Efficient Modulation of Hydrogen-Bonding Interactions by Remote Substituents

Article abstract of DOI:10.1021/ol035954j

(Matrix presented) A series of tetralactam macrocycles having different substituents were prepared, and their binding affinities for an adipamide guest were investigated in CDCl₃ by ¹H NMR titrations. The association constants strong

Full text of DOI:10.1021/ol035954j

ORGANIC
LETTERS
2004
Vol. 6, No. 2
181-184
Efficient Modulation of
Hydrogen-Bonding Interactions by
Remote Substituents
Sung-Youn Chang, Hung Sop Kim, Kyoung-Jin Chang, and Kyu-Sung Jeong*
Center for BioactiVe Molecular Hybrids and Department of Chemistry,
Yonsei UniVersity, Seoul 120-749, S. Korea
ksjeong@yonsei.ac.kr
Received October 7, 2003
ABSTRACT
A series of tetralactam macrocycles having different substituents were prepared, and their binding affinities for an adipamide guest were
investigated in CDCl3 by 1H NMR titrations. The association constants strongly depend on the substituents, varying up to ∆∆G ) 3.4 kcal/
mol; electron-donating substituents (OMe, NMe2) decrease the binding affinity, while electron-withdrawing groups (Cl, NO ) increase it. These
2
large substituent effects have been rationalized by secondary repulsions and partial perturbations of intramolecular hydrogen bonds.
A large variety of molecular motifs1 have been developed
and utilized over the last two decades to understand
hydrogen-bonding interactions. Studies with these motifs
have revealed that the stability of the complex depends not
only on the number and type of the hydrogen bond but also
on the arrangement of hydrogen-bonding donor and acceptor
atoms. Furthermore, the strength of the hydrogen bonds can
be conveniently modulated in several ways,1,2 especially by
electrochemical oxidation and reduction as nicely demon-
strated by Rotello.2
such as rotaxanes and pseudorotaxanes.3 In the course of
our own studies with the tetralactam macrocycles derived
from pyridine-2,6-dicarboxamide scaffold,4 we found that
the affinities for dicarbonyl compounds were highly sensitive
to the substituents at the para position of the pyridine rings.
To carry out more systematic studies on the substituent
effects, eight mono- and bis-substituted tetralactam macro-
cycles 2a-d and 3a-d bearing either electron-donating groups
(3) (a) Vo¨gtle, F.; Du¨nnwald, T.; Schmidt, T. Acc. Chem. Res. 1996,
29, 451-460. (b) Schalley, C. A.; Beizai, K.; Vo¨gtle, F. Acc. Chem. Res.
2001, 34, 465-476. (c) Gatti, F. G.; Leigh, D. A.; Nepogodiev, S. A.;
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5983-5989. (d) Leigh, D. A.; Wong, J. K. Y.; Dehez, F.; Zerbetto, F. Nature
2003, 424, 174-179. (e) Altieri, A.; Gatti, F. G.; Kay, E. R.; Leigh, D. A.;
Martel, D.; Paolucci, F.; Slawin, A. M. Z.; Wong, J. K. Y. J. Am. Chem.
Soc. 2003, 125, 8644-8654 and references are therein.
(4) (a) Jeong, K.-S.; Cho, Y. L.; Song, J. U.; Chang, H.-Y.; Choi, M.-G.
J. Am. Chem. Soc. 1998, 120, 10982-10983. (b) Jeong, K.-S.; Cho, Y. L.;
Chang, S.-Y.; Park, T.-Y.; Song, J. U. J. Org. Chem. 1999, 64, 9459-
9466. (c) Jeong, K.-S.; Choi, J. S.; Chang, S.-Y.; Chang, H.-Y. Angew.
Chem., Int. Ed. 2000, 39, 1692-1695. (d) Chang, S.-Y.; Jang, H.-Y.; Jeong,
K.-S. Chem. Eur. J. 2003, 9, 1535-1541. (e) Jeong, K.-S.; Chang, K.-J.;
An, Y.-J. Chem. Commun. 2003, 1450-1451. (f) Chang, S.-Y.; Um, M.-
C.; Uh, H.; Jang, H.-Y. Chem. Commun. 2003, 2026-2027.
Tetralactam macrocycles have been widely used as the
ring component for the synthesis of interlocked molecules
(1) For recent reviews, see: (a) Zimmerman, S. C.; Corbin, P. S. Struct.
Bonding 2000, 96, 63-94. (b) Prins, L. J.; Reinhoudt, D. N.; Timmerman,
P. Angew. Chem., Int. Ed. 2001, 40, 2382-2426. (c) Archer, E. A.; Gong,
H.; Krische, M. J. Tetrahedron 2001, 57, 1139-1159. (d) Sherrington, D.
C.; Kirsti, A. T. Chem. Soc. ReV. 2001, 30, 83-93. (e) Schmuck, C.;
Wienand, W. Angew. Chem., Int. Ed. 2001, 40, 4363-4369. (f) Sijbesma,
R. P.; Meijer, E. W. Chem. Commun. 2003, 5-16.
(2) For reviews, see: (a) Niemz, A.; Rotello, V. M. Acc. Chem. Res.
1999, 32, 44-52. (b) Tucker, J. H. R.; Collinson, S. R. Chem. Soc. ReV.
2002, 31, 147-156. (c) Cooke, G.; Rotello, V. M. Chem. Soc. ReV. 2002,
31, 275-286.
10.1021/ol035954j CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/17/2003

(NMe2, OMe) or electron-withdrawing groups (NO2, Cl)
were prepared in addition to the unsubstituted one 1 (Figure
1).
weak N(pyridine)‚‚‚HN(amide) hydrogen bonds are present.8
As a result, all of the amide NHs in the macrocycles 1, 2a-
d, and 3a-d are inwardly oriented so that they can form
simultaneously four hydrogen bonds, two pairs of bifurcated
bonds, with an appropriate diamide guest. On the basis of
computer modeling and preliminary binding studies, N,N,N′N′-
tetraethyladipamide (7) was chosen as the guest for binding
studies.
Binding behaviors of the reference macrocycle 1 toward
the guest 7 were investigated in CDCl3 at 23 ( 1 °C by 1H
NMR spectroscopy. The NH signal of 1 was gradually shifted
from 8.95 to 10.25 ppm upon addition of 7, indicative of
the hydrogen bonding formation between the amide NH of
1 and the carbonyl oxygen of 7. The association constant
was estimated to be 780 M-1 by nonliner least-squares fitting9
of the titration curve. On the other hand, the NH signal of 1
was little changed (∆δ < 0. 2 ppm) when excess (∼10 equiv)
of a monoamide, N,N-diethylbutanamide, was added. This
is clear evidence for the structure where two carbonyl
oxygens at both ends of 7 are simultaneously bound to 1 in
a bridging manner, one to each pyridine-2,6-dicarboxamide
unit as shown in Figure 3. A Job plot10 also supported a 1:1
complex between 1 and 7, showing that maximum com-
plexation occurs at a mole fraction of 0.5 (see the Supporting
Information).
Figure 1. Structures of tetralactam macrocycles 1, 2a-d, and
3a-d and a diamide guest 7.
Association constants between substituted macrocycles
2a-d and 3a-d and 7 were determined under the same
conditions, and the results are summarized in Table 1. The
trend in the magnitudes of the association constants is
apparent. That is, electron-withdrawing substituents (Cl, NO2)
increase the association constant, but electron-donating
substituents (NMe2, OMe) decrease it. For example, in a
series of monosubstituted macrocycles 2a-d, the association
constants are 240 M-1 for 2a (NMe2), 550 M-1 for 2b
(OMe), 1360 M-1 for 2c (Cl), and 4730 M-1 for 2d (NO2),
respectively.
The macrocycles 1, 2a-d, and 3a-d were synthesized
from a diamine 45 and 4-substituted pyridine-2,6-dicarbonyl
dichlorides 56 according to the literature procedure for the
preparation of 1 (Scheme 1).5,7 Structures of the macrocycles
were fully characterized by elemental analyses, NMR, and
mass spectroscopy (see the Supporting Information).
Scheme 1. Synthesis of Tetralactam Macrocyclesa
A series of bis-substituted macrocycles 3a-d show more
drastic variations in the association constants, ranging from
70 M-1 for 3a (NMe2) to 24 200 M-1 for 3d (NO2),
corresponding to the difference in free energy (∆∆G) of 3.4
kcal/mol.
The large substituent effects on the binding affinities
observed here may be attributed to the electrostatic repulsion
between the pyridyl nitrogen of the macrocycle and incoming
carbonyl oxygen of the guest (Figure 2). This repulsion can
(5) Hunter, C. A. J. Am. Chem. Soc. 1992, 114, 5303-5311.
(6) (a) Bhattacharya, S.; Snehalatha, K.; George, S. K. J. Org. Chem.
1998, 63, 27-35. (b) Bradshaw, J. S.; Maas, G. E.; Lamb, J. D.; Izatt, R.
M.; Christensen, J. J. J. Am. Chem. Soc. 1980, 102, 467-474 and references
are therein.
(7) (a) Hunter, C. A. J. Chem. Soc., Chem. Commun. 1991, 749-751.
(b) Hunter, C. A.; Shannon, R. J. Chem. Commun. 1996, 1361-1362.
(8) (a) Hunter, C. A.; Purvis, D. H. Angew. Chem., Int. Ed. Engl. 1992,
31, 792-795. (b) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem.
Soc. 1997, 119, 10587-10593. (c) Crisp, G. T.; Jiang, Y.-L. Tetrahedron
1999, 55, 549-560.
(9) (a) Wilcox, C. S. In Frontiers in Supramolecular Organic Chemistry
and Photochemistry; Schneider, H.-J., Du¨rr, H., Eds.; VCH: Weinheim,
1991; pp 123-143. (b) Macomber, R. S. J. Chem. Educ. 1992, 69, 375-
378.
a Key: (a) i-Pr2NEt, 0 °C to rt, 12-34%; (b) i-Pr2NEt, 0 °C to
rt, 23-66%.
A key molecular component of these macrocycles is the
pyridine-2,6-dicarboxamide skeleton where intramolecular,
(10) Conners, K. A. Binding Constants; John Wiley & Sons: New York,
1984; p 24.
182
Org. Lett., Vol. 6, No. 2, 2004

Table 1. Association Constants (Ka), Free Energy (∆G°), NH Chemical Shifts (δFree) of Free Macrocycles, and Observed (δmax (obsd))
a
and Calculated (δmax (calcd)) Maximum Chemical Shifts upon Complexation at 23 ( 1 °C in CDCl3
macrocycle
Ka (M-1
)
∆G° (kcal/mol)
-3.9
δ
free (NH, ppm)
8.95
δ
max (obsd) (NH, ppm)
10.25
δ
max (calcd) (NH, ppm)
10.36
1 (H)
780
m on osu bstitu ted
2a (NMe2)
2b (OMe)
2c (Cl)
2d (NO2)
240
550
1360
4730
-3.2
-3.7
-4.2
-5.0
8.96, 9.12
8.95, 9.00
8.94, 8.87
8.95, 8.83
10.02, 10.07
10.16, 10.16
10.28, 10.26
10.23, 10.25
10.34, 10.35
10.36, 10.34
10.35, 10.34
10.34, 10.34
bis-su bstitu ted
3a (NMe2)
3b (OMe)
3c (Cl)
3d (NO2)
70
410
2430
-2.5
-3.5
-4.6
-5.9
9.12
9.00
8.86
8.82
9.74
10.13
10.29
10.34
10.36
10.35
10.34
10.36
24 200
a Titrations were at least duplicated, and errors in Ka were within ( 10% for Ka < 104 M-1 and ( 25% for Ka >104 M-1. Initial concentrations of
macrocycles and guest for titrations were 0.9-2 and 5-20 mM, respectively, depending on the magnitudes of the association constants and on their solubility
in CDCl3.
be considered as a new type of secondary hydrogen bonding
interactions, originally proposed by Jorgensen.11 Due to the
direct resonance between substituents and the pyridyl
nitrogen, the electron density at the nitrogen is highly
sensitive to the nature of the substituents. In other words,
the electron-withdrawing groups (NO2, Cl) reduce the
electron density at the nitrogen. Consequently, the electro-
static repulsion between the nitrogen and the oxygen
decrease, thus increasing binding affinities. The exact op-
posite is true for the electron-donating groups (NMe2, OMe).
This explanation is also supported by liner free-energy
In addition, possible perturbation of intramolecular hy-
drogen bonds upon the complex formation may be also
-
relationship,12 plotting log(K/KH) vs σp (Figure 3b).13 For
a series of monosubstituted macrocycles, 2a-d gave the
reaction constant (F) of 0.63 with a nice correlation (R2
),0.996). As expected, F was found to be nearly twice as
large (1.24) for a series of bis-substituted macrocycles 3a-
d.
Along with the electron density on the pyridyl nitrogen,
the hydrogen-bonding donor ability of the amide hydrogen
in the macrocycle may be partially responsible for the
substituent effects. The electron-withdrawing substituents
increase the donor ability, while the electron-withdrawing
substituents decrease it. The association constants increase
also in parallel with the donor abilities of the amide NHs of
the substituted macrocycles.
Figure 3. (a) Complexations between macrocycles 1, 2a-d, and
3a-d and guest 7. (b) Linear free energy plots of log(K/KH) vs
σp-. 2: monosubstituted macrocycles, Y ) 0.63x + 0.023, R2 )
0.996. b: bis-substituted macrocycles, Y ) 1.24x + 0.035, R2 )
0.992.
Figure 2. Schematic representation of possible electrostatic
repulsions between the pyridyl nitrogen of macrocycles and the
incoming carbonyl oxygen of guest.
Org. Lett., Vol. 6, No. 2, 2004
183

contributed to the substituent effects. As mentioned previ-
ously, intramolecular N(pyridine)‚‚‚HN(amide) hydrogen
bonds exist in the macrocycles. The relative positions of the
NH signals of free macrocycles (δfree) reflect well the
presence and strength of intramolecular hydrogen bonds, as
seen in Table 1.
tion could be greater in the macrocycles containing stronger
intramolecular hydrogen bonds, which results in the decrease
of the association constants. Accordingly, the order of the
association constants (3d > 3c > 1 > 3b > 3a) is reverse
to that of intramolecular hydrogen bonding interactions based
on the relative positions of the amide NH signals.
The NH signal of the unsubstituted macrocycle 1 appears
at 8.95 ppm in CDCl3. The signals of 3a (NMe2, 9.12 ppm)
and 3b (OMe, 9.00 ppm) are downfield shifted, while those
of the macrocycles 3c (Cl) and 3d (NO2) appeared at 8.86
and 8.82 ppm, respectively. As the electron density on the
pyridyl nitrogen increases, the NH signals are more down-
field shifted because intramolecular hydrogen bonding
interactions become stronger. On the other hand, the NH
chemical shifts of all macrocycles when complexed become
constant: calculated NH chemical shifts of the complexes,
δmax (calcd), in all cases are approximately 10.35 ppm,
implying that local environments around hydrogen-bonded
sections of the complexes are nearly identical regardless of
the nature of the substituents. This situation can be envisioned
when the intramolecular hydrogen bonds are partially
perturbed until it is balanced with intermolecular hydrogen
bonds between the macrocycles and the guest. The perturba-
In conclusion, we have demonstrated that using a series
of tetralactam macrocycles and an adipamide guest the
binding energy can be effectively modulated by remote
substituents that alter considerably electron densities around
hydrogen bonding sites. The capability of modulating
intermolecular interactions is essential for the development
of supramolecular devices or materials that can be responsive
to external stimuli. We are currently pursuing this goal by
replacing the pyridine unit of the macrocycle with other
scaffolds, e.g., pyrazine, whose electron densities can be
conveniently modified either by acid/base chemistry or by
redox chemistry.
Acknowledgment. This work was financially supported
by Korea Institute of Science & Technology Evaluation and
Planning (M10213030001-02B1503-00310).
(11) (a) Jorgensen, W. L.; Pranata, J. J. Am. Chem. Soc. 1990, 112,
2008-2010. (b) Pranata, J.; Wierschke, S. G.; Jorgensen, W. L. J. Am.
Chem. Soc. 1991, 113, 2810-2819, and also see: (c) Jeong, K.-S.; Tjivikua,
T.; Rebek, J., Jr. J. Am. Chem. Soc. 1990, 112, 3215-3217. (d) Murray, T.
J.; Zimmerman, S. C. J. Am. Chem. Soc. 1992, 114, 4010-4011.
(12) Sykes, P. A. Guide to Mechanism in Organic Chemistry; Long-
man: London, New York, 1985; Chapter 13, pp 358-395.
Supporting Information Available: Experimental pro-
cedures, physical properties, and spectroscopic data for the
1
macrocycles 1, 2a-d, and 3a-d; H NMR titration data;
and Job’s plot. This material is available free of charge via
the Internet at http://pubs.acs.org.
(13) σp- values for the dissociation constants of anilinium ions in water
at 25 °C were used for these plots. Fujio, M.; McIver, R. T., Jr.; Taft, R.
W. J. Am. Chem. Soc. 1981, 103, 4017-4029.
OL035954J
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Org. Lett., Vol. 6, No. 2, 2004