Fluorescence switch-on sensor for Cu2+ by an amide linked lower rim 1,3-bis(2-picolyl)amine derivative of calix[4]arene in aqueous methanol

Article abstract of DOI:10.1016/j.tetlet.2009.03.109

A highly selective fluorescence switch on sensor, L for detecting Cu²⁺ has been synthesized by introducing a bis-(2-picolyl)amine moiety at the lower rim of a calix[4]arene platform via amide linkage. Binding properties of L toward ten different biologically relevant Mⁿ⁺ ions have been studied by fluorescence and absorption spectroscopy in methanol and aqueous methanol. L was found to detect Cu²⁺ selectively down to a concentration of 196 and 341 ppb, respectively, in methanol and 1:1 aqueous methanol even in the presence of other metal ions. The composition of the complex has been found to be 1:1 based on the Job plot and is further confirmed by ESI MS. The role of calix[4]arene platform as well as the pre-organized binding core in the selective recognition of Cu²⁺ has been demonstrated by studying appropriate reference molecules. The possible modes of binding of L with Cu²⁺ have been modeled by computational calculations. L and its Cu²⁺ complex could very well be differentiated based on the nano-structural features observed in SEM and AFM.

Full text of DOI:10.1016/j.tetlet.2009.03.109

Tetrahedron Letters 50 (2009) 2735–2739
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
2+
Fluorescence switch-on sensor for Cu by an amide linked lower rim
,3-bis(2-picolyl)amine derivative of calix[4]arene in aqueous methanol
1
Roymon Joseph, Balaji Ramanujam, Amitabha Acharya, Chebrolu P. Rao *
Bioinorganic Laboratory, Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076, India
a r t i c l e i n f o
a b s t r a c t
A highly selective fluorescence switch on sensor, L for detecting Cu2+ has been synthesized by introducing
a bis-(2-picolyl)amine moiety at the lower rim of a calix[4]arene platform via amide linkage. Binding
Article history:
Received 14 January 2009
Revised 7 March 2009
Accepted 14 March 2009
Available online 20 March 2009
n+
properties of L toward ten different biologically relevant M ions have been studied by fluorescence
2+
and absorption spectroscopy in methanol and aqueous methanol. L was found to detect Cu selectively
down to a concentration of 196 and 341 ppb, respectively, in methanol and 1:1 aqueous methanol even in
the presence of other metal ions. The composition of the complex has been found to be 1:1 based on the
Job plot and is further confirmed by ESI MS. The role of calix[4]arene platform as well as the pre-orga-
Keywords:
2+
Cu sensor
2
+
nized binding core in the selective recognition of Cu has been demonstrated by studying appropriate
Fluorescence switch-on
Calix[4]arene appended with bis-(2-
picolyl)amine
2
+
reference molecules. The possible modes of binding of L with Cu have been modeled by computational
calculations. L and its Cu2 complex could very well be differentiated based on the nano-structural fea-
tures observed in SEM and AFM.
+
Nano structure
Ó 2009 Elsevier Ltd. All rights reserved.
10
Detections of cations, anions and molecular species are some of
the challenging areas of current research relevant to the receptor
design and development. Copper is one of the essential trace ele-
1H NMR, 13C NMR, ESI MS, IR, and elemental analysis. The cone
1
conformation of L has been confirmed by H NMR spectroscopy.
The metal ion binding studies of L and its control molecules
were demonstrated by fluorescence spectroscopy. The metal ions,
viz., Mn , Fe , Co , Ni , Cu , Zn , Na , K , Ca , and Mg , were
subjected to recognition studies with L and the control molecules.
The studies were carried out by exciting the solutions at 285 nm
and recording the fluorescence spectra in the range of 295–
420 nm in methanol as well as in 1:1 aqueous methanol (SI 02).
During the titration in methanol, the fluorescence intensity of L in-
1
ments of transition metals which serves as a cofactor by taking
2
2+
2+
2+
2+
2+
2+
+
+
2+
2+
an active part in a large variety of enzymes. As copper can easily
access both +1 and +2 oxidation states, it can act as electron car-
3
rier. Both excessive copper intake and copper deficiency lead to
several disorders.2
b,2c,4
Therefore, the detection of copper by vari-
ous synthetic receptors is an emerging area of current research.
Enhancement in the fluorescence intensity as a result of metal
ion binding is more attractive than quenching. There are several re-
ports in the literature in which appropriately functionalized calix-
2
+
creases as a function of Cu addition (Fig. 1a) and shows about 7
2+
fold enhancement and saturates around 2 equiv of Cu addition
5
2+
arenes have been used as host molecules for ions and neutral
(Fig. 1b). Thus the titration of L with Cu results in a stoichiome-
6
2+
molecular species , among them those for Cu are rather limited.
To our knowledge, only an upper rim functionalized calix[4]arene
having an aminoquinoline moiety connected through schiff’s base
tric reaction. However, when similar titrations were carried out
2
+
2+
2+
2+
2+
+
with other metal ions, such as, Mn , Fe , Co , Ni , Zn , Na ,
+
2+
2+
K , Ca , and Mg , only a minimal enhancement or minimal
quenching has been observed (Fig. 1c). Since aqueous solutions
are of paramount importance in order to have a wide range of
applicability of the receptor, similar titrations were carried out in
1:1 aqueous methanol and a ꢀ12 fold increase in the fluorescence
2
+
7
3
exhibited a fluorescence enhancement with Cu in CH CN , while
others exhibited quenching.8 Therefore in this Letter we report
selective ion recognition features of 1,3-di-derivative of calix[4]ar-
ene containing a bis-(2-picolyl)amine moiety at its lower rim con-
nected by an amide linkage toward Cu(II).
2
+
intensity of L with Cu (Fig. 1b and c) was found though the satu-
ration was found around 5–6 equiv. The observed enhancement in
the fluorescence intensity can be explained to the reversal of PET
The receptor molecule, L, viz., 5,11,17,23-tert-butyl-25,27-bis-
(
(N,N-bis(pyridine-2-yl)methylamine)carbonylmethoxy)-26,28-
9
2+
dihydroxycalix[4]arene, was synthesized by four known steps
starting from p-tert-butyl calix[4]arene (Scheme 1, SI 01). All
the molecules including L were characterized satisfactorily by
when Cu binds to the nitrogens of pyridyl moieties. The binding
constant of L with Cu was calculated by Benesi–Hildebrand equa-
tion and the corresponding association constant, K was found to
be 17,547 ± 1000 and 30,221 ± 1600 M , respectively, in methanol
and 1:1 aqueous methanol. The quantum yield of L and its complex
with Cu were found to be 0.0118 and 0.0559 in methanol and
2
+
a
ꢁ1
*
Corresponding author. Tel.: +91 22 2576 7162; Fax: +91 22 2572 3480.
2
+
E-mail address: cprao@iitb.ac.in (C.P. Rao).
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.109

2
736
R. Joseph et al. / Tetrahedron Letters 50 (2009) 2735–2739
N
N
N N
EtO
OEt
HO
OH
Cl
Cl
N
N
O
O
O
O
O
O
O
O
OH OH OH OH
O
OH OH O
O
OH OH O
O
OH OH O
O
OH OH O
b
c
d
a
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
2
3
4
L
1
Scheme 1. Synthesis of lower rim calix[4]arene-1,3-di-derivatives, L: (a) bromoethylacetate/K
picolyl)amine/Et N/THF. R = tert butyl.
2
3
CO /acetone; (b) NaOH/C
2
H
5 2
OH, reflux; (c) SOCl /benzene, reflux; (d) bis(2-
3
(
a)
(b)
(c)
7
6
5
4
3
2
1
00
00
00
00
00
00
00
0
12
10
8
1
2
0
8
6
4
2
0
1
6
4
2
0
-2
-4
N
a
K
C
a
M
g
M
n
F
e
Co
N
i
C
n
3
00 320 340 360 380 400
0
2
4
6
+
8
10
2
Wavelength, nm
[Cu ]/[L]
2+
Figure 1. Fluorescence titration of L with different metal ions: (a) Spectral traces during the titration of L with Cu in methanol, (b) plot of relative fluorescence intensity
2
+
versus number of equivalents of Cu added in methanol (unfilled) and in 1:1 aqueous methanol (filled) and (c) histogram representing the fluorescence enhancement and
quenching fold exhibited by L with different metal ions studied in methanol (unfilled) and in 1:1 aqueous methanol (filled).
0
.0127 and 0.0980 in aqueous methanol with respect to naphtha-
which L can detect Cu2+ has been found to be 196 ppb in methanol
and 341 ppb in aqueous methanol (SI 04).
lene as standard.
In order to support the binding of L by Cu2+, absorption titra-
tions were carried out. The spectral changes were suggestive of
The competition of Cu toward L against other metal ions has
2+
n+
been explored by titrating a solution containing L and M in
2
+
+
+
2+
2+
binding of Cu with L (Fig. 2). Absorption spectra recorded at high-
er concentrations exhibited a d–d transition band at 655 nm which
also demonstrates the interaction of ligand with metal ion (Fig. 2a,
inset, SI 03). Plot of absorbance versus added [Cu2 ] clearly indi-
cated the formation of the complex (Fig. 3a) and the complex
formed was found to be 1:1 based on Job’s plot (Fig. 3b) in both
the solvent systems.
1:30 ratio in the case of Na , K , Ca , Mg and 1:5 ratio in the case
2
+
2+
2+
2+
2+
2+
of Mn , Fe , Co , Ni , Zn with Cu of different concentrations.
These studies resulted in no significant change in the fluorescence
+
2+
intensity observed with the {L+Cu } species and thereby revealed
that the Cu could replace M . This clearly conforms to the strong
binding nature of L toward Cu in the presence of other M ions
(Fig. 4).
2
+
n+
2
+
n+
The 1:1 stoichiometry of the complex has been further sup-
ported based on the molecular ion peak observed at m/z value of
The role of calix[4]arene platform and the pre-organized nitro-
gen core in the recognition process has been proven by studying
1
189 in ESI MS titration (Fig. 3c). The isotopic peak pattern pro-
fluorescence properties of the reference molecules (Fig. 5), viz., L
1
11
vides an unambiguous assignment to this peak by confirming the
presence of Cu in the complex. The minimum concentration at
and L
2
with different metal ions. The control molecule L
1
possess-
2
+
ing the calixarene moiety has been prepared by the same method
0
0
0
0
0
0
0
.6
.5
.4
.3
.2
.1
.0
(
a) 0.06
(b)
0.4
0
0
0
.04
.02
0
.3
0.2
.1
0.0
.00
5
00
600
700
800
0
2
40
270
300
330
240
270
300
330
Wavelength, nm
Wavelength, nm
Figure 2. Absorption spectral titration of L with Cu2+: (a) spectral traces observed during the titration in the region 230–350 nm, inset shows the spectral traces in the region
00–800 nm as measured at a higher concentration in methanol and (b) spectral traces observed in aqueous methanol medium.
5

R. Joseph et al. / Tetrahedron Letters 50 (2009) 2735–2739
2737
(c)
(
a)
(b)
0
0
0
0
0
0
0
.28
.24
.20
.16
.12
.08
.04
0
.16
255 nm
2
2
85 nm
48 nm
0.12
0.08
285 nm
0
0
.04
.00
0
1
2
3
4
5
6
0.0 0.2 0.4 0.6 0.8 1.0
2
+
nm
[Cu ]/[L]
Figure 3. (a) Absorbance versus mole ratio of [Cu2+]/[L] added in methanol (unfilled) and in 1:1 aqueous methanol (filled), (b) Job’s plot of n
versus A ꢂ n
, where n
is mole
m
m
m
fraction of the metal ion added and A is absorbance as studied in methanol (unfilled) and aqueous methanol (filled) and (c) Molecular ion peak indicating the isotopic peak
pattern for the Cu2 complex of L as obtained from ESI mass spectrum.
+
1
1
2
0
8
6
4
2
0
that has been discussed for L by coupling diacid chloride derivative
of calix[4]arene, 4, with 2-aminomethyl pyridine. On the other
1
1,12
hand, L
2
, a molecular system that has only one strand of L
without any calixarene platform, has been synthesized by using
p-tert-butyl phenol as starting material instead of calix[4]arene
(
SI 01).
The structural features of the control molecule L
1
has already
1
contains a methyl pyridine moiety in-
1
2
been reported by us. The L
stead of two pyridine moieties that were present in L. The role of
2+
N
a
K
C
a
M
g
M
n
Fe
C
o
N
i
Cu
Z
n
calix[4]arene platform in the selective binding of Cu with L has
been further established by studying the metal ion binding proper-
ties of L
2 1
. The fluorescence titration studies of L showed no selec-
2
+
Figure 4. Relative fluorescence intensity of L upon the addition of 3 equiv of Cu in
2+
2+
2+
tivity toward any metal ions, while Fe , Zn , and Cu exhibited a
fluorescence quenching (Fig. 6a). Though Cu exhibited a minimal
fluorescence quenching of 2.8 fold, such minimal response is not
the presence of 30 equiv of Na , K , Ca , and Mg and 5 equiv of Mn , Fe , Co2+
Ni , and Zn , carried out in methanol (unfilled) and in 1:1 aqueous methanol
+
+
2+
2+
2+
2+
,
2
+
2+
2+
(
filled).
n+
sufficient enough to detect a particular M ion and hence reflects
on the lack of pre-organized binding core. The lack of calix[4]arene
platform makes L a non-selective molecule toward all the metal
2
ions studied (Fig. 6b). The results obtained from the control mole-
cules suggest that a pre-organized hetero core is required for Cu2+
binding. However, L contains two picolyl moieties and a calixarene
platform that makes it suitable for selective binding.
N
N
O
N
N
NH
NH
N
In order to understand the structural features of the 1:1 com-
O
O
2
+
O
plex formed between L and Cu , computational calculations were
carried out at HF/3-21G followed by HF/6-31G levels using GAUSSIAN
O
OH OH O
13
0
3
package. The computations were initiated by taking the coor-
1
4
dinates of L from its crystal structure and by replacing the tert-
0
0
butyl moiety by a hydrogen atom to result in L . The L has been
optimized at both HF/3-21G and HF/6-31G before carrying out
the computation for the complex (SI 05.). Even the DFT level com-
putations carried out with 6-31G basis set exhibited same confor-
mation as that obtained at HF/6-31G level. Computations for the
complex species have been initiated by placing the Cu2+ at a
non-interacting distance that is well above the pyridyl core of
R
R
R
R
R
L
1
L
2
Figure 5. Schematic structures of the control molecules L
1
2
and L . R = tert butyl.
(
a)
(b)
1.0
1.0
0.8
0.6
0.4
0.2
0.0
0.8
0.6
0.4
0.2
0.0
0
2
4
6
8
10
0
2
4
6
8
10
n+
n+
[
M
]/[L1]
[M ]/[L2]
0 1 2
Figure 6. Plots of (I/I ) as a function of metal to the ligand mole ratio during the fluorescence titration in methanol, (a) L , (b) L ;
. The symbols corresponds to j = Mn2+
= Fe2 ; N = Co ; . = Ni ;J = Cu ; I = Zn ; ꢀ = Na ; s = K ; h = Ca ; d = Mg
.
+
2+
2+
2+
2+
+
+
2+
2+
4

2
738
R. Joseph et al. / Tetrahedron Letters 50 (2009) 2735–2739
Figure 7. HF/6-31G optimized structure of (a) L and (b) [CuL ]2+; (c) Cu2+ coordination site as in (b), and (d) Cu2+ coordination site from plastocyanin (PDB id: 1BXU).
0
0
2
+
Coordination core angles in (°) for Cu in (c): N1–Cu–N2 = 89.8; N1–Cu–N3 = 92.1; N1–Cu–N4 = 128.4; N2–Cu–N3 = 128.4; N2–Cu–N4 = 127.2 and N3–Cu–N4 = 89.8.
Coordination core angles in (°) for Cu in (d): N1–Cu–N2 = 101.4; N1–Cu–S = 98.8; N1–Cu–S = 121.4; N2–Cu–S = 86.0; N2–Cu–S = 131.0 and S –Cu–S = 107.7.
M C M C M C
2
+
the derivative and optimized at HF/3-21G level and the output
from this has been taken through HF/6-31G. Based on these calcu-
lations it has been found that the formation of the complex has
been accompanied by an energy stabilization of ꢁ422.8 kcal/mol
ied. Fluorescence titration of L with Cu2+ has been found to be stoi-
chiometric and the observed enhancement provided a handle for
the detection and quantification of this ion by L even in aqueous
solutions. Convincing evidences were provided for the determina-
tion of the stoichiometry of the complex based on absorption and
ESI MS and the complex has been found to be 1:1 between L and
at HF/6-31G. The optimization brought the N
4
core of the pyridyl
0
moieties in L into the coordination range (Fig. 7a and b) and re-
sulted in a tetra-coordinated Cu2 center where all the four pyridyl
moieties were involved in binding. The coordination of Cu2+ center
is highly distorted tetrahedral where the angles range from 89° to
+
2+
Cu . Based on the studies of the competitive metal ion titration,
2+
it is possible to conclude that Cu can be sensed even in the pres-
ence of some biologically relevant ions in aqueous solutions. Both
the calix[4]arene platform and the pyridyl binding core are
1
28° that is very much similar to that observed for the same in blue
2
+
copper proteins, viz., plastocyanin (Fig. 7c and d). Such highly dis-
torted tetrahedral center observed for Cu2 in blue copper proteins
has been interpreted to the ease with which the protein could ful-
fill the coordination requirement for Cu1 during the electron
transfer process.
required for selective recognition of Cu , as established upon com-
paring the results obtained with the relevant control molecules.
+
2
+
The computationally obtained structure for Cu complex exhib-
ited a tetra-coordinated geometry that was found even in the blue
copper protein, viz., plastocyanin. The structural differences
observed in SEM and AFM are good enough to differentiate the
+
Further, in order to confirm the structural changes that exist at
nano level between the receptor L and its Cu2 complex, studies
were carried out by scanning electron microscopy (SEM) and atom-
+
2+
receptor from its complex with Cu . Thus the selective recognition
2
+
of Cu by L has been demonstrated by a more variety of methods
than the corresponding upper rim based quinoline derivative that
ic force microscopy (AFM). While L shows rod-like structure of
m, its Cu2 complex shows a smooth
+
appeared in the literature recently.
7
length varying from 4 to 20
l
surface of smaller particles (1–2
l
m) of irregular shape though
these are approximately closer to spherical ones (SI 06). AFM of L
shows spherical particles of three different sizes (Fig. 8). While
the smallest one has a size of 37 nm and a height of 4 nm, the
medium- and large-sized particles are exactly double and triple
to this, respectively, indicating that the smallest unit shows little
Acknowledgments
C.P.R. acknowledges the financial support by DST, CSIR and
BRNS-DAE. R.J. thanks UGC and A.A. thanks CSIR for SRF. The
authors thank SAIF, IIT Bombay for ESI MS data and also IIT Bombay
for AFM (DST-FIST, Department of Physics) and SEM (at MEMS)
facilities.
2
+
aggregation. However, this aggregation is severe in the Cu com-
plex of L leading to the formation of large-sized clusters with size
+
>
250 nm and height >35 nm. Thus L and its Cu2 complex are
distinguishable based on their SEM and AFM features.
In this Letter, we demonstrate the synthesis and characteriza-
tion of a receptor molecule L and its selective binding ability
References and notes
2
+
1. Mertz, W. Science 1981, 213, 1332.
toward Cu by switch-on fluorescence, among the ten metal ions,
2.
(a) Frausto da Silva, J. J. R.; Williams, R. J. P. The Biological Chemistry of the
Elements: The Inorganic Chemistry of Life; Clarendon Press: Oxford, 1991; (b)
Lonnerdal, B. Am. J. Clin. Nutr. 1996, 63, 821S; (c) Linder, M. C.; Hazegh-Azam,
M. Am. J. Clin. Nutr. 1996, 63, 797S.
viz., Mn2+, Fe2+, Co , Ni , Zn , Cu , Na , K , Ca , and Mg stud-
2+
2+
2+
2+
+
+
2+
2+
3.
(a) Solomon, E. I.; Chen, P.; Metz, M.; Lee, S.-K.; Palmer, A. E. Angew. Chem., Int.
Ed. 2001, 40, 4570; (b) Mirica, L. M.; Ottenwaelder, X.; Stack, T. D. P. Chem. Rev.
2004, 104, 1013; (c) Klinman, J. P. Chem. Rev. 1996, 96, 2541; (d) Roat-Malone,
R. Bioinorganic chemistry: a short course; John Wiley & Sons: Hoboken, New
Jersey, 2002.
4
.
.
(a) Pang, Y.; MacIntosh, D. L.; Ryan, P. B. J. Nutr. 2001, 131, 2171; (b) Scheinberg,
I. H.; Sternlieb, I. Am. J. Clin. Nutr. 1996, 63, 842S; (c) Harris, Z. L.; Gitlin, J. D. Am.
J. Clin. Nutr. 1996, 63, 836S; (d) Olivares, M.; Uauy, R. Am. J. Clin. Nutr. 1996, 63,
846S; (e) Wu, J.; Ricker, M.; Muench, J. J. Am. Board. Fam. Med. 2006, 19, 191; (f)
Kumar, N. Mayo. Clin. Proc. 2006, 81, 1371.
(a) Gutsche, C. D. Calixarenes; Royal Society of Chemistry: Cambridge, U.K.,
5
1
989; (b) Mandolini, L.; Ungaro, R. Calixarenes in Action; Imperial College Press:
Figure 8. AFM images of (a) L and (b) Cu2+ complex of L.
London, 2000.

R. Joseph et al. / Tetrahedron Letters 50 (2009) 2735–2739
2739
6
.
(a) Lee, J. Y.; Kim, S. K.; Jung, J. H.; Kim, J. S. J. Org. Chem. 2005, 70, 1463; (b) Ho,
I.-T.; Lee, G.-H.; Chung, W.-S. J. Org. Chem. 2007, 72, 2434; (c) Chang, K.-C.; Su,
I.-H.; Leeb, G.-H.; Chung, W.-S. Tetrahedron Lett. 2007, 48, 7274; (d) Kim, J. S.;
Quang, D. T. Chem. Rev. 2007, 107, 3780; (e) de Silva, A. P.; Gunaratne, H. Q. N.;
Gunnlaugsson, T.; Huxley, A. J. M.; McCoy, C. P.; Rademacher, J. T.; Rice, T. E.
Chem. Rev. 1997, 97, 1515; (f) Ji, H.-F.; Brown, G. M.; Dabestani, R. Chem.
Commun. 1999, 609; (g) Leray, I.; O’Reilly, F.; Habib Jiwan, J.-L.; Soumillionb, J.-
Ph.; Valeur, B. Chem. Commun. 1999, 795; (h) Bodenant, B.; Weil, T.; Businelli-
Pourcel, M.; Fages, F.; Barbe, B.; Pianet, I.; Laguerre, M. J. Org. Chem. 1999, 64,
V.; Ferguson, G.; Gallagher, J. F.; Lough, A. J.; McKervey, M. A.; Madigan, E.;
Moran, M. B.; Phillips, J.; Williams, G. J. Chem. Soc., Perkin Trans. 1 1993, 1521.
10. Yield (35%, 0.52 g) C72
H
N
82 6
O
6
(1127.50): Anal. (% found) C, 75.18; H, 7.34; N,
7.34, C72
cm ): 1641 (
1.27 (s, 18H, C(CH
H
82
N
m
6
O
6
. C
C@O), 3394 (
), 3.27 (d, 4H, Ar-CH
Ar, J = 13.14 Hz), 4.71, 4.94 (s, 8H, NCH ), 4.97 (s, 4H, OCH
2 5
H OH (% requires) C, 75.71; H, 7.56; N, 7.16). FTIR: (KBr,
ꢁ
1
1
m
OH). H NMR: (CDCl
-Ar, J = 13.14 Hz), 4.34 (d, 4H, Ar-CH
), 6.76 (s, 4H, Ar-H),
3 3 3
, d ppm): 0.93 (s, 18H, C(CH ) ),
3
)
3
2
2
-
2
2
7.02 (s, 4H, Ar-H), 7.04 (t, 2H, Py-H, J = 6.40 Hz), 7.13 (t, 2H, Py-H, J = 6.42 Hz),
7.25–7.27 (m, 2H, Py-H), 7.40 (d, 2H, Py-H, J = 7.90 Hz), 7.51–7.58 (m, 6H, Py-H
and OH), 8.41 (d, 2H, Py-H, J = 4.88 Hz) 8.52 (d, 2H, Py-H, J = 4.88 Hz). 13C NMR:
7
034; (i) Kim, H. J.; Bok, J. H.; Vicens, J.; Suh, I.-H.; Ko, J.; Kim, J. S. Tetrahedron
Lett. 2005, 46, 8765; (j) Métivier, R.; Leray, I.; Valeur, B. Chem. Commun. 2003,
96; (k) Metivier, R.; Leray, I.; Valeur, B. Chem. Eur. J. 2004, 10, 4480; (l) Kim, S.
(CDCl
(C(CH
3
, 100 MHz d ppm): 31.1, 31.8 (C(CH
3 3 2
) ), 31.9 (Ar-CH -Ar), 33.9, 34.0
9
3
)
3
), 51.4, 52.2 (NCH2), 74.5 (OCH CO), 122.2, 122.25, 122.5, 125.1, 125.7,
2
K.; Kim, S. H.; Kim, H. J.; Lee, S. H.; Lee, S. W.; Ko, J.; Bartsch, R. A.; Kim, J. S.
Inorg. Chem. 2005, 44, 7866; (m) Kim, J. S.; Kim, H. J.; Kim, H. M.; Kim, S. H.; Lee,
J. W.; Kim, S. K.; Cho, B. R. J. Org. Chem. 2006, 71, 8016; (n) Buie, N. M.; Talanov,
V. S.; Butcher, R. J.; Talanova, G. G. Inorg. Chem. 2008, 47, 3549; (o) Bu, J.-H.;
Zheng, Q.-Y.; Chen, C.-F.; Huang, Z.-T. Org. Lett. 2004, 6, 3301; (p) Kim, H. J.;
Kim, S. K.; Lee, J. Y.; Kim, J. S. J. Org. Chem. 2006, 71, 6611; (q) Schazmann, B.;
Alhashimy, N.; Diamond, D. J. Am. Chem. Soc. 2006, 128, 8607; (r) Miao, R.;
Zheng, Q.-Y.; Chen, C.-F.; Huang, Z.-T. Tetrahedron Lett. 2004, 45, 4959; (s) Beer,
P. D.; Drew, M. G. B.; Hesek, D.; Shadea, M.; Szemes, F. Chem. Commun. 1996,
127.9, 132.7, 136.7, 136.9, 141.3, 147.3, 148.9, 149.9, 150.8, 156.4, 157.3 (Py-C
and calix-Ar-C), 169.2 (C@O). m/z (ES-MS) 1127.78 ([M]+ 70%), 1128.80
+
([M+H] 40%,).
11. Joseph, R.; Ramanujam, B.; Acharya, A.; Khutia, A.; Rao, C. P. J. Org. Chem. 2008,
73, 5745.
12. Yield (43%, 0.40 g) C24
11.20, C24 (% requires) C, 74.00; H, 6.98; N, 10.78). FTIR: (KBr, cm ):
1660 ( , d ppm): 1.21 (s, 9H, C(CH ), 4.68 (d, 4H, NCH
C@O. 1H NMR: (CDCl
J = 8.55 Hz), 4.88 (s, 2H, OCH ), 6.79 (d, 2H, Ar-H, J = 9.17 Hz), 7.08 (t, 1H, Py-H,
H N O (389.48): Anal. (% found) C, 73.80; H, 6.89; N,
27 3 2
ꢁ
1
27 3 2
H N O
m
3
)
3 3
2
,
2
2
161; (t) Zheng, Y.-S.; Zhang, C. Org. Lett. 2004, 6, 1189; (u) Liu, S.-Y.; He, Y.-B.;
Wu, J.-L.; Wei, L.-H.; Qin, H.-J.; Meng, L.-Z.; Hu, L. Org. Biomol. Chem. 2004, 2,
582.
J = 5.04 Hz), 7.13 (t, 2H, Py-H, J = 6.87 Hz), 7.16–7.21 (m, 3H, Ar-H and Py-H),
7.50 (t, 1H, Py-H, J = 7.63 Hz), 7.55 (t, 1H, Py-H, J = 7.79 Hz), 8.40 (d, 1H, Py-H,
1
J = 6.42 Hz), 8.50 (d, 1H, Py-H, J = 5.81 Hz). 13C NMR: (CDCl
3
, 100 MHz d ppm):
), 51.5, 52.4 (NCH2), 67.6 (OCH ), 114.3, 121.7,
7
8
.
.
Li, G.-Ke.; Xu, Z.-X.; Chen, C.-F.; Huang, Z.-T. Chem. Commun. 2008, 1774.
(a) Bodenant, B.; Weil, T.; Businelli-Pourcel, M.; Fages, F.; Barbe, B.; Pianet, I.;
Laguerr, M. J. Org. Chem. 1999, 64, 7034; (b) Liu, J.-M.; Zheng, Q.-Y.; Yang, J.-L.;
Chen, C.-F.; Huang, Z.-T. Tetrahedron Lett. 2002, 43, 9209; (c) Cao, Y.-D.; Zheng,
Q.-Y.; Chen, C.-F.; Huang, Z.-T. Tetrahedron Lett. 2003, 44, 4751; (d) Chang, K.-C.;
Luo, L.-Y.; Diau, E. W.-G.; Chung, W.-S. Tetrahedron Lett. 2008, 49, 5013; (e)
Quang, D. T.; Jung, H. S.; Yoon, J. H.; Lee, S. Y.; Kim, J. S. Bull. Korean Chem. Soc.
31.6 (C(CH
3 3
) ), 34.2 (C(CH
)
3 3
2
122.5, 122.7, 126.8, 126.3, 136.8, 144.2, 149.2, 150.0, 155.9, 156.3, 157.1 (Ar-C
+
and Py-C) 169.4 (C@O). m/z (ES-MS) 390.16 ([M+H] 100%).
13. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H.P.; Cross, J.B.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz,
J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. GAUSSIAN 03,
Revision C.02; Gaussian: Wallingford, CT, 2004.
2
1
007, 28, 682; (f) Liang, Z.; Liu, Z.; Jiangc, L.; Gao, Y. Tetrahedron Lett. 2007, 48,
629; (g) Xu, Z.; Kim, S.; Kim, H. N.; Han, S. J.; Lee, C.; Kim, J. S.; Qian, X.; Yoon, J.
Tetrahedron Lett. 2007, 48, 9151; (h) Kumar, R.; Bhalla, V.; Kumar, M.
Tetrahedron 2008, 64, 8095; (i) Bhalla, V.; Kumar, R.; Kumar, M.; Dhir, A.
Tetrahedron 2007, 63, 11153; (j) Dhir, A.; Bhalla, V.; Kumar, M. Tetrahedron Lett.
2
008, 49, 4227.
9
.
(a) Rao, P. V.; Rao, C. P.; Kolehmainen, E.; Wegelius, E. K.; Rissanen, K. Chem.
Lett. 2001, 1176; (b) Ali, A.; Salunke-Gawali, S.; Rao, C. P.; Linares, J. Inorg. Chem.
Commun. 2004, 7, 1298; (c) Kraf, D.; Loon, J.-D.; Owens, M.; Verboom, W.; Vogt,
W.; McKervey, M. A.; Boihmer, V.; Reinhoudt, D. N. Tetrahedron Lett. 1990, 31,
4
941; (d) Collins, E. M.; McKervey, M. A.; Madigan, E.; Moran, M. B.; Owens, M.;
Ferguson, G.; Harris, S. J. J. Chem. Soc., Perkin Trans. 1 1991, 3137; (e) Bohmer,
14. Joseph, R.; Rao, C. P. Unpublished crystal structure data.