Enhanced small-molecule assembly through directional intramolecular forces

Article abstract of DOI:10.1021/ol051768x

(Chemical Equation Presented) Directional intramolecular interactions play a critical role in the self-assembly of donor-σ-acceptor molecules in solution. Amide functions on the periphery of the tricyclic core stabilize a C₃-symmetric monomer c

Full text of DOI:10.1021/ol051768x

ORGANIC
LETTERS
2005
Vol. 7, No. 20
4471-4474
Enhanced Small-Molecule Assembly
through Directional Intramolecular
Forces
Andrew J. Lampkins, Osama Abdul-Rahim, Hengfeng Li, and
Ronald K. Castellano*
Department of Chemistry, UniVersity of Florida, P.O. Box 117200,
GainesVille, Florida 32611-7200
castellano@chem.ufl.edu
Received July 26, 2005
ABSTRACT
Directional intramolecular interactions play a critical role in the self-assembly of donor-
σ
-acceptor molecules in solution. Amide functions on
the periphery of the tricyclic core stabilize a C3-symmetric monomer conformation by intramolecular hydrogen bonding and dipole
−dipole
interactions. The molecules are effective organogelators and show long-range ordering in the bulk.
Directional noncovalent interactions, such as hydrogen
bonding and π-π stacking, underlie self-assembly strategies
to control the association and alignment of functional organic
molecules in solution wherefrom useful macromolecular
properties and architectures emerge.1,2 We recently demon-
strated3 that suitably functionalized donor-σ-acceptor (D-σ-
A) molecules 14 (Figure 1) are prone to self-assemble in
solution, thus introducing σ-coupled donor-acceptor inter-
actions5-7 as complements to traditional forces in the directed
self-organization of small molecules.8 Tribenzyl 1-aza-
adamantanetrione 1a, for example, shows organogelation
behavior and the formation of fibrous structures from the
gel phase.3,9
In this communication we demonstrate how the macro-
molecular properties and solid-state ordering of D-σ-A
molecules can be uniquely modulated by substituents that
experience specific intramolecular interactions with the core.
(6) (a) Verhoeven, J. W.; Dirkx, I. P.; de Boer, T. J. Tetrahedron Lett.
1966, 7, 4399-4404. (b) Dekkers, A. W. J.; Verhoeven, J. W.; Speckamp,
W. N. Tetrahedron 1973, 29, 1691-1696. (c) Worrell, C.; Verhoeven, J.
W.; Speckamp, W. N. Tetrahedron 1974, 30, 3525-3531. (d) Pasman, P.;
Verhoeven, J. W.; de Boer, T. J. Tetrahedron 1976, 32, 2827-2830.
(7) (a) Hoffmann, R. Acc. Chem. Res. 1971, 4, 1-9. (b) Gleiter, R.
Angew. Chem., Int. Ed. Engl. 1974, 13, 696-701. (c) Paddon-Row, M. N.
Acc. Chem. Res. 1982, 15, 245-251.
(1) Lehn, J.-M. Supramolecular Chemistry; VCH: Weinheim, 1995.
(2) (a) Whitesides, G. M.; Mathias, J. P.; Seto, C. T. Science 1991, 254,
1312-1319. (b) Lawrence, D. S.; Jiang, T.; Levett, M. Chem. ReV. 1995,
95, 2229-2260. (c) Hof, F.; Craig, S. L.; Nuckolls, C.; Rebek, J., Jr. Angew.
Chem., Int. Ed. 2002, 67, 8291-8298. (d) Elemans, J. A. A. W.; Rowan,
A. E.; Nolte, R. J. M. J. Mater. Chem. 2003, 13, 2661-2670. (e) Hoeben,
F. J. M.; Jonkheijm, P.; Meijer, E. W.; Schenning, A. Chem. ReV. 2005,
105, 1491-1546.
(8) For the self-assembly of π-conjugated donor-acceptor chromophores,
see: Yao, S.; Beginn, U.; Gress, T.; Lysetska, M.; Wu¨rthner, F. J. Am.
Chem. Soc. 2004, 126, 8336-8348 and references therein.
(3) Li, H.; Homan, E. A.; Lampkins, A. J.; Ghiviriga, I.; Castellano, R.
K. Org. Lett. 2005, 7, 443-446.
(4) For the original synthesis of the 1-aza-adamantanetrione core, see:
Risch, N. J. Chem. Soc., Chem. Commun. 1983, 532-533.
(5) Cookson, R. C.; Henstock, J.; Hudec, J. J. Am. Chem. Soc. 1966,
88, 1060-1062.
(9) (a) Terech, P.; Weiss, R. G. Chem. ReV. 1997, 97, 3133-3159. (b)
Abdallah, D. J.; Weiss, R. G. AdV. Mater. 2000, 12, 1237-1247. (c)
Gronwald, O.; Snip, E.; Shinkai, S. Curr. Opin. Colloid Interface Sci. 2002,
7, 148-156.
10.1021/ol051768x CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/03/2005

hexamethylenetetramine (HMTA)3,4 in 2-propanol at reflux
provides tricyclic targets 2. The moderate yield of the final
step is offset by the simple purification of the products that
only involves filtration and at most a single recrystallization
(for 2b).
Solubility studies of amides 2 in common organic solvents
immediately reveal their unusual solution-phase behavior and
propensity for aggregation. Trianilide 2a is sparingly soluble
in most organic solvents, and surprisingly limited improve-
ment comes with even dodecyl (2b) substituents on the
aromatic rings. This behavior is in contrast to 1b (Figure 1),
which shows good solubility in a broad range of organic
solvents at room temperature. Most interesting is the behavior
of 2b in halogenated solvents (e.g., chloroform, carbon
tetrachloride, and 1,1,2,2-tetrachloroethane) where it rapidly
(in minutes) forms optically clear gels9 following heating
and cooling. For chloroform, the most effectively gelled
solvent, complete immobilization of the solution is observed
at ∼0.5 wt % (the critical gelation concentration) with a sol-
gel transition temperature (Tgel) of 57 °C, the highest value
that we have observed for this class of gelators thus far.
Moreover, the chloroform gels of 2b show no sign of
precipitation after months at room temperature. The DMSO
gels of 1a are comparatively less stable,3 but this difference
can only partially be attributed to the additional alkyl chains
of 2b. Derivative 1b requires both higher concentration (ca.
2 wt %) and lower temperature (-15 °C) for aggregation,10
with the compound remaining freely soluble in chloroform
at room temperature.
Figure 1. Aryl-functionalized donor-σ-acceptor molecules.
Triamides of the 1-aza-adamantanetriones 2 are introduced
that show enhanced aggregation properties relative to 1 and
form stable and ordered assemblies in solution, the gel phase,
and the bulk. Studies implicate the amide groups in this
disparate behavior, but not through their participation in
traditional intermolecular hydrogen-bonding interactions.
Featured are intramolecular seven-membered ring N-
H(amide)‚‚‚O(ketone) H-bonding and favorable electrostatic
interactions between the opposing core and amide dipoles.
The effects mutually stabilize (1) a C3-symmetric conforma-
tion of the monomer that is “active” in self-assembly and
(2) ground state σ-coupled donor-acceptor interactions at
the core. The latter intramolecular “solvation” of the D-σ-A
core by peripheral dipolar functional groups appears as a
new way to tune the electronic and macromolecular proper-
ties of these systems.
The synthesis of the 1-aza-adamantanetrione triamides 2
is outlined in Scheme 1. Bromomethylated phloroglucinol
Freeze-dried samples of the chloroform gels of 2b were
studied by SEM (Figure 2a,b). Unlike the fibrous morphology
of the dried gels of 1a and many organogelators,9 here a
lamellar architecture is observed that in some regions appears
as layered slabs of fairly uniform thickness (200-500 nm,
Figure 2a) and in others more typical curved, wrinkled sheets
(Figure 2b).11 X-ray diffraction (XRD) studies (Figure 2c)
also reveal this long-range periodic order for the neat (solid)
samples of 2b where an intense low-angle peak is observed
at a d-spacing of 30.1 Å (001) and two higher-order
reflections are found at 15.1 Å (002) and 9.7 Å (003). Also
evident is a diffuse band attributable to packing of the alkyl
side chains (d ) 4.7 Å). Of particular relevance to 2b, similar
layered (smectic) structural order has been characterized for
propeller-shaped metallomesogens12 and for bowl-shaped
CTVs and calixarenes.13,14 Interestingly, both 1a and 1b,
which lack amide functions, show significantly weaker XRD
Scheme 1. Synthesis of Amide-Functionalized
1-Aza-adamantanetriones 2
(10) At these conditions the mixture is turbid and stable to inversion.
The material “melts” sharply at ca. -5 °C upon warming.
(11) For recent examples of gelators that show lamellar architectures,
see: (a) Ko¨lbel, M.; Menger, F. M. Chem. Commun. 2001, 275-276. (b)
Jung, J. H.; Shinkai, S.; Shimizu, T. Chem. Eur. J. 2002, 8, 2684-2690.
(c) Park, S. M.; Lee, Y. S.; Kim, B. H. Chem. Commun. 2003, 2912-
2913. (d) Jang, W.-D.; Aida, T. Macromolecules 2003, 36, 8461-8469.
(e) John, G.; Jung, J. H.; Masuda, M.; Shimizu, T. Langmuir 2004, 20,
2060-2065. (f) Moreau, J. J. E.; Vellutini, L.; Wong Chi Man, M.; Bied,
C.; Dieudonne´, P.; Bantignies, J.-L.; Sauvajol, J.-L. Chem. Eur. J. 2005,
11, 1527-1537. (g) Tanaka, S.; Shirakawa, M.; Kaneko, K.; Takeuchi, M.;
Shinkai, S. Langmuir 2005, 21, 2163-2172.
derivative 33 is converted to tricarboxylic acid 4 through
benzylic substitution with cyanide followed by base-catalyzed
hydrolysis of the nitrile functions. Activation of the triacid
and subsequent amide bond formation with an appropriate
aniline derivative gives 5. In addition to aniline (to afford
5a), 15N-enriched aniline imparts an isotopic probe (5a*),
and p-dodecylaniline introduces a solubilizing substituent
(5b). Deprotection of the core with BBr3 and cyclization with
(12) Zheng, H.; Swager, T. M. J. Am. Chem. Soc. 1994, 116, 761-762.
(13) Lunkwitz, R.; Tschierske, C.; Diele, S. J. Mater. Chem. 1997, 7,
2001-2011.
4472
Org. Lett., Vol. 7, No. 20, 2005

Figure 3. Computational analysis:15 (a) top view of the low-energy
conformation of a simplified version of 2a; (b) the “active” self-
assembling conformation of 2a based on computation and spec-
troscopic studies (top view as a space-filling representation); (c)
the superimposed energy-minimized structures of 1a (orange)3 and
2a; hydrogen atoms have been omitted for clarity. Hydrogen
bonding is shown by the dashed lines. All molecules are racemic.
that a symmetric H-bonded conformation of triamide 2 exists
as the “active” self-assembled conformer follows through
spectroscopic studies in solution and the solid state.
To assess H-bonding within 2 we performed IR and NMR
studies with 2a,b and commercially available N-phenyl-
acetamide 6 (Figure 4a, inset).20 The model shows predict-
able amide behavior in solution (solid line); at 0.2 M in
CHCl3 a sharp absorption is observed at 3440 cm-1 that
represents the solvent-associated (“free”) NH stretch, while
a broad absorption is detectable at 3325 cm-1 arising from
intermolecular amide-amide H-bonding.21,22 The latter peak
grows in at higher concentrations and is not seen below ca.
10 mM. The IR spectrum of 2b (Figure 4a, dashed line)
shows a single, moderately sharp NH absorption at 3360
cm-1 in CHCl3 at 3.4 mM (0.25 wt %).23 The shift of the
amide NH absorption of 2b to this unique frequency is
consistent with seven-membered ring H-bonding involving
the amide NH and ketone carbonyl group; similar frequencies
are reported for intramolecularly H-bonded γ-ketoamides24
(ν N-H‚‚‚O ) 3335-3380 cm-1 and ν N-Hfree ) 3440
Figure 2. Structural order within amide-functionalized 1-aza-
adamantanetriones 2: (a, b) SEM images of a xerogel formed from
freeze-drying the 0.5 wt % chloroform gel of 2b; (c) X-ray
diffraction pattern of neat 2b at 21 °C.
patterns and numerous Bragg peaks at room temperature for
their solids (not shown).
The role of the amide functions in the self-assembly
behavior of 2 could be probed through IR and NMR
measurements and by computational analysis. The lowest
energy conformer15 of the simplified aza-adamantanetrione
core bearing one anilide substituent and two methyl substit-
uents (Figure 3a) displays seven-membered ring H-bonding
between the amide NH and the core carbonyl. Also apparent
in this conformation is how the dipole of the D-σ-A core
and dipole of the peripheral amide are favorably opposed.16
Transposing this lowest energy single arm conformation to
all three arms of 2 creates the C3-symmetric (and racemic),
propeller-shaped17 conformer of 2a shown as an energy-
minimized space-filling model (Figure 3b). Superimposition
shows that this conformation18,19 is pseudoisosteric with the
predicted low-energy structure of 1a (orange bonds, Figure
3c) previously implicated in self-assembly.3 Direct evidence
(19) Opposition of the peripheral amide dipoles and donor-σ-acceptor
core dipole reduces the molecular dipole moment (at the HF/6-31G* level
1a ) 4.1 D, 2a ) 3.4 D) but stabilizes the σ-coupled donor-acceptor
interactions at the core based on the large downfield 1H NMR chemical
shift of the core N-R-CH2 protons3 of 2 relative to 1 (∆δ ∼0.5 ppm) in
halogenated and polar solvents.
(20) That the amides of 2 and 6 are electronically comparable comes
through NMR studies of the monomeric species in DMSO-d6 (ca. 10 mM):
1
NH H NMR chemical shift, 2a ) 10.0 ppm, 6 ) 9.8 ppm; amide CdO
13C NMR chemical shift, 2a ) 168.0 ppm, 6 ) 168.4 ppm.
(21) In the bulk (Nujol), exclusive intermolecular H-bonding is observed
for 6 given as a broad NH absorption at 3288 cm-1. This is consistent with
the X-ray crystal structure of 6 (CSD code ACANIL01), which shows
intermolecular hydrogen bonding with an N‚‚‚O distance of 2.91 Å.
(22) For detailed studies of intramolecular hydrogen-bonding phenomena,
see: (a) Gellman, S. H.; Dado, G. P.; Liang, G.-B.; Adams, B. R. J. Am.
Chem. Soc. 1991, 113, 1164-1173. (b) Dado, G. P.; Gellman, S. H. J. Am.
Chem. Soc. 1993, 115, 4228-4245.
(14) Dodecyl 2b does exhibit an endothermic phase transition at ca. 185
°C (DSC) where a viscous, birefringent texture is also observed by polarized
light microscopy. The phase behavior of both 2a and 2b is currently being
explored.
(15) See the Supporting Information for computational details.
(16) The related H-bonded substituent conformation that inverts the amide
group (not shown) is calculated to be 3.7 kcal mol-1 higher in energy (at
the HF/6-31G* level).
(23) The NH stretch frequency and NH 1H NMR chemical shift (vide
infra) are concentration-independent within the 3-fold concentration range
permitted by instrument sensitivity at lower concentrations and extensive
aggregation at higher concentrations. The peak at 3360 cm-1 is observed
as the sole band in the NH region in the bulk (Nujol) and the gel phase (at
0.50 wt % by ATR-IR spectroscopy).
(17) Mislow, K. Acc. Chem. Res. 1976, 9, 26-33.
(18) The C1-symmetric conformer with two amides H-bonded to a single
carbonyl suffers from steric repulsion between the aromatic rings.
(24) (a) Chiron, R.; Maisonneuve, P.; Graff, Y. C. R. Acad. Sci. Paris,
Ser. C 1973, 276, 105-108. (b) Chiron, R.; Graff, Y. Spectrochim. Acta,
Part A 1976, 32, 1303-1310.
Org. Lett., Vol. 7, No. 20, 2005
4473

the upfield limiting chemical shift of 7.0 ppm that represents
the monomeric species in this solvent.26 That the amide
chemical shift of 2b remains downfield of this value at the
highest accessible NMR temperature reflects stable ag-
gregates in solution and exclusive intramolecular H-bonding
to the core.
Final evidence for the C3-symmetric conformation pro-
posed for 2 (Figure 3b) comes through solid-state NMR
studies performed with 15N-enriched 2a* (Scheme 1). The
15N CPMAS NMR spectrum (Figure 4b) shows one sharp
peak for the three equivalent amide nitrogens at -241.9 ppm,
while the 13C CPMAS NMR spectrum (Figure 4c) reveals
two carbonyl resonances, one from the amides (169.5 ppm)
and one from the three equivalent core ketones (197.0 ppm).27
These results importantly contrast with the previously
obtained 13C CPMAS NMR data for 1a, which revealed
multiple 13C resonances and a loss of symmetry in the solid
state.3 Taken together with the powder XRD results, 2 shows
both long-range and local order in the bulk. With these data
in hand and ready access to derivatives through synthesis
(Scheme 1), we are undertaking detailed structural investiga-
tions to elucidate a general model for the packing of 2.13,28
In summary, amide-functionalized D-σ-A molecules 2
show enhanced self-assembly properties in solution and
significantly more order in the solid state relative to
congeners 1. Spectroscopic and computational studies im-
plicate a unique interplay between the amide functions and
the donor-σ-acceptor core in this behavior, where intramo-
lecular hydrogen bonding and dipolar interactions stabilize
the C3-symmetric conformation of the monomer required for
self-assembly. We are currently exploring in more detail how
neighboring dipolar functional groups can tune the σ-coupled
donor-acceptor interactions in these molecules toward
further controlling their macromolecular behavior in solution.
Figure 4. (a) The IR spectrum of 6 at 0.2 M in chloroform (solid
line) shows both a “free” amide NH stretch (3440 cm-1) and
evidence for intermolecular H-bonding (3325 cm-1); the spectrum
of 2b at 3.4 mM (0.25 wt %; dashed line) shows exclusive
intramolecular H-bonding (3360 cm-1); the 15N (b) and 13C (c)
CPMAS NMR spectra of 2a* reveal a symmetrical monomer in
the solid state. Starred peaks represent sidebands.
Acknowledgment. We are grateful to the University of
Florida for financial support. A.J.L. is a UF Alumni Graduate
Fellow. We thank Dr. Kerry Siebein of the UF Major
Analytical Instrumentation Center (UF MAIC) for the SEM
measurements, Dana Horoszewski and Prof. Colin Nuckolls
(Columbia University) for assistance with the X-ray diffrac-
tion, Prof. Joanna Long for the solid-state NMR measure-
ments, and Dr. Phil Britt of the Center for Nanophase
Materials Sciences at Oak Ridge National Laboratories for
insightful discussions.
cm-1 (at 1 mM in CCl4)). That no “free” NH stretch is
detectable for 2b in dilute solution (to the detection limit,
∼0.10 wt %) demonstrates that intramolecular H-bonding
is uniquely present, presumably coupled with monomer
aggregation.
The IR studies are qualitatively supported by NMR
measurements.22 Not unexpectedly, the 1H NMR spectra of
2b in deuterated halogenated solvents are broadened, indica-
tive of extensive aggregation. This is even the case for 2b
in CDCl3 at low concentration (2 mM) and elevated
temperature (323 K), although the amide NH remains a fairly
sharp singlet at 7.62 ppm (downfield of TMS). VT NMR
measurements of 2b at 13 mM in the higher boiling C2D2Cl4
confirm a very small temperature dependence for the amide
proton (7.60-7.44 ppm from 298 to 398 K; ∆δ/∆T ) -1.6
ppb/K), consistent with intramolecular H-bonding.22,25 For
comparison, the -NH shift of 6 in C2D2Cl4 at 298 K and
the amide molar equivalent concentration of 39 mM is 7.1
ppm. Dilution experiments for 6 confirm that this is near
Supporting Information Available: Synthetic details and
characterization data, computational protocols, additional
XRD data, and relevant NMR data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL051768X
(26) Luo, W. C.; Chen, J. S. Z. Phys. Chem. (Muenchen) 2001, 215,
447-459.
(27) For comparison, 15N-enriched 6 shows single 15N and 13C (carbonyl
carbon) resonances at -244.1 and 171.4 ppm, respectively.
(28) (a) Maltheˆte, J.; Collet, A. J. Am. Chem. Soc. 1987, 109, 7544-
7545. (b) Serrette, A. G.; Lai, C. K.; Swager, T. M. Chem. Mater. 1994, 6,
2252-2268. (c) Sawamura, M.; Kawai, K.; Matsuo, Y.; Kanie, K.; Kato,
T.; Nakamura, E. Nature 2002, 419, 702-705.
(25) Stevens, E. S.; Sugawara, N.; Bonora, G. M.; Toniolo, C. J. Am.
Chem. Soc. 1980, 102, 7048-7050 and references therein.
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