New C2-symmetric 2,2′-bipyridine crown macrocycles for enantioselective recognition of amino acid derivatives

Article abstract of DOI:10.1016/j.tet.2005.06.014

A series of new C₂-symmetric 2,2′-bipyridine-contaning crown macrocycles 1-4 has been developed for enantiomeric recognition of amino acid derivatives. These new macrocycles have been showed to be strong complexing agents for primary organic ammonium salts (with K up to 4.83×10 ⁵ M^-1 and -ΔG₀ up to 32.4 kJ mol ^-1) and also useful chromophores for UV-vis titration studies. These macrocyclic hosts exhibited enantioselective binding towards the (S)-enantiomer of phenylglycine methyl ester hydrochloride (Am1) with K_(S)/K _(R) up to 2.10 (ΔΔG₀=-1.84 kJ mol ^-1) in CH₂Cl₂ with 0.25% CH₃OH. The structure-binding relationship studies showed that the aromatic subunit and the ester group of the ammonium guests are both important for good enantioselectivity. In addition, the host-guest complexes have been studied using various NMR experiments.

Full text of DOI:10.1016/j.tet.2005.06.014

Tetrahedron 61 (2005) 7924–7930
0
New C -symmetric 2,2 -bipyridine crown macrocycles for
2
enantioselective recognition of amino acid derivatives
a
Chi-Sing Lee, Pang-Fei Teng, Wing-Leung Wong, Hoi-Lun Kwong
a
a
a,
b
*
and Albert S. C. Chan
a
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drugs Discovery and Synthesis and Department of
Biology and Chemistry, City University of Hong Kong, Hong Kong, China
b
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis and Department of Applied
Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
Received 22 February 2005; revised 2 June 2005; accepted 7 June 2005
Available online 1 July 2005
0
Abstract—A series of new C -symmetric 2,2 -bipyridine-contaning crown macrocycles 1–4 has been developed for enantiomeric
2
recognition of amino acid derivatives. These new macrocycles have been showed to be strong complexing agents for primary organic
5
ammonium salts (with K up to 4.83!10 M and KDG up to 32.4 kJ mol ) and also useful chromophores for UV–vis titration studies.
K1
K1
0
These macrocyclic hosts exhibited enantioselective binding towards the (S)-enantiomer of phenylglycine methyl ester hydrochloride (Am1)
K1
0 2 2 3
with K(S)/K(R) up to 2.10 (DDG ZK1.84 kJ mol ) in CH Cl with 0.25% CH OH. The structure–binding relationship studies showed that
the aromatic subunit and the ester group of the ammonium guests are both important for good enantioselectivity. In addition, the host–guest
complexes have been studied using various NMR experiments.
q 2005 Elsevier Ltd. All rights reserved.
1
. Introduction
developing various types of pyridine-containing ligands for
1
2
asymmetric catalysis, we are interested in developing new
artificial receptors for enantiomeric recognition of amino
One of the most remarkable features of many biomolecules,
such as enzymes, is their abilities to distinguish enantiomers
in biological reactions. Most of the amino acids and their
derivatives, which are basic building blocks of many
biologically important molecules, are chiral. The develop-
ment of artificial receptors for these interesting compounds
becomes an important research area because it can provide
valuable information for a better understanding of the
interactions between molecules in nature. Moreover, the
studies of their recognition properties may also lead to
the development of useful molecular devices and materials
0
acid derivatives based on 2,2 -bipyridine (bpy).
Bpys have been used widely as metal chelating ligands due
to their strong chelating ability towards various metals and
1
3
ease of functionalization. For instance, the bpy–ruthenium
complexes have been studied extensively due to their
1
4
interesting photochemical and other properties. The
results of these studies had led to the development of
1
5
various types of bpy–ruthenium complexes-based sensors.
In contrast, the study of the interaction between bpy-
1
6
1
,2
3
containing macrocycles and organic cationic substrates
remains an unexplored area. Herein, we report the synthesis
of a series of new bpy crown macrocycles (Fig. 1), and the
study of their enantiomeric recognition properties towards
amino acid derivatives and chiral organic ammonium salts.
in biochemical and pharmaceutical studies, separation
processes, catalysis and sensing.
4
5
6
In the passed decade, chiral pyridine-containing macro-
cycles have been an attractive research area due to their
ability of chiral discrimination towards organic ammonium
7
–11
salts and the amino acid derivatives.
The pyridine
2. Results and discussion
subunit of these macrocycles were reported to be important
for the tripod hydrogen bonding formation with the primary
ammonium salts and the p–p interaction with the aromatic
2
.1. Preparation of new chiral bpy crown macrocycles
7
moiety of the ammonium guests. Since, we have been
Bpy crown macrocycles 1–4 could be readily prepared via
the two-step one-pot protocol shown in Scheme 1, which
Keywords: Amino acid derivatives; Macrocyclic hosts; Enantioselectivity.
*
0
17
involved deprotonation of (R,R)-6,6 -bipyridinediol 5
followed by cyclization with the appropriate ethyl glycol
Corresponding author. Tel.: C852 2788 7304; fax: C852 2788 7406;
e-mail: bhhoik@cityu.edu.hk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.014

C.-S. Lee et al. / Tetrahedron 61 (2005) 7924–7930
7925
Figure 1. Chiral bpy crown macrocycles 1–4 (hosts) and chiral organic ammonium salts Am1–Am7 (guests).
Scheme 1. Synthesis of chiral bpy crown macrocycles 1–4.
ditosylate (6–9). To determine the optimal conditions for the
cyclization process, reaction of diol 5 with triethylene
glycol ditosylate (6) was first investigated using potassium
hydride in THF under high dilution conditions. Since bpy
crown macrocycle 1 contains a pseudo 18-crown-6 frame
work, the presence of potassium ions was expected to give
high dilution conditions to afford the desired chiral bpy
crown macrocycles 2–4 in 17–40% isolated yields
(Scheme 1). The structures of this new series of bpy
crown macrocycles were characterized using the same
methods as 1. However, reaction between 5 and di(ethylene
glycol)ditosylate gave only trace amounts of the expected
cyclization product. This poor result may be due to the high
ring strain of the bipyridino-15-crown-5 structure of the
cyclization product.
1
8
the optimal template effect on the cyclization process.
After 2 days stirring at room temperature, diol 5 was
consumed and the MS-ESI analysis of the crude product
mixture shows the formation of the bpy crown macrocycle.
However, only 15% of the cyclization product (1) was
isolated. Bpy crown macrocycle 1 was characterized
unambiguously by elemental analysis, MS-ESI and NMR
2.2. Enantiomeric recognition studies using UV–vis
method
1
13
experiments. The H and C NMR spectra of 1 show only
one set of signals for the two pyridine rings of the bpy
subunit and a singlet for the two t-butyl groups, which
With the new macrocyclic hosts prepared, we first examined
the binding properties of bpy crown macrocycle 1 towards
(R)-(K)-2-phenylglycine methyl ester hydrochloride ((R)-
Am1 in Fig. 1) using the UV–vis titration method. The
indicate that the C -symmetry of bpy diol 5 is unaffected
2
after the incorporation of the crown moiety. Moreover, the
signals corresponding to the ethylene glycol units are also
well resolved, which suggested that the bpy crown
macrocycle is well accommodated in the pseudo 18-
crown-16 frame work.
concentration of the macrocyclic host was fixed at 2.5!
M in CH Cl with 0.25% of CH OH because of the
2 2 3
K5
10
solubility of the guest. The UVKvis signals with the guest
concentration varied from 0 to 6!10 M were then
observed. As shown in Figure 2, the absorption peak at
K5
The cyclization protocol was then investigated using
sodium hydride under the same reaction conditions.
Surprisingly, these conditions afforded the cyclization
product in a much higher isolated yield (35%). These
results suggested that the template effect of alkaline metal
ion may not be effective in this system, due to the rigid bpy
subunit of the macrocycle. In addition, the solvent effect had
also been studied. Cyclization using NaH in DMF under the
high dilution condition gave a similar yield of 1 (33%) in
2 days. However, switching to DMSO resulted in only trace
amounts of the cyclization product with 56% of diol 5
recovered under the same conditions.
After optimizing the cyclization conditions, diol 5 was
deprotonated using sodium hydride in THF followed by
treatment of the corresponding ditosylate (7–9) under the
Figure 2. UV–vis titration of 1 with (R)-Am1 at 298 K in CH
2
Cl
OH: [1]Z2.5!10 M and [(R)-Am1]Z0, 0.5, 1,
1.5, 3, 4.5, 6!10 M.
2
K5
containing 0.25% CH
3
K5

7926
C.-S. Lee et al. / Tetrahedron 61 (2005) 7924–7930
2
98 nm for 1 decreased gradually upon addition of the guest
The equilibrium binding constant (K) was estimated using
Eq. 1, where A and A are the absorbance of the inclusion
and a new absorption peak for the inclusion complex started
to appear at 320 nm forming the isosbestic point at 305 nm.
In contrast, binding studies using dimethylether of 5 led to
only small and irregular change in the UV spectrum. This
result indicated that the crown portion of the macrocycle
is essential for binding. The Job’s plot based on the
absorbance at 320 nm supported the 1:1 stoichiometry of
the host–guest complex (Fig. 3).
0
complex at lmaxZ320 nm with concentration of free AmZ
[Am] and 0, respectively, 3 and 3 are the molar absorption
i
0
coefficients for the free and Am-bound bpy macrocycle at
lmaxZ320 nm, respectively. Since the assumption of [Am]i
being equal to the total concentration of Am is not adequate
in our system, the values of [Am] were calculated using the
i
1
Taylor’s series approximation. The plot of A /(A KA)
9
0
0
against 1/[Am] showed good linear relationship with RZ
i
0
binding constants were determined by the ratio of
.998 for (R)-Am1 (Fig. 4) and 0.992 for (S)-Am1. The
2
0
y-intercept to the slope, which gave K( Z9.86G0.77!
R)
K1
4
0 M
K1
4
1 and K Z20.7G1.29!10 M . These equi-
librium binding constants are considered to be large among
the analogous pyridine-containing crown macrocycles.
(S)
7
,8
To study the effect on the cavity size of the macrocyclic
hosts, the binding properties of bpy crown macrocycles 2–4
towards Am1 were studied using the same UV–vis titration
method. As shown in Table 1, all the bpy crown
macrocycles showed enantioselectivity towards (S)-Am1
regardless of the cavity size of the macrocycles. Bpy crown
macrocycle 1 showed the best enantiomeric recognition
2 2
Figure 3. Job’s plot of bpy crown macrocycle 1 and (R)-Am1 in CH Cl
K5
ability towards Am1 with K /K equals 2.1 (DDG Z
(S) (R) 0
K1
containing 0.25% CH
3
OH at 298 K with [1]C[(R)-Am1]Z5.0!10 M.
K1.84 kJ mol ). The high enantioselectivity of 1 might
due to its pseudo 18-crown-6 frame work, which seems to
provide a good environment for hydrogen bonding and p–p
ꢀ
ꢁ
7
interaction with the guest molecule.
A0
30
1
Z
1 C
(1)
A0 KA 30 K3
K½Amꢀi
After optimizing the cavity size of the macrocyclic host, the
effect on the structure of the ammonium guest was then
investigated. A number of amino acid derivatives and chiral
organic ammonium salts were submitted for the enantio-
meric recognition studies with bpy crown macrocycle 1 and
the results were summarized in Table 2. Generally, the
ammonium guests containing an aromatic side-chain
exhibited higher enantioselectivity than those containing
an alkyl side-chain. The ammonium guest bearing a phenyl
side-chain (Am1) showed the strongest binding between the
host and the guest, and it also gave the highest K(S) to K(R)
ratio (Table 2, entries 1–4). However, the benzyl derivative,
phenylalanine methyl ester hydrochloride (Am2), showed a
significantly lower enantioselectivity. These results
suggested that the extra methylene group of the benzyl
moiety in Am2 may orientate the phenyl ring of Am2 poorly
for p–p interaction with the bpy subunit of the host. In
addition, tryptophan methyl ester hydrochloride (Am3) was
Figure 4. The plot of A
0
/(AKA
binding model of bpy crown macrocycle 1 with (R)-Am1.
0
) versus 1/[Am]
i
at 320 nm based on the 1:1
Table 1. Enantiomeric recognition studies of bpy crown macrocycles 1–4 towards Am1 in CH
method
2
Cl
2
3
with 0.25% CH OH at 298 K using UV–vis titration
a
b
4
K (!10 M
K1
K1
)
c
K1
(kJ mol
Entry
Host
Guest
)
K(S)/K(R)
KDG
0
(kJ mol
DDG
0
)
R
1
2
3
4
5
6
7
8
1
1
2
2
3
3
4
4
(R)-Am1
(S)-Am1
(R)-Am1
(S)-Am1
(R)-Am1
(S)-Am1
(R)-Am1
(S)-Am1
9.9G0.8
21G1.3
7.5G0.5
12G0.6
7.6G0.6
9.7G1.6
7.8G0.8
14G1.1
29
30
28
29
28
28
28
29
0.998
0.992
0.996
0.998
0.997
0.986
0.991
0.992
2.1
1.6
1.3
1.8
K1.9
K1.2
K0.6
K1.4
a
K5
K3
The concentration of the hosts: 2.5!10 mol dm
Am1: 2-Phenylglycine methyl ester hydrochloride.
DDG ZKnRT ln(K(S)/K(R)).
0
.
b
c

C.-S. Lee et al. / Tetrahedron 61 (2005) 7924–7930
7927
Table 2. Enantiomeric recognition studies of bpy crown macrocycle 1 towards amino acid derivatives and chiral organic ammonium salts at 298 K using UV–
vis and NMR titration methods
a
2
K (!10 M
K1
K1
b
0
K1
(kJ mol
Entry
Method
Guest
)
K(S)/K(R)
KDG
0
(kJ mol
)
DDG
)
R
c
1
2
3
4
5
6
7
8
9
UV–vis
UV–vis
UV–vis
UV–vis
UV–vis
UV–vis
UV–vis
UV–vis
(R)-Am1
(S)-Am1
(R)-Am2
(S)-Am2
(R)-Am4
(S)-Am4
(R)-Am5
(S)-Am5
(R)-Am1
(S)-Am1
(R)-Am6
(S)-Am6
990G77
2100G130
300G42
480G41
470G37
490G66
81G9
110G9
2.7
29
30
26
27
27
27
22
23
14
17
16
16
0.998
0.992
0.996
0.998
0.998
0.995
0.993
0.988
—
c
c
c
c
c
c
c
2.1
1.6
1.0
1.3
3.7
1.1
K1.9
K1.2
K0.1
K0.8
K3.2
0.1
d
NMR
NMR
NMR
NMR
d
10
11
12
10
6.0
5.7
—
—
—
d
d
a
Am1: 2-Phenylglycine methyl ester hydrochloride; Am2: Phenylalanine methyl ester hydrochloride; Am4: Alanine methyl ester hydrochloride; Am5: Valine
methyl ester hydrochloride; Am6: (a-Phenylethyl)ammonium chloride.
b
c
d
DDG
0
ZKnRT ln (K(S)/K(R)).
K5 K3
The concentration of 1 is 2.5!10 mol dm in CH
2
Cl
2
3
with 0.25% CH OH.
K3
The initial concentration of 1 is 5.1!10 M in CD
2
Cl with 10% CD
2
3
OD.
also submitted for the recognition study. However, the
equilibrium binding constant could not be determined
because of overlap between the UV signals corresponding
to the host and the guest.
2
F Z Sðdobsd Kdave
Þ
2
Z S½dobsd;i KX d Kð1 KX Þd ꢀ
(2)
f;i
f
f;i
c
Among the ammonium guests bearing alkyl side-chains,
alanine methyl ester hydrochloride (Am4) showed almost
no enantioselectivity and the more bully valine methyl ester
hydrochloride (Am5) showed slightly higher enantio-
selectivity than Am4. These results suggested that the steric
effect of the ammonium guest is important for good
enantioselectivity when no aromatic group is available for
p–p interaction. In addition, (a-phenylethyl)ammonium
chloride (Am6) and (a-(1-naphthyl)ethyl)ammonium
chloride (Am7) were used to study effect of the binding
properties without the ester subunit. Unfortunately, no new
UV signal corresponding to the host–guest complex was
observed upon addition of Am6, and the UV signals
between Am7 and the macrocyclic host 1 was found to be
overlapped.
where dobsd is the chemical shift of the bpy crown
macrocycle signal of interest and dave is the weighted
average of the same signal or the free and complexed bpy
crown macrocycle. d is the chemical shift of the same signal
f
of the free crown macrocycle and X is the mole fraction of
f
the free bpy crown macrocycle.
As shown in Table 2 entries 9–12, the equilibrium binding
constants for Am1 and Am6 observed under the NMR
conditions (10% CD OD in CD Cl ) are much smaller
3
2
2
(about 200-fold for (S)-Am1 and more than 300-fold for
(R)-Am1) than those observed under the UV–vis conditions
(0.25% CH OH in CH Cl ). To investigate this dramatic
3 2 2
effect on different methanol content, the recognition study
between 1 and Am1 was carried out in CH Cl with 10%
2
2
CH OH using the UV–vis method. These conditions also
3
2.3. Enantiomeric recognition studies using NMR
titration method
K1
K1
gave small K values (K Z3500 M and K Z1800 M ),
(S)
(R)
which is roughly in the same order of magnitude as the
results obtained by the NMR titration method. Though the
NMR study showed almost no enantioselectivity for Am6, it
showed the good binding ability of Am6 towards 1, which
was not observed by the UV–vis method. These results
suggested that the ester subunit of the ammonium guest is
important for the formation of the new UV signal for the
host–guest complex, and it is also important for the high
enantiomeric recognition ability. The equilibrium binding
constant between Am7 and 1 could not be determined due to
overlap between signals corresponding to the naphthalane
ring and the bpy moiety.
Since the binding studies with Am6 and Am7 could not be
carried out using UV–vis spectroscopic method, their
binding studies with bpy crown macrocycle 1 were then
2
1–23
carried out using the NMR titration method.
binding study with Am1 using the NMR titration method
The
was also carried out for comparison. A 10% of CD OD in
3
CD Cl solution was used due to the solubility of the
2
2
ammonium guests. The initial concentration of 1 was set to
be 5.1!10 M in order to obtain reasonable H NMR
K3
1
K3
signals and this solution was titrated with 40.5!10 M of
the ammonium guest in the same solvent system with
tetramethylsilane (TMS) as the internal standard. By using
the non-linear least squares treatment, the equilibrium
binding constants and the chemical shift of the host–guest
2.4. Characterization of the host–guest complex
The host–guest complexes were characterized using various
NMR experiments. 2D NOESY and ROESY spectra of a
roughly 1:1 mixture of 1 and (S)-Am1 in CD Cl with 5%
complex signal of interested (d ) can be calculated through
c
2
4
the minimization of the error function F (Eq. 2),
2
2

7928
C.-S. Lee et al. / Tetrahedron 61 (2005) 7924–7930
pattern for the phenyl proton signals (Fig. 6), indicating the
p-systems of 1 and (S)-Am1 are in close vicinity.
Although, the 2D NOESY and ROESY experiments showed
no correlation between 1 and (S)-Am1, the structure–
1
binding relationship studies and the H NMR spectra
strongly suggested that the presence of p–p interaction
between bpy crown macrocycle 1 and Am1. Figure 7
showed the conformations of the 1$(S)-Am1 and 1$(R)-
Am1 complexation models with the ester group and the
side-chain at the a-position pointing away from the t-butyl
group of the macrocyclic host. The 1$(S)-Am1 complexa-
tion model is considered to be more stable due to the extra
stabilization energy from the p–p interaction between the bpy
subunit of the macrocyclic host and the phenyl ring of the
ammonium guest. These transition state models seem to be
able to account for the high enantioselectivity of (S)-Am1.
Figure 5. The signals correspond to the a-protons of (G)-Am1 (5.0!
K3
10
2 2 3
M) in CD Cl with 5% CD OD with (a) no bpy crown macrocycle,
K3
and (b) bpy crown macrocycle 1 (5.0!10 M).
CD OD did not show any correlation between the phenyl
3
protons of the ammonium guest and the bpy protons of the
macrocyclic host. These results could be due to the fast
7
,23
exchange rate between the host and the guest molecules.
1
The H NMR spectrum of (G)-Am1 (with the
S)-enantiomer in slightly excess) showed a singlet signal
for the a-protons (Fig. 5a), which was spilt into two peaks
in the presence of 1 (Fig. 5b). Moreover, the H NMR
spectrum of 1$(S)-Am1 complex showed a distinct 2:3
(
3. Conclusion
1
In summary, we have developed a series of new C -sym-
2
metric bpy crown macrocycles (1–4) and studied their
enantiomeric recognition properties towards a number of
amino acid derivatives and chiral organic ammonium salts
using UV–vis and NMR methods. The macrocycles were
found to be strong chelating agents for organic ammonium
5
K1
salts (with K up to 4.8!10 M ) and useful chromophore
for UV–vis titration studies. Bpy crown macrocycle 1,
bearing the pseudo 18-crown-6 type structure, exhibited the
highest enantioselectivity towards (S)-Am1 with K /K
(
S) (R)
equals 2.1. The structure–binding relationship studies
showed that the p–p interaction between the phenyl
group of the ammonium guest and the bpy subunit of the
macrocycle host is important for high enantioselectivity.
This observation was also supported by the NMR studies of
the 1$(S)-Am1 complex. Moreover, the recognition study of
1 with Am6 suggested that the ester group of the ammonium
guests is important for both high enantioselectivity and the
new UV signal formation for the host–guest complex.
Figure 6. The signals correspond to the benzene rings of (a) (G)-Am1
alone (5.0!10 M); (b) (R)-Am1 (5.0!10 M) and (c) (S)-Am1 (5.0!
K3
K3
K3
K3
M) with bpy crown macrocycle 1 (5.0!10 M) in CD
10
2 2
Cl with 5%
CD
3
OD.
4. Experimental
4
.1. Materials and apparatus
2
,6-Bipyridinediol (5) was prepared according to the
literature procedures. AR-grade CH Cl and CH OH
1
5
2
2
3
1
were used for the UV–vis titration experiments. The H
and C NMR spectra were obtained by a 300 MHz
instrument. The 2D NOESY and ROESY spectra were
obtained by a 500 MHz instrument.
1
3
4.2. General procedures for the synthesis of ethylene
glycol ditosylate 6–9
The corresponding ethylene glycol (3.0 mmol) in dry THF
(
20 mL) was added dropwise to a vigorously stirred
suspension of NaH (0.23 g, 9.6 mmol) in dry THF (5 mL)
at 0 8C. The reaction mixture was slowly warmed and
refluxed for 4 h and then cooled to 0 8C. After addition of
tosyl chloride (1.43 g, 7.5 mmol) in dry THF (10 mL) at
0 8C, the mixture was warmed to room temperature and
Figure 7. Interactions between bpy crown macrocycle 1 with Am1.

C.-S. Lee et al. / Tetrahedron 61 (2005) 7924–7930
7929
stirred for 48 h. The reaction mixture was concentrated
under reduced pressure and the residue was treated
cautiously with water and extracted with diethyl ether
4.3.2. (R,R)-7,21-Di-tert-butyl-8,11,14,17,20-pentaoxa-
2
,6
26,27-diaza-tricyclo[20.3.1.1 ]heptacosa-1(26),2(27),
3,5,22,24-hexaene (2). The above procedures were fol-
lowed with tetra(ethylene glycol)di-p-tosylate 7. Bpy crown
macrocycle 2 was isolated as an amorphous solid (0.19 g,
(
anhydrous MgSO , filtered and concentrated. The residue
3!20 mL). The combined organic extracts were dried over
4
2
5
K1
was purified by silca gel column chromatography (petro-
leum ether/ethyl acetate) to provide the corresponding
ditosylate compound.
40%): [a]D C15.6 (c 0.5, CH Cl ); IR (neat, cm ) 2953,
2 2
1
2868, 1571, 1438, 1107; H NMR (CDCl ): d 0.99 (s, 18H),
3
2.66–2.81 (m, 2H), 2.84–3.02 (m, 4H), 3.04–3.14 (m, 2H),
3.22–3.34 (m, 2H), 3.40–3.50 (m, 2H), 3.62–3.73 (m, 2H),
4
.2.1. Tri(ethyl glycol)ditosylate (6) and penta(ethylene
glycol)ditosylate (7). Both compounds are commercially
3.87–3.99 (m, 2H), 4.32 (s, 2H), 7.41 (d, JZ7.5 Hz, 2H),
1
3
7.77 (t, JZ7.8 Hz, 2H), 8.26 (d, JZ7.2 Hz, 2H); C NMR
(CDCl ): d 26.2, 35.9, 69.0, 69.8, 71.5, 72.0, 92.5, 119.1,
22.3, 135.9, 154.7, 161.3; Positive ion MS-ESI m/z: 487
available.
3
1
C
C
C
4.2.2. Tetra(ethylene glycol)ditosylate (8). The above
procedures were followed with tetra(ethylene glycol) as the
(MH ), 509 (MCNa ), 525 (MCK ). HRMS m/z: Calcd
for C28 : 486.3094; found 486.3090.
H N O
42 2 5
starting material. The isolated yield for 8 is 1.39 g (92%):
H NMR (CDCl ): d 2.45 (s, 6H), 3.55–3.58 (m, 8H), 3.64–
1
3
4.3.3. (R,R)-7,24-Di-tert-butyl-8,11,14,17,20,23-hexaoxa-
2
,6
9,30-diaza-tricyclo[23.3.1.1 ]triaconta-1(29),2(30),
3
.70 (m, 4H), 4.11–4.17 (m, 4H), 7.34 (d, JZ8.1 Hz, 4H),
.79 (d, JZ8.7 Hz, 4H).
2
3
7
,5,25,27-hexaene (3). The above procedures were fol-
lowed with penta(ethylene glycol)di-p-tosylate 8. Bpy
crown macrocycle 3 was isolated as a pale yellow oil
4.2.3. Hexa(ethylene glycol)ditosylate (9). The above
procedures were followed with hexa(ethylene glycol) as
2
0.10 g, 19%): [a]D C19.3 (c 0.5, CH Cl ); IR (neat, cm
5
K1
(
2
)
953, 2868, 1571, 1438, 1107; H NMR (CDCl ): d 0.98 (s,
2
2
1
the starting material. The isolated yield for 9 is 1.68 g
(
3
1
95%): H NMR (CDCl ): d 2.45 (s, 6H), 3.58–3.70 (m,
3
18H), 3.13–3.82 (m, 20H), 4.34 (s, 2H), 7.44 (d, JZ7.8 Hz,
13
2
0H), 4.14–4.17 (m, 4H), 7.35 (d, JZ7.8 Hz, 4H), 7.80 (d,
2
H), 7.78 (t, JZ7.8 Hz, 2H), 8.23 (d, JZ7.8 Hz, 2H);
C
NMR (CDCl ): d 26.4, 36.0, 70.3, 70.5, 70.7, 70.9, 71.8,
JZ8.4 Hz, 4H).
3
9
2.1, 119.4, 122.4, 136.3, 154.9, 160.2; Positive ion MS-ESI
C
C
C
4.3. General procedures for the synthesis of bpy crown
macrocycle 1–4
m/z: 531 (MH ), 553 (MCNa ), 569 (MCK ). HRMS
m/z: Calcd for C H N O : 530.3356; found 530.3354.
3
0 46 2 6
To a vigorously stirred suspension of NaH (0.080 g,
4
.3.4. (R,R)-7,27-Di-tert-butyl-8,11,14,17,20,23,26-hepta-
3
.2 mmol) in dry THF (3 mL) at 0 8C was added dropwise
a solution of di-tert-butyl-2,6-bipyridinedimethanol 6
0.33 g, 1.0 mmol) in dry THF (10 mL). The resulting
2,6
oxa-32,33-diaza-tricyclo[26.3.1.1 ]tritriaconta-1(32),
(33),3,5,28,30-hexaene (4). The above procedures were
2
(
followed with hexa(ethylene glycol)di-p-tosylate 9. Bpy
crown macrocycle 5 was isolated as a pale yellow oil
mixture was stirred at 0 8C for 30 min and heated under
reflux for 2 h. The mixture was then cooled to room
temperature and treated with a solution of the corresponding
ethylene glycol di-p-tosylate (1.2 mmol) in dry THF
25
0.10 g, 17%): [a]D K46.4 (c 0.5, CH Cl ); IR (neat, cm
K1
(
)
953, 1572, 1441, 1107; H NMR (CDCl ): d 0.98 (s, 18H),
2
2
1
2
3
7
3
.37–3.65 (m, 24H), 4.29 (s, 2H), 7.44 (d, JZ7.8 Hz, 2H),
(
25 mL) dropwise. The resulting mixture was stirred at
13
.80 (d, JZ7.8 Hz, 2H), 8.26 (d, JZ7.8 Hz, 2H); C NMR
room temperature for 2–6 days. After removal of the solvent
under aspirator vacuum, the residue was treated with water
and extracted with CH Cl (3!15 mL). The combined
(CDCl ): d 26.5, 35.8, 69.7, 70.6, 70.8, 70.9, 71.2, 91.8,
3
1
19.5, 122.4, 136.6, 155.0, 160.8; positive ion MS-ESI m/z:
2
2
C
75 (M ), 597 (MCNa ), 613 (MCK ). HRMS m/z:
C
C
5
Calcd for C H N O : 574.3618; found 574.3616.
organic extracts were dried over anhydrous MgSO , filtered
4
3
2 50 2 7
and concentrated. The residue was purified by silca gel
column chromatography (petroleum ether/ethyl acetate) to
yield bpy crown macrocycle 1–4.
Acknowledgements
4
.3.1. (R,R)-7,18-Di-tert-butyl-8,11,14,17-tetraoxa-23,24-
2
,6
diaza-tricyclo[17.3.1.1 ]tetracosa-1(23),2(24),3,5,19,21-
hexaene (1). The above procedures were followed with
tri(ethylene glycol)di-p-tosylate 6. Bpy crown macrocycle 1
was isolated as an off-white solid (0.15 g, 35%): mp 142–
Financial support for this research project from the City
University of Hong Kong (SRG 7001611) and the Area of
Excellence Scheme established under the University Grants
Committee of the Hong Kong SAR, China (Project No.
AoE/P-10/01) are gratefully acknowledged.
2
5
K1
1
2
2
3
46 8C [a] K107.6 (c 0.5, CH Cl ); IR (neat, cm
)
968, 1577, 1109; H NMR (CDCl ): d 1.05 (s, 18H), 2.59–
D
2
2
1
3
.68 (m, 2H), 2.76–2.84 (m, 2H), 3.15–3.21 (m, 2H), 3.22–
.29 (m, 2H), 3.40–3.47 (m, 2H), 3.76–3.83 (m, 2H), 4.05
(
7
6
s, 2H), 7.23 (d, JZ7.8 Hz, 2H), 7.72 (t, JZ7.8 Hz, 2H),
13
.94 (d, JZ7.8 Hz, 2H); C NMR (CDCl ): d 26.4, 35.7,
References and notes
3
8.5, 70.2, 71.0, 91.2, 120.4, 123.0, 135.8, 157.3, 160.4.
Anal. Calcd for C H N O : C, 70.56; H, 8.65; N, 6.33.
6 38 2 4
1. For a review on Supramolecular Technology, see: Reinhoudt,
D. N., Ed.; Comprehensive Supramolecular Chemistry;
Pergamon: New York, 1996; Vol. 10.
2
Found: C, 70.46; H, 8.55; N, 6.49; Positive ion MS-ESI m/z:
C
43 (MH ), 465 (MCNa ), 481 (MCK ). HRMS m/z:
C
C
4
Calcd for C H N O : 442.2832; found 442.2834.
2. (a) Murakami, Y.; Kikuchi, J.-i.; Hisaeda, Y.; Hayashida, O.
2
6 38 2 4

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(
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24. The association constant (K) for 1:1 complexation can be
expressed by Eq. 3
½Cꢀ
½Cꢀ
K Z
Z
(3)
½
Hꢀ½Gꢀ ð½Hꢀ K½CꢀÞð½Gꢀ K½CꢀÞ
0
0
353–367. (i) Bradshaw, J. S.; Huszthy, P.; Redd, J. T.; Zhang,
X. X.; Wang, T.; Hathaway, J. K.; Young, J.; Izatt, R. M. Pure
Appl. Chem. 1995, 67, 691–695. (j) Wang, T.; Bradshaw, J. S.;
Huszthy, P.; Izatt, R. M. Supramol. Chem. 1995, 5, 9–13.
0 0
where [H] and [G] are the initial concentrations of the host
and guest, respectively, and [H], [G] and [C] are the
concentrations of the host, guest and complex at equilibrium,
respectively. By substitution of [C]Z[H] (1KX ) into Eq. 3,
(k) Zhang, X. X.; Izatt, R. M.; Zhu, C. Y.; Bradshaw, J. S.
Supramol. Chem. 1996, 92, 64–69. (l) Samu, E.; Huszthy, P.;
´
Horv a´ th, G.; Sz o¨ ll o˝ sy, A.; Neszm e´ lyi, A. Tetrahedron:
0
f
Xf became the unknown of the quadratic equation (Eq. 4):
ꢀ
ꢁ
1
1
Xf K Z 0
K
2
f
Asymmetry 1999, 10, 3615–3626.
0. Wong, W.-L.; Huang, K.-H.; Teng, P.-F.; Lee, C.-S.; Kwong,
H.-L. Chem. Commun. 2004, 384–385.
½
Hꢀ X C ½Gꢀ K½Hꢀ C
(4)
0
0
0
K
1
1
Therefore,
1. For references on molecular recognition studies of amino
acid derivatives using different crown macrocycles, see:
pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
2
Kð½Gꢀ K½Hꢀ C1=KÞG ð½Gꢀ K½Hꢀ C1=KÞ K4½Hꢀ ðK1=KÞ
0
0
0
0
0
Xf Z
(
a) Peacock, S. S.; Walba, D. M.; Gaeta, F. C. A.; Helgeson,
R. C.; Cram, D. J. J. Am. Chem. Soc. 1980, 102, 2043–2052.
b) Tsukube, H.; Uenishi, J.; Higaki, H.; Kikkawa, K. Chem.
2
½Hꢀ
0
(
5)
(
Since
Lett. 1992, 12, 2307–2310. (c) Badis, M.; Tomaszkiewicz, I.;
Joly, J.-P.; Rogalska, E. Langmuir 2004, 20, 6259–6267.
2. (a) Kwong, H.-L.; Lee, W.-S.; Ng, H.-F.; Chiu, W.-H.; Wong,
W.-T. J. Chem. Soc., Dalton Trans. 1998, 6, 1043–1046.
1
2
F Z Sðdobsd Kdave
Þ
(
b) Kwong, H.-L.; Lau, K.-M.; Lee, W.-S.; Wong, W.-T. New
2
J. Chem. 1999, 23, 629–632. (c) Kwong, H.-L.; Lee, W.-S.
Tetrahedron: Asymmetry 1999, 10, 3791–3801. (d) Lee, W.-S.;
Kwong, H.-L.; Chan, H.-L.; Choi, W.-W.; Ng, L.-Y.
Tetrahedron: Asymmetry 2001, 12, 1007–1013.
Z S½dobsd;i KX d Kð1 KX Þd ꢀ
(2)
f;i
f
f;i
c
c
K and d were calculated by minimization of the error function
F using a computer program developed by us.