Design and synthesis of a unique ditopic macrocyclic fluorescent receptor containing furan ring as a spacer for the recognition of dicarboxylic acids

Article abstract of DOI:10.1016/j.tet.2008.04.086

A macrocyclic fluorescent receptor was designed and synthesised and the binding study with three different types of dicarboxylic acids was performed with the receptor being found to have appreciable association constants. Downfield shifts of specific amide protons in 1:1 binding by ¹H NMR and the quenching in the fluorescence spectra reveal strong binding and thus unambiguously support the complexation of the receptor 1 with dicarboxylic acids.

Full text of DOI:10.1016/j.tet.2008.04.086

Tetrahedron 64 (2008) 6358–6363
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Design and synthesis of a unique ditopic macrocyclic fluorescent receptor
containing furan ring as a spacer for the recognition of dicarboxylic acids
,
b
a
Shyamaprosad Goswami a , Swapan Dey , Subrata Jana
*
a Department of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah 711103, India
b Department of Applied Chemistry, Indian School of Mines University, Dhanbad 826 004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 April 2008
Received in revised form 22 April 2008
Accepted 23 April 2008
Available online 29 April 2008
A macrocyclic fluorescent receptor was designed and synthesised and the binding study with three
different types of dicarboxylic acids was performed with the receptor being found to have appreciable
association constants. Downfield shifts of specific amide protons in 1:1 binding by 1H NMR and the
quenching in the fluorescence spectra reveal strong binding and thus unambiguously support the
complexation of the receptor 1 with dicarboxylic acids.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Molecular recognition
Macrocyclic receptors
Fluorescent sensors
Dicarboxylic acids
1. Introduction
to bind both mono and dicarboxylic acids.7 A common strategy was
applied to design receptors of dicarboxylic acid as well as some bi-
The development of artificial receptors for the detection of bi-
ologically and environmentally important substrates like carboxylic
acids and carboxylate anion is an important topic in molecular rec-
ognition research and such receptors have received considerable
attention in supramolecular chemistry.1 During the last decade,
substantial improvement has been made for the recognition of car-
boxylic acids by a number of synthetic receptors of various archi-
tectures. The design of synthetic receptors for neutral molecules
ologically active molecules that involved linking two aminopyridine
groups through the spacer.8,9 Photoinduced electron transfer (PET)
chemosensors possessing two binding sites were also reported for
the recognition of anions like dicarboxylates and pyrophosphate.10
Previously, we have successfully applied the Troger’s base spacer
and also an azo-linked photo responsive spacer using pyridine
amides for the chain length selection of dicarboxylic acids.11
A
complete study with discrimination of aromatic dicarboxylic acids
over aliphatic dicarboxylic acids in the recognition process of sev-
eral macrocyclic receptors has also been accomplished previously
in our laboratory. We therefore targeted the synthesis of a distinc-
tive macrocyclic receptor to recognise three different types of di-
carboxylic acids as well as to selectively choose the chain length.
involves p–p stacking and hydrogen-bonding interactions between
the host and guest.2 According to their strength and directional na-
ture compared to other intermolecular non-covalent interactions,3
hydrogen bonds are the most important and are extremely useful to
design the structure of molecular crystals. It is worth mentioning
that the stability of supramolecular structure can be enhanced by an
entropy effect, if additional binding sites are present in the host
molecules.4 Synthetic receptors for monocarboxylic acids and highly
selective chiral terpyridine macrocyclic fluorescent sensors have
already been reported for the recognition of amino acids and its
derivatives.5,6 Like monocarboxylic acids, di and tricarboxylic acids
are also biologically important and their recognition is of contem-
porary interest among the supramolecular community. The re-
ceptors, where 2-aminopyridine derivatives were linked to an
isophthalic acid spacer with wide range applications were reported
Based on hydrophobic, hydrogen bonding and
p-stacking in-
teractions, the designed receptor for neutral molecules is able to
complex with the complementary partner.
Such interesting features of carboxylic acid functionality have
manifold applications in supramolecular chemistry. For example,
being a useful hydrogen-bonding synthon, carboxylic acid has been
significantly exploited in generating solid-state supramolecular
structures with different architectures.
2. Results and discussion
Macrocyclic molecular receptors, which are formed by cyclic
arrays having naphthalene rings, are of interest since they can form
* Corresponding author. Tel.: þ91 33 2668 4561-3; fax: þ91 33 2668 2916.
E-mail address: spgoswamical@yahoo.com (S. Goswami).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.086

S. Goswami et al. / Tetrahedron 64 (2008) 6358–6363
6359
NBS in the presence of a catalytic amount of AIBN refluxing in dry
CCl4. 5-Hydroxymethyl-furan-2-carbaldehyde (3) was obtained
from sucrose by the reported procedure with the use of I2 in
refluxing dry DMF.14 Compound 4, which was prepared by the re-
duction of compound 3 with NaBH4 in ethanol, was coupled with
compound 2 in the presence of NaH using dry THF as solvent under
N2 atmosphere to afford compound 5. Under refluxing conditions,
compound 5 was hydrolysed with 4 M KOH (H2O–EtOH, 1:1) to give
diamino compound 6. The diamino compound 6 and the diacid
chloride of 7 were then coupled using high dilution condition under
N2 atmosphere to obtain the macrocyclic receptor 1 (Schemes 1–4).
O
O
O
O
O
O
HO
O
OH
O
N
N
N
N
NH
NH
NH
HN
O
O
O
O
O
O
O
O
Macrocyclic receptor 1
Macrocyclic receptor 1 with dicarboxylic acids
2.2. Complexation studies by PCMODEL program
Figure 1. Receptor 1 and its possible complex structure with dicarboxylic acids.
The energy minimisation15 predicts the stable geometry of the
molecule and depending on the electron environment of the re-
ceptors and the guests, the geometries of the complexes are found
to be different in different complexes. The hydrogen-bonding
points are well established in a concave manner (in–in) out of the
three possible conformations in–in, in–out, out–out with compa-
rable energy values in MMX energy calculations. The two pyridine
rings in the receptor 1 lie in parallel planes to each other, but
twisted in the anti direction. The distances between the two pyri-
dine ring nitrogens and the two-amide protons are 9.16 Å and
7.91 Å, respectively. The lengths between the two carboxyl moieties
in terephthalic acid and isophthalic acid are 5.68 Å and 5.03 Å, re-
spectively. So these two acids can easily be incorporated into the
cavity of the receptor 1. Among these two acids, terephthalic acid
might be expected to make a tighter complex with a higher asso-
ciation constant as it has the optimum fitting length. The size and
length of 1,4-phenylenediacetic acid is significantly larger, implying
it should exhibit a lower association constant. The calculated values
of stabilization energy,15 of the receptor 1 with the acids are
reported in the Supplementary data, and the mentioned acids have
shown the lowest stabilisation energy. However, on complexation
with the carboxylic acids all hydrogen-bonding groups become
deep, electron-rich cavities. Furthermore, as Glass et al.12 have re-
cently shown, the fluorescence properties of a naphthalene core
can allow the sensitive detection of complexes formed between the
guest molecules and such naphthalene ring based receptors.13 Our
particular interest has been in designing new receptors, which
could be effective hosts for the recognition of dicarboxylic acids.
The designed neutral fluorescent macrocyclic receptor 1 has two
pyridyl amide moieties as hydrogen-bonding (HB) points and
a naphthalene moiety to encircle the dicarboxylic acids by com-
bined hydrogen bonding to acid carbonyl (HB acceptor) as well as
its two NH atoms (HB donor) (Fig. 1). It was also designed on the
basis of complementarity between the host and guest involving
hydrogen bonding and stacking interactions for specific recognition
of aliphatic, aromatic and unsaturated dicarboxylic acids to exam-
ine the possible higher association with all types of dicarboxylic
acids employing effective multiple points for hydrogen bonding.
The incorporation of the fluorescent chromophore naphthalene in
receptor 1 was intended to allow possible p-stacking with aromatic
dicarboxylic acids.
2.1. Synthesis of the macrocyclic receptor 1
N-(6-Bromomethyl-pyridin-2-yl)-2,2-dimethyl-propionamide
(2) has been photochemically synthesised in our laboratory using
O
O
O
Br
O
O
O
i,ii
i
O
O
N
N
+
piv
N
H
piv
N
H
piv
N
H
N
2
N
N
Br
NH
O
HN
O
O
O
CO2H
HO2C
7
Scheme 1. Reagents and conditions: (i) NBS, AIBN, h
n
, CCl4, reflux, 6 h, 60%.
i
ii
Sucrose
CHO
O
4
O
Macrocyclic receptor 1
HO
HO
OH
3
Scheme 4. Reagents and conditions: (i) Oxalyl dichloride, DMF (one drop), dry CH2Cl2,
rt, 4 h; (ii) compound 6, Et3N, dry CH2Cl2, rt, high dilution, 12%.
Scheme 2. Reagents and conditions: (i) I2, DMF, 140 ꢀC, 56%; (ii) NaBH4, EtOH, rt, 12 h,
78%.
O
O
O
O
O
O
i
ii
2
+
4
N
N
N
N
NH
NH2
6
HN
H2N
5
O
O
Scheme 3. Reagents and conditions: (i) NaH, dry THF, rt, 12 h, 70%; (ii) 4 M KOH in 1:1 EtOH and H2O, 6 h, 95%.

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S. Goswami et al. / Tetrahedron 64 (2008) 6358–6363
Figure 2. Energy minimised complex structures of receptor 1 with pimelic, terephthalic and acetylenedicarboxylic acids.
properly arranged to make a stable intermolecular complex. The
alignments of the -stacking interaction between the aromatic
carboxylic acids with receptor 1 are realised from the docking
another acid group so that the first acidity constant (pKa1¼1.9) is
more than fumaric acid (pKa1¼3.5) that has the two acid groups in
the anti positions. A different 1H NMR spectrum is identified in the
case of fumaric acid on complexation with receptor 1. The amide
p
structures of the receptor–substrate complex (Fig. 2).
protons of receptor 1 appear at two positions,
d 9.47 ppm and
d
9.43 ppm. This indicates that the environments of the two-amide
2.3. Complexation (1:1) studies in 1H NMR
protons are not the same on complexation with fumaric acid. But no
extra amide peak is observed in case of the maleic acid complex.
Acetylenedicarboxylic acid is a straight chain (sp-hybridised) di-
The 1H NMR spectra of receptor 1 in CDCl3 and 1:1 NMR of the
complex with the corresponding acids in 2% DMSO-d6 in CDCl3 are
also reported. The receptor is freely soluble in CDCl3. To solubilise
the acids freely and to make the homogeneity in complex’s solution
we used 2% DMSO-d6 in all the cases. The amide proton was only
displaced towards downfield from its position by 0.06 ppm in 2%
DMSO-d6 in CDCl3 compared to CDCl3 itself. A significant downfield
chemical shift of amide proton and peri protons of naphthalene ring
of receptor 1 was caused by all nine dicarboxylic acids.
carboxylic acid and shows a downfield
9.50 ppm; Dd¼1.45 ppm).
d-shift (from d 8.05 ppm to
d
2.4. Complexation studies by UV–vis and fluorescence
methods and determination of association constants (Ka)
Receptor 1 has absorbance maxima in its UV–vis spectrum at
lmax¼240 nm and 279 nm in chloroform. In all the cases, a contin-
uous decrease of absorbance is observed on addition of the guest
solution (Fig. 4). Here it is to be noted that all dicarboxylic acid
guests are dissolved in 1% DMSO in chloroform. This change in UV–
vis spectrum could conveniently be used for binding constant cal-
culation, since the lower concentration gives rise to more accurate
determination of the value of the association constant of the acids.
Wavelength at 279 nm (lmax) has been selected as the excitation
wavelength for all the fluorescence studies. Performing the study,
we have achieved an excited state spectrum showing maxima at
lmax¼345 nm in chloroform. The receptor showed quenching at
lmax¼345 nm (Fig. 5). Among the six aliphatic dicarboxylic acids
[(CH2)n, n¼2–6], the maximum association constant was observed
for pimelic acid [(CH2)n, n¼5]. Adipic and suberic acids have
association constant values somewhat less than pimelic acid
(Table 1). The association constants are evaluated by a similar
method in CHCl3. So according to the chain length and size, among
these aliphatic dicarboxylic acids, pimelic acid is found to be best fit
for the incorporation into the cavity of the receptor 1. Though the
Among the three aliphatic dicarboxylic acids, adipic, pimelic and
suberic acids, pimelic acid on complexation with receptor 1 shows
a larger downfield shift of the amide proton from
d 8.05 ppm to
d
9.41 ppm (Dd 1.36 ppm) (Fig. 3). The other two acids caused
downfield shifts of Dd 1.10 ppm and Dd 1.13 ppm, respectively.
The chemical shift of the amide proton in receptor 1 on com-
plexation with terephthalic acid is less than that with 1,4-phenyl-
enediacetic acid (Dd 1.32 ppm and Dd 1.45 ppm, respectively). With
isophthalic acid the amide proton undergoes a downfield shift (Dd
0.65 ppm) on complexation. In all the cases, the peri protons of the
naphthalene ring are also significantly shifted towards downfield
on complexation with acids. Significant downfield shifts of the
amides and peri protons in all cases and the appearance of methy-
lene protons of the guest acids in the spectra are conclusive for
the desired complexation. Chemical shifts on complexation of
the amide proton of receptor 1 with dicarboxylic acids are
summarised in Supplementary data.
The hydroxyl group (in cis form) in maleic acid is in-
tramolecularly hydrogen-bonded with the carboxyl oxygen of
Figure 3. One representative partial 1H NMR spectra of receptor 1 and its complex with pimelic acid in CDCl3 and 2% DMSO-d6 in CDCl3, respectively.

S. Goswami et al. / Tetrahedron 64 (2008) 6358–6363
6361
(b)
(a)
0.4
0.3
0.2
0.1
0.0
0.012
0.220
0.215
0.210
0.205
0.200
0.008
280
Wave length (nm)
0.004
for AdipicAcid
for 1,4-phenylenediacetic
Acid
for Pimelic Acid
for Suberic Acid
for terephthalic Acid
for Fumaric Acid
for MaleicAcid
for Acetylenedicarboxylic
Acid
0.000
for isophthalic Acid
260
280
300
Wave length (nm)
320
340
0
1
2
[G]/[H]
3
4
Figure 4. (a) Titration spectra of receptor 1 with pimelic acid and (b) titration curve of receptor 1 with dicarboxylic acids by UV-vis technique. Inset: expanded area (270 nm–290 nm).
(a)
(b)
300
250
200
150
100
50
400
300
200
100
0
for Adipic Acid
for Pimelic Acid
for Suberic Acid
for isophthalic Acid
for terephthalic Acid
for 1,4-phenylenediacetic Acid
for Fumaric Acid
for Maleic Acid
for Acetylenedicarboxylic Acid
0
320
360
Wave length (nm)
400
440
0
1
2
3
4
5
[G]/[H]
Figure 5. (a) Titration spectra of receptor 1 with pimelic acid and (b) titration curve of receptor 1 with dicarboxylic acids by fluorescence technique.
spacer in aliphatic dicarboxylic acids is flexible, chain length se-
lectivity can thus be observed.
binding constant. No geometrical problem has been indicated for
the first two acids and the cavity size, almost significant to ac-
commodate terephthalic acid, is not big enough for 1,4-phenyl-
enediacetic acid. When the same receptor’s solution was excited at
279 nm, we got similar spectra with regular quenching of the
Though the edge-face p-stacking interaction is a common factor
for the three common aromatic acids like isophthalic, terephthalic
and 1,4-phenylenediacetic acids, the geometry of the acid groups,
steric factor and also the length cause differences in association.
Both terephthalic and 1,4-phenylenediacetic acids have the two
acid groups straight, but there is an angle (120ꢀ) between the two
acid groups in isophthalic acid, which may cause it to have a lower
fluorescence intensity
constant values of terephthalic acid are higher compared to the
other aromatic dicarboxylic acids.
(
lmax¼345 nm). But overall association
A similar result with the aromatic acids was obtained with
regular quenching (lmax¼345 nm). Among the three acids, acety-
lenedicarboxylic acid possesses the highest association constant
(Ka) values, which may be due to the strongest acidity of CO2H
group (sp-hybrid acetylenic carbon is more electronegative than
sp2 carbon in fumaric or maleic acid).
Table 1
Calculation of the association constant (Ka ꢃ5–8%) values by UV-vis and fluores-
cence methods
Entry
Guest (dicarboxylic acid)
UV–vis method
Fluorescence method
The macrocyclic receptor 1 contains one heterocycle furan ring
and one naphthalene ring opposite to each other. So there may be
(Ka, Mꢂ1
)
(Ka, Mꢂ1
)
1.
2.
3.
4.
5.
6.
7.
8.
9.
Adipic acid
Pimelic acid
Suberic acid
Isophthalic acid
Terephthalic acid
1,4-Phenylenediacetic acid
Fumaric acid
Maleic acid
Acetylenedicarboxylic acid
1.4ꢁ104
4.1ꢁ104
1.2ꢁ104
5.4ꢁ104
1.1ꢁ105
3.9ꢁ104
6.2ꢁ104
9.7ꢁ103
8.7ꢁ104
1.3ꢁ105
1.4ꢁ105
3.1ꢁ104
1.4ꢁ105
1.8ꢁ105
1.3ꢁ104
2.8ꢁ105
1.7ꢁ104
5.7ꢁ105
some possibility of
p-stacking interaction of the guest aromatic
acids with naphthalene, which will help increasing the binding
constant of aromatic acids. The binding of isophthalic, terephthalic
and 1,4-phenylenediacetic acids with receptor 1 has been studied
and indicated more selectivity towards terephthalic acid
[Ka¼1.1ꢁ105 Mꢂ1 (UV-vis) and 1.8ꢁ105 Mꢂ1 (fluorescence)]. Among
the three aliphatic dicarboxylic acids, pimelic acid binds with
higher affinity [Ka¼4.1ꢁ104 Mꢂ1 (UV-vis) and 1.4ꢁ105 Mꢂ1

6362
S. Goswami et al. / Tetrahedron 64 (2008) 6358–6363
(fluorescence)], which proves that the chain length of pimelic acid
is optimum, corresponding to that of the spacer for the above-
mentioned receptor. Acetylenedicarboxylic acid shows strong
binding [Ka¼8.7ꢁ104 Mꢂ1 (UV-vis) and 5.7ꢁ105 Mꢂ1 (fluores-
cence)] than the other two unsaturated acids.
portions from this solution, initially the fluorescence spectra were
recorded. Then adding the guest solutions (dissolved in different
amounts of acids in 1% DMSO–CHCl3 to form solutions of concen-
trations of ca. 1ꢁ10ꢂ5) fluorescence titration was carried out for
each time for all the guests.
The sigmoidal plots of [G]/[H] versus
versus F in fluorescence reveal the 1:1 complexation and linear fit
plots of 1/[G] versus I0/ I in UV-vis and 1/[G] versus F0/ F in fluo-
DI in UV-vis and [G]/[H]
D
4.4. N-(6-Bromomethyl-pyridin-2-yl)-2,2-dimethyl-
propionamide (2)
D
D
rescence help calculating the binding constant values. The binding
constant calculations of macrocyclic receptor 1 with the mentioned
dicarboxylic acids were performed at lmax¼279 nm (in UV) and at
lmax¼345 nm (in fluorescence).16
2,2-Dimethyl-N-(6-methyl-pyridin-2-yl)-propionamide (1.0 g,
5.20 mmol) was taken in dry CCl4 (50.0 mL). Then AIBN (0.20 g,
1.2 mmol) was added as a radical initiator and the solvent was
refluxed for 30 min in the presence of 60 W lamp. Recrystallised
NBS (0.95 g, 5.20 mmol) was added to the refluxing solution. Then
the solution turned brown and the whole system was refluxed for
6 h. After usual work-up the compound was isolated as a brown
semi-solid (yield 60%).
3. Conclusion
Macrocyclic receptor 1 binds three different types of acids with
considerable association constants. Shifting of the NH protons in
1:1 1H NMR and the quenching of the fluorescence intensity in the
excited state unambiguously concluded complexation with the
acids. Terephthalic acid shows higher affinity towards receptor 1
among all nine acids. Though the selectivity towards pimelic acid is
the unique feature of this type of receptors where furan moiety
is used instead of conventional aromatic moiety. The receptor 1 is
therefore, an interesting design for complexation with the di-
carboxylic acids, which showed interesting physico-chemical
behaviour.
1H NMR (CDCl3, 200 MHz):
d
8.16 (d,1H, J¼8.2 Hz), 8.02 (br s,1H),
7.66 (t, 1H, J¼7.9 Hz), 7.12 (d, 1H, J¼7.7 Hz), 4.46 (s, 2H), 1.30 (s, 9H).
13C NMR (CDCl3, 100 MHz):
113.3, 39.7, 33.1, 27.3.
d 177.2, 154.7, 151.3, 139.3, 119.0,
LC–MS (m/z, %): 273.1 (Mþ2, 100), 271.1 (Mþ, 90), 255.2 (20),
199.1 (30), 192.2 (15).
4.5. 5-Hydroxymethyl-furan-2-carbaldehyde (3)
Iodine (3.50 g, 0.013 mol) dissolved in dry DMF (10.0 mL) was
added to a sucrose solution (150.0 g in 200.0 mL dry DMF) of
boiling DMF. This was a strongly exothermic reaction and pouring it
into ice water immediately quenched the reaction. After cooling,
the mixture was extracted with ethyl acetate continuously several
times and dried over sodium sulfate to afford a blackish liquid
product (yield 56%).14
4. Experimental
4.1. General
Melting points (mp) were recorded on an A. D. and Co. hot-coil
stage melting point apparatus and are uncorrected. NMR spectra
were recorded in CDCl3 unless otherwise mentioned with TMS as
the internal standard with either Bruker AM 500 MHz or 400 MHz
1H NMR (CDCl3, 500 MHz):
d
9.55 (s, 1H), 7.23 (d, 1H, J¼3.5 Hz),
6.52 (d, 1H, J¼3.5 Hz), 4.70 (s, 2H), 3.31 (br s, 1H).
or 300 MHz NMR instruments. Chemical shifts are given in d (ppm)
scale and J values in Hertz. IR spectra were measured in KBr disk
with a JASCO FT/IR-460 plus spectrometer. UV–vis and fluorescence
spectra were recorded on a JASCO V-530 and Perkin Elmer LS-55,
respectively. HRMS of the macrocyclic receptor 1 was recorded on
a Qtof Micro YA263 instrument. LC–MS of the compounds was
recorded on ABI-Q-Trap (ABI-Applied Bioscience). All solvents were
dried prior to use by common methods. Silica gel (60–120 and 100–
200 mesh) was used for all chromatographic purifications. For
preparative thin layer chromatographic (PTLC) purification, the
layer was formed on a glass plate using water gel-GF 254 silica gel.
Starting materials were either commercially available (purchased
from Fluka and Aldrich) or synthesised according to the cited lit-
erature procedures. All the reactions were carried out under ni-
trogen atmosphere in anhydrous solvents.
4.6. (5-Hydroxymethyl-furan-2-yl)-methanol (4)
5-Hydroxymethyl-2-furfural 1 (2.50 g, 0.19 mmol) was taken in
a round-bottomed flask (50.0 mL). Then ethanol (10.0 mL) and so-
dium borohydride (0.75 g, 0.2 mmol) were added to it and stirred
for 12 h. A more polar compound was produced, which did not
respond to UV, but absorbed iodine. Maximum product was so-
lidified when it was dipped into ice. The residue was purified
through column chromatography (silica gel 100–200 mesh) using
2% methanol in chloroform. An off-white solid material was iso-
lated (1.98 g, yield 78%, mp 76–78 ꢀC).
1H NMR (CDCl3, 500 MHz):
d 6.17 (s, 2H), 4.52 (s, 4H), 3.42
(s, 2H).
13CNMR(CDCl3 þ 2dropsDMSO-d6,100 MHz):
d130.0,115.0,29.5.
LC–MS (m/z, %): 130.4 (Mþ2Hþ, 71), 120.2 (9), 101.0 (67).
4.2. General procedure for UV–vis titration
4.7. N-(6-{5-[6-(2,2-Dimethyl-propionylamino)-pyridin-2-
ylmethoxymethyl]-furan-2-ylmethoxymethyl}-pyridin-2-yl)-
2,2-dimethyl-propionamide (5)
Stock solution of receptor 1 was prepared at a concentration of
ca. 1ꢁ10ꢂ5 mol/mL in CHCl3. Acids were dissolved in 1% DMSO in
CHCl3 in ca. 1ꢁ10ꢂ4 mol/dm3 concentration. DMSO (1%) was added
to make a homogeneous solution. Then the guest solution was
added to the receptor solution (taking 2.0 mL in the UV-cell) and
continuous decreases of absorbance in UV spectra were recorded
each time.
To a solution of 2,5-dihydroxymethylfuran 4 (260 mg, 2.0 mmol)
in dry tetrahydrofuran (8.0 mL), sodium hydride (240 mg;
10.0 mmol) was added and stirred under nitrogen atmosphere for
1 h. The solution of compound 2 in dry THF was added dropwise to
the reaction mixture under nitrogen and stirred for 10 h. After
completion of the reaction, THF was removed under vacuum and
dichloromethane was added to the crude solid. The organic layer
was washed with brine solution several times and dried over an-
hydrous sodium sulfate. Then the solvent was evaporated and the
residue was purified by column chromatography (60–120 silica gel)
4.3. Fluorescence titration and binding study
Receptor 1 (0.7 mg, 4.40252ꢁ10ꢂ5 mmol/mL) was dissolved in
dry chloroform (25.0 mL) in a volumetric flask. Then the solution
was diluted 10 times to 4.40252ꢁ10ꢂ6 mmol/mL. Taking 2.0 mL

S. Goswami et al. / Tetrahedron 64 (2008) 6358–6363
6363
by using 8% ethyl acetate in petroleum ether (60 ꢀC–80 ꢀC) to yield
a brownish material (semi-solid, 710 mg, yield 70%).
13C NMR (CDCl3, 125 MHz):
d
171.5, 157.5, 156.6, 152.1, 150.9,
139.4, 136.1, 129.5, 124.9, 118.0, 116.5, 112.9, 110.9, 106.8, 72.6, 66.8,
64.9, 34.7, 25.3.
1H NMR (CDCl3, 500 MHz):
d
8.15 (t, 2H, J¼9.1 Hz), 8.00 (br s,
2H), 7.70 (dd, 2H, J¼7.8, 7.9 Hz), 7.16 (dd, 2H, J¼7.4, 7.4 Hz), 6.31 (s,
MS (FAB) (m/z, %): 659.1 (MþNaþ, 65), 637.2 (MþHþ, 100), 528.2
(35).
2H), 4.62 (s, 4H), 4.55 (s, 4H), 1.25 (s, 18H).
13C NMR (CDCl3, 100 MHz):
d
184.6, 155.9, 151.7, 151.3, 139.2,
HRMS (ESþ) calcd for C36H36N4O7Na (MþNaþ): 659.2482.
117.4, 113.1, 110.4, 71.9, 64.7, 38.4, 27.2.
MS (ESI) (m/z, %): 531.2 (MþNaþ, 80), 421.2 (100).
HRMS (ESþ) Calcd for C28H36N4O5Na (MþNaþ): 531.2584.
Found: 531.2587.
Found: 659.2482.
FTIR (KBr, nmax): 2923, 2360, 1732, 1698, 1634, 1540, 1456,
1210 cmꢂ1
.
FTIR (KBr, nmax): 2923, 2852, 2360, 1732, 1716, 1698, 1456 cmꢂ1
.
Acknowledgements
4.8. 6-{[(5-{[(6-Amino-2-pyridyl)methoxy]methyl}-2-
furyl)methoxy]methyl}-2-pyridinamine (6)
Authors thank DST [SR/S1/OC-13/2005] (Government of India)
for financial support. S.D. thanks CSIR (Government of India) for
providing Research Associateship [8/3(41)(48) EMR-1].
Compound 5 (1.0 g, 1.96 mol) was dissolved in ethanol (5.0 mL)
containing aqueous 4 M KOH (5.0 mL). The mixture was refluxed
for 6 h. The solvent was removed and water was added to the
residue and extracted with ethyl acetate. The organic layer was
separated and dried over anhydrous sodium sulfate and evaporated
to yield a brownish solid material (640 mg, yield 95%, mp 118 ꢀC).
Supplementary data
NMR (1H and 13C) spectra, MS-spectra, UV-vis and fluorescence
titration spectra of receptor with dicarboxylic acids, titration curves
and the association constants calculation curves (both UV-vis and
fluorescence method), and energy minimised structures are also
available. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.04.086.
1H NMR (CDCl3, 500 MHz):
d
7.41 (t, 2H, J¼7.7 Hz), 6.77 (d, 2H,
J¼7.3 Hz), 6.38 (d, 2H, J¼8.1 Hz), 6.30 (s, 2H), 4.54 (s, 4H), 4.48 (s,
4H) (amine proton not observable).
13C NMR (CDCl3, 100 MHz):
110.3, 107.5, 72.5, 64.6.
d 158.0, 156.1, 151.8, 138.4, 111.5,
LC–MS (m/z, %): 341.2 (MþHþ, 17), 299.4 (11), 217.3 (100), 189.1
(39).
References and notes
HRMS (ESþ) Calcd for C18H20N4O3Na (MþNaþ): 363.1433.
1. Comprehensive Supramolecular Chemistry; Atood, J. L., Davies, J. E. D., MacNicol,
D. D., Vogetle, F., Eds.; Elsevier: Exeter, 1996 and references cited therein.
2. (a) Diederich, F. Cyclophanes; The Royal Society of Chemistry: Cambridge, UK,
1991; (b) Rebek, J., Jr. Acc. Chem. Res. 1990, 23, 399–404.
Found: 363.1436.
FTIR (KBr, nmax): 2963, 1619, 1466, 1261, 1094, 1020, 799 cmꢂ1
.
3. Lehn, J.-M. Supramolecular Chemistry Concepts and Perspectives; VCH: Wein-
heim, 1995.
4.9. Macrocyclic receptor 1
4. Konig, B.; Moller, O.; Bubenitschck, P. J. Org. Chem. 1995, 60, 4291–4293.
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Yang, T. Tetrahedron 2004, 60, 4309–4314.
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15. Energy minimisation was carried out using MMX (PCMODEL Serena Software
1993). Molecular modelling was performed using standard constants and the
dielectric constant was maintained at 1.5.
The acid 7 (58 mg, 0.176 mmol) was taken in a round-bottomed
flask (25.0 mL) and to this dry dichloromethane (10.0 mL) was
added. The system was kept under nitrogen atmosphere. Oxalyl
dichloride (0.10 mL) and one drop of dry DMF were added to the
above solution. It was stirred for 3 h. The solvent was removed to
get the acid dichloride of compound 7 to be used for the next step.
In a two-necked round-bottomed flask fitted with two dropping
funnels, dichloromethane (20.0 mL) was taken and the system was
kept under nitrogen. Diamine 6 (60 mg, 0.176 mmol) was dissolved
in CH2Cl2 (10.0 mL). Then the volume was made up with dry
dichloromethane (30.0 mL) and to this, triethylamine (0.10 mL) was
added and the mixture was taken in a dropping funnel. Acid
dichloride of compound 7 was also dissolved in dry dichloro-
methane (30.0 mL) and taken in another dropping funnel. Both
solutions were added dropwise to the two-necked round-bottomed
flask for a period of 2 h and stirred continuously for 10 h at room
temperature under nitrogen atmosphere. Then the solvent was
removed and fresh CH2Cl2 was added to the reaction mixture.
Washing with saturated sodium bicarbonate solution, the organic
layer was dried over anhydrous sodium sulfate. The solvent was
then evaporated to dryness and the crude mixture was purified by
preparative TLC using 4% methanol in chloroform (off-white solid;
yield 12%, 13.4 mg, mp 142–45 ꢀC).
1H NMR (CDCl3, 300 MHz):
d
8.05 (d, 2H, 2NH, J¼8.2 Hz), 7.60 (t,
16. (a) Connors, K. A. Binding ConstantdThe Measurement of Molecular Complex
Stability; John Wiley & Sons: New York, NY, 1987; (b) Chou, P.-T.; We, G.-R.; Wei,
C.-Y.; Cheng, C.-C.; Chang, C.-P.; Hung, F.-T. J. Phys. Chem. B 2000, 104, 7818–
7829; (c) Liao, J.-H.; Chen, C.-T.; Chou, H.-C.; Cheng, C.-C.; Chou, P.-T.; Fang,
J.-M.; Slanina, Z.; Chow, T. J. Org. Lett. 2002, 4, 3107–3110.
2H, J¼7.9 Hz), 7.48 (4H, d, J¼9.7 Hz), 7.18 (s, 2H), 7.01 (d, 2H,
J¼7.1 Hz), 6.89 (d, 2H, J¼7.3 Hz), 6.16 (s, 2H), 4.39 (s, 4H), 4.36 (s,
4H), 4.06 (t, 4H, J¼5.9 Hz), 2.59–2.55 (m, 4H), 2.21 (t, 4H, J¼6.0 Hz).