Macrocycles with two exclusive hydrogen-bonding modes

Article abstract of DOI:10.1016/j.tetlet.2006.09.127

A series of large, 44-membered macrocycles 7a-e were synthesized and characterized, which display two different diagonal binding modes. The unsubstituted macrocycle 7a strongly binds naphthalene-2,6-dicarboxylate through hydrogen bonds with the associatio

Full text of DOI:10.1016/j.tetlet.2006.09.127

Tetrahedron Letters 47 (2006) 8217–8220
Macrocycles with two exclusive hydrogen-bonding modes
Min Kyung Chae, Geun-Young Cha and Kyu-Sung Jeong*
Center for Bioactive Molecular Hybrids and Department of Chemistry, Yonsei University, Seoul 120-749, South Korea
Received 16 August 2006; revised 21 September 2006; accepted 25 September 2006
Available online 10 October 2006
Abstract—A series of large, 44-membered macrocycles 7a–e were synthesized and characterized, which display two different diag-
onal binding modes. The unsubstituted macrocycle 7a strongly binds naphthalene-2,6-dicarboxylate through hydrogen bonds with
the association constant (Ka 15%) of 4500 Mꢀ1 in 40% (v/v) CD3CN/CDCl3 at 23 1 °C. Introduction of an electron-withdraw-
ing substituent (Cl) at all four corners increases the binding affinity (22,000 Mꢀ1 for 7b), while that of an electron-donating substi-
tuent (pyrrolidinyl) greatly decreases it (150 Mꢀ1 for 7c). The same propensity has been observed with macrocycles 7d and 7e
bearing different substituents at two diagonal corners, suggesting that the relative population of the binding modes would be
modulated by controlling the electron density of the aromatic ring.
Ó 2006 Elsevier Ltd. All rights reserved.
A large number of interlocked supermolecules such as
pseudorotaxanes and rotaxanes have been prepared in
the last decade to develop molecular-level machines,
switches and motors, etc.1 The supermolecules have
two or more distinct modes of complexation between a
macrocycle and a threading molecule, and their relative
population can be reversibly controlled by an external
stimulation. Most of the examples were derived from
the threading component bearing two different binding
sites for the macrocycle, allowing for co-conformation
switching based on the shuttling motion of the macro-
cycle. However, only limited examples of the rotaxanes
derived from the macrocycle with two different binding
sites have been reported to date possibly due to the syn-
thetic difficulty of such a macrocycle, and a representa-
tive example was described by Sauvage and co-workers.2
Herein we report the synthesis and binding properties of
macrocycles 7a–e with two different binding modes
when dicarboxylate 8 is diagonally placed inside the cav-
ity via hydrogen bonds. The relative population of two
binding modes can be controlled by varying the substit-
uents at the corners, implying that the system can be
potentially applicable to the development of (pseudo)
rotaxane-based molecular machines (Fig. 1).
Figure 1. Schematic representation of a possible molecular machine
working by rotational movement.
N(pyridine)ꢁ ꢁ ꢁHN(amide) hydrogen bonds.3 This is a
crucial feature for the efficient synthesis of large macro-
cycles, otherwise extremely challenging due to polymer-
ization. Macrocycles 7a–e were prepared in a stepwise
manner as outlined in Scheme 1. Pyridine-2,6-dicarb-
onyl dichloride (X = H or Cl) was coupled with a
BOC-protected amine 2 to yield compound 3 (92–
97%). The selective de-protection of one of the BOC
groups was carried out as follows: Compound 3 was dis-
solved in 10% (v/v) CF3CO2H/CHCl3 (approximately
0.02 M) in an iced water bath (0–5 °C), and the reaction
was quenched with 1 N aqueous NaOH solution when
the corresponding diamine was detected on thin layer
chromatography (TLC) usually in 1–2 h. After the
resulting mixture was purified, this process was repeated
twice more with the recovered 3, which gave the desired
product in total yields of 69–89%. Coupling of 4
(2 equiv) with dichloride 1 (Y = H, or Cl, 85–96%
yields), followed by de-protection (1:1 v/v CF3CO2H/
CHCl3, 90–93% yields), gave diamine 6, which was in
turn reacted with a dichloride 1 (X = H, or Cl) using a
syringe pump method to give macrocycles 7a, 7b and
For the synthesis of macrocycles 7a–e, pyridine-2,6-
dicarboxamide was selected as a building block due to
its conformational rigidity resulting from internal
*
Corresponding author. Tel.: +82 2 2123 2643; fax: +82 2 364 7050;
e-mail: ksjeong@yonsei.ac.kr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.127

8218
M. K. Chae et al. / Tetrahedron Letters 47 (2006) 8217–8220
O
X
O
H
N
NHR
X
Y
H
NHBOC
N
N
H
NH2
X
N
N
H
O
O
N
NHR
N
i
O
O
+
N
iii
O
O
O
Cl
Cl
N
NHBOC
Cl
Cl
O
N
H
H
O
2
1
NHR
N
H
N
H
N
N
Y
Y
3 R = BOC
4 R = H
ii
O
5 R = BOC
6 R = H
iv
O
O
X
Y
N
N
X
N
v
N
H
H
N
7a X = Y = H
7b X = Y = Cl
7c X = Y =
H
H
H
H
O
O
O
O
N
N
O
O
Cl
Cl
N
N
N
7d X = H, Y = Cl
7e X = H, Y =
N
N
H
N
H
N
N
Y
X
O
O
Scheme 1. Reagents and conditions: (i) NEt3, CHCl3, 0 °C to room temperature, 30 min, 92–97%; (ii) 10% (v/v) CF3CO2H/CHCl3, 0–5 °C, 1–2 h,
69–89%; (iii) NEt3, CHCl3, 0 °C to room temperature, 30 min, 85–96%; (iv) 1:1 v/v CF3CO2H/CHCl3, 90–93%; (v) NEt3, CHCl3, room temperature,
13 h, 42–83%.
7d. The yields of this final step are in the range of
42–83%, which is surprisingly high when considering
the cyclization of the 44-membered rings.4 This result is
attributed in part to the conformational restriction by
internal hydrogen bonds in the pyridine-2,6-dicarbox-
amide unit as mentioned above. Finally, pyrrolidine-
substituted ones 7c (76%) and 7e (72%) were prepared
by simply refluxing the corresponding chloro-substi-
tuted ones 7b and 7d in pyrrolidine.5
the titration curve7 gave the association constant
(Ka 20%) of 4500 Mꢀ1. A 1:1 complexation between
7a and 8 was confirmed by the continuous variation
method (Fig. 2c, inset).8 For a comparison, the associa-
tion constant of mono-carboxylate 9 with 7a was
determined to be 640 Mꢀ1 under identical titration
conditions. This result clearly suggests that the NHs at
two diagonal corners of 7a are simultaneously involved
in hydrogen bonds with 8 as shown in Figure 2 (top).
An energy-minimized structure of 7a indicates that all of
The substituent effects can be clearly seen in the binding
studies with macrocycles 7b and 7c. As shown in Table
1, an electron-withdrawing group (Cl) at the pyridyl cor-
ners of 7b increases the binding affinity (Ka 22,000 Mꢀ1),
while an electron-donating group (pyrrolidinyl) of 7c
greatly decreases it (Ka 150 Mꢀ1). This phenomenon
can be explained with repulsive interactions between
the pyridyl nitrogen and the incoming carboxylate as
suggested previously.9 The electron-withdrawing group
at the 4-position of the pyridyl corner reduces the
electron density on the nitrogen, thus decreasing the
repulsion forces and in turn the binding affinity. The
electron-donating group leads to an exactly opposite
consequence.
the amide hydrogens are directed inside the cavity with
6
˚
the diagonal distance of approximately 12 A. Bis(tetra-
butylammonium) naphthalene-2,6-dicarboxylate (8) was
selected as a guest, which has a complementary distance
between the two carboxylate groups. In addition, 8 is a
rigid molecule without any bendable bond so that two
carboxylates are oriented in an opposite direction, thus
enabling to simultaneously form hydrogen bonds with
two diagonal corner NHs of 7a.
-
-
CO2
2 N+Bu4
CO2
N+Bu4
-O2C
9
8
Finally, the binding properties of 7d and 7 e were inves-
tigated, showing two unequal binding modes resulted
from different substituents at the diagonal corners (H
vs Cl for 7d, and H vs pyrrolidinyl for 7e). The macro-
cycles 7d and 7e showed two well resolved NH signals
for the unsubstituted (H) and substituted (Cl or pyrrol-
idinyl) sides. Moreover, degrees of the complexation-
induced chemical shifts (CIS) of two NH signals are
clearly different when guest 8 was added. For example,
the NH signal at the chloro-substituted corners of 7d
The titration experiments were carried out in 40% (v/v)
CD3CN/CDCl3 at 24 1 °C, with macrocycles 7a, 7b
and 7c that have identical substituents at all four cor-
1
ners. When 8 was added, the H NMR signals for the
amide NHs of the macrocycles were characteristically
downfield shifted owing to the hydrogen bond forma-
tion. For example, the NH signals of 7a were shifted
from 9.75 to 10.47 ppm when the concentration of guest
8 gradually increased. The non-linear squares fitting of

M. K. Chae et al. / Tetrahedron Letters 47 (2006) 8217–8220
8219
O
H
O
7d or 7e + 8
N
H
-O
N
N
H
N
H
40% CD CN/CDCl
3
O
O
N
N
O
O
3
O
7a +
8
O
O
O
O
O
N
N
Y
Y
-
N
N
H
H
N
H
-O
N
H
O
N
H
H
O-
H
N
N
N
N
N
H
H
N
N
H
H
H
H
O
O
N
N
O
O
O
N
N
O
O
O
O
O
O
O
O
N
N
O
N
N
-O
H
O-
H
H
N
N
H
N
H
N
N
N
H
N
H
N
Y
Y
O
O
O
O
7d Y = Cl
30%
63%
70%
37%
7e Y =
N
Scheme 2. Relative populations of two different binding modes of
complexes between macrocycles 7d and 7e, and dicarboxylate 8 in a
40% CD3CN/CDCl3 at 24 1 °C.
try would be employed to modulate the electron density
for future application to (pseudo)rotaxane-based mole-
cular-level machines.
In conclusion, with macrocycles displaying two different
binding modes, it has been nicely demonstrated that the
relative distribution of each mode can be tuned by mod-
ulating the electron density of the pyridyl ring by intro-
ducing different substituents. The modification of this
system is underway to develop a rotaxane-based mole-
cular machine.
Figure 2. Partial 1H NMR spectra (500 MHz, 40% CD3CN/CDCl3) of
(a) 7a (1 mM) and (b) 7a (1 mM) + 8 (2 mM); here the signals marked
1
with filled circles are for aromatic hydrogens of guest 8, (c) H NMR
titration curve and a Job plot (inset) between 7a (1 mM) and 8 in 40%
CD3CN/CDCl3 at 24 1 °C.
Table 1. Association constants (Ka 20%, Mꢀ1) of 7a–c and guests, 8
and 9, in 40% CD3CN/CDCl3 at 24 1 °Ca
Acknowledgements
Host
Guest
Ka (Mꢀ1
)
dfree (NH, ppm)
dcomp (calcd)
(NH, ppm)
This work was financially supported by the Ministry
of Commerce, Industry and Energy, Korea (Project
no. 10022947) and the Center for Bioactive Molecular
Hybrids (CBMH).
7a
7a
7b
7c
8
9
8
8
4500
640
22,000
150
9.75
9.75
9.71
9.79
10.57
10.30
10.72
10.28
a The 1H NMR titration experiments were all duplicated and initial
concentration of macrocycles and guests were 0.8–1 and 5–30 mM,
respectively.
References and notes
1. For reviews, see: (a) Balzani, V.; Credi, A.; Raymo, F. M.;
Stoddart, J. F. Angew. Chem., Int. Ed. 2000, 39, 3348–
3391; (b) Harada, A. Acc. Chem. Res. 2001, 34, 456–464;
(c) Schalley, C. A.; Beizai, K.; Vo¨gtle, F. Acc. Chem. Res.
2001, 34, 465–476; (d) Collin, J.-P.; Dietrich-Buchecker,
shifted from 9.71 to 10.74 ppm, while that at the unsub-
stituted (H) corners shifted from 9.75 to 10.23 ppm
upon addition of 8 (1 equiv, ꢂ0.8 mM in a 40%
CD3CN/CDCl3) when added at room temperature. Rel-
ative population of each binding mode can be estimated
based on the CIS values and the chemical shifts of the
free and its complex (Scheme 2).10 As expected, the elec-
tron-withdrawing group (Cl) increases the population
up to 70%, but the electron-donating group (pyrrolidin-
yl) decreases it (37%) relative to the unsubstituted side,
implying that the relative population of the binding
modes would be modulated by controlling the electron
density of the aromatic ring. More practical methods
including an electrical or electrochemical redox chemis-
C.; Gavina, P.; Jimenez-Molero, M. C.; Sauvage, J.-P.
˜
Acc. Chem. Res. 2001, 34, 477–487.
2. (a) Raehm, L.; Kern, J.-M.; Sauvage, J.-P. Chem. Eur. J.
1999, 5, 3310–3317; (b) Poleschak, I.; Kern, J.-M.;
´
Sauvage, J.-P. Chem. Commun. 2004, 474–476; (c) Leti-
nois-Halbes, U.; Hanss, D.; Beierle, J. M.; Collin, J.-P.;
Sauvage, J.-P. Org. Lett. 2005, 7, 5753–5756.
3. (a) Hunter, C. A.; Purvis, D. H. Angew. Chem., Int. Ed.
Engl. 1992, 31, 792–795; (b) Jeong, K.-S.; Cho, Y. L.;
Chang, S.-Y.; Park, T.-Y.; Song, J. U. J. Org. Chem. 1999,
64, 9459–9466.
4. Representative procedure for the synthesis of macrocycle
7a: A solution of the 2,6-pyridine dicarbonyl dichloride

8220
M. K. Chae et al. / Tetrahedron Letters 47 (2006) 8217–8220
(1.16 g, 1.1 mmol) in dry CHCl3 (25 mL) and a solution of 5. Sammakia, T.; Hurley, T. B. J. Org. Chem. 2000, 65,
6 (0.22 g, 1.1 mmol) and NEt3 (0.3 mL, 2.2 mmol) in dry
CHCl3 (25 mL) were prepared separately. Two solutions
were simultaneously added via a motor driven syringe
pump to a flask containing only dry CHCl3 (800 mL) over
9 h. The reaction mixture was then stirred for additional
2–3 h. The solvent was removed under reduced pressure.
The solution was washed with saturated NaHCO3 and
brine, dried over anhydrous MgSO4 and concentrated
under reduced pressure. The residue was sequentially
washed with minimum amount of CHCl3, MeOH and
diethyl ether to give 7a (0.8 g, 82%) as a white solid.
Physical and spectroscopic properties. Compound 7a:
mp >300 °C; 1H NMR (400 MHz, CDCl3) d (ppm) 9.12 (s,
8H, NH), 8.58 (d, 8H, J = 7.6 Hz), 8.22 (t, 4H,
J = 7.6 Hz), 2.28 (s, 48H); MALD-TOF (m/z) [MH]+
calcd for C68H69N12O8 1181.54; found 1181.68.
974.
6. The modelling study was carried out using MM2* force
field implemented in MacroModel 7.1 program on a
Silicon Graphics Indigo IMPACT workstation.
7. (a) Macomber, R. S. J. Chem. Educ. 1992, 69, 375–378; (b)
Chang, S.-Y.; Jang, H.-Y.; Jeong, K.-S. Chem. Eur. J.
2003, 9, 1535–1541.
8. (a) Connors, K. A. Binding Constants; John Wiley & Sons:
New York, 1987; (b) Schneider, H.-J.; Yatsimirsky, A. K.
Principles and Methods in Supramolecular Chemistry; John
Wiley & Sons: New York, 2000.
9. Chang, S.-Y.; Kim, H. S.; Chang, K.-J.; Jeong, K.-S. Org.
Lett. 2004, 6, 181–184, and also see Ref. 3b.
10. The relative population of each binding mode was
calculated as follows. Let us assume two complexes C1
and C2 between 7d (7e) and 8.
Compound 7b: mp >300 °C; 1H NMR (400 MHz, CDCl3)
d (ppm) 9.03 (s, 8H, NH), 8.56 (s, 8H), 2.26 (s, 48H);
MALD-TOF (m/z) [MH]+ calcd for C68H65Cl4N12O8
1319.38 (three as 35Cl and one as 37Cl); found 1319.52.
Compound 7c: mp >300 °C; 1H NMR (400 MHz, CDCl3)
d (ppm) 9.28 (s, 8H, NH), 7.57 (s, 8H), 3.52 (m, 16H), 2.25
(s, 48H), 2.10 (m, 16H); MALD-TOF (m/z) [MH]+ calcd
for C84H97N16O8 1457.77; found 1457.95.
Percentage of C1 ¼ f½C1ꢃ=ð½C1ꢃ þ ½C2ꢃÞg ꢄ 100
½C1ꢃ ¼ ½Hꢃ0 ꢄ fðd1 ꢀ d1freeÞ=ðd1comp ꢀ d1freeÞg
¼ Dd1=Dd1max
½C2ꢃ ¼ ½Hꢃ0 ꢄ fðd2 ꢀ d2freeÞ=ðd2comp ꢀ d2freeÞg
¼ Dd2=Dd2max
Compound 7d: mp >300 °C; 1H NMR (400 MHz, CDCl3)
d (ppm) 9.13 (s, 2H, NH), 9.05 (s, 2H, NH), 8.59 (s, 4H),
8.57 (s, 4H), 8.56 (s, 8H), 8.23 (t, 2H, J = 7.8), 2.27 (s,
24H), 2.26 (s, 24H); MALD-TOF (m/z) [MH]+ calcd for
C68H67Cl2N12O8 1249.46; found 1249.60.
Here, [H]0 is the initial concentration of a macrocycle (7d
or 7e), and d1 and d2 are observed NH chemical shifts for
the substituted and unsubstituted sites, respectively, when
8 was added. Dd1max and Dd2max were deduced from the
Ddmaxvalues obtained with 7a, 7b and 7c in Table 1. Com-
pounds 7a, 7b and 7c have four identical pyridinedicarb-
oxamide units, only two of them being hydrogen-bonded
upon complexation. Consequently, in the calculation of
[C1] and [C2], Dd1max and Dd2max were assumed equal
to 2Ddmax. Errors in the relative population are within
2%, regardless of the amount of added guest 8.
Compound 7e: mp >300 °C; 1H NMR (400 MHz, CDCl3)
d (ppm) 9.29 (s, 4H, NH), 9.11 (s, 4H, NH), 8.57 (d, 4H,
J = 8 Hz), 8.21 (t, 2H, J = 8 Hz), 7.58 (s, 4H), 3.52
(m, 8H), 2.27 (s, 48H), 2.11 (m, 8H); MALD-TOF
(m/z) [MH]+ calcd for C76H83N14O8 1319.65; found
1319.80.