Self-assembly mediated by the Donor-Donor-Acceptor·Acceptor-Acceptor- Donor (DDA·AAD) hydrogen-bonding motif: Formation of a robust hexameric aggregate [12]

Full text of DOI:10.1021/ja981862r

9092
J. Am. Chem. Soc. 1998, 120, 9092-9093
Scheme 1
Self-Assembly Mediated by the
Donor-Donor-Acceptor‚Acceptor-Acceptor-Donor
(DDA‚AAD) Hydrogen-Bonding Motif: Formation of
a Robust Hexameric Aggregate
Sergei V. Kolotuchin and Steven C. Zimmerman*
Department of Chemistry, 600 South Mathews AVe.
UniVersity of Illinois, Urbana, Illinois 61801
ReceiVed May 28, 1998
There is currently intense interest in hydrogen bond mediated
self-assembly.1 Considerable effort in this area has focused on
discrete, cyclic assemblies containing between 3 and 10 mol-
ecules.1,2 A few hydrogen-bonding motifs have dominated this
work, including those found in the cyanuric acid-melamine
system,1a,2a carboxylic acid2b or pyridone dimers,2c,d and 2-ami-
nopyridine-carboxylic acid complexes.2e Despite the synthetic
accessibility of compounds possessing these various functional
groups, the hydrogen bonding contacts that they make have
distinct drawbacks. First, the contacts are rather weak (Kassoc
≈
stronger (Kassoc g 104 M-1 in CDCl3) than those used in the cyclic
aggregates described above.3,5
100 M-1 in CDCl3).3 Furthermore, at appropriate concentrations
the closed assemblies are formed because they are enthalpically
favored over polymeric ones, not because hydrogen-bonding
specifically guides the formation of cyclic aggregates.
The synthesis of 1 started with the chloronaphthyridine 26 and
a first generation dendron 3, which was synthesized by a
convergent approach similar to that used by Fre´chet7 (Scheme
1). The alkylation of 2 (R ) COC4H9) with 3 produced both O-
and N-alkylated regioisomers in an almost 1:1 ratio. Although
the desired isomer was isolated in ca. 30% yield, a superior
procedure used BOC derivative 5, prepared via 4. Deprotection
of 6 and subsequent cyclization8 with N-ethyl guanidine, generated
in situ from sodium hydride and an excess of its sulfate salt,
produced 1 in 55% yield.
Herein we describe an especially stable, hexameric, disk-shaped
aggregate (1)6 containing 18 hydrogen bonds formed by the
pairing of self-complementary DDA and AAD sites in 1.4 The
information in the DDA‚AAD hydrogen-bonding motif is unam-
biguous, dictating formation of a cyclic aggregate from 1.
Additionally, six (secondary) hydrogen bonds may be present in
(1)6 because the 2-NH group can serve as a long-range donor to
The elemental analysis and FAB mass spectra (M + H ) 783.5
for C49H62N6O3) were consistent with the proposed structure of
1. The structure was further corroborated by 1H NMR in DMSO-
d6 (60 °C), conditions in which 1 was expected to be monomeric
due to the competitive nature of the solvent. Most importantly,
the methylene of the N-ethyl group appears as a quintet indicating
splitting by the neighboring methyl and 2-NH groups. Thus, the
ethyl group is attached to N-2 and not N-3, as it would be in the
regioisomeric product of the reaction between 6 (BOC-depro-
tected) with N-ethyl guanidine. All other signals in the spectrum
are consistent with the assigned structure in the desired tautomeric
form although other forms could not be ruled out.
1
The corresponding H NMR spectra of 1 in THF-d8, CDCl3,
and toluene-d8 are very sharp and quite similar (Table 1). The
slightly further downfield shifts in toluene might indicate stronger
hydrogen bonding or a specific solvent effect. A COSY experi-
ment allowed definitive assignment of all the protons of 1. Of
particular note are the chemical shifts of the NH groups which
are far downfield of the analogous nonassociated NH groups in
7 and 8, but in the region where NH groups appear in hydrogen-
bonded complexes such as 10‚9 and 10‚11. A NOESY spectrum
N-1.3,5 Even without this auxiliary contact the DDA‚AAD
contacts in (1)6 are likely to be at least 2 orders of magnitude
(3) Zimmerman, S. C.; Murray, T. J. Philos. Trans. R. Soc. London, Ser.
A 1993, 345, 49-56 and references therein.
(4) During the course of this work a bicyclic system similar the tricyclic
one described herein was reported by Lehn and Mascal: Marsh, A.; Silvestri,
M.; Lehn, J.-M. Chem. Commun. 1996, 1527-1528. Mascal, M.; Hext, N.
M.; Warmuth, R.; Moore, M. H.; Turkenburg, J. P. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2204-2206.
(1) For reviews see: (a) Whitesides, G. M.; Simanek, E. E.; Mathias, J.
P.; Seto, C. T.; Chin, D. N.; Mammen, M.; Gordon, D. M. Acc. Chem. Res.
1995, 28, 37-44. (b) Conn, M. M.; Rebek, J., Jr. Chem. ReV. 1997, 97, 1647-
1668. (c) Lawrence, D. S.; Jiang, T.; Levett, M. Chem. ReV. 1995, 95, 2229-
2260. Philp, D.; Stoddart, J. F. Angew. Chem., Int. Ed. Engl. 1996, 35, 1154-
1196.
(2) For selected examples see: (a) Vreekamp, R. H.; van Duynhoven, J.
P. M.; Hubert, M.; Verboom, W.; Reinhoudt, D. N. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1215-1218. (b) Zimmerman, S. C.; Zeng, F.; Reichert, D. E.
C.; Kolotuchin, S. V. Science 1996, 271, 1095-1098. (c) Zimmerman, S. C.;
Duerr, B. F. J. Org. Chem. 1992, 57, 2215-2217. (d) Boucher, E.; Simard,
M.; Wuest, J. D. J. Org. Chem. 1995, 60, 1408-1412. (e) Yang, J.; Fan, E.;
Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1993, 115, 5314-5415.
(5) Jorgensen, W. L.; Pranata, J. J. Am. Chem. Soc. 1990, 112, 2008-
2010. Pranata, J.; Wierschke, S. G.; Jorgensen, W. L. J. Am. Chem. Soc. 1991,
113, 2810-2819. Zimmerman, S. C.; Murray, T. J. Tetrahedron Lett. 1994,
4077-4080.
(6) Fenlon, E. E.; Murray, T. J.; Baloga, M. H.; Zimmerman, S. C. J. Org.
Chem. 1993, 58, 6625-6628.
(7) Hawker, C. J.; Wooley, K. L.; Frechet, J. M. J. J. Chem. Soc., Perkin
Trans. 1 1993, 21, 1287-1297.
(8) Taylor, E. C.; Wong, G. S. K. J. Org. Chem. 1989, 54, 3618-3624.
S0002-7863(98)01862-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/21/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 35, 1998 9093
Table 1. 1H NMR Chemical Shifts (ppm) of NH Groups in 1 and Model Compoundsa
proton observed
NH-3
13.96
compd or complex
solvent
NH-2
10.89
NH-8
concn (% hexamer)b
1
CDCl3
THF-d8
10.33
10.48
10.87
10.32
10.38
10.26
10.40
0.3-13 mM (80)
90 µM to 10 mM (70)
35 µM to 14 mM (70)
4.2 mM (100)
4.8 mM (100)
2.4 to 16 mM (70)
6 mM (70)
11.00
11.18
10.86
10.94
10.66
11.00
4.80
14.04
14.28
13.94
13.94
13.89
14.00
toluene-d8
CD2Cl2
dioxane-d8
10% DMSO-d6/CDCl3
8% H2O/THF-d8
CDCl3
8
7
CDCl3
CDCl3
CDCl3
5.04
9‚10
10‚11
13.90c (10)
13.27c (11)
a Not all NH protons were seen in complexes. Compound 7 was prepared from 7-amino-2,4-dimethyl-1,8-naphthyridine and 3. Compounds
8-11 were available from a previous study (see ref 3). b For ranges, value represents percent of hexamer at lowest concentration. c Value represents
∆δmax obtained by curve fitting 1:1 binding isotherms.
of 1 in toluene-d8 shows a strong cross-peak between the 8-NH
and 3-NH groups that is also consistent with the pairing shown
a stable aggregate present from 0.25 to 14 mM. Heating a
in (1)6. Whereas the methylene groups of the benzylic ether
solution of 1 in toluene-d8 to 90 °C did not significantly alter the
groups resonate as singlets in DMSO-d6, they appear as AB
1H NMR spectra. Most strikingly, the aggregate persists across
a broad concentration range in apolar solvents, and remains the
quartets in the less polar solvents of Table 1. Molecular modeling
suggests that the methyl groups in the center of (1)6 alternate up
predominant species at millimolar concentrations in 8% v/v
aqueous THF and 10% DMSO-chloroform. Our previously
reported2b hexameric aggregate fully dissociated in THF,10 and
the cyclic hexamer was favored over linear oligomeric aggregates
only when peripheral steric interactions prevented formation of
the latter.11 The present results confirm the utility of the DDA‚
AAD hydrogen-bonding motif. Its superior stability and unam-
biguous information content make it an outstanding element for
supramolecular construction.
and down out of the plane of 1 so that the assembly has S6
symmetry and all methylene protons are diastereotopic.
To determine the structure of the aggregate, molecular weight
determinations were carried out by using size exclusion chroma-
tography (SEC) calibrated with polystyrene standards. In either
chloroform or dichloromethane, 1 interacts strongly with the
matrix of the SEC column, and is fully retained. This absorption
is attributed to the polar hydrogen-bonding sites interacting with
the column matrix. The same SEC retention is observed for 7 in
toluene and in dichloromethane. In pure toluene the aggregate
of 1 is not adsorbed and its SEC peak is sharp and symmetrical;
and the elution time is independent of the injection concentration
(from 10 mM to 4 µM). It is estimated that g90% of the injected
sample is eluted as determined by UV analysis of the collected
peak. The aggregate has a polystyrene equivalent molecular
weight between 5660 and 6050 Da, a value that is 20-29% higher
than that calculated for a hexamer (4698 Da) and 3-10% higher
than that calculated for a heptamer (5481 Da). Because of the
uncertainties in using polystyrene as a standard, dendrimer 12
was prepared as a covalent analogue of (1)6.2c,9 Molecular
modeling suggests a very similar size for 12 and (1)6. Indeed,
these compounds exhibit identical SEC elution times in toluene.
Combined with the fact that a heptamer cannot be constructed
with CPK models, the SEC results suggest formation of a
hexameric aggregate from 1.
Acknowledgment. The authors thank Prof. P. A. Petillo and Drs. B.
Fink, T. Hamada, V. Mainz, and F. Zeng for helpful discussions and Dr.
P. A. Thiessen for providing starting material. Earlier synthetic investiga-
tions on a related molecule by Dr. E. E. Fenlon are gratefully
acknowledged. S.V.K. thanks the University of Illinois for a graduate
fellowship. The National Institutes of Health is gratefully acknowledged
for funding (GM-39782).
Supporting Information Available: Synthetic schemes and charac-
terization data for compound 12 (9 pages, print/PDF). See any current
masthead page for ordering information and Web access instructions.
JA981862R
(10) A referee asked for a quantitative comparison of the thermodynamic
stability of the two hexameric aggregates. Despite significant effort we have
been unable to determine a K6 value for 1 in solvents where monomer and
hexamer coexist.
(11) Peripheral crowding was used in Whitesides’ rosette assembly:
Mathias J. P.; Simanek E. E.; Whitesides G. M. J. Am. Chem. Soc. 1994,
116, 4326-4340.
1
The stability of the aggregate was further investigated by H
NMR experiments in various solvents (Table 1). The results of
a dilution experiment in toluene-d8 mirrored the SEC results with
(9) The synthesis of 12 is described in the Supporting Information.