Ion pair driven self-assembly of a flexible bis-zwitterion in polar solution: Formation of discrete nanometer-sized cyclic dimers

Article abstract of DOI:10.1021/ja056465c

The self-complementary flexible bis-zwitterion 1 forms discrete nanometer-sized cyclic dimers via ion pair driven self-assembly even in polar solvents. The existence of such dimers was confirmed by DOSY NMR, FAB-MS, and scattering experiments (DLS, SANS)

Full text of DOI:10.1021/ja056465c

Published on Web 01/13/2006
Ion Pair Driven Self-Assembly of a Flexible Bis-Zwitterion in Polar Solution:
Formation of Discrete Nanometer-Sized Cyclic Dimers
Carsten Schmuck,*,† Thomas Rehm,† Franziska Gro¨hn,‡ Katja Klein,‡ and Frank Reinhold‡
UniVersity of Wu¨rzburg, Institute of Organic Chemistry, Am Hubland, 97074 Wu¨rzburg, Germany,
and Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
Received September 20, 2005; Revised Manuscript Received January 3, 2006; E-mail: schmuck@chemie.uni-wuerzburg.de
The reversible self-association of individual molecules can lead
to the formation of complex macroscopic assemblies with new and
interesting properties.1 For example, hydrogen bond-based self-
assembly of self-complementary DDAA binding motifs2 can lead
to supramolecular polymers.3,4 But the use of H-bonds limits the
self-assembly to organic solvents. Only in addition with π-stacking5
or metal-ligand6 interactions is aggregation in even more polar
solvents possible. There are very few reports for controlled self-
assembly in aqueous solvents solely based on electrostatic interac-
tions (H-bonds and ion pairs), in most cases limited to the
heterodimerization of rather rigid molecules derived from calix-
arenes or cyclodextrins.7 We present here a fully flexible self-
complementary bis-zwitterion 1 that forms discrete nanometer-sized
cyclic dimers in DMSO-water mixtures.
We could recently show that a guanidiniocarbonyl pyrrole
carboxylate zwitterion forms extremely stable dimers even in water
based on intermolecular ion pair formation.8 Linking two such
Figure 1. Schematic representation of the monomer/dimer equilibrium of
1 and the FAB-MS showing the coexistence of monomer and dimer in
solution (c < 10 mM in DMSO).
zwitterions via a spacer provides self-complementary bis-zwitterions
capable, in principle, of both intra- and intermolecular self-assembly,
depending on the nature of the spacer.9 For the first example 1, we
Scheme 1. Flexible Bis-Zwitterion 1 and Its Synthesis
chose a flexible and hydrophilic triethylene glycol chain as spacer.
δ-Aminocaproic acid methyl ester 3 was thus attached to the pyrrole
benzyl ester 2 via activation of the guanidino group by triflic
anhydride (Scheme 1).10 After hydrolysis of the methyl ester group
in 4 the resulting free acid 5 was reacted with 0.5 equiv of diamino
triethylene glycol 6. Deprotection of 7 first with H2/Pd and then
TFA provided, after pH adjustment, the flexible bis-zwitterion 1
in 89% yield.
The self-association properties of 1 were first investigated by
NMR dilution studies11 in DMSO-d6 in the concentration range of
0.5-50 mM (see Supporting Information [SI]). The NMR data
revealed a concentration-dependent equilibrium of two different
species in solution. However, in both species a fully associated
ion pair is present according to the observed chemical shifts. The
same results were also found for DMSO-water mixtures (DMSO-
d6/D2O mixtures). To obtain more information about these two
species, their corresponding hydrodynamic radii rH were determined
using DOSY experiments in DMSO-d6.12 The species predominating
in dilute solutions (1 mM) has a similar molecular dimension (rH
) 0.73 nm) as the protected monomer 7, which due to the lack of
charges cannot self-assemble (rH ) 1.03 nm). The species present
at higher concentrations (30 mM) is twice as large (rH ) 2.0 nm)
pointing to a monomer/dimer equilibrium as also supported by MS
experiments (Figure 1). Distinct signals for the monomer and a
concentration of 1, the monomeric loops then dimerizes to form
discrete spherical particles. The formation of such structures is
dimer (but no larger aggregates) were detected both in FAB and
supported by molecular mechanics calculations (see SI).
ESI-MS experiments. The triethyleneglycol spacer in 1 is long and
The formation of discrete particles of nanometer-sized dimension
by self-assembly of 1 in DMSO could also be confirmed by
dynamic light scattering (DLS) and small-angle neutron scattering
flexible enough to allow an intramolecular ion pairing between the
two zwitterionic moieties even in the monomer. With increasing
studies (SANS). DLS shows the existence of a single diffusion
mode corresponding to particles with a hydrodynamic radius of
† University of Wu¨rzburg.
‡ Max Planck Institute for Polymer Research.
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10.1021/ja056465c CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
leads to stable nanometer-sized discrete particles in DMSO-water
mixtures even without any structural bias within the molecule. We
are currently exploring how the aggregation behavior of such bis-
zwitterions (e.g., dimers vs oligomers and polymers) can be
deliberately controlled by variation of the spacer between the two
zwitterionic moieties.
Acknowledgment. This work was supported by the DFG and
the Fonds der Chemischen Industrie (FCI). SANS experiments were
performed at the Institute Laue Langevin (ILL) Grenoble, France,
at beamline D11 with support by Drs. P. Lindner and R. Schweins.
Supporting Information Available: Details on the synthesis, the
NMR, DOSY, ESI-MS, DLS, and SANS experiments and the molecular
mechanics calculations.
Figure 2. Intensity weighted distribution of hydrodynamic radii resulting
from CONTIN analysis of the DLS data measured at a scattering angle of
90° (c ) 50 mM in DMSO).
References
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Figure 3. Scattering curve (top) and Guinier plot (bottom) resulting from
the SANS experiments (c ) 45 mM in DMSO).
rH ≈ 3.0 (( 0.1) nm at c ) 50 mM in DMSO, in reasonably good
agreement with the DOSY NMR experiments.13 The size distribu-
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autocorrelation function is shown in Figure 2 and is characterized
by a standard deviation of 50% (relative peak width).14 Further
information about particle size and shape of these aggregates were
obtained from SANS measurements (Figure 3).15 The linearity of
the Guinier plot is consistent with a spherical particle shape. The
radius of gyration extracted from Guinier extrapolation in the
appropriate range of the scattering curve is rG ) 2.9 (( 0.2) nm,
once more in good agreement with both the NMR and the DLS
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(16) A closer analysis of the SANS data showed that in addition to monomers
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up to 11 nm is also present in solution under these conditions.
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In conclusion, the fully flexible bis-zwitterion 1 presented here
is, to the best of our knowledge, the first example for a homodimer-
ization solely based on a H-bond-enforced ion pair formation which
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