Hydrogen-bonded cyclic tetramers based on ureidopyrimidinones attached to a 3,6-carbazolyl spacer

Article abstract of DOI:10.1021/ol200946b

Direct attachment of two 2-ureido-4-[1H]-pyrimidinone (UPy) subunits to a 3,6-carbazolyl core gives rise to a highly viscous, supramolecular polymer. However, insertion of a methylene spacer between the UPy's and the carbazole leads to a well-defined, cyclic tetramer, in a belt-shaped arrangement, as evidenced by MALDI-TOF, DOSY, and NOESY spectra.

Full text of DOI:10.1021/ol200946b

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3186–3189
Hydrogen-Bonded Cyclic Tetramers
Based on Ureidopyrimidinones Attached
to a 3,6-Carbazolyl Spacer
Yong Yang, Min Xue, Laura J. Marshall, and Javier de Mendoza*
Institute of Chemical Research of Catalonia (ICIQ), 43007-Tarragona, Spain
jmendoza@iciq.es
Received April 27, 2011
ABSTRACT
Direct attachment of two 2-ureido-4-[1H]-pyrimidinone (UPy) subunits to a 3,6-carbazolyl core gives rise to a highly viscous, supramolecular
polymer. However, insertion of a methylene spacer between the UPy’s and the carbazole leads to a well-defined, cyclic tetramer, in a belt-shaped
arrangement, as evidenced by MALDI-TOF, DOSY, and NOESY spectra.
Self-assembly based on hydrogen bonding has been
widely employed to build up large rosette-like, often flat
supramolecular structures.1,2 In addition to cyanuric acidꢀ
melamine combinations,3 hydrogen bonded scaffolds
inspired by G-C pairs,4 G-quartet mimics,5 or on pyridines,6
hydrazides,7 and carboxylic acids,8 among others,9 have
been reported. In this context, the 2-ureido-4-[1H]-
pyrimidinone (UPy) scaffold has been efficiently em-
ployed to design and build up self-assembled supramole-
cular architectures,10 due to the remarkable strength of the
dimers arising from its quadruple hydrogen bonding edge
[Ka (chloroform) >107 Mꢀ1].11 Well-defined rosettes
(4) (a) Marsh, A.; Silvestri, M.; Lehn, J.-M. Chem. Commun. 1996,
1527. (b) Mascal, M.; Hext, N. M.; Warmuth, R.; Moore, M. H.;
Turkenburg, J. P. Angew. Chem., Int. Ed. Engl. 1996, 35, 2204.
(c) Mascal, M.; Hext, N. M.; Warmuth, R.; Arnall-Culliford, J. R.; Moore,
M. H.; Turkenburg, J. P. J. Org. Chem. 1999, 64, 8479. (d) Mascal, M.;
Farmer, S. C.; Arnall-Culliford, J. R. J. Org. Chem. 2006, 71, 8146.
(e) Kolotuchin, S. V.; Zimmerman, S. C. J. Am. Chem. Soc. 1998, 120,
9092. (f) Ma, Y.; Kolotuchin, S. V.; Zimmerman, S. C. J. Am. Chem. Soc.
2002, 124, 13757. (g) Fenniri, H.; Mathivanan, P.; Vidale, K. L.; Sherman,
D. M.; Hallenga, K.; Wood, K. V.; Stowell, J. G. J. Am. Chem. Soc. 2001,
123, 3854. (h) Fenniri, H.; Deng, B. L.; Ribbe, A. E. J. Am. Chem. Soc. 2002,
124, 11064. (i) Fenniri, H.; Deng, B. L.; Ribbe, A. E.; Hallenga, K.; Jacob,
J.; Thiyagarajan, P. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 6487.
(j) Moralez, J. G.; Raez, J.; Yamazaki, T.; Motkuri, R. K.; Kovalenko, A.;
Fenniri, H. J. Am. Chem. Soc. 2005, 127, 8307. (k) Johnson, R. S.; Yamazaki,
T.; Kovalenko, A.; Fenniri, H. J. Am. Chem. Soc. 2007, 129, 5735.
(5) For reviews on G-quartets, see: (a) Davis, J. T. Angew. Chem., Int. Ed.
2004, 43, 668. (b) Davis, J. T.; Spada, G. P. Chem. Soc. Rev. 2007, 36, 296.
(6) Asadi, A.; Patrick, B. O.; Perrin, D. M. J. Am. Chem. Soc. 2008,
130, 12860.
(1) (a) Lindoy, L. F.; Atkinson, I. M. Self-assembly in Supramolecular
Systems; Royal Society of Chemistry: Cambridge, 2000. (b) Pelesko, J. A. Self
Assembly: The Science of Things That Put themselves Together; Chapman &
Hall/CRC, Taylor & Francis Group: Boca Raton, FL, 2007. (c) Lehn, J.-M.
Science 2002, 295, 2400. (d) Whitesides, G. M.; Grzybowski, B. Science 2002,
295, 2418. (e) Philp, D.; Stoddart, J. F. Angew. Chem., Int. Ed. Engl. 1996, 35,
1154.
(2) For a discussion on the factors that favour rosettes over open-chain
oligomers, see: Ballester, P. de Mendoza, J. In Modern Supramolecular
Chemistry: Strategies for Macrocycle Synthesis; Diederich, F., Stang, P. J.,
Tykwinski, R. R., Eds.; WileyꢀVCH: Weinheim, 2008; pp 69ꢀ111.
(3) For reviews on cyanuric acidꢀmelamine rosettes, 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. (b) Lawrence, D. S.;
Jiang, T.; Levett, M. Chem. Rev. 1995, 95, 2229. (c) Prins, L. J.; Reinhoudt,
D. N.; Timmerman, P. Angew. Chem., Int. Ed. 2001, 40, 2382. (d) Mateos-
Timoneda, M. A.; Crego-Calama, M.; Reinhoudt, D. N. Chem. Soc. Rev.
2004, 33, 363. (e) Vazquez-Campos, S.; Crego-Calama, M.; Reinhoudt,
D. N. Supramolecular Chem. 2007, 19, 95.
(7) Yang, Y.; Xue, M.; Xiang, J.-F.; Chen, C.-F. J. Am. Chem. Soc. 2009,
131, 12657.
r
10.1021/ol200946b
Published on Web 05/24/2011
2011 American Chemical Society

result when two UPy subunits are attached to a suitable
rigid spacer. Thus, cyclic pentamers with 20 hydrogen bonds
are favored with 1,3-disubstituted adamantyl (109° angle),
whereas hexamers containing 24 hydrogen bonds arise
from m-phenylene (120°).10b Similarly, cyclic tetramers
are formed when a metalloporphyrin containing UPy’s
at two vicinal meso-positions (90°) is employed.10d
We reasoned that a 3,6-disubstituted carbazolyl spacer
with an angle of ∼90° would also favor tetrameric cyclic
arrangements, stabilized by 16 hydrogen bonds, and we were
curious to discover whether flat rosette-like or tubular belt-
like aggregates would predominate. To test this idea, we first
synthesized compounds 1 and 2 (Figure 1) from the corre-
sponding readily available nitro-derivatives, resulting in the
direct attachment of the UPy moiety to the carbazole ring.
ill-defined spectrum. Addition of a trace of trifluoroacetic
acid greatly decreased the viscosity, resulting in full solubili-
zation of the species, and a well resolved spectrum compatible
with monomer 2 emerged. It is likely that linear oligomers or
polymers 2n were favored over the desired, though rigid and
crowded, cyclic tetramer 24. CPK modeling studies12 gave a
clearer insight into the explanation for this observation. With
the UPy moieties attached directly to the carbazole ring,
flexibility would be a significant factor when considering the
formation of hydrogen bonds between the monomers. The
assembly of a flat, rosette-like structure would ultimately
result in twisting of the structure (torsional strain) and
subsequent unfavorable hydrogen-bonding angles due to
the presence of the undecyl chains at the inner region of the
rosette. This is highly unfavorable due to steric interactions,
and models show that there is clearly not sufficient space
inside a flat rosette to accommodate the long alkyl chains.
Therefore, the assembly of linear oligomers or polymers is
likely to dominate.
To increase the flexibility, a methylene group was inserted
between the UPy subunits and the carbazole spacer. Thus
compound 4 and the corresponding control 3were prepared.
In 4, the UPy subunits can adopt multiple conformations
(Figure 2) that could generate cyclic oligomers of various
sizes and shapes. Once again, model inspection clearly shows
that a flat trimer or tetramer cannot be built for torsional and
steric reasons. On the contrary, folded structures can easily
be arranged. Indeed, model optimizations12 for either cyclic
trimers or tetramers are fully compatible with propeller-like
shapes where both UPy subunits in each monomer are
pointing to opposite sides (Figure 3a and 3b). In the case
of the tetramer, a very favorable, sterically unhindered
tubular (belt-like) shape can be generated with both UPy
subunits being mirror images pointing to the same side of the
carbazole spacer (Figure 3c).
Figure 1. Mono- and disubstituted carbazoles with UPy sub-
units 1 (12 dimer shown) and 2 (monomer), and schematic
representation of linear oligomers 2n.
Although the well-defined, typical signature for a UPy
1
dimer 12 was observed in the H NMR spectrum of com-
pounds 1 in CDCl3 (sharp peaks at 13.20, 12.36, and 12.25
ppm) in the downfield region,10,11 compound 2 showed only
limited solubility (ca. 5 mM), high viscosity, and a broad,
(8) (a) Zimmerman, S. C.; Duerr, B. F. J. Org. Chem. 1992, 57, 2215. (b)
Boucher, E.; Simard, M.; Wuest, D. J. J. Org. Chem. 1996, 60, 1408. (c)
Zimmerman, S. C.; Zeng, F.; Reichert, D. E. C.; Kolotuchin, S. V. Science
1996, 271, 1095.
(9) (a) Corbin, P. S.; Lawless, L. J.; Li, Z.; Ma, Y.; Witmer, M. J.;
Zimmerman, S. C. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 5099. (b) Todd,
E. M.; Zimmerman, S. C. J. Am. Chem. Soc. 2007, 129, 14534. (c) Todd,
E. M.; Zimmerman, S. C. Tetrahedron 2008, 64, 8558.
ꢀ
(10) (a) Gonzalez, J. J.; Prados, P.; de Mendoza, J. Angew. Chem.,
ꢀ
Int. Ed. 1999, 38, 525. (b) Keizer, H. M.; Gonzalez, J. J.; Segura, M.;
Prados, P.; Sijbesma, R. P.; Meijer, E. W.; de Mendoza, J. Chem.;Eur.
ꢀ
J. 2005, 11, 4602. (c) Hahn, U.; Gonzalez, J. J.; Huerta, E.; Segura, M.;
Eckert, J.-F.; Cardinali, F.; de Mendoza, J.; Nierengarten, J.-F.
Chem.;Eur. J. 2005, 11, 6666. (d) Ohkawa, H.;Takayama, A.;Nakajima,
S.; Nishide, H. Org. Lett. 2006, 8, 2225. (e) Huerta, E.; Metselaar, G. A.;
Fragoso, A.; Santos, E.; Bo, C.; de Mendoza, J. Angew. Chem., Int. Ed. 2007,
46, 202. (f) Huerta, E.; Cequier, E.; de Mendoza, J. Chem. Commun. 2007,
5016.
(11) (a) Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.;
Hirschberg, J. H. K. K.; Lange, R. F. M.; Lowe, J. K. L; Meijer, E. W.
Science 1997, 278, 1601. (b) Beijer, F. H.; Kooijman, H.; Spek, A. L.;
Sijbesma, R. P.; Meijer, E. W. Angew. Chem., Int. Ed. 1998, 110, 79.
(c) Folmer, B. J. B.; Sijbesma, R. P.; Kooijman, H.; Spek, A. L.; Meijer,
Figure 2. Mono- and disubstituted carbazoles 3 (32 dimer
shown) and 4 (monomer), and schematic representation of
conformations around the UPy subunits.
€
E. W. J. Am. Chem. Soc. 1999, 121, 9001. (d) Sontjens, S. H. M.;
Sijbesma, R. P.; van Genderen, M. H. P.; Meijer, E. W. J. Am. Chem.
Soc. 2000, 122, 7487.
Org. Lett., Vol. 13, No. 12, 2011
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In this arrangement, all alkyl chains at both edges of the
hydrogen bonded belt orient away from the assembly
(Figure 3d and 3e), and into the bulk solvent, thus providing
greater solubility and reduced steric hindrance compared to
the flat systems.
Figure 4. MALDI-TOFþ Mass spectrum of compound 4
showing the presence of the monomer, dimer, trimer, and
tetramer.
Figure 3. Schematic representation of cyclic aggregates from 4.
(a) Propeller-shaped trimer. (b) Propeller-shaped tetramer. (c)
Tubular-shaped tetramer. Side (d) and top (e) views of opti-
mized tubular-shaped 44 aggregates.
Spectroscopic data were in full agreement with our pre-
dictions of a tubular belt-like assembly. Unlike 2, both
1
compounds 3 and 4 showed sharp H NMR signals in
CDCl3 with three well-defined singlets for the UPy’s NH
signature (compound 3: 13.03, 11.96, and 10.82 ppm;
compound 4: 13.03, 12.07, and 10.83 ppm). Also, com-
pound 4 showed increased solubility (>40 mM in CDCl3)
relative to 2, and the viscosity of the solution was almost the
same as that of the solvent itself.
Molecular masses of the trimer and the tetramer were
clearly observed by MALDI-TOFþ (m/z 2761 and 3682,
respectively), accompanied by the monomer and the
dimer, but no peaks were observed for higher aggregates
(Figure 4 and Supporting Information; see Figure
SS22).
Also, the DOSY spectrum (CDCl3) at different concen-
trations showed a well-defined signal on the D axis,
indicating the presence of a discrete species in solution at
the NMR time scale (Figure 5). The spectra show the slight
change of D with the concentration increase, which favors
cyclic oligomers.2
Figure 5. DOSY spectrum of compound 4 (CDCl3) at 7 mM
(blue), 10 mM (pink), and 25 mM (light blue) concentrations.
theoretical one, which can be approximately calculated
bytaking the average ofthe length, width, and height ofthe
dissolved species,14 as measured on the optimized models
for the different cyclic oligomers.12 The average estimated
3
radii/volumes for a tetramer (9.95 A/ 4126 A ) and a
˚
˚
3
˚
˚
pentamer (11.8 A/6882 A ) strongly point toward a tetra-
mer as the dominant species in solution.
Using the StokesꢀEinstein equation, the experimentally
Low temperature NMR allowed us to unequivocally
assign the structure shown in Figure 3d and 3e for the most
populated aggregate. At 213 K (10 mM in CDCl3), the
spectrum shows a unique set of sharp signals for the UPy
subunits, accounting for a symmetric structure with a
plane of symmetry bisecting the carbazole core. As ex-
pected, the methylene protons attached to the carbazolyl
found diffusion coefficients can be converted to an ap-
proximate hydrodynamic radius.13 Thus, a value of 9.29 A
˚
results at a 25 mM concentration, which translates into a
3
“sphere” volume of 3358 A . This experimental value for
˚
the hydrodynamic radius can be compared with a
(12) Structures were minimized in vacuo by molecular mechanics
using Augmented MM3 parameters (OG_MM-MM3 protocol) within
the SCIGRESS 7.7.0.47 software (Fujitsu Ltd.)
(14) Timmerman, P.; Weidmann, J.-L.; Jollife, K. A.; Prins, L. J.;
Reinhoudt, D. N.; Shinkai, S.; Frish, L.; Cohen, Y. J. Chem. Soc., Perkin
Trans. 2 2000, 2077.
(13) rh = kbT/(6πηD), in which the solute is a spherical species.
3188
Org. Lett., Vol. 13, No. 12, 2011

core split into two doublets, accounting for a rigid struc-
ture with different environments for each proton (Figure
6). These findings strongly point to a belt-shaped tetra-
meric assembly, like that shown in Figure 3d and 3e. In
good agreement with this geometry, the NOESY spectrum
at 213 K shows contacts between H1 and the 4-carbazolyl
proton as well as with the urea protons (Figure 6, arrows c,
g, and f). H2, however, is coupled with the 2-carbazolyl
proton and also to the urea protons, but to a lesser extent
than H1. This indicates that both hydrogen-bonded edges
are oriented anti with respect to the carbazolyl N-
substituent.
In summary, we have demonstrated that 2-ureido-
4-[1H]-pyrimidinone (UPy) subunits attached to a 3,6-
carbazolyl core self-assemble into tubular cyclic tetra-
mers, in which substituents are oriented to both edges of
the ring. Due to the possibility of carbazole-based
polymers displaying interesting optical and electrical
properties,15 it is likely that modification of the central
cores to allow self-assembly of a second array of UPy
partners would provide an easy access to polymeric
carbazolyl nanotubes possessing interesting optical
and electrical properties. We are currently exploring
these possibilities.
Figure 6. Low temperature (CDCl3, 213 K) NOESY spectrum of
compound 4 (partial section showing contacts with methylene
H1 and H2 protons).
Acknowledgment. The Ministry of Science and Innova-
tion of Spain (Grants CTQ2008-00183 and Consolider
Ingenio 2010 CSD 2006-0003) and the ICIQ Foundation
are kindly acknowledged.
Supporting Information Available. Experimental de-
tails, characterization and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.
org.
(15) Li, J.; Grimsdale, A. C. Chem. Soc. Rev. 2010, 39, 2399.
Org. Lett., Vol. 13, No. 12, 2011
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