Hydrogen-bond-mediated self-assembly of aminopyrazolones: Macrocyclic quartets - Single and stacked one-dimensional motifs

Article abstract of DOI:10.1002/anie.200502539

The fab four: Aminopyrazolones which incorporate two ditopic hydrogen-bond donor-acceptor pairs of amide and amidine functional groups can self-assemble through formation of four hydrogen bonds. Single-crystal X-ray diffraction analysis reveals that homom

Full text of DOI:10.1002/anie.200502539

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ular components has garnered considerable success as a
procedure for the spontaneous generation of well-defined
discrete and recurrent architectures.[2,3] Hydrogen-bond-
mediated self-assembly has proven especially effective,[3]
largely because of the design of tailored recognition elements
in the form of hydrogen-bond donor–acceptor arrays, which
allows the free energy and “orthogonality” of recognition
events to be tuned.[3c] The utility of hydrogen-bond recog-
nition elements is highlighted by their application to the
design of oligomers (foldamers) that adopt specific secondary
structures,[4,5] molecular strands that engage in specific modes
of intermolecular aggregation,[6] polymers possessing non-
covalent main chains[7] and side chains,[8] as well as the self-
assembly of dendritic macromolecules.[9]
We recently developed duplex molecular strands based on
the aminotriazine and diaminopyridazine hydrogen-bonding
motifs as part of a program concerning hydrogen-bond-
mediated self-assembly.[10] These systems engage in high-
affinity twofold self-association, as established by isothermal
1
titration calorimetry (ITC), H NMR dilution studies, vapor
pressure osmometry (VPO), and single-crystal X-ray diffrac-
tion analysis. With the goal of developing synthetic strands
that self-assemble to form transmembrane channels,[11] we
sought oligomers incorporating recognition elements that
direct fourfold self-association. While quadruplexes based on
guanosine and their structural relatives are commonplace,[12]
other heterocyclic molecules that participate in hydrogen-
bond-mediated fourfold self-association are exceptionally
uncommon.[13] 3,5-Disubstituted pyrazoles are known to
form dimers A, as well as cyclic trimers B and tetramers C,
in solution and in the solid state (Scheme 1).[14] It was
postulated that the hitherto unexplored aminopyrazolones 1
should preferentially engage in fourfold self-association
through heteromeric aggregation (amide–amidine), as the
quadruplex type arrangement is reinforced by four additional
hydrogen bonds as in 14. However, homomeric association
(amide–amide, amidine–amidine) of aminopyrazolone 1 may
compete to provide 1-dimensional motif 1n. Finally, because
ditopic association is relatively weak, arrangements involving
unrequited hydrogen-bond donor–acceptor sites are probable
in the solid state.[15]
Self-Assembly
DOI: 10.1002/anie.200502539
Hydrogen-Bond-Mediated Self-Assembly of
Aminopyrazolones: Macrocyclic Quartets—
Single and Stacked One-Dimensional Motifs**
Aminopyrazolones 1a–1c were synthesized according to a
literature procedure.[16] Specifically, ethyl cyanoacetate was
subjected to exhaustive alkylation followed by hydrazination
to afford dibutylaminopyrazolone 1a, didodecylaminopyra-
zolone 1b, and dibenzylaminopyrazolone 1c. Synthesis of the
optically pure C2-symmetric bis(aminopyrazolone) 1d was
achieved through the alkylation of a chirally modified
cyanoacetate ester based on (1S,2R,4R)-10-dicyclohexylsulf-
amoylisoborneol (Scheme 2).[17]
Single crystals of compounds 1a–1d were obtained and
subjected to X-ray diffraction analysis to determine the mode
of assembly in the solid state. Analysis of crystals of
dibutylaminopyrazolone 1a obtained from ethyl acetate
reveal a 1-dimensional hydrogen-bonding motif involving
homomeric association of the ditopic hydrogen-bond donor–
acceptor sites (amide–amide, amidine–amidine; Figure 1).
Hegui Gong and Michael J. Krische*
A broad goal of modern research resides in the development
of selective protocols for the organization of matter across
length scales.[1] Toward this end, the self-assembly of molec-
[*] H. Gong, Prof. M. J. Krische
University of Texas at Austin
Department of Chemistry and Biochemistry
1 University Station–A5300
Austin, TX 78712-1167 (USA)
Fax: (+1)512-471-8696
E-mail: mkrische@mail.utexas.edu
[**] Acknowledgment is made to the Research Corporation Cottrell
Scholar Award (CS0927), the Alfred P. Sloan Foundation, the
Dreyfus Foundation, and the NSF-CAREER Program.
À
À
The N H···N and N H···O hydrogen bonds in the linear
aggregate (1a)n have equal lengths of 3.07 Š. In contrast, X-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Figure 1. Top: Solid-state structure of dibutylaminopyrazolone 1a.
Bottom: Solid-state structure of C2-symmetricbis(aminopyrazolone)
1d. Solvent is omitted for clarity.
Scheme 1. Assembly modes established for 3,5-disubstituted pyrazoles
and those proposed for aminopyrazolones 1.
Figure 2. Solid-state structure of didodecylaminopyrazolone 1b.
aggregate are 3.02 Š and 2.93 Š, respectively. A pore size of
approximately 2.6 Š is estimated when the van der Waals
radii are taken into account; hence, the pore size is sufficiently
large to accommodate lithium, sodium, and potassium ions.
The solid-state structure of dibenzylaminopyrazolone 1c
reveals a non-coplanar arrangement of the aminopyrazolone
rings.[18] The energetic driving force represented by the
packing preferences of the phenyl moieties in 1c, appears to
supercede the free energy of hydrogen-bond formation, as
only one of the four hydrogen-bond donor–acceptor sites
forms a contact with another aminopyridazine molecule.
Finally, X-ray diffraction analysis of a crystal of C2-symmetric
bis(aminopyrazolone) 1d obtained from 1,3-dimethyl-2-imi-
dazolidinone reveals a stacked 1-dimensional motif. In this
Scheme 2. Synthesis of bis(aminopyrazolone) 1d. Reagents: a) PCl5
(100 mol%), Et2O (0.3m), 258C. b) R*OH (50 mol%), AgCN
(75 mol%), PhCH3 (0.1m), 608C, 70% over two steps. c) LDA
(120 mol%), 1,3-diiodopropane (50 mol%), HMPA (150 mol%), THF
(0.1m), À788C to 258C, 38%. d) LiOH in MeOH (1.83n,
1830 mol%), 258C, 83%. e) PCl5 (212 mol%), Et2O (0.1m). f) MeOH
(excess), 258C, 97% over two steps. g) NH2NH2-H2O (1000 mol%),
1058C, 70%. LDA=lithium diisopropylamide, HMPA=hexamethyl
phosphoramide.
À
À
stacked motif, N H···N and N H···O hydrogen-bond lengths
of 3.01/3.02 Š and 2.89 Š are observed, respectively.
ray diffraction analysis of crystals of didodecylaminopyrazo-
lone 1b obtained from 1,2-dichloroethane reveals the desired
cyclic quartet structure (1b)4 derived through heteromeric
association (amide–amidine, amide–amidine; Figure 2). The
In summary, initial studies on the hydrogen-bond-medi-
ated self-assembly of aminopyrazolones have established that
two primary modes of aggregation are evident for n-alkyl-
substituted aminopyrazolones 1a, 1b, and 1d in the solid
À
À
N H···N and N H···O hydrogen-bond lengths in the cyclic
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Received: July 20, 2005
Published online: October 7, 2005
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[13] To our knowledge, other than guanosines and pyrazoles, only
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[14] For an exhaustive account of the self-assembly of 3,5-disubsti-
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[15] 2-Aminopyrimidines which incorporate ditopic hydrogen-bond
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[17] N. Martin, A. Martinez-Grau, C. Seoane, J. L. Marco, A. Albert,
F. H. Cano, J. Heterocycl. Chem. 1996, 33, 27 – 31.
Keywords: donor–acceptor systems · host–guest systems ·
hydrogen bonds · noncovalent interactions · self-assembly
.
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