Anthracene-based open and macrocyclic receptors in the flurometric detection of urea

Article abstract of DOI:10.1039/b909536e

Anthracene-based open and macrocyclic receptors 1 and 2 have been designed and synthesized for the recognition of urea in less polar CHCl₃ and more polar CH₃CN solvents. Receptor 1 binds urea strongly in CHCl₃ and exhibits

Full text of DOI:10.1039/b909536e

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PAPER
www.rsc.org/njc | New Journal of Chemistry
Anthracene-based open and macrocyclic receptors in the flurometric
detection of ureaw
Kumaresh Ghosh* and Goutam Masanta
Received (in Victoria, Australia) 13th May 2009, Accepted 16th June 2009
First published as an Advance Article on the web 15th July 2009
DOI: 10.1039/b909536e
Anthracene-based open and macrocyclic receptors 1 and 2 have been designed and synthesized for
the recognition of urea in less polar CHCl3 and more polar CH3CN solvents. Receptor 1 binds
urea strongly in CHCl3 and exhibits a significant increase in the emission of the anthracene.
Macrocyclic analogue 2 shows higher binding and good sensibility towards urea due to the
macrocyclic effect. In CH3CN, the binding constant values are lower in magnitude, but the trend
is similar to that seen in CHCl3. Both the receptors 1 and 2 are examples of PET sensors for the
recognition of urea.
shown that a pyridine amide-based macrocyclic receptor can
form a strong inclusion complex with urea.16
Introduction
Molecular recognition between molecules is one of the most
Thus, the noteworthy progress made in this area inspired us
fundamental processes in both chemistry and biology. The
to work on the recognition of urea, and accordingly, we have
study of synthetic molecules to detect biologically important
designed, synthesized and envisioned the sensing properties of
species is important in the area of molecular recognition.1,2
acyclic 1 and macrocyclic receptor 2 for urea in both CHCl3
Considerable efforts have been made in last few decades to
and CH3CN. Herein, we report the synthesis of 1 and 2, and
design molecules for the development of good receptors for
our findings on their abilities to recognize and sense urea using
1H NMR, fluorescence and UV-vis spectroscopic methods.
specific tasks. It is worth mentioning that the recognition
and detection of bioactive substrates like urea,3 biotin,4
carbohydrates,5 carboxylic acids,6 amino acids,7 etc. have been
considerably successful. Among these substrates of biological
significance, urea is important because it is toxic, a pollutant
and causes serious biological disorders.8,9 The detection of this
small molecule by a suitable synthetic receptor is therefore
important. Fluorescent receptors with high sensitivity and
selectivity in this aspect are mentionable. To the best of our
knowledge, very few fluorescent receptors for urea recognition
are known in the literature. Goswami et al. reported the
fluorometric detection of urea by a macrocyclic receptor.10
A
2,6-bis(2-benzimidazole)pyridine receptor, as developed by
Chetia and Iyer, showed urea binding with a concomitant
change in fluorescence.11 Non-fluorescent urea receptors
with a considerable binding ability are also known. Crown
ether-based receptors, as developed by Pedersen,3 and the
carboxylic acid-containing crown ether receptor of Reinhoudt
et al.12 are known to bind urea. Reinhoudt et al. have also
explored the concept of using an electrophilic center to bind
urea in the cavity of a crown ether.13 Bell and Liu reported the
synthesis of naphthyridine-fused polyaza heterocycles, which
are potentially effective for urea recognition.14 Goswami and
Mukherjee reported the solubilization and recognition of urea
using a simple dinaphthyridine receptor.15 Recently, we have
Results and discussion
Receptors 1 and 2 were synthesized according to Scheme 1 and
Scheme 2, respectively. Initially, Schiff base 3 was obtained by
condensing 9-anthraldehyde with ethylamine in CH3OH. The
reduction of 3 using NaBH4 afforded amine 4, which, on
reaction with 2-N-(pivaloyl)-6-bromomethylpyridine in the
presence of K2CO3 in dry acetone, gave product 5 in 75%
yield. The cleavage of the amide linkage of 5 using 30% KOH
in aqueous ethanol produced amine 6 in 78% yield. The
reaction of amine 6 with isothaloyl diacid chloride in dry
THF afforded open receptor 1 in 64% yield.
Similarly, diamine 10, the precursor of macrocycle 2, was
obtained from 9-anthraldehyde by performing sequential
reactions, as shown in Scheme 2. The high dilution reaction
of diamine 10 with isothaloyl diacid chloride in the presence of
Et3N in dry THF yielded macrocycle 2 in 12% yield.
Department of Chemistry, University of Kalyani, Kalyani 741235,
India. E-mail: ghosh_k2003@yahoo.co.in; Fax: +91 3325828282;
Tel: +91 3325828750
w Electronic supplementary information (ESI) available: Absorption
and emission spectra of 1 and 2 in CHCl3, methods for the Job plot,
and methods for the determination of binding constant values. See
DOI: 10.1039/b909536e
In designed receptors 1 and 2, the anthracene acts as a
fluorescent probe that is connected to the binding sites via a
–CH2– linkage to fulfil the characteristic feature of a PET
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Scheme 1 The synthesis of receptor 1.
Scheme 2 The synthesis of receptor 2.
system.17 In 1 and 2, the amide NHs are well arranged in the
cavities for complexation of the urea carbonyl oxygen. The
other hydrogen bond acceptors, including the pyridine ring
nitrogens, are also correctly oriented for effective complexation
of the –NH2 groups of urea.
urea protons to the protons of receptor 1 revealed a 1 : 1
stoichiometry for the complex. Dilution of this complex in
CDCl3 did not cause any positional movement of the amide
signals. This indicates the strong complexation of urea in the
open cleft of 1. A similar study was performed using thiourea.
In the presence of thiourea, the amide protons of 1 underwent
a minor downfield chemical shift (Dd = 0.09), and a weak
signal for the thiourea protons at d 5.87 was observed
(Fig. 2(c)). This indicates a weak interaction of receptor 1
with thiourea.
The optimization of the geometries of 1 and 2 was
performed at the AM1 level.18 It is evident from Fig. 1 that
the open cleft of 1 is able to form a strong complex with a urea
molecule by utilizing all the hydrogen bond donors and
acceptors together. In comparison, the disposition of the two
anthracene moieties of macrocycle 2 creates partial steric
crowding during the complexation of urea (Fig. 1(b)).
Fig. 1(c) shows the mode of complexation of urea in the
cavity, where the urea molecule is found to interact from
outside the cavity.
Simultaneously, similar experiments were performed with
macrocyclic receptor 2. Fig. 3, shows the changes in the
1H NMR spectrum of 2 upon the complexation of urea and
thiourea.
Interestingly, here, the amide protons did not exhibit any
observable change upon complexation with urea. However a
signal at d 4.58 for the –NH2 groups of urea was seen
(Fig. 3(b)). This finding is in accordance with the molecular
modelling study (Fig. 1(c)), where the urea molecule interacts
from outside of the macrocycle, possibly due to steric congestion.
In connection with this, our previous report on urea binding
by a pyridine-based macrocycle16 also supports the present
observation. The stoichiometry of the complex was 1 : 1,
as established from the integration ratio in the 1H NMR
spectrum. In contrast to this, the amide protons of macrocycle
To look into the binding properties of 1 and 2 in solution,
1H NMR spectra were recorded in dry CDCl3. Urea powder
was added to CDCl3 solutions of 1 and 2, followed by
thorough sonication for about 10 min. The excess urea was
1
removed by filtration, and the filtrate was used to record H
NMR spectra. Significant downfield shifts of the amide
protons (Dd = 0.89) and the isophthaloyl peri proton
(Dd = 0.1) in 1 were observed in the presence of urea. In
addition, a new peak at d 4.95 for the urea protons was
observed (Fig. 2). The integration ratio of the signals for the
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Fig. 1 (a) AM1-optimized geometries of the 1Áurea complex (heat of formation = 391.17 kcal), (b) macrocycle 2 (heat of formation = 257.28 kcal)
and (c) 2Áurea complex (heat of formation = 213.16 kcal).
(Dd = 0.01), although the thiourea protons appeared at d 5.88.
These 1H NMR experiments thus corroborate that receptors 1
and 2 effectively interact with urea rather than thiourea in
CDCl3.
To understand the sensing and binding potencies of 1 and 2
for urea and thiourea, UV and fluorescence titrations were
performed by careful dilution of the 1 : 1 complexes of urea
and thiourea with the receptors in CHCl3. Fig. 4 shows the
change in absorbance of the anthracene moiety with 1Áurea
complex concentration; the linear change in absorbance at 368 nm
with complex concentration indicates a 1 : 1 stoichiometry of
the complex of 1 with urea (see inset of Fig. 4). A similar
finding was also observed for thiourea with receptor 1.w
Likewise, the complexation-induced change in absorbance
of 2 in the presence of urea and thiourea was recorded in
Fig. 2 (a) Partial 1H NMR spectra of receptor 1 (c = 2.58 Â 10À3 M),
CHCl3. Fig. 5 represents the change in absorption of the
complex of 2 with urea upon dilution with CHCl3. Here
also, the change in absorbance at 370 nm with complex
concentration was found to be linear, which confirms the
1 : 1 stoichiometry of the complex.
(b) a 1 : 1 complex of receptor 1 with urea and (c) a 1 : 1 complex of
receptor 1 with thiourea.
To evaluate the sensing properties of receptor 1, fluorescence
titrations were performed in the presence and absence of urea
Fig. 3 (a) Partial 1H NMR spectra of receptor 2 (c = 2.69 Â 10À3 M),
(b) a 1 : 1 complex of receptor 2 with urea and (c) a 1 : 1 complex of
receptor 2 with thiourea.
Fig. 4 UV spectra of the 1Áurea complex (c = 1 Â 10À5 M) and its
change in absorbance upon dilution. Inset: a plot of absorbance vs.
concentration of the 1 : 1 complex of urea with 1.
2 were found to be almost non-interacting with thiourea,
as evidenced from the negligible shift of the amide protons
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Fig. 7 The change in emission of receptor 1 (c = 1 Â 10À5 M) in
CHCl3 in the presence of stoichiometric amounts of urea, and dilution
spectra of the 1 : 1 complex (lex = 368 nm). Inset: plot of fluorescence
intensity vs. concentration of the 1 : 1 complex of urea with 1.
Fig. 5 UV spectra of the 2Áurea complex (c = 1 Â 10À5 M) and its
change in absorbance upon dilution. Inset: a plot of absorbance vs.
concentration of the 1 : 1 complex of urea with 2.
Fig. 6 The change in emission of receptor 1 (c = 1 Â 10À5 M) and its
Fig. 8 The change in emission of receptor 2 (c = 1 Â 10À5 M) in
CHCl3 in the presence of stoichiometric amounts of urea, and dilution
spectra of the 1 : 1 complex (lex = 368 nm). Inset: plot of fluorescence
intensity vs. concentration of the 1 : 1 complex of urea with 2.
1 : 1 complexes with urea and thiourea in CHCl3.
and thiourea. It is evident from Fig. 6 that the emission at
416 nm in CHCl3 is markedly increased, or ‘switched on’, with
a red shift of 7 nm, in presence of an equivalent amount of
urea and thiourea. During complexation, no peak at a higher
wavelength was observed due to an excimer between the
pendant anthracenes. The change in emission of the anthracene
moiety upon dilution of the 1 : 1 complex of 1 with urea by
CHCl3 (Fig. 7) is almost linear in nature, and is shown in the
inset of Fig. 7. The increase in emission of 1 upon complexa-
tion is explained by inhibition of the photoinduced electron
transfer (PET) from the binding site to the excited anthracene
moiety.
complex concentration. In the presence of thiourea, the
increase in the emission of 2 was relatively less than that
observed with urea.w
Thus, the PET-based fluorescence behaviors of receptors 1
and 2 in presence of urea are potentially applicable to
detect urea in less polar solvents. Both open and macrocyclic
receptors 1 and 2, in this regard, can act as good sensors
for urea.
Binding constant values were determined by the dilution
method10 from a fluorescence titration in pure dry CHCl3
(Table 1). It is evident from Table 1 that macrocyclic receptor
2 shows a stronger binding with urea than open receptor 1.
Acyclic receptor 1 also shows a marked selectivity for urea
over thiourea. On the other hand, receptor 2 exhibits about a
Under similar experimental conditions, the sensitivity and
selectivity of receptor 2 was evaluated in CHCl3 at an
excitation wavelength of 368 nm. In the presence of an
equivalent amount of urea, the emission of the anthracene
moiety at 425 nm was increased (Fig. 8), without showing any
extra peaks at higher wavelengths corresponding to excimer or
exciplex formation. The increase in the emission of the
anthracene moiety of 2, with a red shift of 5 nm, in presence
of urea we also attribute to the inhibition of the PET process
from the binding site to the excited anthracene moiety, as for
receptor 1. The change in emission of the anthracene moiety at
425 nm for the 1 : 1 complex of 2 with urea is presented in the
inset of Fig. 8, showing an almost linear response with
Table 1
fluorescence method
Binding constant values (Ka/MÀ1
)
in CHCl3 by the
Guest
Receptor 1
Receptor 2
Urea
Thiourea
1.14 Â 105
1.97 Â 106
2.71 Â 104
1.35 Â 106
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10 times higher binding constant value for urea due to the
macrocyclic effect. Surprisingly, the macrocycle shows a poor
selectivity in binding between urea and thiourea. We suggest
that receptor 2 interacts with urea and thiourea outside the
cavity of the macrocycle, as supported by our 1H NMR study
described above.
The binding constants for receptors 1 and 2 with urea
in CH3CN were determined by both fluorescence and UV
methods20 (Table 2).
As can be seen from Table 2, receptor 2 binds urea and
thiourea more effectively than the receptor 1. It is notable that
in CH3CN, binding constant values are lower in magnitude
than those obtained in CHCl3. This is due to the more polar
character of CH3CN, in which the hydrogen bonding inter-
actions between the receptor and the urea/thiourea molecule
are significantly reduced.
We further investigated the hydrogen bonding interactions
of 1 and 2 with urea and thiourea in the polar solvent CH3CN
by the direct titration method. The recognition properties of 1
and 2 were evaluated by analyzing the changes in both
fluorescence and absorption spectra. In CH3CN, the emission
of 1 (c = 1 Â 10À5 M) appeared as triplet, with lmax = 415 nm,
when excited at 368 nm. Upon adding urea, the fluorescence
intensity of 1 at 415 nm increased gradually without producing
any other physical change (Fig. 9(a)). No such significant
response was observed for thiourea (Fig. 9(b)). Thus, the
increase in the emission of 1 upon increasing the concentration
of urea is attributed to the strong complexation of urea, for
which the PET process occurring in between the binding site
and excited state of anthracene of 1 is deactivated. Due to the
bigger size of thiourea, the open cleft of 1 is less capable
of strong binding, as well as inhibiting the PET process
effectively.
Conclusion
We have designed and synthesized charge-neutral, anthracene-
based, both open and macrocyclic receptors as fluorescent
chemosensors for the detection and sensing of the biologically-
important substrate urea in the less polar solvent CHCl3, as
well as in the more polar solvent CH3CN. The binding
constant values determined are variously moderate and
appreciable. The receptors act as good PET sensors by
fulfilling the criteria of a PET system. The intrinsic fluorescence
of the anthracene moiety in the receptors effectively senses the
presence of notoriously insoluble urea in CHCl3 solution by
exhibiting a significant increase in emission upon complexation.
The same is true in the more polar solvent CH3CN. Both
receptors effectively bind urea in CHCl3. CH3CN, being more
polar than CHCl3, reduces hydrogen bonding interactions
between the receptors and the urea/thiourea molecules. This
is evident from the lower binding constant values of the
receptors for urea and thiourea. To the best of our knowledge,
such anthracene-based PET systems for the detection of urea
are unknown in the literature.
Under identical conditions, receptor 2 also showed a similar
behavior. The change in emission of 2 in the presence of
70 equivalents of urea and thiourea is shown in Fig. 10(a).
While the emission of the anthracene moiety in 2 increased in
the presence of urea, it decreased in presence of thiourea. The
change in emission of 2 upon gradually adding urea is
represented in Fig. 10(b).
Furthermore, in the presence of urea, the intensity of
absorption of the anthracene moiety in receptor 1 decreased
gradually. Fig. 11(a) shows the change in absorption of
receptor 1 in the presence of urea. In the presence of thiourea,
the intensity of absorption of the anthracene moiety in
receptor 1 decreased, and an isosbestic point at 275 nm
(Fig. 11(b)) was observed. This indicates the presence of two
species (receptor and receptor–thiourea complex) existing in
equilibrium.
Experimental
Syntheses
N1-[(E)-1-(9-Anthryl)methylidene]-1-ethanamine (3). To an
MeOH solution of 9-anthraldehyde (1 g, 4.85 mmol) at room
temperature was slowly added ethylamine (0.28 mL,
4.97 mmol). After stirring at room temperature for 30 min,
the resulting solution was refluxed for 9 h. After cooling, the
precipitated yellow solid was filtered and washed with ether.
The crude yellow product was recrystallised from ethanol to
yield almost pure Schiff base 3 (0.95 g) in 84% yield (mp 62 1C).
A UV-vis titration of macrocyclic receptor 2 was carried out
in the presence of urea and thiourea. Fig. S3 and Fig. S4 in the
ESI show the change in absorbance of receptor 2 in the
presence of urea and thiourea, respectively.w
The 1 : 1 stoichiometry of the urea complexes of both 1 and
2 was determined by a UV Job plot (Fig. 12).19
Fig. 9 The fluorescence change of receptor 1 (c = 1 Â 10À5 M) in presence of (a) urea and (b) thiourea in CH3CN.
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Fig. 10 (a) A comparison of the fluorescence change of receptor 2 upon adding of 70 equivalents of guests (c = 1 Â 10À5 M) and (b) the
fluorescence change of receptor 2 (c = 1 Â 10À5 M) in presence of urea in CH3CN.
Fig. 11 The change in absorption of receptor 1 (c = 1 Â 10À5 M) in the presence of (a) urea and (b) thiourea in CH3CN.
1H NMR (400 MHz, CDCl3) d: 9.43 (s, 1H), 8.46 (d, J = 8
Hz, 3H), 8.01 (d, J = 8 Hz, 2H), 7.75–7.44 (m, 4H), 3.98
(q, J = 8 Hz, 2H) and 1.52 (t, J = 4 Hz, 3H). FT-IR (KBr):
3040, 2967, 2842, 1636 and 1515 cmÀ1
.
N1-(6-{[(9-Anthrylmethyl)(ethyl)amino]methyl}-2-pyridyl)-2,2-
dimethylpropanamide (5)
Schiff base 3 (0.8 g, 3.43 mmol) was dissolved in MeOH
(20 mL), to which a slight excess of solid NaBH4 (0.26 g,
6.84 mmol) was added slowly to the methanolic solution; the
resulting solution was refluxed with stirring for 4 h. After
cooling the reaction mixture, 2 M HCl was added to destroy
the excess sodium borohydride. Once the effervescence had
stopped, 2 M NaOH was added until pH 9 was obtained. The
yellow solution was then extracted into CHCl3, washed three
times with water, separated and dried over anhydrous
Na2SO4. Removal of solvent under reduced pressure afforded
crude amine 4 (0.72 g, yield 89%). Crude amine 4 (0.6 g,
2.55 mmol) (without further purification) and 2-N-(pivaloyl)-
6-bromomethylpyridine (0.69 g, 2.55 mmol) were dissolved in
dry acetone (30 mL) containing K2CO3 (0.7 g, 5.07 mmol),
and the mixture refluxed for 5 h. The solvent was removed
under reduced pressure and the resulting mass extracted into
CHCl3. After removal of the solvent, the crude product was
purified by column chromatography (ethyl acetate: petroleum
Fig. 12 UV-vis Job plot of receptors 1 and 2 with urea; [host] +
[guest] = 1 Â 10À5 M.
Table 2 Binding constant (Ka/MÀ1) values in CH3CN
Fluorescence method
UV method
Receptor 1
Receptor 2
Receptor 1
Receptor 2
Guest
Urea
Thiourea
3.05 Â 103
9.27 Â 103
2.56 Â 103
5.07 Â 103
a
a
1.27 Â 103
2.69 Â 103
a
It was difficult to obtain an accurate value due to the minor changes
in fluorescence.
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ether 60–80 = 1 : 9), providing 5 (0.81 g, yield 75%) as a
gummy product.
N1,N3-Di[(E)-1-(9-anthryl)methylidene]-1,3-propanediamine
(7)
1H NMR (200 MHz, CDCl3) d: 8.53 (d, J = 8 Hz, 2H), 8.37
(s, 1H), 7.99–7.92 (m, 4H including NH), 7.55–7.40 (m, 5H),
6.87 (d, J = 8 Hz, 1H), 4.67 (s, 2H), 3.66 (s, 2H), 2.76 (q,
J = 6 Hz, 2H) and 1.35–1.20 (m, 12H). 13C NMR (75 MHz,
CDCl3) d: 176.9, 158.8, 150.3, 138.3, 134.0, 131.3, 130.0, 129.0,
127.5, 127.1, 125.5, 125.0, 124.7, 118.7, 111.5, 59.1, 50.4, 48.9,
27.4 and 12.0. FT-IR (KBr): 3433, 3054, 2967, 3932, 2871,
1682 and 1578 cmÀ1. UV (CHCl3; c = 5.05 Â 10À5 M;
To a solution of 9-anthraldehyde (1 g, 4.85 mmol) in dry
MeOH (40 mL) was added 1,3-propanediamine (0.2 mL,
2.4 mmol), and the reaction mixture was stirred under reflux
for 11 h. The solution was cooled and stirred at 0 1C for 2 h to
give a yellow precipitate. The precipitate was filtered off and
washed with MeOH several times, and finally dried under
vacuum to give foam-like yellow solid 7 (0.87 g, yield: 81%)
(mp: 128–130 1C).
l
max/nm): 258, 283, 350, 368 and 388. MS (FAB):
1H NMR (300 MHz, CDCl3) d: 9.55 (s, 2H), 8.56 (d,
J = 9 Hz, 4H), 8.50 (s, 2H), 8.04–8.01 (m, 4H), 7.52–7.41
(m, 8H), 4.21 (t, J = 6.6 Hz, 4H) and 2.57–2.53 (m, 2H).
FT-IR (KBr): 3047, 3024, 2866, 2841, 1637, 1517 and
1442 cmÀ1. EI-MS: m/z = 451.1 [M + H]+ and 473.1
[M + Na]+.
m/z = 426 [M + H]+, 396, 248 and 191.
6-[(9-Anthrylmethyl)(ethyl)amino]methyl-2-pyridinamine (6)
Compound 5 (0.5 g, 1.176 mmol) was dissolved in a 30%
KOH aqueous ethanol (1 : 4) solution (50 mL) and the
reaction mixture refluxed for 11 h. The solvent was removed
under vacuum and extracted with CH2Cl2 (3 Â 60 mL). The
organic layer was separated, washed with water and dried over
anhydrous Na2SO4. The solvent was then removed by rotary
evaporation. Finally, the crude product was purified by
column chromatography using 20% ethyl acetate in petroleum
ether 60–80 as the eluent to give brownish solid 6 (0.32 g, yield
78%) (mp: 136–138 1C).
N1-6-[((9-Anthrylmethyl)-3-[(9-anthrylmethyl)(6-[(2,2-
dimethylpropanoyl)amino]-2 pyridylmethyl)amino]-
propylamino)methyl]-2-pyridyl-2,2-dimethylpropanamide (9)
To a stirred solution of Schiff base 7 (0.8 g, 1.77 mmol) in dry
MeOH (30 mL) was added NaBH4 (0.335 g, 8.81 mmol)
portion-wise at 0 1C; the reaction mixture was then refluxed
for 4 h. The solvent was removed under vacuum and the crude
mass extracted with CH2Cl2 (3 Â 60 mL). The organic
layer was washed with water and dried over anhydrous
Na2SO4. The solvent was removed and the crude solid
product remaining was pure enough to be used in the next
step.
1H NMR (400 MHz, CDCl3) d: 8.55 (d, J = 8 Hz, 2H), 8.36
(s, 1H), 7.96 (d, J = 8 Hz, 2H), 7.50–7.41 (m, 4H), 7.26 (1H,
obscure by the CDCl3 peak), 6.67 (d, J = 8 Hz, 1H), 6.25 (d, J
= 8 Hz, 1H), 4.58 (s, 2H), 4.29 (s, 2H, NH2), 3.60 (s, 2H), 2.67
(q, J = 8 Hz, 2H) and 1.19 (t, J = 8 Hz, 3H). FT-IR (KBr):
3438, 3303, 1627, 1595, 1575, 1465 and 1444 cmÀ1. EI-MS: m/z
= 342.1 [M + H]+ and 191.1.
Compound 8 (0.7 g, 1.54 mmol) was dissolved in dry
acetone (25 mL) containing K2CO3 (1.05 g, 7.61 mmol), and
to this solution was added 2-N-pivaloyl-6-bromomethyl-
pyridine (0.85 g, 3.14 mmol). The reaction mixture was
refluxed for 7 h under a nitrogen atmosphere. The reaction’s
progress was monitored by TLC. After completion of
the reaction, the K2CO3 was filtered off and the filtrate
concentrated. The thick gummy mixture was dissolved in
CH2Cl2. The organic layer was washed with water and dried
over anhydrous Na2SO4. After removal of the solvent under
vacuum, the crude product was obtained and purified by
column chromatography using 15% ethyl acetate in petroleum
ether 60–80 as the eluent to give light yellow solid 9 (0.82 g,
yield: 64%) (mp: 86–90 1C).
N1,N3-Di(6-[(9-anthrylmethyl)(ethyl)amino]methyl-2-
pyridyl)isophthalamide (1)
To a stirred solution of 6 (0.2 g, 0.586 mmol) and Et3N
(0.2 mL, 1.44 mmol) in dry THF (10 mL) was added
isophthaloyl diacid chloride (0.06 g, 0.295 mmol). The reaction
mixture was stirred at room temperature under a nitrogen
atmosphere for 16 h. The solvent was removed under vacuum
and extracted with CH2Cl2 (3 Â 30 mL). The organic layer was
washed with 20% aqueous NaHCO3 solution, separated, dried
over anhydrous Na2SO4 and the solvent removed under
reduced pressure. Finally, the crude product was purified by
column chromatography using 20% ethyl acetate in petroleum
ether 60–80 as the eluent to give 1 (0.153 g, yield 64%) as a
white solid (mp: 102–104 1C).
1H NMR (300 MHz, CDCl3) d: 8.40 (m, 4H), 8.34 (s, 2H),
7.96–7.93 (m, 6H), 7.82 (s, 2H), 7.44–7.37 (m, 10H), 6.80
(d, J = 7.5 Hz, 2H), 4.48 (s, 4H), 3.56 (s, 4H), 2.52 (t,
J = 7.2 Hz, 4H), 1.87 (m, 2H) and 1.24 (s, 18H). 13C
(75 MHz, CDCl3) d: 176.9, 158.6, 150.3, 138.2, 134.0, 131.3,
129.9, 128.9, 127.5, 125.4, 124.9, 124.7, 118.8, 111.5, 59.9, 53.6,
51.2, 39.6, 27.4 and 24.6. FT-IR (KBr): 3433, 2962, 1687, 1598,
1577, 1517 and 1452. EI-MS: m/z = 835.3 [M + H]+ and
857.2 [M + Na]+.
1H NMR (500 MHz, CDCl3) d: 8.57 (s, 2H), 8.52 (d,
J = 9 Hz, 4H), 8.45 (s, 1H), 8.34 (s, 2H), 8.09–8.05 (m, 4H),
7.94 (d, J = 8.50 Hz, 4H), 7.60 (t, J = 10 Hz, 1H), 7.52–7.48
(m, 6H), 7.42 (t, J = 7.65 Hz, 4H), 6.97 (d, J = 7.50 Hz, 2H),
4.61 (s, 4H), 3.66 (s, 4H), 2.74 (q, J = 7 Hz, 4H) and 1.23
(t, J = 2 Hz, 6H). 13C (100 MHz, CDCl3) d: 164.2, 159.2,
149.9, 138.4, 134.8, 131.4, 131.3, 130.7, 130.1, 129.3, 128.9,
127.5, 125.7, 125.5, 125.0, 124.7, 119.3, 111.7, 59.1, 50.5, 49.1
and 12.1. FT-IR (KBr): 3325, 2929, 2849, 1679, 1599, 1524 and
1453 cmÀ1. UV (CHCl3; c = 1.725 Â 10À5 M; lmax/nm): 258,
283, 350, 368 and 388. EI-MS: m/z = 813.3 [M + H]+, 637.2
and 623.3.
Synthesis of macrocycle 2
Compound 9 (0.75 g, 0.897 mmol) was dissolved in 30%
aqueous ethanolic KOH (50 mL), and the reaction mixture
was refluxed for 42 h. After completion of the reaction,
the volume of solvent was reduced and extracted with CH2Cl2
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(60 Â 3 mL). The organic layer was separated and dried over
anhydrous Na2SO4, and the solvent removed under vacuum.
Finally, the crude product was purified by column chromato-
graphy using 3% MeOH in CHCl3 as the eluent to give
brownish solid 10 (0.43 g, 72%) (mp: 92–94 1C). This material
was used directly in the next step.
Acknowledgements
We thank CSIR, New Delhi, India for financial support and
DST, Government of India for providing facilities under the
DST-FIST programme. G. M. thanks CSIR, Government of
India for a fellowship.
Compound 10 (0.4 g, 0.6 mmol) was dissolved in dry THF
(25 mL) containing Et3N (0.1 mL, 0.72 mmol) in a dropping
funnel. Isophthaloyldiacid chloride (0.061 g, 0.3 mmol) was
dissolved in dry THF (25 mL) in another dropping funnel. The
two dropping funnels were positioned over a two-necked
round-bottomed flask containing dry THF (25 mL). The
solutions from the dropping funnels were added dropwise
to dry THF solvent (25 mL) over 8 h under a nitrogen
atmosphere. The reaction mixture was then stirred for 36 h
at room temperature. The solvent was removed under vacuum
and extracted with CH2Cl2 (3 Â 60 mL). The organic layer was
washed with a 20% aqueous NaHCO3 solution, separated and
dried over Na2SO4, and the solvent removed using a rotary
evaporator. Finally, the crude product was purified by column
chromatography using 10% ethyl acetate in petroleum ether
60–80 as the eluent to give white solid 2 (0.057 g, yield: 12%)
(mp: 152–154 1C).
References
1 H. Dugas, Bio-organic Chemistry: A Chemical Approach To
Enzyme Action, Springer-Verlag, Inc., New York, 1996.
2 J. M. Lehn, Supramolecular Chemistry: Concepts and Perspectives,
Wiley-VCH, Weinheim, 1995.
3 C. J. Pedersen, J. Org. Chem., 1971, 36, 1690.
4 S. Goswami and S. Dey, J. Org. Chem., 2006, 71, 7280 and
references cited therein.
5 M. Mazic, M. Kuschel and W. Sicking, Org. Lett., 2006, 8, 855 and
references cited therein.
6 S. Goswami, K. Ghosh and S. Dasgupta, J. Org. Chem., 2000, 65,
1907.
7 H. Wang, W.-H. Chan and A. W. M. Lee, Org. Biomol. Chem.,
2006, 6, 929.
8 J. Cooke, Nature, 1962, 194, 1262.
9 J. G. Morris and E. Payne, J. Agric. Sci., 1970, 74, 259.
10 S. Goswami, R. Mukherjee and J. Ray, Org. Lett., 2005, 7, 1283.
11 B. Chetia and P. K. Iyer, Tetrahedron Lett., 2006, 47, 8115.
12 C. J. van Staveren, V. M. L. J. Aarts, P. D. J. Grootenhuis, W. J.
H. Droppers, J. van Eerden, S. Harkema and D. Reinhoudt,
J. Am. Chem. Soc., 1988, 110, 8134 and references cited therein.
13 C. J. van Staveren, J. van Eerden, F. C. J. M. Veggel, S. Herkema
and D. N. Reinhoudt, J. Am. Chem. Soc., 1988, 110, 4994.
14 T. W. Bell and J. Liu, J. Am. Chem. Soc., 1988, 110, 3673.
15 S. Goswami and R. Mukherjee, Tetrahedron Lett., 1997, 38, 1619.
16 K. Ghosh, S. Adhikari and R. Frohlich, Tetrahedron Lett., 2008,
49, 5063.
17 (a) A. A. P. de Silva, H. Q. N. Gunaratne and C. P. McCoy,
Nature, 1993, 364, 42; (b) B. A. P. de Silva and K. R. A.
S. Sandanayake, Angew. Chem., Int. Ed. Engl., 1990, 29, 1173.
18 Calculations were performed using Chem 3D version 7.0,
CambridgeSoft, Cambridge, MA, USA.
1H NMR (500 MHz, CDCl3) d: 9.78 (s, 2H), 9.15 (s, 1H),
8.36–8.32 (m, 6H), 8.21 (s, 2H), 7.86 (d, J = 8 Hz, 2H), 7.81
(d, J = 8.5 Hz, 4H), 7.71 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 8
Hz, 4H), 7.27–7.24 (m, 4H), 7.20 (t, J = 7.5 Hz, 2H), 5.97
(d, J = 7.5 Hz, 2H), 4.35 (s, 4H), 3.40 (s, 4H), 2.24 (t,
J = 6.5 Hz, 4H) and 1.89 (m, 2H). 13C (100 MHz, CDCl3)
d: 163.8, 156.3, 150.8, 137.9, 134.2, 134.1, 131.9, 131.2, 131.0,
130.1, 129.6, 128.6, 127.5, 125.4, 125.2, 124.6, 118.7, 111.1,
61.7, 54.7, 50.8 and 28.2. FT-IR (KBr): 3423, 1683, 1604, 1575,
1539 and 1454 cmÀ1. UV (CHCl3; c = 4.15 Â 10À5 M;
19 P. Job, Ann. Chim., 1928, 9, 113.
20 P. T. Chou, G. R. Wu, C. Y. Wei, C. C. Cheng, C. P. Chang and
F. T. Hung, J. Phys. Chem. B, 2000, 104, 7818.
l
max/nm): 288, 350, 370 and 390. EI-MS: m/z = 797.3
[M + H]+, 701.5, 679.5 and 605.3.
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This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009
1972 | New J. Chem., 2009, 33, 1965–1972