by aramidocalix[4]arenes 3 and 4 for nitrate anion is likely due to the planar arrangement of the NH groups, which form an unusual six-hydrogen-bond scheme with nitrate anion.

Full text of DOI:10.1016/j.tetlet.2007.09.046

Tetrahedron Letters 48 (2007) 7986–7989
Aramidocalix[4]arenes as new anion receptors
Francesco Troisi,a Alessio Russo,a Carmine Gaeta,a Giuseppe Bifulcob and Placido Neria,*
a
`
Dipartimento di Chimica, Universita di Salerno, Via Ponte don Melillo, I-84084 Fisciano (Salerno), Italy
`
Dipartimento di Scienze Farmaceutiche, Universita di Salerno, Via Ponte don Melillo, I-84084 Fisciano (Salerno), Italy
b
Received 4 July 2007; revised 2 August 2007; accepted 7 September 2007
Available online 12 September 2007
Abstract—Calix[4]arenes bearing aromatic amide (aramid) moieties at the upper rim display interesting recognition properties
toward anions and in particular versus planar trigonal nitrate and Y-shaped benzoate. Molecular modeling and DFT calculations
indicate that the high affinity displayed by aramidocalix[4]arenes 3 and 4 for nitrate anion is likely due to the planar arrangement of
the NH groups, which form an unusual six-hydrogen-bond scheme with nitrate anion.
Ó 2007 Elsevier Ltd. All rights reserved.
The development of synthetic molecules designed to
bind anionic guests is an intensively active area of
research in supramolecular chemistry,1 since anions play
important roles in a wide range of natural processes.2,3
matic rings) have been reported and considered for an-
ion recognition.10
This observation prompted us to investigate the
introduction of aromatic amide (aramid)11 moieties at
the upper rim of a tetracarboxylated calix[4]arene
macrocycle.
Calixarenes4 have become one of the leading host sys-
tems, currently most studied in the context of anion
receptor development, as shown recently by a few
reviews.5 The main reason for this success, besides their
ready availability, is their easy chemical modification,
which allows the introduction of appropriate functional
groups able to create complementarity with anionic
guests. Thus, calixarenes featuring cobaltocenium6 or
ferrocene7 groups have been used for electrochemical
sensing of anions in polar solvents.
In this Letter, we wish to report the synthesis of
N-linked aramidocalix[4]arene derivatives 1–5 (Fig. 1),
and their recognition properties versus anionic guests.
N-Acetyl-p-aramidocalix[4]arene 1 was readily obtained
in 30% yield by coupling the known calix[4]arenetetra-
carboxylic acid 6,12 with 12 equiv of p-acetamidoaniline
7,13 in the presence of DCC as the coupling reagent and
DMAP, in a mixture of dry CH2Cl2/DMF as the solvent
(Scheme 1).14
However, more recently an increasing attention has
also been devoted to the synthesis of electroneutral cal-
ixarene hosts bearing hydrogen-bond-donor units such
as amide1c,8 and urea groups,1c,9 which often display
remarkable host properties. The majority of the inves-
tigated amide derivatives have the amide carbonyl
groups linked to the lower rim or to amino groups at
the para position of the aromatic rings (C-linked
amides).5,8 Unexpectedly, only a very limited number
of the corresponding N-linked derivatives (with the
NH amide groups linked to p-carboxycalixarene aro-
The structure of 1 was assigned by means of spectral
analysis. In particular, the presence of a pseudomolecu-
lar ion peak at m/z 1297 in the ESI(+) mass spectrum
confirmed the molecular formula. The C4v symmetrical
1
structure was confirmed by pertinent signals in the H
and 13C NMR spectra in DMSO-d6. In fact, two singlets
were present at low field (9.83 and 9.73 ppm, 4H each) in
1
the H NMR spectrum, due to the NH protons, while
the ArCH2Ar groups give rise to an AX system at
3.43/4.49 ppm (J = 13.6 Hz, 8H), and the terminal Me
groups originate a singlet at 2.01 ppm (12H). The 13C
NMR spectrum displayed two characteristic resonances
at 167.9 and 164.7 ppm relative to the two –CONH–
groups.
Keywords: Calixarenes; Aromatic amides; Anion recognition; Hydro-
gen bonds.
*
Corresponding author. Tel.: +39 089 969 572; fax: +39 089 969
603; e-mail: neri@unisa.it
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.046

F. Troisi et al. / Tetrahedron Letters 48 (2007) 7986–7989
7987
In fact, p-aramidocalix[4]arene derivatives 3–5 were
obtained from compound 9 by coupling with the
corresponding acyl chloride 10, 11, or 12,13 in the
presence of NEt3 in dry THF (Scheme 2).14 The structure
of p-aramidocalix[4]arene derivatives 3–5 was readily as-
signed by spectral analysis.14
R
R
O
R
R
O
O
O
NH
(b)
HN
NH
HN
O
O
NH
NH
(a)
The binding ability of p-aramidocalix[4]arene deriva-
tives 1 and 3–5 toward anionic guests was studied by
standard H NMR titrations, in which the host concen-
HN
NH
O
O
O
1
tration was kept constant while the guest concentration
was varied (Table 1). The addition of anions, in the form
of tetrabutylammonium salts, to the solution of each
receptor caused significant downfield shifts of the signals
O
O
O
1
relative to both amide hydrogen atoms in the H NMR
spectrum. This indicated that these groups were engaged
in hydrogen bonding interactions with the anionic guest
with a fast complexation equilibrium.
1
R = Me
R = O-t-Bu
R = t-Bu
2
3
4
In each binding experiment, a 1:1 stoichiometry of the p-
aramidocalix[4]arene/anion complex was determined by
means of mole ratio or Job plots.15–17 The titration data
were analyzed by nonlinear least-squares fitting proce-
dures and in all cases, a good fit of the experimental data
with the theoretical model confirmed the 1:1 stoichiom-
etry of the complexes.
R = C(Ph)3 (Trityl)
O
5
R =
NHMe
(c)
Figure 1. Aramidocalix[4]arene derivatives 1–5.
The binding properties of 3 and 4 were studied in
CDCl3, whereas, due to solubility problems, 1 and 5
were investigated in a mixture of CDCl3/DMSO-d6
(9/1, v/v) instead. For each compound addition of
aliquots of the anion solution led to a downfield shift
of both NHa and NHb (Fig. 2) signals, which were
assigned by means of a 2D-NOESY spectrum. Usually,
NHa exhibited higher shifts indicating a preference for
this recognition site.
O
O
OH
OH
O
HO
O
O
OH
O
R
HN
DCC, DMAP
1-2
+
O
O
dry CH2Cl2 / DMF, rt, 20 h
NH2
6
7
8
R = COCH3
R = Boc
Receptor 3 exhibited aÀlower affinity for spherical ClÀ
and tetrahedral H2PO4 anions (Table 1) and interest-
inglyÀ displayed a good selectivity for trigonal planar
(Ka = 14,000 MÀ1 and Y-shaped PhCOOÀ
)
Scheme 1. Synthesis of aramidocalix[4]arenes 1 and 2.
NO3
In a similar way, the corresponding Boc-protected deriv-
ative 2 was obtained by coupling tetracarboxylic acid 6
with Boc-protected p-phenylenediamine 813 (Scheme
1). Compound 2 proved to be very useful because its
N-Boc deprotection with TFA in dry CH2Cl2 afforded
the key intermediate 9 which was used for the synthesis
of additional aramidocalix[4]arenes (Scheme 2).14
(Ka = 13,500 MÀ1).
This selectivity for nitrate anion was unexpected because
of the different symmetry between guest and host (C3 vs
C4)18 and is likely due to the planar arrangement of the
four NH groups.19 A possible structure of the complex
between N-pivaloyl-p-aramidocalix[4]arene 3 and nitrate
O
NH2
10
NH2
Cl
NH2
NH2
Table 1. Complexation constants (Kass) of receptors 1 and 3–5 toward
O
selected anions determined by 1H NMR titrations at 298 K (400 MHz)
Ph
Ph
Ph
11 Cl
Kass (MÀ1
)
O
O
O
O
NH
NH
CF3COOH
12
NH
O
HN
NHMe
O
O
1a
70
80
330
90
3b
4b
5a
Cl
O
2
3-5
ClÀ
3100
850
1700
14,000
13,500
1200
—
570
2000
5700
30
40
c
NEt3, dry THF
r.t. 90 min.
CH2Cl2, r.t., 2h
CH3COOÀ
À
O
H2PO4
NO3
PhCOOÀ
O
À
40
50
160
a 1H NMR titrations were carried out in CDCl3/DMSO-d6, 9/1, v/v.
b 1H NMR titrations were carried out in CDCl3.
c No changes in NMR spectra were observed. (Kass, error < 15%).
9
Scheme 2. Synthesis of aramidocalix[4]arenes 3–5.

7988
F. Troisi et al. / Tetrahedron Letters 48 (2007) 7986–7989
9.8
For N-triphenylacetyl-p-aramidocalix[4]arene
4
a
reduction in binding constant values was observed in
comparison to 3 (Table 1), likely because of the steric
crowding of trityl groups that should hamper the access
to the binding site. The complexation properties of
N-acetyl-p-aramidocalix[4]arene 1 and elongated bis-
aramidocalix[4]arene 5, bearing additional hydrogen
bond-donating sites (NHc, Fig. 1), were studied in
CDCl3/DMSO-d6 (9/1, v/v). Compared to 3 and 4, both
derivatives 1 and 5 showed an expected lower anion-
binding ability (Table 1) due to the H-bond-acceptor
competing the solvent. In addition, a lower selectivity
was observed probably because of a poorer preorganiza-
tion of the binding site due to the lack of the rigidifying
NHb interchain H-bonds, which would be destroyed by
solvent interactions.
9.6
9.4
9.2
9.0
8.8
8.6
8.4
8.2
8.0
7.8
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
7.8 8.0 8.2 8.4 8.6 8.8 9.0 9.2 9.4 9.6 9.8
a
δ (ppm) NH
0
1
2
3
4
5
6
7
8
[tetrabutylammonium nitrate] / 10-3 M
In conclusion, we have demonstrated that N-linked
amidocalix[4]arene derivatives are effective receptors
for anion recognition, which may show different
properties with respect to the C-linked counterparts.23
In particular, pivaloyl and triphenylacetyl aramido-
calix[4]arene derivatives, 3 and 4, reported here, show
a good selectivity for trigonal planar nitrate and
Y-shaped benzoate anions. The high affinity for nitrate
anion is probably due to the planar disposition of the
amide hydrogen atoms and an unsual six-hydrogen-
bond arrangement. Further studies are in progress in
our laboratory with the aim to extend the investigation
on the properties of other N-linked amidocalix[4]arene
derivatives and to exploit p-aramidocalix[4]arene recep-
tors for anion sensing.24
Figure 2. 1H NMR titration curve of p-aramidocalix[4]arenes 3 with
tetrabutylammonium nitrate (400 MHz, CDCl3). Inset: corresponding
mole ratio plot.
anion was obtained by molecular modeling,20 and its
geometry was refined by means of DFT calculations21
(Fig. 3) to obtain a more accurate positioning of the
nitrate ion. A careful analysis of the structure shows that
À
the NO3 anion is almost coplanar with the amide
hydrogen atoms NHa of 3, forming an unusual six-
hydrogen-bond arrangement.22 In particular, all the
oxygen atoms of the nitrate anion exhibit a similar
hydrogen bond pattern, forming one strong (NHÁ Á ÁO
˚
distance, 1.78–2.12 A) and one weak (NHÁ Á ÁO distance,
˚
2.42–2.54 A) H-bond with two amide hydrogen atoms
(Fig. 3). Interestingly, the terminal amide NHb groups
Acknowledgments
are engaged in two rigidifying interchain H-bonds.
Thanks are due to Dr. P. Iannece (Dip. di Chimica,
In a similar way, DFT calculations indicated that the
high affinity of 3 for benzoate anion could be ascribed
to favorable H-bonds conjugated to CH–p or p–p inter-
actions between aromatic rings of both guest and host.
`
Universita di Salerno) for ESI MS measurements and
`
to Dr. P. Oliva (Dip. di Chimica, Universita di Salerno)
for NMR spectra acquisition.
Supplementary data
1
Synthetic details, H/13C and 2D NMR data, binding
isotherms, details of molecular modeling and DFT cal-
culations. Supplementary data associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2007.09.046.
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9a
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