Role of pyridine hydrogen-bonding sites in recognition of basic amino acid side chains

Article abstract of DOI:10.1021/ja0273694

A series of three, new artificial receptors for guanidinium and ammonium guests has been synthesized. All three receptors have highly preorganized clefts bearing two carboxylate groups. They differ in the number of nitrogen atoms contained in their clefts

Full text of DOI:10.1021/ja0273694

Published on Web 11/02/2002
Role of Pyridine Hydrogen-Bonding Sites in Recognition of
Basic Amino Acid Side Chains
Thomas W. Bell,*,† Alisher B. Khasanov,† and Michael G. B. Drew‡
Contribution from the Department of Chemistry/216, UniVersity of NeVada,
Reno, NeVada 89557-0020, and Department of Chemistry, The UniVersity, Whiteknights,
Reading, RG6 6AD, U.K.
Received June 19, 2002
Abstract: A series of three, new artificial receptors for guanidinium and ammonium guests has been
synthesized. All three receptors have highly preorganized clefts bearing two carboxylate groups. They
differ in the number of nitrogen atoms contained in their clefts, as follows: four N atoms in receptor 3,
three N atoms in 4, and two nitrogens in 5. Crystallographic studies have produced the solid-state structures
+
of the following guanidinium complexes of each receptor: 3‚2CH3CH2NHC(NH2)2+, 4‚2CH3NHC(NH2)2
,
and 5‚2C(NH2)3+. The conformations of the receptor molecules in all three complexes are very similar.
N-Alkylguanidinium guests are bound in the clefts of 3 and 4 in similar manners, despite the loss of one
hydrogen-bond acceptor nitrogen in 4 and the possible hindrance of the cavity by a CH group. In the
guanidinium complex of 5, neither guest enters the cavity containing two CH groups. Complexation studies
were conducted in methanol by 1H NMR titration for several guanidinium and ammonium guests, including
derivatives of the amino acids arginine and lysine. Receptor 5 binds all such guests weakly (Ks < 4000),
while 3 binds most guests very strongly (Ks > 100 000). Receptor 3 is selective for arginine versus lysine,
while 4 binds lysine better than does 3. The results generally underscore the importance of receptor
preorganization and hydrogen-bonding complementarity in the design of receptors that can serve as probes
for biomolecules.
tional activator tat4-6 and the Rev protein4,7 are arginine-rich
RNA-binding proteins that regulate important steps in replication
Introduction
Events of noncovalent bonding between biological molecules
are processes of major significance that regulate various
functions in living systems. In many biological processes, basic
amino acid residues such as arginine and lysine are critical in
recognition of functionally important proteins. The recognition
of specific plasma lipoproteins by the low-density lipoprotein
(LDL) cell surface receptors on human fibroblasts, which
initiates a series of events regulating intracellular cholesterol
metabolism, depends on the presence of lysine and arginine
residues.1 The same residues in apoliprotein B, an essential
structural protein required for the assembly of triglyceride-rich
low-density lipoproteins by the liver, are found to be critical
for its binding to microsomal triglyceride transfer protein.2 RNA
recognition processes have become important targets for the
development of antiviral and antibiotic drugs.3 The transcrip-
of the human immunodeficiency virus type I (HIV-1). The
structure of the HIV-1 nucleocapsid protein bound to the
genomic Ψ-RNA recognition element8 displays a specific
arginine-base interaction (Arg32-A8). Synthetic receptors ca-
pable of selective binding to arginine and lysine residues could
lead to novel pharmaceuticals, as well as molecular probes that
could facilitate the understanding and characterization of vital
biological processes.
Previously designed receptors for guanidinium and alkylam-
monium ions are mostly crown ether derivatives.9 More recent
approaches involve polyaza-aromatic hexagonal lattice receptors
for unsubstituted guanidinium ion,10 tweezer-type receptors that
can bind alkylguanidinium guests including arginine,11 and
(4) (a) Ellington, A. D. Curr. Biol. 1993, 3, 375-377. (b) Varani, G. Acc.
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13, 649-660.
* To whom correspondence should be addressed. E-mail: twb@unr.edu.
Fax: 775/784-6804.
† University of Nevada.
‡ The University, Reading.
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J. AM. CHEM. SOC. 2002, 124, 14092-14103
10.1021/ja0273694 CCC: $22.00 © 2002 American Chemical Society

Pyridine Hydrogen-Bonding Sites
A R T I C L E S
Figure 1. Structures of guanidinium receptors: (a) “molecular tweezers”;15 (b) the “arginine fork” of the HIV-1 tat-TAR complex;6 (c) hexagonal lattice
receptors.
polyanionic cyclophanes.12 Receptors derived from cucurbi-
turil,13 calixarenes,14 and xylylene bisphosphonate15 have also
been designed to bind alkylammonium ions.
N-alkylguanidinium guests even in methanol (Kd ≈ 2 mM). This
can be attributed to incomplete preorganization of hydrogen-
bond acceptor sites in 2, which allows free rotation about several
single bonds, requiring that part of the binding energy be used
to conformationally organize the receptor.
Several research groups have reported the formation of
complexes with host molecules having hydrogen-bonding sites
that are partially preorganized by attachment to or embedding
within cyclic structures.16 Our approach to recognition of small,
planar molecules is through hexagonal lattice design10,17 of
relatively rigid receptor molecules with defined planar arrays
of hydrogen-bonding groups. Following this approach, we
designed and synthesized a water-soluble receptor for the
N-alkylguanidinium cation (3, Figure 1c). This artificial receptor
binds arginine in water (Ka ≈ 103 M-1) with about 7-fold
selectivity over lysine, and it binds the dipeptide diarginine (Ka
To be useful for biological applications, a receptor for arginine
or lysine must be reasonably soluble in water, it must have high
affinity for N-alkylguanidinium or N-alkylammonium side
chains, and it must display selectivity relative to other cations.
One can develop such a receptor by imitating natural patterns
of recognition or by employing a new, improved design.
Following the biomimetic approach, Schrader15b synthesized
“molecular tweezers” containing two phosphonate groups
capable of binding guanidinium cations by four hydrogen bonds
(Figure 1a). The structure of the resulting complex resembles
that of the critical arginine residue of tat (Arg52) bound to
phosphodiesters P22 and P23 of HIV-1 TAR RNA, a feature
dubbed the “arginine fork” (Figure 1b) by Frankel et al.6
However, molecular tweezer 2 shows only modest binding of
(16) Examples: (a) Hamilton, A. D.; van Engen, D. J. Am. Chem. Soc. 1987,
109, 5035-5036. (b) Kelly, T. R.; Maguire, M. P. J. Am. Chem. Soc. 1987,
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R. P. J. Am. Chem. Soc. 1990, 112, 4549-4550. (d) Rebek, J., Jr. Acc.
Chem. Res. 1990, 23, 399-404. (e) Kelly-Rowley, A. M.; Lynch, V. M.;
Anslyn, E. V. J. Am. Chem. Soc. 1995, 117, 3438-3447. (f) Metzger, A.;
Gloe, K.; Stephan, H.; Schmidtchen, F. P. J. Org. Chem. 1996, 61, 2051-
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(17) (a) Bell, T. W.; Liu, J. J. Am. Chem. Soc. 1988, 110, 3673-3674. (b) Bell,
T. W.; Firestone, A.; Liu, J.; Ludwig, R.; Rothenberger, S. D. In Inclusion
Phenomena and Molecular Recognition; Atwood, J. L., Ed.; Plenum: New
York, 1990; pp 49-56. (c) Bell, T. W.; Santora, V. J. J. Am. Chem. Soc.
1992, 114, 8300-8302. (d) van Straaten-Nijenhuis, W. F.; de Jong, F.;
Reinhoudt, D. N.; Thummel, R. P.; Bell, T. W.; Liu, J. J. Membr. Sci.
1993, 82, 277-283. (e) Beckles, D. L.; Maioriello, J.; Santora, V. J.; Bell,
T. W.; Chapoteau, E.; Czech, B. P.; Kumar, A. Tetrahedron 1995, 51, 363-
376. (f) Bell, T. W.; Hou, Z.; Luo, Y.; Drew, M. G. B.; Chapoteau, E.;
Czech, B. P.; Kumar, A. Science 1995, 269, 671-674. (g) Bell, T. W.;
Hou, Z.; Zimmerman, S. C.; Thiessen, P. A. Angew. Chem., Int. Ed. Engl.
1995, 34, 2163-2165. (h) Bell, T. W.; Hou, Z. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1536-1538. (i) Bell, T. W.; Hext, N. M.; Khasanov, A. B.
Pure Appl. Chem. 1998, 70, 2371-2378. (j) Bell, T. W.; Khasanov, A. B.;
Drew, M. G. B.; Filikov, A.; James, T. Angew. Chem., Int. Ed. 1999, 38,
2543-2547. (k) Tamaru, S.; Yamamoto, M.; Shinkai, S.; Khasanov, A.
B.; Bell, T. W. Chem.-Eur. J. 2001, 7, 5270-5276. (l) Tamaru, S.; Shinkai,
S.; Khasanov, A. B.; Bell, T. W. Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
4972-4976.
(9) (a) Madan, K.; Cram, D. J. J. Chem. Soc., Chem. Commun. 1975, 427-
428. (b) Kyba, E. P.; Helgeson, R. C.; Madan, K.; Gokel, G. W.; Tarnowski,
T. L.; Moore, S. S.; Cram, D. J. J. Am. Chem. Soc. 1977, 99, 2564-2571.
(c) Cram, D. J.; Cram, J. M. Acc. Chem. Res. 1978, 11, 8-14. (d) Lehn,
J.-M.; Vierling, P.; Hayward, R. C. J. Chem. Soc., Chem. Commun. 1979,
296-298. (e) Bandy, J. A.; Truter, M. R.; Wingfield, J. N.; Lamb, J. D. J.
Chem. Soc., Perkin Trans. 2 1981, 1025-1030. (f) Behr, J.-P.; Lehn, J.-
M.; Vierling, P. HelV. Chim. Acta 1982, 65, 1853-1867. (g) de Boer, J.
A. A.; Uiterwijk, J. W. H. M.; Geevers, J.; Harkema, S.; Reinhoudt, D. N.
J. Org. Chem. 1983, 48, 4821-4830. (h) Uiterwijk, J. W. H. M.; van
Staveren, C. J.; Reinhoudt, D. N.; den Hertog, H. J., Jr.; Kruise, L.;
Harkema, S. J. Org. Chem. 1986, 51, 1575-1587. (i) Sutherland, I. O.
Pure Appl. Chem. 1989, 61, 1547-1554. (j) Kremer, F. J. B.; Chiosis, G.;
Engbersen, J. F. J.; Reinhoudt, D. N. J. Chem. Soc., Perkin Trans. 2 1994,
677-681.
(10) (a) Liu, J. Ph.D. Thesis, State University of New York at Stony Brook,
1990. (b) Bell, T. W.; Liu, J. Angew. Chem., Int. Ed. Engl. 1990, 29, 923-
925.
(11) (a) Eliseev, A. V.; Nelen, M. I. J. Am. Chem. Soc. 1997, 119, 1147-1148.
(b) Schrader, T. Chem.-Eur. J. 1997, 3, 1537-1541.
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J. Am. Chem. Soc. 1999, 121, 1192-1201.
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A R T I C L E S
Bell et al.
Scheme 1
≈ 2 × 104 M-1) with 5-fold selectivity over dilysine.17j Receptor
3 has two negatively charged carboxylate groups, which make
it soluble in water. The nitrogen and oxygen hydrogen-bond
acceptor sites in 3 are preorganized for the formation of a robust
hydrogen-bonding network with guanidinium ion. Conjugation
between the carboxylate groups and the neighboring pyridine
rings should stabilize the coplanar conformation. Rotation about
the pyridine-carboxylate bond is expected, but the symmetry
of the carboxylate group produces identical structures via 180°
rotation about this bond.
and N-alkylammonium cations. Thus, the affinity of 5 for these
cations should be much less than those of receptors 3 and 4.
Results and Discussion
Our general strategy for the synthesis of target compounds
3, 4, and 5 involves a sequence of two Friedla¨nder condensations
of ketones with appropriate aminoaldehydes (Scheme 1). In the
case of compound 3, the key ketoacid (10) was obtained from
quinaldine (6). The benzene ring of 6 was selectively reduced
by catalytic hydrogenation with palladium on carbon in tri-
fluoroacetic acid, using the procedure of Vierhapper and Eliel.18
Condensation of 7 with benzaldehyde in acetic anhydride gave
dibenzylidene derivative 8. Ozonolysis19 of 8 with reductive
workup gave keto aldehyde 9, which was oxidized to ketoacid
10 with Jones’ reagent or hydrogen peroxide and formic acid.
Friedla¨nder condensation of 10 with 4-aminopyrimidine-5-
carboxaldehyde20 gave 11, which was hydrolyzed to aminoal-
dehyde 12 with dilute hydrochloric acid. A second condensation
of 10 with 12 in refluxing ethanol gave receptor 3 as the
dipotassium salt (3‚2K+), which was isolated in 22% overall
yield from quinaldine after purification by recrystallization.
The combination of receptor preorganization and attractive
electrostatic interactions between the dianionic host and cationic
guest makes complexes of 3 with N-alkylguanidinium stable
even in aqueous media. To investigate how modification of
binding sites in the cavity of this type of receptor affects binding
motifs and affinities toward various guests, we designed
molecules 4 and 5 (Figure 1c). In the structure of 4, one of the
pyridine rings of 3 is replaced with a benzene ring, introducing
one hydrogen atom directly into the cavity. In complexes of 3,
this pyridine ring acts as a spacer between the 1,8-naphthyridine
and carboxylate hydrogen-bond acceptors and also provides a
stabilizing secondary electrostatic N‚‚‚H interaction.17i The
absence of this attractive interaction and steric interference
between the benzene hydrogen atom and the planar N-alkyl-
guanidinium guest is expected to decrease the stabilities of the
complexes of 4. Because of the smaller size of N-alkylammo-
nium relative to N-alkylguanidinium, this modification may not
decrease the affinity of 4 toward the former guest. Replacement
of both pyridine rings in 3 with benzene rings makes the cavity
of 5 even more congested for binding both N-alkylguanidinium
To obtain compound 5, 1-tetralone-7-carboxylic acid (13)21
was used as a main building block (Scheme 2). As in the
synthesis of 3, 4-aminopyrimidine-5-carboxaldehyde20 was used
(18) Vierhapper, F. W.; Eliel, E. L. J. Org. Chem. 1975, 40, 2729-2734.
(19) Pappas, J. J.; Keaveney, W. R.; Gancher, E.; Berger, M. Tetrahedron Lett.
1966, 4273.
(20) (a) Bredereck, H.; Simchen, G.; Traut, H. Chem. Ber. 1967, 100, 3664. (b)
Bell, T. W.; Beckles, D. L.; Debetta, M.; Glover, B. R.; Hou, Z.; Hung,
K.-Y.; Khasanov, A. B. Org. Prep. Proced. Int. 2002, 34, 359-364.
(21) Baddeley, G.; Williamson, R. J. Chem. Soc. 1956, 4647-4653.
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Pyridine Hydrogen-Bonding Sites
A R T I C L E S
Scheme 2
in the first Friedla¨nder condensation with tetralone derivative
13. The product of this condensation was obtained in the
carboxylic acid form (14), which was hydrolyzed to aminoal-
dehyde 15. The condensation of 13 with 15 required a higher
reaction temperature than that used in the synthesis of 3;
therefore, butanol was added as a higher boiling cosolvent to
facilitate the formation of 5. After recrystallization from an
ethanol/water mixture, microanalytically pure 5‚2K+ was
obtained in 23% overall yield from 13. The use of the same
ketone (10 or 13) in both Friedla¨nder condensations provided
the molecular symmetry of 3 and 5. However, two different
ketones could be used to make unsymmetrical molecules of this
type. This was successfully demonstrated by condensation of
aminoaldehyde 15, obtained from tetralone 13, with ketoacid
10. The resulting unsymmetrical compound 4 was obtained in
73% yield as its dipotassium salt (Scheme 2).
the hydrated complex with N-ethylguanidinium, 3‚2CH3CH2-
NHC(NH2)2 .
+ 17j Two molecules of the complex 3‚2CH3CH2-
NHC(NH2)2+ form a centrosymmetric, hydrogen-bonded dimer
with eight water molecules in the solid state (Figure 2). As
described previously,17j one ethylguanidinium guest (A) in each
complex resides in the receptor cavity, and the other cation (B)
binds externally to one carboxylate group of the same receptor.
In the dimer structure (Figure 2), this second ethylguanidinium
guest (B) and a water molecule (O53) bridge to the carboxylate
at the opposite end of the other receptor. The other six water
The dipotassium salts of diacids 3, 4, and 5 have good
aqueous solubilities (ca. 0.3 M for 3‚2 K+), which makes them
very promising compounds for biological and medicinal studies.
They are also slightly soluble in methanol, but are insoluble in
dimethyl sulfoxide, dichloromethane, and chloroform. However,
the solubilities of the corresponding neutral diacids are reversed.
They have very low solubility in water (<4 µM), but are
moderately soluble in dimethyl sulfoxide.
Addition of guanidine hydrochloride, N-methylguanidine
hydrochloride, or N-ethylguanidine sulfate to aqueous solutions
of dipotassium salts of 3, 4, or 5 results in the formation of
yellow precipitates. According to results of combustion mi-
croanalysis and 1H NMR spectroscopy, dried samples of these
precipitates consisted of the receptor dianion and the corre-
sponding guanidinium cation in an exactly 1:2 ratio. The
predicted binding motif of receptor 3 to guanidinium ion was
proven by X-ray crystallographic analysis of a single crystal of
Figure 2. Crystal structure of complex 3‚2CH3CH2NHC(NH2)2+ showing
two centrosymmetrically related N-ethylguanidinium cations positioned with
respect to the two host receptors and four pairs of hydrogen-bonded water
molecules (red spheres). Hydrogen bonds shown as dotted lines. Atom
colors: gray, carbon; blue, nitrogen; red, oxygen; cyan, hydrogen.
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A R T I C L E S
Bell et al.
Figure 3. Crystal structure of complex 4‚2CH3NHC(NH2)2+ showing two centrosymmetrically related N-methylguanidinium cations positioned with respect
to the two host receptors. The N-methyl group and hydrogen-bonded methanol solvent molecule are disordered over two possible pairs of centrosymmetric
sites with 64% occupancy in A, and 36% occupancy in B. Atom colors: gray, carbon; blue, nitrogen; red, oxygen; cyan, hydrogen.
molecules in the dimer form hydrogen bonds to the remaining
ethylguanidinium NH groups, and one also bridges to a
carboxylate oxygen.
+
The complex 4‚2CH3NHC(NH2)2 packs in a very similar
centrosymmetric dimer pattern, with one guest (A) in the
receptor cleft and the second bound externally to a carboxylate
(Figure 3). The crystal contains one methanol molecule per 1:2
complex. This solvent molecule and the position of the internally
bound guest (A) methyl group are disordered between two
alternate trigonal positions. These disordered positions are
apparently correlated as shown in Figure 3, because the best
refinement was obtained with 64% weighting of the structure
shown in Figure 3A and 36% weighting of the structure shown
in Figure 3B. In both cases, the methanol molecule forms a
hydrogen-bonding bridge between the CH3NH donor of the
internal guest and the nicotinic carboxylate of the host. Alternate
positions of the guest methyl group were correlated with
+
switching of the methanol bridge from the carboxylate of the
receptor in the same 1:2 complex to the same carboxylate
oxygen atom of the other receptor in the dimer.
Figure 4. Crystal structure of complex 5‚2C(NH2)3 showing positions
of the two independent guanidinium cations with respect to the receptor
and six hydrogen-bonded water molecules (red spheres). Atom colors: gray,
carbon; blue, nitrogen; red, oxygen; cyan, hydrogen.
+
In contrast, 5‚2C(NH2)3 crystallizes without a guest in the
cleft and also lacks the eight-membered carboxylate-guani-
dinium chelate ring observed in the complexes of receptors 4
and 5. The two guanidinium guests form six-membered chelate
rings, one (A) with a water molecule O(501) occupying the
central cavity of the receptor and the second (B) with a
carboxylate oxygen (Figure 4). This water molecule is hydrogen-
bonded to a second bridging water O(502), and two other water
molecules are disordered between four positions, each with 50%
occupancy.
All three receptors adopt relatively planar conformations, as
judged from the deviations of the heteroatoms lining the cleft
(2-4 nitrogens and 2 oxygens) from the least squares planes
defined by these atoms (Table 1). In the series 3-4-5, the angle
between this plane and the more coplanar guest increases from
7 to 58°, showing that sequential replacement of pyridine by
benzene increasingly excludes the guest from the receptor cavity.
In the guanidinium complex of receptor 5, the central water
molecule lies only 0.07 Å from the plane of the 1,8-naphthy-
ridine unit of this receptor.
The conformations of receptors 3-5 in their complexes are
also described by key torsion angles given in Table 2. The angles
for X-C-C-N and X-C-C-O fragments within the cleft
(X ) N or C) fall in the range of 0-27°, while the torsion
angles of the external C-CH2-CH2-C bridges range from 25
to 53°. The signs of the ethylene bridge torsions are opposite
in the cases of 3 and 5, but they are the same for receptor 4.
These relationships indicate approximate mirror and C2 sym-
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Pyridine Hydrogen-Bonding Sites
A R T I C L E S
Table 1. Deviations (Å) of Oxygen and Nitrogen Atoms from
Receptor Planes and Angles (deg) between Least Squares Planes
in Complexes of Receptors 3, 4, and 5 (Errors Given in
Parentheses)
Table 3. Stability Constants (Ks, 103 M-1) of 1:1 Complexes As
Determined by 1H NMR Titration in CD3OD (25 °C)
receptor
guest
3
4
5
Plane 1: The Host Molecule
3
4
5
O(21) -0.18, N(14) 0.19, N(15) 0.03, N(16) -0.07, N(1) -0.13, O(18) 0.16
O(21) 0.03, N(15) -0.02, N(16) -0.05, N(1) 0.11, O(18) -0.07
O(21) 0.00, N(15) -0.01, N(16) 0.00, O(18) 0.00
methylguanidine HCl
creatine
NR-acetyl-L-arginine
L-arginine
>100
3.9 ( 0.4
<1.0
1.0 ( 0.1
<1.0
3.9 ( 2
1.1 + 0.2
1.1 ( 0.1
<1.0
<1.0
1.6 ( 0.2
1.4 ( 0.3
14.5 ( 1.0
>100
1.2 ( 0.2
>100
>100
29 ( 3
>100
27 ( 10
>100
1.2 ( 0.1
angles
L-lysine
>100
NR-acetyl-L-lysine
6-aminocaproic acid
1-propylamine HCl
Nꢀ-acetyl-L-lysine
>100
3
4
5
>100
between planes 1 and 2a
6.9(3)
25.6(2)
58.0(6)
>100
between planes 1 and 3ab 29.6(2), 14.6(2) 5.7(2), 17.8(2) 4.8(6), 24.9(6)
1.4 ( 0.3
between planes 3bb and 4c 22.6(1)
between planes 1 and 4 51.8(1)
25.2(2)
20.6(2)
73.2(4)
a Plane 2: guest A (in cavity in complexes of 3 and 4). b Planes 3a and
3b: carboxylates containing O(18), O(19) and O(21), O(22), respectively.
c Plane 4: guest B (hydrogen bonded to carboxylate a in complexes of 3
and 4).
In less polar solvents, aggregation of these compounds should
decrease, and determination of stability constants is expected
to be easier than it was in water. Therefore, methanol-d4 was
chosen as a solvent for measurements of host-guest interactions.
Dilute solutions of tetramethylammonium salts of receptors 3,
4, and 5 (0.1 mM) in CD3OD were used for titrations. Various
guests containing alkylguanidinium and alkylammonium groups
were investigated for binding ability toward receptors 3, 4, and
5. Downfield shift of the 1,8-naphthyridine protons of the host
was observed, suggesting that the cationic guest binds first to
the cavity. The calculated stability constants for 1:1 complexes
are shown in Table 3. As expected, receptor 3 binds guani-
dinium-containing guests with very high affinity, and complex-
ation shifts were not observed beyond 1:1 guest/host ratio. The
1:1 stability constants (Ks) of its complexes with N-meth-
ylguanidinium, arginine, and NR-acetyl-L-arginine in CD3OD
exceed 105 M-1 and cannot be measured accurately. However,
the complex of 3 with lysine is less stable (Ks ) 29 000 M-1).
Thus, receptor 3 has a more than 3-fold selectivity toward
binding arginine relative to lysine. Surprisingly, the affinity for
NR-acetyl-L-lysine and propylammonium chloride was also
found to be very high (Ks g 105 M-1).
Receptor 4 displays a preference for binding primary alkyl-
ammonium guests, including L-lysine, NR-acetyl-L-lysine, 6-ami-
nocaproic acid, and 1-propylamine (Ks g 105 M-1). Among
guanidinium guests, only arginine binds with very high affinity
to 4. The complex of 4 with N-methylguanidinium has a
significantly smaller stability constant (Ks ) 3900 M-1).
Apparently, the smaller cavity of 4 cannot comfortably accom-
modate the large guanidinium ion, but it accepts the smaller
ammonium side chain of lysine. Creatine and NR-acetyl-L-
arginine form moderate to weak complexes with 4. The arginine
complex of 4 is apparently further stabilized by electrostatic
interaction between the R-ammonium group and one of the host
carboxylates.
Table 2. Torsion Angles (deg) in Receptor Molecules in the
+
Crystal Structures of 3‚2CH3CH2NHC(NH2)2+, 4‚2CH3NHC(NH2)2
,
+
and 5‚2C(NH2)3 (Errors Given in Parentheses)
receptor
c
3a
4b
5
inner fragments:
X(14)-C(13)-C(20)-O(21)
X(14)-C(14A)-C(14B)-N(15)
Y(1)-C(16B)-C(16A)-N(16)
Y(1)-C(2)-C(17)-O(18)
outer CCH2CH2C bridges:
C(8A)-C(9)-C(10)-C(10A)
C(4A)-C(5)-C(6)-C(6A)
11.9(5)
19.0(5) -16.9(6)
-17.9(5)
26.5(6)
15.0(7)
0.7(13)
-13.9(10)
16.6(10)
-0.0(6)
15.4(8)
11.5(15)
51.0(4) -50.2(6)
-52.7(5) -24.8(14)
-50.4(11)
53.2(11)
a X ) Y) N. b X ) C, Y ) N. c X ) Y ) C.
metry, respectively. These variations suggest that such com-
plexes are relatively conformationally mobile in solution.
Head-to-tail stacking interactions appear to be important in
the crystallization of the complexes of all three receptors (Figure
5). In the N-ethylguanidinium complex of 3 (Figure 5A), the
receptor molecules stack in pairs such that each naphthyridine
nitrogen atom lies about 3.5 Å from an electronically comple-
mentary carbon atom of its neighbor. Receptor 4 forms similar
dimers, which produce linear chains by stacking with other
dimers with a larger offset between ring atoms (Figure 5B). In
the complex of receptor 5, a herringbone pattern is produced
by continuously offset chains of head-to-tail stacked receptor
molecules (Figure 5C).
1
All H NMR signals of the dipotassium salts of 3, 4, and 5
in D2O solutions exhibit downfield shifts upon dilution from
0.1 M to 0.1 mM, with chemical shift differences up to 1.6
ppm. This effect can be attributed to the aggregation of these
molecules in aqueous solutions through hydrophobic interactions
between nonpolar regions of the molecules that are remote from
the charged carboxylate groups. Particularly, the aggregation
is enhanced by the molecular planarity, which provides a large
hydrophobic contact surface between stacked molecules. Similar
head-to-tail stacking is observed in the crystal structures of the
complexes (cf. Figure 5), but the proposed tail-to-tail stacking
in water would not interfere with solvation of the polar,
carboxylate headgroups. Addition of guanidinium or N-alkyl-
guanidinium salts to aqueous solutions of 3, 4, or 5 significantly
increases aggregation and upfield shifts, probably because the
closer proximity of opposite charges in a complex makes the
complex less polar than the dianionic receptor.
In the case of receptor 5, the binding to almost all guests is
weak. The cavity size of 5 is apparently too small to fit either
ammonium or guanidinium ions. In general, receptor 5 does
not discriminate between the cationic guests that were inves-
tigated. Apparently, its binding properties are dictated almost
purely by attraction of opposite charges without stabilization
from multiple hydrogen bonding.22 Receptors 3 and 4 can form
arrays of hydrogen bonds as well as electrostatic interactions
with the investigated guests. These hydrogen bonds significantly
(22) As pointed out by a referee, the binding constants exhibitied by 5 are in
line with results of studies done on the binding of carboxylate guests with
guanidinium hosts: (a) Schiessl, P.; Schmidtchen, F. P. Tetrahedron Lett.
1993, 34, 2449-2452. (b) Schmuck, C. Chem.-Eur. J. 2000, 6, 709-718.
9
J. AM. CHEM. SOC. VOL. 124, NO. 47, 2002 14097

A R T I C L E S
Bell et al.
Figure 5. Stacking interactions between receptor molecules in the crystal structures of (A) 3‚2CH3CH2NHC(NH2)2+; (B) 4‚2CH3NHC(NH2)2+; and (C)
+
5‚2C(NH2)3
.
increase the stabilities of the complexes; thus it is clear that the
composition of the cavity critically determines the molecular
recognition properties of these receptors.
steric interference of the hydrogen atom in the cavity of 4 causes
the guanidinium ion to twist away from the plane of the cavity.
This twist is shown in the crystal structure of the complex of 4
with the methylguanidinium ion (Figure 3). This increases the
hydrogen-bond lengths and distorts their linear orientations and,
as a result, decreases their stabilities. The binding motif of a
smaller ammonium ion is not affected by the decrease in the
cavity size of 4, and its binding energy resulting from
electrostatic attraction and some hydrogen bonding may be
similar to that of 3. Yet replacement of fewer solvent molecules
from the cavity of 4 costs less energy than for 3, which makes
complexes of 4 with alkylammonium guests more stable.
The stabilities of complexes of 3 with zwitterionic guests also
depend on the proximity of the negatively charged carboxylate
groups of 3 and these guests. The comparison of the binding
strengths of 3 with arginine and creatine demonstrates this
dependence. Assuming the same binding motif of the guani-
dinium group with 3, the carboxylate group of creatine should
be less remote from the carboxylate of receptor 3 than that of
arginine. Therefore, the repulsive interaction between carboxy-
Receptor 4 tends to have higher affinity toward alkylammo-
nium guests than alkylguanidinium, while receptor 3 binds
alkylguanidinium molecules more strongly. This selectivity
might be explained in terms of the energies of cavity solvation.
The compact ammonium ion has a higher charge density than
the planar guanidinium cation. Therefore, the alkylammonium
ion is expected to form stronger attractive electrostatic interac-
tions. The alkylguanidinium ion, on the other hand, is able to
form more hydrogen bonds with the planar receptors 3 and 4.
The larger cavity of 3 is more highly solvated prior to binding
than the smaller cavity of 4. Upon replacement of multiple
solvent molecules in the cavity of 3 with guests, the host
desolvation energy is better compensated with multiple hydrogen
bonds to the guanidinium ion than to the compact ammonium
ion. In receptor 4, the cavity is smaller and less solvated as
compared to 3. The guanidinium ion cannot form as energeti-
cally favorable hydrogen bonds with 4 as with 3, because the
9
14098 J. AM. CHEM. SOC. VOL. 124, NO. 47, 2002

Pyridine Hydrogen-Bonding Sites
A R T I C L E S
days. All volatile materials were then removed by rotary evaporation
at 80 °C, and the remaining dark oil was fractionally distilled under
vacuum. The fraction boiling at 140-160 °C (0.3 mm) was collected,
mixed with 200 mL of hot ethanol, and stirred at 70 °C to form an
emulsion. The stirred mixture was cooled to room temperature and
seeded with crystals of the product to facilitate crystallization. The
precipitate was collected by vacuum filtration, washed with 40 mL of
ethanol, and dried under vacuum to give 126 g (79%) of pale yellow
late groups of creatine and 3 is enhanced, which results in a
weaker complex with creatine (Ks ) 14 500 M-1) than with
arginine or other guanidinium-containing guests (Ks g 105 M-1).
The close proximity between the R-ammonium and carboxylate
groups of Nꢀ-acetyl-L-lysine also leads to consistently weak
complexes for all three receptors. A more detailed interpretation
of the binding results presented in Table 3 would require
additional thermodynamic data, such as enthalpic and entropic
contributions to binding free energies.
1
crystals of 8, mp 76-80 °C. H NMR (300 MHz, CDCl3): δ 8.13 (s,
1H), 7.1-7.8 (m, 14H), 2.8-3.0 (m, 4H), 1.86 (m, 2H). 13C NMR (75
MHz, CDCl3): δ 153.1, 152.4, 138.2, 137.3, 137.1, 135.7, 131.9, 131.3,
129.7 (2C), 128.7, 128.6 (2C), 128.1 (2C), 128.0, 127.3, 127.0 (2C),
126.7, 120.4, 29.7, 28.0, 22.9. EI-MS (70 eV) m/z (rel intensity): 324
(M + 1, 11), 323 (M, 59), 322 (100), 231 (19), 91 (20), 77 (12). Anal.
Calcd for C24H21N: C, 89.13; H, 6.54; N, 4.33. Found: C, 88.92; H,
6.76; N, 4.64.
Conclusions
The results presented here show that simple charge stabiliza-
tion is not sufficient for strong binding of arginine and lysine
side chains. High preorganization of hydrogen-bonding sites on
a receptor and size complementarity between a receptor’s cavity
and a guest make a great contribution to the stabilization of a
complex. Receptors 3 and 4 could lead to molecular probes that
are specific for arginine and lysine residues in biomolecules.
Simple modifications of these receptors, such as introducing
groups for attachment to other host molecules, should produce
useful building blocks for construction of receptors capable of
recognizing particular peptides and proteins.
6,7-Dihydro-8(5H)-quinolinone-2-carboxaldehyde (9). To a 1 L
round-bottomed flask were added 20.0 g (61.8 mmol) of 8-benzylidene-
2-styryl-5,6,7,8-tetrahydroquinoline (8), 300 mL of CH2Cl2, and 100
mL of methanol. The solution was cooled to -77 °C by means of a
dry ice/acetone bath, and a stream of O3/O2 was bubbled through the
solution until it turned distinctly blue. The solution was purged by
bubbling nitrogen gas for 1 h, and then 10 mL of dimethyl sulfide was
added via syringe. The solution was allowed to warm to room
temperature overnight, and then the solvents were removed by rotary
evaporation below 25 °C, and the remaining oil was dried under vacuum
(0.3-1.0 mm) for 11 h at room temperature. Next 400 mL of ether
was added to the oily residue, and the mixture was cooled in a freezer
(-15 to -20 °C) for 10 h. The white precipitate was collected by
vacuum filtration, washed with 30 mL of ether, and dried under vacuum
to give 7.06 g of 9. Ether was removed from the mother liquor by
rotary evaporation, and the remaining oil was dissolved in 300 mL of
CH2Cl2. This solution was washed with 40 mL of water, dried over
Na2SO4, and the solvent was evaporated. The remaining oil was dried
under vacuum for 4 h, and then 300 mL of ether was added, and the
mixture was cooled in a freezer for 10 h. The crystals were collected
by vacuum filtration, washed with 20 mL of ether, and dried under
vacuum to give 2.60 g of the second crop. Total yield: 9.7 g (89%),
mp 164-168 °C. For microanalysis, a sample was recrystallized from
Experimental Section
Water used as a solvent for spectroscopic measurements was
deionized and degassed by double distillation, followed by boiling
immediately prior to use. Other solvents were purchased from Fisher
Scientific Co. and were used as received. UV-visible spectra were
recorded at 2 nm wavelength resolution using a cell of 1 cm path length.
Chemical shifts in 1H and 13C NMR spectra were referenced to solvent
resonances. Melting points are uncorrected. Elemental analyses were
performed by Numega Resonance or Desert Analytics.
2-Methyl-5,6,7,8-tetrahydroquinoline (7).18 A Morton flask equipped
with a stirring bar was charged with 71.6 g (0.5 mol) of quinaldine (6)
(Acros, 97%) and cooled in an ice bath. Next 200 mL of trifluoroacetic
acid (Acros, 99%) and 7 g of palladium on activated carbon (Acros,
10% Pd) were added, and the flask was attached to a low-pressure
hydrogenation apparatus. The entire system was evacuated at water
aspirator pressure (20-30 mm) and filled with hydrogen gas. The
evacuation/filling procedure was repeated three more times. The
contents were stirred vigorously at room temperature over a period of
60 h, resulting in the consumption of 30.2 L (1.07 mol) of hydrogen.
The catalyst was removed by vacuum filtration through Whatman
number 2 filter paper and washed with 50 mL of water. The acidic
solution was diluted with 250 mL of water, cooled by means of an ice
bath, and basified to pH 10 with NaOH pellets. The product was
extracted with hexanes (3 × 100 mL). The combined hexane extracts
were washed with water (2 × 50 mL) and dried over Na2SO4. Solvent
was evaporated under water aspirator pressure, and the remaining oil
was dried overnight under vacuum (0.3 mm) to give 72.2 g (98%) of
product as a colorless oil, pure by gas chromatography (column HP-1,
injection temp 250 °C, column temp 80-250 °C, 10 °C/min, helium
carrier gas). 1H NMR (300 MHz, CDCl3): δ 7.22 (d, J ) 7.8 Hz, 1H),
6.86 (d, J ) 7.8 Hz, 1H), 2.87 (t, J ) 6.4 Hz, 2H), 2.70 (t, J ) 6.4 Hz,
2H), 2.47 (s, 3H), 1.85 (m, 2H), 1.79 (m, 2H). 13C NMR (75 MHz,
CDCl3): δ 156.4, 155.0, 137.0, 128.8, 120.3, 32.5, 28.3, 24.0, 23.2,
22.8. EI-MS (70 eV) m/z (rel intensity): 147 (M+, 100), 146 (100),
132 (36), 119 (48), 77 (19).
1
ethyl acetate and dried under vacuum (0.1 mm, 25 °C, 2 d). H NMR
(300 MHz, CDCl3): δ 10.20 (s, 1H), 8.05 (d, J ) 7.8 Hz, 1H), 7.86
(d, J ) 7.8 Hz, 1H), 3.16 (t, J ) 5.9 Hz, 2H), 2.88 (t, J ) 6.4 Hz, 2H),
2.25 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 195.5, 192.7, 152.0,
148.4, 145.2, 139.0, 123.8, 39.6, 29.4, 22.2. EI-MS (70 eV) m/z (rel
intensity): 175 (M+, 28), 147 (79), 119 (100), 91 (53), 64 (45), 63
(32), 62 (26), 55 (50), 51 (27), 40 (29), 39 (45). Anal. Calcd for C10H9-
NO2: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.82; H, 5.02; N, 8.31.
6,7-Dihydro-8(5H)-quinolinone-2-carboxylic Acid (10). Method
A. To a 500 mL Erlenmeyer flask were added 7.0 g (40 mmol) of
5,6-dihydro-8(7H)-quinolinone-2-carboxaldehyde (9) and 500 mL of
acetone. The solution was vigorously stirred, and 13.0 mL of Jones’
reagent (CrO3 (Acros, 99.7%) 26.7 g (0.27 mol) dissolved in 23 mL of
concentrated H2SO4 and 50 mL of water, and then diluted to 100 mL
with water) was added dropwise over a period of 2 h at room
temperature. The mixture was stirred for another 30 min, and 0.5 mL
of 2-propanol was added. The acetone solution was decanted from the
green precipitate, filtered through a sintered glass filter, and evaporated
to dryness to give a solid organic residue. A solution of the green
inorganic precipitate in 100 mL of 1 N aqueous sulfuric acid was
extracted with CH2Cl2 (6 × 30 mL). The combined CH2Cl2 extracts
were washed with 20 mL of water, dried over Na2SO4, and evaporated
to dryness to give a second solid organic residue. Both organic residues
were combined and dissolved in 15 mL of hot ethanol. This solution
was cooled in a freezer (-15 to -20 °C) for 3 h, and white crystals
8-Benzylidene-2-styryl-5,6,7,8-tetrahydroquinoline (8). A 1 L
round-bottomed flask equipped with a stirring bar, condenser, and gas
inlet was charged with 72.2 g (0.49 mol) of 2-methyl-5,6,7,8-
tetrahydroquinoline (7), 208 g (1.96 mol) of benzaldehyde (Acros,
98+%), and 201 g (1.97 mol) of acetic anhydride (Acros, 99.4%). The
mixture was heated under reflux at 150-160 °C under nitrogen for 5
9
J. AM. CHEM. SOC. VOL. 124, NO. 47, 2002 14099

A R T I C L E S
Bell et al.
were collected by vacuum filtration, washed with 5 mL of ice cold
ethanol, and dried under vacuum to give 5.4 g (70%) of 10, mp 167-
170 °C.
(d, J ) 7.8 Hz, 1H), 8.00 (s, 1H), 7.92 (d, J ) 7.8 Hz, 1H), 7.68 (s,
2H), 3.02 (t, J ) 6.8 Hz, 2H), 2.87 (t, J ) 6.8 Hz, 2H). 13C NMR (75
MHz, DMSO-d6): δ 192.9, 166.2, 157.5, 154.5, 150.5, 147.5, 143.9,
139.4, 137.1, 125.0, 122.5, 113.0, 27.4, 25.2. FAB-MS m/z (rel
intensity): 270.3 (M + 1, 100). Anal. Calcd for C14H11N3O3: C, 62.45;
H, 4.12; N, 15.61. Found: C, 62.28; H, 4.15; N, 15.67.
Method B. To a 500 mL Erlenmeyer flask equipped with a stirring
bar were added 30.0 g (0.17 mol) of 6,7-dihydro-8(5H)-quinolinone-
2-carboxaldehyde (9) and 34 g (0.74 mol) of formic acid (Acros, 98%).
The mixture was stirred until a clear solution was formed. The mixture
was then cooled by means of an ice bath, and 56 g of 30% H2O2 solution
in water (Aldrich) was added dropwise over a period of 30 min
(Caution: The reaction is highly exothermic in the beginning and may
cause splashes). The resulting suspension was swirled every 3-5 min
for a period of 1 h and left at room temperature for 2 h. Next 100 mL
of water was added, and the mixture was swirled one more time and
refrigerated for 24 h. The white precipitate was collected by vacuum
filtration, washed with ice cold water (3 × 10 mL), and dried under
vacuum (0.1 mm) over P2O5 over a period of 2 days to give 28.8 g
5,6,9,10-Tetrahydro[1,10]phenanthrolino[2,3-b][1,10]phenan-
throline-2,13-dicarboxylic Acid, Potassium Salt (3‚2K+). A 500 mL
round-bottomed flask equipped with a stirring bar, condenser, and
nitrogen gas inlet was charged with 1.00 g (3.71 mmol) of 5,6-dihydro-
9-amino-8-formyl[1,10]phenanthrolinecarboxaldehyde-2-carboxylic acid
(12), 0.71 g (3.71 mmol) of 5,6-dihydro-8(7H)-quinolinone-2-carboxylic
acid (10), and 200 mL of ethanol. The mixture was heated to boiling,
and then a solution of KOH in methanol was added dropwise over a
period of 10 min to achieve pH 9 (approximately 7.0 mL of 1.06 N
KOH solution was required). The resulting mixture was heated at reflux
under nitrogen for 3 days, resulting in the formation of a gray colored
precipitate. One-half of the solvent was removed by rotary evaporation,
and 200 mL of ether was added to the mixture. The resulting gellike
precipitate was collected by vacuum filtration, washed with 10 mL of
ethanol, and dried under vacuum (0.1 mm) to give 1.64 g (88%) of
potassium salt 3‚2K+, which was pure by 1H NMR spectroscopy. For
microanalysis, a sample of 3‚2K+ was dissolved in hot water, and hot
ethanol was added until the solution remained cloudy. After storage in
a refrigerator, the precipitate was collected by vacuum filtration and
1
(88%) of product 10, mp 167-170 °C. H NMR (300 MHz, CDCl3):
δ 8.30 (d, J ) 7.8 Hz, 1H), 7.94 (d, J ) 7.8 Hz, 1H), 3.15 (t, J ) 6.1
Hz, 2H), 2.86 (t, J ) 6.6 Hz, 2H), 2.26 (m, 2H). 13C NMR (75 MHz,
CDCl3): δ 194.9, 163.8, 146.4, 145.4, 144.9, 140.2, 126.4, 39.4, 29.1,
22.1. EI-MS (70 eV) m/z (rel intensity): 147 (M - 44, 80), 119 (25),
118 (43), 93 (48), 91 (100), 64 (23), 55 (29), 39 (28). Anal. Calcd for
C10H9NO3: C, 62.82; H, 4.74; N, 7.33. Found: C, 64.66; H, 4.97; N,
7.87.
5,6-Dihydropyrimido[4,5-b][1,10]phenanthroline-2-carboxylic Acid,
Potassium Salt (11). A 250 mL round-bottomed flask equipped with
a stirring bar, condenser, and nitrogen gas inlet was charged with 2.00
g (16.2 mmol) of 4-amino-5-pyrimidinecarboxaldehyde,20 3.10 g (16.2
mmol) of 5,6-dihydro-8(7H)-quinolinone-2-carboxylic acid (10), and
100 mL of methanol. The mixture was heated to boiling, and then a
solution of 15% KOH in methanol (w/v) was added dropwise over a
period of 10 min to achieve pH 9, as measured by adding a drop of the
solution to wet pH paper. The resulting mixture was heated at reflux
under nitrogen for 24 h, resulting in the formation of a gray colored
precipitate. The mixture was cooled to room temperature and refriger-
ated overnight. The precipitate was collected by vacuum filtration,
washed with 10 mL of ethanol, and dried under vacuum (0.1 mm) to
give 4.00 g (78%) of potassium salt 11. For microanalysis, crude 11
was recrystallized from water and dried under vacuum (0.1 mm, 65
1
dried under vacuum (0.1 mm, 60 °C, 3 d), dec > 340 °C. H NMR
(300 MHz, D2O): δ 7.85 (d, J ) 7.8 Hz, 2H), 7.66 (d, J ) 7.8 Hz,
2H), 7.54 (s, 2H), 2.90 (s, 8H). 13C NMR (75 MHz, D2O): δ 172.1
(2C), 153.8 (2C), 153.1, 152.4 (2C), 148.5 (2C), 137.9 (2C), 137.8
(2C), 135.1 (2C), 133.3 (2C), 125.2 (2C), 122.5, 26.3 (2C), 26.2 (2C).
IR (KBr): 3382 (br), 2929 (w), 2842 (w), 1612 (s), 1559 (s), 1383 (s),
1253 (w), 1216 (w), 1159 (w), 1097 (w), 1072 (w), 1025 (w), 926 (w),
869 (w), 829 (w), 803 (w), 778 (m), 745 (w), 708 (w), 698 (w), 631
(w) cm-1. FAB-MS m/z (rel intensity): 501 (M + 1, 38), 499 (41),
498 (100). Anal. Calcd for C24H14K2N4O4‚2H2O: C, 53.71; H, 3.38;
N, 10.44. Found: C, 53.30; H, 3.78; N, 10.19.
5,6,9,10-Tetrahydro[1,10]phenanthrolino[2,3-b][1,10]phenan-
throline-2,13-dicarboxylic Acid (3‚2H+). To a 50 mL Erlenmeyer flask
equipped with a stirring bar were added 1.64 g (3.27 mmol) of
potassium salt 3‚2K+ and 20 mL of water. The solution was stirred,
and 15% aqueous HCl solution was added dropwise until the pH of
the mixture reached 3-4. The resulting yellow precipitate was collected
by vacuum filtration, washed with 10 mL of water, and dried under
vacuum (0.1 mm) to give 1.34 g (97%) of crude diacid 3‚2H+. The
crude product was dissolved in 2.5 L of CHCl3/MeOH (3:1, v/v), which
was heated under reflux over a period of 2 days. The resulting mixture
was filtered through Whatman No. 5 filter paper, and the filtrate was
slowly concentrated to a volume of 60 mL by evaporation. The
precipitated solid was collected by vacuum filtration, washed with 10
mL of methanol, and dried under vacuum (0.1 mm) to give 0.70 g of
a yellow product (3‚2H+), mp 240-242 °C (dec). 1H NMR (300 MHz,
DMSO-d6): δ 8.32 (s, 2H), 8.06 (d, J ) 8.3 Hz, 2H), 7.98 (d, J ) 8.3
Hz, 2H), 3.18 (m, 4H), 3.16 (m, 4H). FAB-MS m/z (rel intensity): 425.4
(M + 1, 100), 381.3 (46), 337.4 (36). Anal. Calcd for C24H16N4O4‚H2O‚
CH3OH: C, 63.29; H, 4.67; N, 11.81. Found: C, 63.58; H, 4.36; N,
12.05.
1
°C, 3 d), dec > 340 °C. H NMR (300 MHz, D2O): δ 9.02 (s, 1H),
8.96 (s, 1H), 7.84 (s, 1H), 7.43 (d, J ) 7.8 Hz, 1H), 7.18 (d, J ) 7.8
Hz, 1H), 2.94 (t, J ) 7.1 Hz, 2H), 2.75 (t, J ) 7.1 Hz, 2H). 13C NMR
(125.7 MHz, D2O): δ 171.1, 160.5, 157.8, 156.3, 154.3, 151.5, 146.0,
138.3, 136.7, 135.3 (2C), 125.6, 118.4, 25.7, 25.0. FAB-MS m/z (rel
intensity): 317.3 (M + 1, 100). Anal. Calcd for C15H9N4O2K‚2H2O:
C, 51.13; H, 3.71; N, 15.90. Found: C, 51.00; H, 3.40; N, 15.73.
5,6-Dihydro-9-amino-8-formyl[1,10]phenanthrolinecarboxal-
dehyde-2-carboxylic Acid (12). A 500 mL round-bottomed flask
equipped with a stirring bar was charged with 4.00 g (12.6 mmol) of
5,6-dihydropyrimido[4,5-b][1,10]phenanthroline-2-carboxylic acid po-
tassium salt (11) and 200 mL of water. The solution was stirred, and
15% aqueous HCl solution was added dropwise until the pH of the
mixture reached 3-4 (approximately 2.5 mL of acid was required). A
yellow precipitate formed, and the resulting suspension was heated
under reflux for 10 h. The mixture was cooled to room temperature,
saturated with NaCl (56 g), and transferred into a liquid-liquid
continuous extractor attached to a 1 L round-bottomed flask containing
500 mL of EtOH/CH2Cl2, 1:7 (v/v). The suspension was extracted over
a period of 4 days. The organic extract was then dried over Na2SO4,
filtered through filter paper, and the solvent was removed by rotary
evaporation. The remaining yellow solid was dried under vacuum (0.1
mm) to give 2.72 g (80%) of aminoaldehyde 12, which was pure by
1H NMR spectroscopy and could be used for the next step. For
microanalysis, 12 was recrystallized from water and dried overnight
under vacuum (0.1 mm) to give yellow, rod-shaped crystals, mp 364-
Complex of 5,6,9,10-Tetrahydro[1,10]phenanthrolino[2,3-b][1,10]-
phenanthroline-2,13-dicarboxylate with Ethylguanidinium (3‚2CH3-
CH2NHC(NH2)2+). A 50 mL round-bottomed flask was charged with
100 mg (0.186 mmol) of 5,6,9,10-tetrahydro[1,10]phenanthrolino[2,3-
b][1,10]phenanthroline-2,13-dicarboxylic acid, dipotassium salt (3‚2K+),
and 3 mL of distilled water. The mixture was heated slightly to form
a clear solution, and then a solution of 50.7 mg (0.276 mmol) of
ethylguanidine sulfate (Aldrich, 98%) in 3 mL of water was added
into the flask. A pale yellow precipitate formed after 30-60 s. Next
15 mL of distilled water was added, and the mixture was heated to
1
366 °C (dec). H NMR (300 MHz, DMSO-d6): δ 9.91 (s, 1H), 8.01
9
14100 J. AM. CHEM. SOC. VOL. 124, NO. 47, 2002

Pyridine Hydrogen-Bonding Sites
A R T I C L E S
boiling until all of the solid dissolved. The hot solution was let to cool
to room temperature and stored undisturbed for 2 days. Some of the
resulting single crystals were removed with some mother liquor to
prevent the loss of solvent from the crystal lattice and were used for
X-ray analysis. The rest of the crystals were collected by vacuum
filtration, washed with 5 mL of cold water, and dried under vacuum
(0.1 mm) at 76 °C for 3 days. Anal. Calcd for C30H34N10O4‚1.5 H2O:
C, 57.58; H, 5.96; N, 22.38. Found: C, 57.47; H, 6.10; N, 22.54.
A solution of KOH in methanol was then added dropwise until the pH
reached 10; about 6 mL of 1.05 N methanolic KOH was required. Next
100 mL of butanol was added, and the mixture was heated at reflux
under nitrogen for 1 week. The solution was cooled to room temperature
and refrigerated overnight. The resulting yellow-green precipitate was
collected by vacuum filtration, washed with 50 mL of cold anhydrous
ethanol, and dried under vacuum (0.1 mm) to give 1.24 g (87%) of
crude dipotassium salt 5‚2K+. Of this material, 0.81 g was dissolved
in 7 mL of water, and this solution was filtered through filter paper.
The solution was heated to 80 °C, and ethanol was added dropwise
until the solution became cloudy. Two drops of water were added to
dissolve the cloudy precipitate, and the solution was refrigerated
overnight. The resulting yellow-greenish solid was collected by vacuum
filtration and dried at 80 °C under vacuum (0.1 mm) for 2.5 days to
5,6-Dihydrobenzo[h]pyrimido[4,5-b]quinoline-2-carboxylic Acid
(14). A 500 mL round-bottomed flask equipped with a magnetic stirring
bar, reflux condenser, and nitrogen gas inlet was charged with 6.5 g
(52.6 mmol) of 4-amino-5-pyrimidinecarboxaldehyde,20 10.0 g (52.6
mmol) of 7-carboxy-1-tetralone (13),21 and 300 mL of HPLC grade
methanol. The contents were heated to boiling, and a solution of KOH
in methanol was added dropwise until the pH reached 10; about 5.7
mL of 1.05 N KOH solution in methanol was required. The reaction
mixture was stirred under nitrogen at reflux temperature for 3 days.
The solution was then concentrated to 150 mL by boiling and acidified
to pH 6 with acetic acid. The resulting mixture was refrigerated
overnight. A yellow precipitate formed, which was collected by vacuum
filtration and dried under vacuum (0.1 mm) to give 10.3 g of
5,6-dihydrobenzo[h]pyrimido[4,5-b]quinoline-2-carboxylic acid (14).
The mother liquor was concentrated by rotary evaporation to a volume
of 50 mL, and then 100 mL of water was added, and the mixture was
refrigerated overnight. The deposited precipitate was collected by
vacuum filtration and dried under vacuum (0.1 mm) to give the second
crop of yellow solid (1.6 g). The combined crops of 14 (11.9 g, 82%)
1
give 0.27 g (33% recovery) of 5‚2K+. H NMR (300 MHz, D2O, 30
mM): δ 8.61 (s, 2H), 7.84 (d, J ) 7.8 Hz, 2H), 7.48 (s, 2H), 7.22 (d,
J ) 7.8 Hz, 2H), 2.70 (m, 8H). IR (KBr): 3160 (bw), 2937 (m), 1712
(s), 1676 (m), 1631 (w), 1604 (m), 1573 (w), 1560 (w), 1541 (w), 1479
(m), 1466 (m), 1439 (w), 1388 (m), 1370 (m), 1314 (w), 287 (w), 1217
(m), 1175 (w), 1119 (w), 1106 (w), 1069 (w), 1025 (m), 772 (m), 735
(w), 706 (w), 624 (w) cm-1. Anal. Calcd for C26H16K2N2O4‚2H2O: C,
58.41; H, 3.77; N, 5.24. Found: C, 58.34; H, 3.42; N, 5.11.
5,6,9,10-Tetrahydrodinaphtho[1,2-b:2′,1′-g][1,8]naphthyridine-
2,13-dicarboxylic Acid (5‚2H+). To a 25 mL Erlenmeyer flask
equipped with a stirring bar were added 1.64 g (3.27 mmol) of
potassium salt 5‚2K+ and 10 mL of water. The solution was stirred,
and 15% aqueous HCl solution was added dropwise until the pH of
the mixture reached 4-3. The yellow precipitate was then collected
by vacuum filtration, washed with 5 mL of water, and dried under
vacuum (0.1 mm) over P2O5 for 2 days to give 0.58 g of crude diacid
5‚2H+. The crude product was dissolved in 10 mL of boiling DMSO,
and 40 mL of water was added to the hot solution. The mixture was
cooled to room temperature, and the precipitated solid was collected
by vacuum filtration, washed with water (5 × 10 mL), then with
methanol (5 × 10 mL), and dried under vacuum (0.1 mm) at 90 °C for
3 days to give 0.47 g (73%) of yellow product 5‚2H+, dec > 400 °C.
1H NMR (300 MHz, DMSO-d6): δ 13.1 (br s, 2H), 9.10 (s, 2H), 8.22
(s, 2H), 7.97 (d, J ) 7.8 Hz, 2H), 7.49 (d, J ) 7.8 Hz, 2H), 3.1 (m,
8H). 13C NMR (125.7 MHz, DMSO-d6): δ 167.2, 154.1, 154.0, 144.3,
134.6, 133.9, 131.0, 130.6, 129.7, 128.6, 126.9, 122.1, 27.4, 27.1. FAB-
MS m/z (rel intensity): 423.4 (M + 1, 100), 278.3 (15). Anal. Calcd
for C26H18N2O4‚H2O: C, 70.90; H, 4.58; N, 6.36. Found: C, 71.04; H,
4.47; N, 6.50.
1
were pure by H NMR and were used without further purification in
the next step. For microanalysis, crude 14 was recrystallized from a
MeOH/AcOH (3:5, v/v) mixture and dried under vacuum (0.1 mm, 90
1
°C) for 5 days, mp 356-360 °C (dec). H NMR (300 MHz, DMSO-
d6): δ 13.2-13.0 (br s, 1H), 9.63 (s, 1H), 9.43 (s, 1H), 9.07 (d, J )
3
4
1.5 Hz, 1H), 8.49 (s, 1H), 8.05 (dd, J ) 7.8 Hz, J ) 2.0 Hz, 1H),
7.55 (d, J ) 7.8 Hz, 1H), 3.09-3.22 (m, 4H). 13C NMR (125.7 MHz,
DMSO-d6): δ 167.0, 161.4, 159.1, 157.9, 156.6, 145.2, 135.1, 133.2
(2C), 131.8, 130.1, 128.9, 127.5, 119.2, 27.1, 27.0. FAB-MS m/z (rel
intensity): 278.3 (M + 1, 100). Anal. Calcd for C16H11N3O2‚0.2H2O:
C, 68.42; H, 4.09; N, 14.96. Found: C, 68.30; H, 4.05; N, 14.86.
2-Amino-5,6-dihydro-3-formylbenzo[h]quinoline-9-carboxylic Acid
(15). A 500 mL round-bottomed flask, equipped with a magnetic stirring
bar and reflux condenser, was charged with 9.24 g (33.3 mmol) of
5,6-dihydrobenzo[h]pyrimido[4,5-b]quinoline-2-carboxylic acid (14),
250 mL of water, and 2 mL of concentrated aqueous HCl solution.
The suspension was heated to boiling and heated at reflux with stirring
over a period of 24 h. The mixture was then refrigerated overnight.
The resulting yellow solid was collected by vacuum filtration, washed
with water (2 × 20 mL), and dried under vacuum (0.1 mm) to give
8.84 g (98%) of 2-amino-5,6-dihydro-3-formylbenzo[h]quinoline-9-
carboxylic acid (15). For microanalysis, crude 15 was recrystallized
from a H2O/AcOH (3:5 v/v) mixture and dried under vacuum (0.1 mm,
Complex of 5,6,9,10-Tetrahydrodinaphtho[1,2-b:2′,1′-g][1,8]-
naphthyridine-2,13-dicarboxylate with Guanidinium (5‚2C(NH2)3+).
A 12 mL centifuge tube was charged with 50 mg (0.10 mmol) of
5,6,9,10-tetrahydrodinaphtho[1,2-b:2′,1′-g][1,8]naphthyridine-2,13-di-
carboxylic acid, dipotassium salt (5‚2K+), and 2 mL of distilled water.
The mixture was heated slightly to form a clear solution. A solution of
38 mg (0.40 mmol) of guanidine hydrochloride (Aldrich, 98%) in 2
mL of water was then added. The solutions were thoroughly mixed
and allowed to stand at 25 °C for 5 h. A pale yellow suspension formed,
which was separated by centrifugation, followed by decantation of the
clear supernatant solution. A solution of the precipitate in 10 mL of
boiling water was slowly cooled to room temperature over a period of
12 h, and was then allowed to stand at 25 °C. Small crystals formed
over a period of 3 d. For microanalysis, some of the crystals were
withdrawn and dried under vacuum (0.1 mm, 76 °C, 3 d). Anal. Calcd
for C28H28N8O4‚0.5H2O: C, 61.19; H, 5.32; N, 20.39. Found: C, 61.10;
H, 5.21; N, 20.26. For X-ray diffraction studies, several small seed
crystals were withdrawn and immediately (to prevent desolvation)
placed into the crystallization chamber, which was filled with water,
of an apparatus for growing crystals by slow diffusion of the reacting
solutions.23 One arm of the apparatus was charged with a solution of
1
95 °C, 5 d), dec > 230 °C. H NMR (300 MHz, DMSO-d6): δ 13.0
(br, 1H), 9.85 (s, 1H), 8.81 (d, J ) 1.5 Hz, 1H), 7.94 (dd, 3J ) 7.8 Hz,
4J ) 2.0 Hz, 1H), 7.93 (s, 1H), 7.5-7.7 (br, 2H), 7.44 (d, J ) 7.8 Hz,
1H), 2.97 (t, J ) 6.6 Hz, 2H), 2.85 (t, J ) 6.8 Hz, 2H). 13C NMR
(125.7 MHz, DMSO-d6): δ 192.7, 167.2, 157.3, 154.8, 144.6, 143.9,
133.4, 130.8, 129.5, 128.5, 126.6, 119.9, 112.5, 27.8, 25.5. FAB-MS
m/z (rel intensity): 269.3 (M + 1, 100). Anal. Calcd for C15H12N2O3‚
0.2H2O: C, 66.27; H, 4.60; N, 10.30. Found: C, 66.28; H, 4.41; N,
10.38.
5,6,9,10-Tetrahydrodinaphtho[1,2-b:2′,1′-g][1,8]naphthyridine-
2,13-dicarboxylic Acid, Dipotassium Salt (5‚2K+). A 250 mL round-
bottomed flask, equipped with a magnetic stirring bar, reflux condenser,
and nitrogen gas inlet, was charged with 0.55 g (2.87 mmol) of
7-carboxy-1-tetralone (13),21 0.77 g (2.87 mmol) of 2-amino-5,6-
dihydro-3-formylbenzo[h]quinoline-9-carboxylic acid (15), and 50 mL
of ethanol. The mixture was stirred and heated to boiling under nitrogen.
(23) Khasanov, A. B. Aldrichimica Acta 1999, 32, 74-90.
9
J. AM. CHEM. SOC. VOL. 124, NO. 47, 2002 14101

A R T I C L E S
Bell et al.
Table 4. Crystal Data and Structure Refinement for Complexes of
Receptors 3, 4, and 5
and 15% aqueous HCl solution was added dropwise until the pH of
the mixture reached 4-3. The yellow precipitate was then collected
by vacuum filtration, washed with 5 mL of water, and dried under
vacuum (0.1 mm) over P2O5 for 2 days to give 0.41 g of crude diacid
4‚2H+. The crude product was stirred and heated at reflux temperature
in 280 mL of CHCl3/MeOH (3:1, v/v) for a period of 2 days. The
mixture was then concentrated by rotary evaporation to a volume of
100 mL and refrigerated overnight. The precipitate was collected by
vacuum filtration, washed with 10 mL of methanol, and dried at 90 °C
under vacuum (0.1 mm) for 3 days to give 0.33 g (73%) of yellow
complex of:
3
4
5
empirical formula
formula weight
temperature/K
wavelength/Å
crystal system,
space group
unit cell dimensions
a/Å
C30H42N10O8
670.74
293(2)
0.71073
triclinic,
P-1
C30H35N9O5
601.67
293(2)
0.71073
monoclinic,
P21/n
C28H36N8O8
612.65
293(2)
0.71073
orthorhombic,
C2cb
10.606(12)
11.412(10)
14.128(15)
70.56(1)
79.36(1)
88.51(1)
13.370(15)
7.690(10)
29.78(4)
(90)
99.50(1)
(90)
21.20(2)
27.35(3)
10.808(12)
(90)
(90)
(90)
1
product 4‚2H+, mp 264-266 °C (dec). H NMR (300 MHz, DMSO-
b/Å
c/Å
d6): δ 13.1 (br s, 2H), 9.16 (s, 1H), 8.32 (s, 1H), 8.29 (s, 1H), 8.09 (d,
J ) 7.8 Hz, 1H), 8.01 (d, J ) 7.8 Hz, 1H), 8.00 (d, J ) 7.8 Hz, 1H),
7.53 (d, J ) 7.8 Hz, 1H), 3.2 (m, 8H). 13C NMR (125.7 MHz, DMSO-
d6): δ 167.1, 166.4, 154.4, 154.2, 153.7, 150.8, 147.8, 144.4, 139.3,
137.5, 134.8, 134.7, 134.0, 133.0, 131.8, 130.8, 129.9, 128.7, 127.0,
125.1, 122.5, 27.4, 27.2, 27.0, 26.8. FAB-MS m/z (rel intensity): 424.3
(M + 1, 100), 380.3 (33). Anal. Calcd for C25H17N3O4‚CH3OH‚
0.5H2O: C, 67.24; H, 4.77; N, 9.05. Found: C, 67.54; H, 4.70; N,
9.25.
R/°
â/°
γ/°
volume/Å3
1639(3)
3020(6)
4, 1.323
6267(12)
8, 1.299
Z, calculated density/ 2, 1.359
Mgm-3
reflections collected/ 5828
unique
6823/4027
4027/0/399
0.0987
10 648/2944
2944/0/416
0.1058
data/restraints/
5828/0/436
parameters
Complex of 5,6,9,10-Tetrahydro[7,8]quino[2,3-b][1,10]phenanthro-
line-2,13-dicarboxylate with Methylguanidinium (4‚2CH3NHC-
(NH2)2+). A 25 mL round-bottom flask was charged with 30.7 mg
(0.066 mmol) of 5,6,9,10-tetrahydro[7,8]quino[2,3-b][1,10]phenanthroline-
2,13-dicarboxylic acid (4‚2H+) and 5 mL of methanol. Next 56 µL of
a 25.4% solution of tetramethylammonium hydroxide in methanol
(Aldrich) was added, and the mixture was stirred to form a clear
solution. A solution of 30 mg (0.27 mmol) of methylguanidine
hydrochloride (Aldrich, 98%) in 1 mL of methanol was then added,
and the mixture was stirred briefly and then allowed to stand at 25 °C.
Small crystals formed over a period of 3 d. Several small crystals were
withdrawn and immediately (to prevent desolvation) placed into the
crystallization chamber of an apparatus for growing crystals by slow
diffusion of the reacting solutions,23 which was then filled with
methanol. One arm of the apparatus was charged with a solution of 31
mg (0.067 mmol) of 5,6,9,10-tetrahydro[7,8]quino[2,3-b][1,10]phenan-
throline-2,13-dicarboxylic acid (4‚2H+) and 58 µL of a 25.4% meth-
anolic solution of tetramethylammonium hydroxide (Aldrich) in 3 mL
of methanol. The other arm was charged with a solution of 32 mg
(0.29 mmol) of methylguanidine hydrochloride (Aldrich, 98%) in 3
mL of methanol. The apparatus was left undisturbed over 2 weeks to
obtain X-ray quality crystals, which were withdrawn and stored with
some of the mother liquor (to prevent desolvation). For microanalysis,
some of the crystals were dried under vacuum (0.1 mm, 90 °C, 5 d).
Anal. Calcd for C29H31N9O4‚1.5H2O: C, 58.38; H, 5.74; N, 21.13.
Found: C, 58.66; H, 5.43; N, 21.16.
Crystallographic Structure Determination. Crystal data were
collected with Mo KR radiation using the MARresearch Image Plate
System. The crystals were positioned at 70 mm from the Image Plate.
A total of 95 frames were measured at 2° intervals with a counting
time of 2 min. Data analysis was carried out with the XDS program.24
The structures were solved using direct methods with the Shelx86
program.25 The complex of receptor 3 contained four solvent water
molecules, each refined with full occupancy. In the complex of 4, one
guest molecule was disordered with the methyl group occupying two
possible sites. Associated with this disorder were two superimposed
methanol molecules, each compatible with one position of the methyl
group. The two possible sets of disordered atoms were refined with
occupancy factors of x and 1 - x, respectively. The value of x in the
refined structure was 0.64(1). In the complex of 5, six solvent water
molecules were found, of which two (O(500) and O(501)) were refined
with full occupancy and the others with 50% occupancy. In all three
structures, all non-hydrogen atoms were refined anistropically (apart
from disordered atoms). Hydrogen atoms bonded to carbon and nitrogen
final R indices
[I > 2σ(I)]
R1 0.0900,
wR2 0.2582
R1 0.1563
0.2712
0.1668
0.3179
0.2794
0.1318
0.3017
R indices (all data)
wR2 0.3002
largest diff. peak
and hole/e Å-3
0.587, -0.367 0.464, -0.336 0.549, -0.268
50 mg (0.10 mmol) of 5,6,9,10-tetrahydrodinaphtho-[1,2-b:2′,1′-g][1,8]-
naphthyridine-2,13-dicarboxylic acid and dipotassium salt (5‚2K+) in
3 mL of distilled water. The other arm was charged with a solution of
28 mg (0.30 mmol) of guanidine hydrochloride (Aldrich, 98%) in 3
mL of water. The apparatus was left undisturbed over 2 weeks to get
X-ray quality crystals, which were withdrawn and stored with some of
the mother liquor to prevent desolvation.
5,6,9,10-Tetrahydrobenzo[7,8]quino[2,3-b][1,10]phenanthroline-
2,13-dicarboxylic Acid, Dipotassium Salt (4‚2K+). A 250 mL round-
bottomed flask equipped with a magnetic stirring bar, reflux condenser,
and gas inlet was charged with 0.55 g (2.9 mmol) of 6,7-dihydro-8(5H)-
quinolinone-2-carboxylic acid (10), 0.77 g (2.9 mmol) of 2-amino-5,6-
dihydro-3-formylbenzo[h]quinoline-9-carboxylic acid (15), and 130 mL
of ethanol. The mixture was stirred and heated to boiling under nitrogen.
A solution of KOH in methanol was then added dropwise until the pH
reached 10; about 2.5 mL of 1.05 N methanolic KOH was required.
The resulting clear solution was stirred at reflux temperature under
nitrogen for 5 days. The solution was then cooled to room temperature,
and 100 mL of ether was added to cause precipitation. The mixture
was refrigerated overnight. The precipitate was collected by vacuum
filtration and dried under vacuum (0.1 mm) to give 1.5 g of crude
dipotassium salt 4‚2K+. A solution of the crude product in 10 mL of
hot water was heated to 80 °C, and 20 mL of ethanol was added
dropwise. The mixture was then refrigerated overnight. The resulting
yellow-greenish solid was collected by vacuum filtration and dried at
80 °C under vacuum (0.1 mm) for 2 days to give 1.05 g (73%) of
4‚2K+. 1H NMR (300 MHz, D2O, 30 mM): δ 8.65 (s, 1H), 7.84 (d, J
) 7.8 Hz, 1H), 7.75 (d, J ) 7.8 Hz, 1H), 7.48 (d, J ) 7.8 Hz, 1H),
7.17 (s, 1H), 7.15 (d, J ) 7.8 Hz, 1H), 7.12 (s, 1H), 2.76 (s, 8H). IR
(KBr): 3422 (bw), 2938 (m), 1709 (s), 1676 (s), 1608 (s), 1573 (w),
1478 (m), 1411 (m), 1374 (w), 1352 (w), 1312 (m), 1267 (m), 1223
(m), 1175 (w), 1131 (w), 912 (w), 809 (w), 770 (m), 736 (w), 707 (w),
618 (w), 577 (w) cm-1. Anal. Calcd for C25H15N3O4K2‚H2O: C, 58.01;
H, 3.31; N, 8.12. Found: C, 58.31; H, 3.13; N, 8.17.
5,6,9,10-Tetrahydrobenzo[7,8]quino[2,3-b][1,10]phenanthroline-
2,13-dicarboxylic Acid (4‚2H+). To a 25 mL Erlenmeyer flask
equipped with a stirring bar were added 0.54 g (1.06 mmol) of
potassium salt 4‚2K+ and 10 mL of water. The solution was stirred,
(24) Kabsch, W. J. Appl. Crystallogr. 1988, 21, 67-71.
(25) Shelx86. Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467-473.
9
14102 J. AM. CHEM. SOC. VOL. 124, NO. 47, 2002

Pyridine Hydrogen-Bonding Sites
A R T I C L E S
Table 5. Hydrogen-Bond Distances (Å) in Complexes of Receptors 3, 4, and 5
3
4
5
O(18)‚‚‚N(36)
O(18)‚‚‚O(54)
O(18)‚‚‚O(100)
O(19)‚‚‚O(100)
O(18)‚‚‚O(200)
N(33)‚‚‚O(200)
O(21)‚‚‚N(35)
O(21)‚‚‚N(45)
O(22)‚‚‚N(46)
N(35)‚‚‚N(15)
N(36)‚‚‚N(16)
2.829(6)
2.710(7)
2.791(8)
O(21)‚‚‚N(46)
2.924(12)
3.245(19)
2.79(2)
2.795(10)
2.825(11)
2.912(15)
2.974(16)
2.823(13)
2.90(3)
3.037(16)
2.90(3)
2.749(18)
2.95(2)
O(21)‚‚‚N(45)
2.995(11)
3.046(12)
2.563(15)
3.380(14)
2.926(7)
2.844(7)
2.837(6)
3.155(8)
3.050(8)
O(21)‚‚‚O(502)
O(21)‚‚‚O(500) $9
O(22)‚‚‚O(500) $1
O(22)‚‚‚N(35) $7
O(22)‚‚‚N(33) $7
O(19)‚‚‚N(43) $8
O(19)‚‚‚O(505) $8
O(19)‚‚‚N(35) $4
O(19)‚‚‚O(505) $5
O(18)‚‚‚O(503)
2.871(5)
2.912(5)
2.848(6)
3.060(5)
2.999(4)
In 3:
O(18)‚‚‚O(504)
N(33)‚‚‚O(54)
N(43)‚‚‚O(52)
N(46)‚‚‚O(51)
O(51)‚‚‚O(52)
O(53)‚‚‚O(52)
O(18)‚‚‚O(52) $1
O(19)‚‚‚O(53) $2
O(19)‚‚‚O(51) $3
O(10)‚‚‚N(45) $4
3.037(7)
2.886(7)
2.890(7)
3.167(10)
2.790(8)
2.882(8)
2.753(6)
2.936(7)
2.932(7)
O(18)‚‚‚N(36) $4
N(16)‚‚‚O(501)
2.994(19)
2.951(12)
3.283(12)
2.925(13)
3.06(3)
N(15)‚‚‚O(501)
O(500)‚‚‚N(43) $2
O(500)‚‚‚O(504) $2
O(501)‚‚‚O(502)
O(501)‚‚‚N(36)
2.78(3)
3.084(18)
3.081(17)
3.25(4)
2.95(3)
3.12(3)
2.81(2)
2.53(4)
2.72(7)
2.86(3)
O(501)‚‚‚N(33)
O(501)‚‚‚O(503)
O(502)‚‚‚N(36)
O(502)‚‚‚O(504) $6
O(503)‚‚‚N(46)
symmetry elements:
$1 2 - x, -y, 2 - z;
$2 x, y, 1 + z;
$3 x - 1, y + 1, z;
$4 1 - x, -y, 2 - z
O(504)‚‚‚O(504) $3
O(505)‚‚‚O(505) $4
O(505)‚‚‚N(45)
In 4:
O(505)‚‚‚N(36) $7
3.02(4)
O(22‚‚‚N(43) $1
O(19)‚‚‚N(43) $2
O(19)‚‚‚N(45) $2
N(33)‚‚‚O(54) $2
2.782(6)
2.771(6)
2.931(6)
2.998(14)
symmetry elements:
$2 x + 1/2, y, -z + 1/2;
$4 x, -y, -z;
$1 x - 1/2, y, -x + 3/2;
$3 x, -y, -z - 1;
$5 x + 1/2, -y, z - 1/2;
$7 x - 1/2, y, -z + 1/2;
$9 x - 1/2, -y, z - 1/2
$6 x, y, 1 + z;
$8 x + 1/2, y, -z - 1/2;
symmetry elements:
$1 1.5 - x, 0.5 + y, 0.5 - z;
$2 1 - x, -1 - y, -z
were included in calculated positions with thermal parameters set at
1.2 times those of the hydrogen atoms to which they were attached.
Hydrogen atoms bonded to the water molecules could not be located
and were not included. The structures were refined on F 2 using
Shelx1.26 Crystal data, data collection parameters, and refinement details
are given in Table 4. Distances between hydrogen-bonded atoms and
symmetry transformations are given in Table 5.
Acknowledgment. We thank the North Atlantic Treaty
Organization for a travel grant to Thomas W. Bell and Michael
G. B. Drew, as well as the E.P.S.R.C. (United Kingdom) and
the University of Reading for funding the Image Plate System
used for X-ray crystallography.
1
Binding Studies. H NMR spectra were measured on a VARIAN
Supporting Information Available: Tables of crystal data,
structure solution and refinement, atomic coordinates, bond
lengths and angles, and anisotropic thermal parameters for
complexes of receptors 3, 4, and 5, as well as tables of 1H NMR
data used for calculation of binding constants in methanol (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
UNITY spectrometer operating at 500 MHz. Chemical shifts were
referenced to the solvent resonances. Stability constants (Ks) were
calculated by fitting the equation described by Wilcox27 to the
experimental data by means of the program “Sigma Plot”.
(26) Shelx1. Sheldrick, G. M. Program for crystal structure refinement;
University of Gottingen, 1993.
(27) Wilcox, C. S. In Frontiers of Supramolecular Organic Chemistry and
Photochemistry; Schneider, H.-J., Du¨rr, H., Eds; VCH: New York, 1991;
pp 123-144.
JA0273694
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J. AM. CHEM. SOC. VOL. 124, NO. 47, 2002 14103