Controlled supramolecular oligomerization of C3-symmetrical molecules in water: The impact of hydrophobic shielding

Article abstract of DOI:10.1002/chem.201002976

The supramolecular oligomerization of three water-soluble C ₃-symmetrical discotic molecules is reported. The compounds all possess benzene-1,3,5-tricarboxamide cores and peripheral Gd^III-DTPA (diethylene triamine pentaacetic acid) m

Full text of DOI:10.1002/chem.201002976

FULL PAPER
DOI: 10.1002/chem.201002976
Controlled Supramolecular Oligomerization of C3-Symmetrical Molecules in
Water: The Impact of Hydrophobic Shielding
Pol Besenius,[a] Kelly P. van den Hout,[a] Harald M. H. G. Albers,[a] Tom F. A. de Greef,[b]
Luuk L. C. Olijve,[b] Thomas M. Hermans,[a] Bas F. M. de Waal,[a] Paul H. H. Bomans,[c]
Nico A. J. M. Sommerdijk,[c] Giuseppe Portale,[d] Anja R. A. Palmans,[a]
Marcel H. P. van Genderen,[a] Jef A. J. M. Vekemans,[a] and E. W. Meijer*[a]
Abstract: The supramolecular oligome-
rization of three water-soluble C3-sym-
metrical discotic molecules is reported.
The compounds all possess benzene-
1,3,5-tricarboxamide cores and periph-
eral GdIII–DTPA (diethylene triamine
pentaacetic acid) moieties, but differ in
their linker units and thus in their pro-
pensity to undergo secondary interac-
tions in H2O. The self-assembly behav-
ior of these molecules was studied in
solution using circular dichroism, UV/
Vis spectroscopy, nuclear magnetic res-
onance, and cryogenic transmission
electron microscopy. The aggregation
concentration of these molecules de-
pends on the number of secondary in-
teractions and on the solvophobic char-
acter of the polymerizing moieties. Hy-
drophobic shielding of the hydrogen-
bonding motif in the core of the discot-
ic is of paramount importance for
yielding stable, helical aggregates that
are designed to be restricted in size
through anti-cooperative, electrostatic,
repulsive interactions.
Keywords: aggregation · hydrogen
bonds · oligomerization · supra-
molecular chemistry
Introduction
cations in diagnostics or biomedical applications,[8–10] such as
regenerative medicine,[11,12] drug delivery,[13,14] or molecular
imaging.[15] When working in aqueous conditions, an essen-
tial design parameter for the self-assembling moiety is a pos-
itive balance between hydrophobic and hydrophilic charac-
ters, ensuring water solubility as well as shielding of the
polymerizing self-assembly code from competing water mol-
ecules. Popular examples are phospholipids,[16,17] amphiphilic
block copolymers,[18–22] peptide amphiphiles,[23–26] low-molec-
ular-weight hydrogelators,[27–32] or foldamers.[33] We have re-
cently reported the anti-cooperative supramolecular oligo-
merization of discotic amphiphiles that form objects of con-
trolled size and shape.[34] We introduced order into the ob-
tained architectures by relying on the well-known C3-sym-
metrical benzene-1,3,5-tricarboxamide (BTA) unit, which in
solution has a strong tendency to form columnar aggregates
based on a triple hydrogen-bonding motif.[35–38] By introduc-
ing highly charged peripheral GdIII–DTPA (diethylene tri-
Controlled supramolecular chemistry in water is an exciting
challenge.[1–4] A significant amount of research activity is
aimed at mimicking constructions found in biological sys-
tems,[5–7] and many more are targeted at technological appli-
[a] Dr. P. Besenius, Dr. K. P. van den Hout, H. M. H. G. Albers,
Dr. T. M. Hermans, B. F. M. de Waal, Dr. A. R. A. Palmans,
Dr. M. H. P. van Genderen, Dr. J. A. J. M. Vekemans,
Prof. Dr. E. W. Meijer
Institute for Complex Molecular Systems and
Laboratory of Macromolecular and Organic Chemistry
Department of Chemical Engineering and Chemistry
Eindhoven University of Technology
P.O. Box 513, 5600 MB Eindhoven (The Netherlands)
Fax : (+31)40-2474706
E-mail: E.W.Meijer@tue.nl
[b] Dr. T. F. A. de Greef, L. L. C. Olijve
Department of Biomedical Engineering
Eindhoven University of Technology
AHCTUNGTREGaNNNU mine pentaacetic acid) groups we managed to restrict the
one-dimensional growth of the objects[34] in a process that
can be referred to as frustrated growth.[39,40] In this study, a
series of structural variations in the polymerizing hydropho-
bic core of discotic amphiphiles is described (Figure 1), high-
lighting the requirement for hydrophobic shielding of the
hydrogen-bonding motif. We have focused on highly charged
GdIII–DTPA discotics, as they might turn out to be valuable
compounds for evaluation as magnetic resonance imaging
(MRI) contrast agents.[15,41–47]
P.O. Box 513, 5600 MB Eindhoven (The Netherlands)
[c] P. H. H. Bomans, Dr. N. A. J. M. Sommerdijk
Laboratory of Materials and Interface Chemistry and
Soft Matter CryoTEM Research Unit
Department of Chemical Engineering and Chemistry
Eindhoven University of Technology
P.O. Box 513, 5600 MB Eindhoven (The Netherlands)
[d] Dr. G. Portale
BM26 - DUBBLE, European Synchrotron Radiation Facility (ESRF)
6 rue Jules Horowitz, BP220, 38043 Grenoble (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002976.
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5193

intermediate was reacted with
0.30 molar equivalents of tri-
mesic chloride in the presence
of DiPEA as a base. Consecu-
tive saponification yielded the
triacid, which was allowed to
react with tetrafluorophenol
using 1-ethyl-3-(3-dimethylami-
nopropyl) carbodiimide (EDC)
as a coupling reagent and in the
presence of a catalytic amount
of
4-dimethylaminopyridine
(DMAP). The trifunctional
ester was coupled to 3.1 molar
equivalents of the fully depro-
tected l-lysine-DTPA analogue
in the presence of DiPEA as a
base. Finally, metal complexes
3a and 3b were prepared by
adding GdACTHUNTRGENN(UG OAc)3 or YACHTUNGTRENNUNG(OAc)3,
respectively (Scheme S3). Struc-
tural characterization of all in-
Figure 1. Structures of the amphiphilic MIII–DTPA discotics 1–3 (1a–3a: MIII =GdIII, 1b–3b: MIII =YIII).
Results and Discussion
termediates was carried out
1
through a combination of analytical techniques, including H
and 13C NMR spectroscopy, IR spectroscopy, MALDI-TOF
MS, and elemental analysis. The metal complexes were char-
acterized with IR and ESI-MS, and the GdIII or YIII content
was determined with inductively coupled plasma mass spec-
trometry (ICP-MS).
The tendency for the various discotics to form ordered
one-dimensional supramolecular polymers will be discussed
below. Of interest is the potential to alter the aggregation
concentration by modifying the opportunities for secondary
interactions, and particularly the importance of hydrophobic
shielding of the intermolecularly H-bonded entities in the
discotic core.
Syntheses of C3-symmetrical GdIII-DTPA discs: The synthet-
ic schemes for the small, medium, and large GdIII– and YIII–
DTPA discotics (1–3) are given in the Supporting Informa-
tion (Schemes S1–S3).
The first C3-symmetrical disc (1) contains l-lysine-func-
tionalized DTPA units,[48,49] which were directly coupled to
the benzene-1,3,5-tricarboxamide core. After deprotection
of the tert-butyl ester moieties, metal complexes 1a and 1b
were prepared by adding GdACHTNUGTRENN(UG OAc)3 or YACHUTGNTREN(NGUN OAc)3, respective-
ly (see Scheme S1). The exact amount of GdIII or YIII
needed was predetermined by performing a UV titration
using xylenol orange as the indicator.[50,51]
The second, medium-sized disc (2) contains additional l-
phenylalanine units in between the core and the MIII–DTPA
moieties. l-Lysine-functionalized DTPA was allowed to
react with N-benzyloxycarbonyl-l-phenylalanine using 2-
Self-assembly in solution: The aggregation behavior of para-
magnetic GdIII complexes 1a–3a was investigated by using
circular dichroism (CD), UV/Vis spectroscopy, and cryogen-
ic transmission electron microscopy (cryoTEM). In addition
we used longitudinal relaxation time (T1) measurements as a
tool to probe the self-assembly of GdIII-loaded amphiphiles,
similarly to reports on biotin–avidin complexes,[53,54] lipo-
somes,[55–58] and micelles.[46,59–62] Furthermore, diffusion-or-
dered 1H NMR (DOSY 1H NMR) spectroscopy was per-
formed on the diamagnetic YIII–DTPA discotic 3b.
(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexa-
fluorophosphate (HBTU) as a coupling reagent and N,N-dii-
sopropylethylamine (DiPEA) as a base; these conditions are
known to prevent racemization of the activated amino
acid.[36,52] The benzyloxycarbonyl group was removed by cat-
alytic hydrogenation, and the resulting intermediate was re-
acted with 0.30 molar equivalents of trimesic chloride in the
presence of triethylamine as a base. Removal of the tert-
butyl groups and complexation of the free DTPA ligands
with GdIII or YIII gave compounds 2a and 2b (Scheme S2).
The third and largest disc (3) contains additional amino-
benzoyl units in between the l-phenylalanine units and the
l-lysine-functionalized MIII–DTPA moieties. Boc-l-PheOH
was allowed to react with methyl-4-aminobenzoate using 2-
(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU) as the coupling reagent and
DiPEA as a base. After deprotection of the Boc group, the
Small MIII–DTPA disc 1: Figure 2 shows the CD and UV/
Vis spectra for compound 1a in water at 293 K and 5.1 mm
GdIII. The CD spectrum of 1a does not show a Cotton
effect, indicating either the absence of helical aggregates or
the presence of equal amounts of P- and M-helices. Solu-
tions with different concentrations of 1a were visualized
with cryoTEM, but no aggregates were observed, strength-
ening the former hypothesis. T1 measurements for the GdIII
complex 1a were performed at between 0 and 18 mm GdIII
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Controlled Supramolecular Oligomerization
FULL PAPER
Figure 2. CD (top) and UV/Vis spectra (bottom) of GdIII complex 1a in
200 mm Tris (pH 7.4) at 293 K; [GdIII]=5.1 mm.
in 200 mm tris(hydroxymethyl)aminomethane (Tris) buffer
(pH 7.4), at 1.5 T and 293 K. Figure 3 shows that the data
points can be fitted by a single regression line, which crosses
the y axis at the measured 1/T1,diamagnetic value of the Tris
buffer. This suggests that the GdIII complex 1a is molecular-
ly dissolved over the whole concentration regime and does
not aggregate, which is in agreement with the optical and
TEM data. The ionic longitudinal relaxivity r1 for 1a is
8.2 mmꢀ1 sꢀ1.
Figure 3. The longitudinal relaxation rate is plotted against the gadolini-
um concentration for GdIII complex 1a: A) concentration regime 0–
18 mm GdIII; B) concentration regime 0.0–1.5 mm GdIII; C) concentration
regime 0.00–0.05 mm GdIII
.
Medium MIII-DTPA disc 2: Figure 4 shows two cryoTEM
images of discs of 2a at different concentrations. Aggregates
were only observed at 13 mm GdIII, but their shape and size
is not clearly visualized. The CD and UV spectra of 2a at
two different concentrations (0.055 and 0.55 mm GdIII) and
different temperatures (293 and 363 K) are depicted in
Figure 5. Both solutions are CD active, but no concentra-
tion- or temperature-dependence is observed. The Cotton
effect is thus inherent to the chiral discotic, and does not
lead to aggregation-induced CD effects at these low concen-
trations.
T1 measurements for the GdIII complex 2a were per-
formed between 0 and 13 mm GdIII in 200 mm Tris buffer
(pH 7.4), at 1.5 T and 293 K (Figure 6). If a line is drawn
through these points, it becomes clear that it is difficult to
describe all the data points with one single regression. At
the lower concentrations, the line crosses the y-axis at the
measured 1/T1,diamagnetic value of the Tris buffer. This suggests
that the molecules are in the molecularly dissolved state.
The ionic relaxivity of molecularly dissolved 2a is approxi-
mately 15 mmꢀ1 sꢀ1, which is comparable to the ionic relaxiv-
ity of a third-generation poly(propylene imine) dendri-
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E. W. Meijer et al.
Figure 4. CryoTEM images of GdIII complex 2a in 200 mm Tris buffer
(pH 7.4): left picture: [GdIII]=1.3 mm; right picture: [GdIII]=13 mm.
Scale bar represents 100 nm.
Figure 6. The longitudinal relaxation rate is plotted against the gadolini-
um concentration for GdIII complex 2a; A) concentration regime 0–
13 mm GdIII; B) concentration regime 0.0–0.42 mm GdIII; C) concentra-
tion regime 0–0.06 mm GdIII; the solid and dotted lines are just to guide
the eye.
thereby, increase the ionic relaxivity.[41,46] In the aggregated
state the latter can only be estimated (ca. 17 mmꢀ1 sꢀ1). In
agreement with the optical and TEM results, the association
constant(s) describing the unknown self-assembly mecha-
nism seems to be very weak, due to the high concentrations
needed for aggregation to be observed.
Figure 5. CD (top) and UV/Vis spectra (bottom) of GdIII complex 2a in
200 mm Tris (pH 7.4) at 293 K (black) and 363 K (gray); straight lines
[GdIII]=0.55 mm and dotted lines [GdIII]=0.055 mm.
mer.[63] At around 0.27 mm GdIII, a subtle deviation from lin-
earity takes place, suggesting that the discs are aggregating.
Aggregation of the paramagnetic discotics would decrease
the rotational tumbling of the GdIII–DTPA complexes, and,
Large GdIII–DTPA disc 3: The CD spectroscopic data of
compound 3a in Tris HCl buffer (200 mm, pH 7.4) indicate
the formation of helical stacks: a bisignate Cotton effect is
observed with maximum intensity at a wavelength of
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Controlled Supramolecular Oligomerization
FULL PAPER
Figure 7. CD spectra of discotic 3a in 200 mm Tris buffer (pH 7.4) at 293 K (A) and 363 K (B); UV/Vis (C) spectra (straight line: 293 K; dashed line:
363 K); [GdIII]=0.2 mm (black), 0.02 mm (dark grey), and 0.004 mm (light gray); normalized and fitted cooling curve ([GdIII]=0.2 mm) from 363 to 293 K
at 1 Kminꢀ1 monitoring the CD signal at 239 nm (D).
239 nm (Figure 7A). Cooling curves from the molecularly
dissolved state at 363 K (Figure 7B) provide evidence for a
Table 1. Diffusion coefficients Dt and hydrodynamic radii RH of diamag-
netic amphiphile 3b in D2O at various concentrations and temperatures.
non-cooperative or anti-cooperative self-assembly process,
as indicated by the sigmoidal temperature-dependent CD
signal (Figure 7D).[34] Fitting of these data gave an apparent
association constant of 5ꢁ104 mꢀ1 at 293 K,[64,65] which re-
mains the same when switching to a 100 mm citrate buffer
(pH 6.0) and is only slightly reduced to 1ꢁ104 mꢀ1 in a
50 mm succinate buffer at pH 6.0 (Figures S1 and S2).[34]
The sizes of the stacks based on the YIII-labelled com-
pound 3b were studied by means of diffusion-ordered NMR
spectroscopy (1H-DOSY NMR) and cryoTEM. Both tech-
niques demonstrate that stable aggregates of a rather de-
fined shape are present in millimolar concentrations within
a broad temperature regime (Table 1, Figures 8 and S3). The
Stokes–Einstein relation[66,67] for the diffusion of a spherical
particle is used to calculate the dimensions of the assem-
blies, because the model of Tirado and Garcia de la Torre[68]
for the diffusion of a cylindrical particle was not valid due
to the low aspect ratio of the one-dimensional stacks (L/d <
2). According to the 1H-DOSY NMR measurements, in a
YIII
[mm]
Temperature
[K]
Dt (stacks)
RH (stacks)
[10ꢀ9 m]
DPw
[10ꢀ10 m2 sꢀ1
]
ACHTUNGTRENNUNG
298
314
327
340
298
293
1.3
2.0
2.8
3.5
1.1
0.6
1.5
1.5
1.4
1.4
1.8
3.1
8–9
8–9
8
1.7
8
8.3
25
10–11
17–18
2.8 mm solution of disc 3b the stacks are about 3.6 nm long.
Similar hydrodynamic diameters were reproduced from H-
1
DOSY NMR experiments in buffered conditions (50 mm
[D6]-succinate buffer in D2O, “pH 6.0”, Table S1). Adopting
an interdisc distance of 0.35 nm,[38] we estimate on average
ten to eleven discotics to be stacked on top of one another
(Figure 9). This is in agreement with the diameter of about
5 nm of the spherical objects visualized with cryoTEM (Fig-
ures 8 and S3).
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E. W. Meijer et al.
Figure 8. CryoTEM images of YIII complex 3b in 200 mm Tris buffer
(pH 7.4): [YIII]=8.3 mm (left picture); [YIII]=25 mm (right picture). Scale
bar represents 50 nm.
Figure 10. SAXS profile for the discotic 3a in citrate buffer (100 mm,
pH 6).
spherical particles are present
in millimolar concentration
ranges.
The
observed
frustrated
growth of highly charged dis-
cotics into well-defined objects
of restricted size is in line with
our previous findings:[34] elec-
trostatic repulsive interactions
are responsible for this phe-
nomenon, and prevent the one-
dimensional columnar aggre-
gates from growing into “infin-
itely long” stacks.[34] We have
postulated a switch to anti-co-
operativity with increased Cou-
lombic repulsive interactions
for building blocks that, in their
core, were coded for a coopera-
tive and hence nucleation elon-
gation-type growth.[34] This anti-
cooperative mechanism is not
Figure 9. Schematic 3D representation of a stack of 11 monomers of 3a: side-view (left) and top-view (right)
of the stack.
Further evidence for the presence of aggregates with an
aspect ratio of close to one was obtained from small-angle
X-ray scattering (SAXS), a powerful technique to determine
the shape and size of colloidal dilute particulate sys-
tems.[69–73] The shape of the aggregates based on discotic 3a
or 3b can be derived directly from the slope of the SAXS
profiles in the region 0.01 < q < 0.06 ꢂꢀ1. Any characteris-
tic slope that would indicate aggregate shape anisotropy is
absent in the SAXS profiles (Figures 10 and S7). The data
could be fitted using a homogeneous monodisperse spherical
form factor (see Supporting Information), leading to calcu-
lated radii of 2.9 nm in 100 mm citrate buffer at pH 6.0
(Figure 10), or 2.5 nm in D2O (Figure S7). The data could
also be fitted assuming a homogeneous monodisperse cylin-
drical form factor, leading to objects with calculated radii of
2.7 nm and lengths of 4.7 nm (Figure 10). Therefore, the low
aspect ratio of the objects justifies the assumption that
distinguishable from an isodesmic process.[64] Substituting
the fluorinated core as reported previously by the hydrogen-
ated equivalent in 3a or 3b reduced the binding affinity by
about an order of magnitude, strengthening our hypothesis
that solvophobic effects and hydrophobic shielding are es-
sential requirements in these enthalpy-driven supramolec-
ular polymerizations.
1
Finally, the H longitudinal relaxation time T1 measure-
ments were performed on the GdIII-labeled compound 3a
(Figure 11) to study the exact nature of the self-assembly
processes. Isodesmic self-assembly processes do not exhibit
critical aggregation concentrations as observed for lipo-
somes or micelles:[55–62] the degree of oligomerization gradu-
ally increases with the monomer concentration (see also
Supporting Information).[64,74–77] If a line to guide the eye is
drawn through these points, it becomes clear that it is im-
possible to describe all the data points with one single line
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Controlled Supramolecular Oligomerization
FULL PAPER
To confirm the dominant role
of hydrogen bonding in the
self-assembly of the large
1
DTPA discotics, H NMR stud-
ies were performed on a 1 mm
solution of 3b in a 90% H2O/
D2O-based 10 mm [D6]-succi-
nate
buffer
at
pH 6.0
(Figure 12). Suppression of the
HOD and H2O protons was
achieved by using the excita-
Figure 11. The 1H longitudinal relaxation rate (R1 in sꢀ1) is plotted against the gadolinium concentration for
GdIII complex 3a in 200 mm Tris (pH 7.4) at 208C and at 1.5 T: concentration regime from 0.0–3.2 mm GdIII
(left graph); 0.0–0.4 mm GdIII (middle graph); 0.00–0.05 mm GdIII (right graph). A model based on Equa-
tion (1) is used to fit the measured data points (Equation (25), Supporting Information): K (fixed parame-
tion-sculpting pulse sequence,[81]
as this sequence does not satu-
rate the exchanging amide pro-
tons. Although the resonances
ter)=5ꢁ104 mꢀ1, r1m =9.2 mmꢀ1 sꢀ1, r1out =25.5 mmꢀ1 sꢀ1, r1in =31.3 mmꢀ1 sꢀ1
.
are broad as a result of aggre-
gation, the 1H NMR spectrum
(Figures 11, S4, and S5). Standard bulk relaxivity measure-
ments were therefore not possible, because the slope of the
relaxation rate R1 curve gradually changes over the whole
GdIII concentration range (Figure S4). To interpret the con-
centration-dependent changes of the relaxivity r1, we devel-
oped a simple model based on Equation (1). The apparent
association constant of 5ꢁ104 mꢀ1 at 293 K, extracted from
the CD data (Figures 7 and S3), was used to fit the mea-
sured water proton longitudinal relaxation rate R1 (Equa-
tion (1) and Figure 10, see also Supporting Information). It
was assumed that three different species based on the C3-
symmetrical molecules are present in solution in varying
molar ratios over the whole concentration range: molecular-
ly dissolved discs A, aggregated discs with only one neigh-
bor Aout (the ends of a stack), and aggregated discs with two
depicted in Figure 12a clearly shows three distinct amide
resonances in a 1:1:1 ratio in the downfield region of the
spectrum. The three resonances correspond to the core (d=
8.84 ppm), middle (d=10.05 ppm), and outer (d=8.40 ppm)
amide protons of the YIII–DTPA discotic 3b (Figure 12a).[82]
Titration of [D6]DMSO resulted in a sharpening of all the
proton resonances and a concomitant downfield shift of the
central aryl-H proton (Figure 12a).[83] Furthermore, in
agreement with various studies on hydrogen-bonded pep-
tides, the addition of [D6]DMSO resulted in a downfield
shift of all the NH protons, as DMSO is a stronger hydro-
gen-bond acceptor (Figure 12b).[84–87] Buffered solutions of
3b in 30% DMSO or CH3CN did not give rise to CD ef-
fects, indicating the absence of ordered aggregates. Alto-
gether these features suggest that after the addition of
33.6% DMSO into the 10 mm [D6]-succinate buffer (H2O/
D2O, 9:1), the stacks based on the YIII–DTPA discotics 3b
fall apart, as a result of the loss of intermolecular hydrogen
bonding.
in
neighbors Ain (Figure 11); r1m, r1out, and r1 are their individ-
d
ual ionic relaxivities, and R1 is the diamagnetic contribu-
tion.
obs
d
m
out
in
R1 ꢀ R1 ¼ r1 ꢁ 3 ½Aꢂ þ r1 ꢁ 3 ½Aoutꢂ þ r1 ꢁ 3 ½Ainꢂ
ð1Þ
Conclusion
Applying this model, three ionic relaxivities and the sum
The self-assembly of three water-soluble C3-symmetrical dis-
cotic molecules has been discussed. To yield stable aggrega-
tion in dilute conditions, the intermolecular hydrogen-bond-
ing motif of the polymerizing BTA core has to be efficiently
shielded through solvophobic effects. This was clearly dem-
onstrated by increasing the hydrophobic spacer lengths be-
tween the peripheral hydrophilic GdIII-DTPA complexes
and the hydrophobic BTA core of the discotics, using fairly
rigid linking units containing several aromatic moieties. The
amphiphilic C3-symmetrical molecules 3a and 3b display re-
stricted growth to form ordered and well-defined objects
with dimensions in the nanometer range, effectively yielding
self-assembled dendritic macromolecules.[88–92]
out
of squares are determined: r1m =9.2 mmꢀ1 sꢀ1, r1
=
25.5 mmꢀ1 sꢀ1, r1in =31.3 mmꢀ1 sꢀ1, and c2 =0.02554. This rela-
tively simple model describes the measured data very well,
even at very low GdIII concentrations. Hence, the suggested
isodesmic mechanism for aggregate formation from the opti-
cal measurements is in full agreement with the results de-
1
duced from H longitudinal relaxation time measurements.
The estimated overall ionic relaxivity of the aggregate
(roughly 30 mmꢀ1 sꢀ1) compares well with that obtained for
fourth or higher generation dendrimers.[63,78–80] Crucially, the
stability of the aggregates based on 3a is very high: it is
only below discotic concentrations of about 5 mm that the
ionic longitudinal relaxivity values are dictated by mono-
meric non-aggregated species (Figures 11 and S4), which is
about two orders of magnitude below that of the medium-
sized discotics 2a.
In addition we have shown that T1 measurements can be
a versatile tool for studying the self-assembly behavior of
amphiphilic discotics bearing GdIII–DTPA moieties. More-
over, we postulate that well-defined assemblies of paramag-
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E. W. Meijer et al.
Figure 12. a) 1H NMR spectra of a 1 mm solution of discotic 3b in a 90% H2O/D2O-based 10 mm [D6]-succinate buffer (pH 6.0) and various volume per-
centages of [D6]DMSO. b) The chemical shift (d) of the three amide groups and the central aryl proton of YIII-DTPA discotic 3b changes with the addi-
tion of [D6]DMSO.
[D4] acid sodium salt (TMSP). The peak positions of the NH resonances
netic discotics may be promising building blocks for the de-
velopment of supramolecular contrast agents for MRI due
to their low aggregation concentrations and high ionic relax-
ivities in the self-assembled state.
as a function of [D6]DMSO content were derived directly from the de-
convolution function provided in the VNMRJ program. The T1 measure-
ments were performed at 60 MHz, 1.5 T, on a Bruker Minispec mq60
NMR analyzer. The sample volume was 300 mL and the samples were
measured in tubes with a diameter of 7.5 mm. Longitudinal relaxation
times were determined with an inversion recovery pulse sequence. IR
spectra were measured at 298 K on a Perkin–Elmer 1605 FTIR spectro-
photometer. Matrix-assisted laser desorption/ionization mass spectra
were obtained on a PerSeptive Biosystems Voyager DE-PRO spectrome-
ter. LC-MS analyses were performed by using a Shimadzu SCL-10 AD
VP series HPLC coupled to a diode array detector (Finnigan Surveyor
PDA Plus detector, Thermo Electron Corporation) and an Ion-Trap
(LCQ Fleet, Thermo Scientific). Chiral HPLC was performed on a Shi-
madzu system consisting of a Shimadzu LC-10 ADvp pump, a Spark
Midas autosampler, and a Shimadzu SPD-10ADvp UV/Vis detector. A
DNBPG column (covalent, 5 mm; 0.46ꢁ25 cm) was used, with a 9/1 (v/v)
hexane/isopropanol mixture as the eluent. GPC measurements were per-
formed on a Shimadzu serial system of a mixed C column (PLgel 5 mm,
Experimental Section
Unless stated otherwise, all reagents and chemicals were obtained from
commercial sources at the highest purity available and used without fur-
ther purification. Water was demineralized prior to use. Reactions were
conducted under an argon atmosphere using standard Schlenk line tech-
niques unless otherwise specified. 1H NMR, 1H-1H COSY, and 13C and
19F NMR spectra were recorded on Varian Mercury 400 and 200 or
Gemini 300 spectrometers at 298 K. The 1H-DOSY and water-suppres-
sion NMR experiments were performed on a Varian Unity Inova 500
spectrometer equipped with a 5 mm ID-PFG probe from Varian. Sup-
pression of the HDO and H2O signal was achieved with the excitation-
sculpting pulse sequence.[81] The selective square pulse length was set to
8 ms. In the water-suppression 1H NMR experiments, a total 512 transi-
ents were acquired with a delay time of 3 s. Chemical shifts were refer-
enced using the chemical shift of the 3-(trimethylsilyl)propionic-2,2,3,3-
200–200000 gmolꢀ1
) and a mixed D column (PLgel 5 mm, 200–
400000 gmolꢀ1) at a flow rate of 1 mLminꢀ1 with THF as the eluting sol-
vent. The injection volume was 20 mL and the Shimadzu instrument was
equipped with an SPD-M10VP diode array detector (190–360 nm). Ele-
mental analyses were carried out using a Perkin–Elmer 2400 instrument.
GdIII and YIII contents were determined by means of inductively coupled
5200
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 5193 – 5203

Controlled Supramolecular Oligomerization
FULL PAPER
plasma mass spectrometry (ICP-MS) conducted by the MiPlaza Materials
Analysis laboratories (Philips Research Europe) in Eindhoven, The
Netherlands. Cryogenic transmission microscopy measurements were per-
formed using the TU/e CryoTitan TEM (FEI), equipped with a field
emission gun (FEG) operating at 300 kV. Images were recorded using a
2k ꢁ 2k Gatan CCD camera equipped with a post column Gatan energy
filter (GIF). CD measurements were performed on a Jasco J-815 spectro-
polarimeter, for which where the sensitivity, time constant, and scan rate
were chosen appropriately. Corresponding temperature-dependent meas-
urements were performed with a Jasco PTC-348WI Peltier-type tempera-
ture controller, with a temperature range of 263–383 K and adjustable
temperature slope. UV/Vis spectra were obtained on a Perkin–Elmer
Lambda 40 spectrometer. The SAXS measurements were performed at
the Dutch–Belgian BM26B beamline at the European Synchrotron Radi-
ation Facility (ESRF) in Grenoble, France.
FTIR (ATR): n˜ =3129, 3042, 2811, 1575, 1440, 1400, 1322, 1086 cmꢀ1
;
ESI-MS (negative mode): m/z calcd for [Mꢀ(2H+6NH3)]2ꢀ: 1225.8;
found: 1225.7; ICP-MS (GdIII) calcd: 19.3 wt%; found: 15.4 wt%.
17: Compound 16 (122 mg, 0.08 mmol) was added as solid material to a
solution of 5a (221 mg, 0.26 mmol) and DiPEA (475 mL, 2.73 mmol) in
[D6]DMSO (2 mL). After the reaction was stirred overnight in an atmos-
phere of argon, the reaction mixture was diluted with water (8 mL) and
acidified to pH < 3 with 2m aqueous HCl. The gel formed was centri-
fuged, the water was decanted, and the remaining gel was washed with
water (30 mL). These consecutive steps were repeated three times, after
which the gel was dissolved in 0.1m NH4OH and lyophilized. The pure
title compound 17 was isolated as
a fluffy, white powder (148 mg,
1
55.4 mmol, 69%). H NMR ([D6]DMSO): d=10.47 (s, 3H), 9.08 (m, 3H),
8.57 (s, 3H), 8.40 + 8.37 (s + s, 1 H + 2H), 7.88 (6H, d, J=8.0 Hz),
7.67 (6H, d, J=8.0 Hz), 7.5–7.1 (m, 15H), 4.91 (q, 3H), 3.6–3.0 (m,
45H), 3.0–2.4 (m, 18H), 1.8–1.2 ppm (m, 18H); 13C NMR ([D6]DMSO):
d=173.5, 171.8, 170.6, 165.8, 165.5, 141.2, 137.9, 134.3, 129.4, 129.2, 128.2,
126.4, 118.6, 63.4, 57.7, 56.1, 52.1, 48.2, 37.2, 28.9, 28.5, 23.7 ppm; FTIR
(ATR): n˜ =3198, 3031, 1603, 1536, 1503, 1457, 1436, 1391, 1313, 1253,
The Supporting Information provides all the reaction schemes, detailed
experimental procedures, and characterization (below only the final com-
pounds are described), additional CD, UV/Vis, as well as 1H-DOSY
NMR and 1H longitudinal relaxation rate data, a cryoTEM picture, the
derivation of the model based on Equation (1), and detailed SAXS pro-
cedures.
1094 cmꢀ1
;
ESI-MS
(negative
mode):
m/z
calcd
for
,
[Mꢀ(2H+6NH4Cl)]2ꢀ
:
1173.21; found: 1173.1 [Mꢀ(2H+6NH4Cl)]2ꢀ
1184.5 [Mꢀ(3H+6NH4Cl)+Na]2ꢀ, 781.7 [Mꢀ(3H+6NH4Cl)]3ꢀ; elemen-
tal analysis calcd (%) for C111H138N18O39·6NH4Cl: C 49.95, H 6.12, N
12.59; found: C 50.48, H 6.63, N 12.26.
7: A 4m HCl-dioxane solution (30 mL) was added dropwise to a solution
of 6 (699 mg, 0.292 mmol) in chloroform (30 mL). After 1 h, the reaction
mixture was concentrated in vacuo at 508C. The concentrate was dis-
solved in water (25 mL) and a 12m aqueous HCl solution (20 mL) was
added dropwise. After being stirred overnight, the reaction mixture was
concentrated in vacuo at 808C. The crude product was dissolved in meth-
anol (5 mL) and precipitated from diethyl ether (20 mL). Finally, the pre-
cipitate was filtered under a flow of argon and lyophilized for three days,
resulting in pure 7 as a yellow–orange hygroscopic solid (503 mg, 92%).
1H NMR (D2O): d=8.19 (s, 3H), 4.81 (s, 24H), 3.58 (t, 3H), 3.5–3.3 (m,
18H), 3.16 (m, 12H), 1.7–1.4 ppm (m, 18H); 13C NMR (D2O): d=175.6,
169.6, 168.9, 135.4, 129.3, 63.8, 55.8, 53.7, 47.0, 40.3, 28.7, 28.2, 24.0 ppm;
3a: Compound 17 (49.2 mg, 18.9 mmol) was dissolved in ultra-pure water
(30 mL) and the pH was adjusted to 7 by adding aliquots of 0.1 N
NH4OH. The gadolinium complex was prepared by adding Gd-
AHCTUNTGREGUN(NN OAc)3·xH2O (57 mmol) as predetermined by UV titration. The solution
was stirred vigorously overnight at room temperature at a pH of 7. After
freeze-drying, 3a was obtained as a white fluffy powder (66.9 mg, quanti-
tative yield). FTIR (ATR): n˜ =3267, 1589, 1539, 1506, 1440, 1405, 1319,
1256, 1185, 1090 cmꢀ1
; ESI-MS (negative mode): m/z calcd for
[Mꢀ(2H+6NH3)]2ꢀ: 1404.8; found: 1405.3 [Mꢀ(2H+6NH3)]2ꢀ, 1415.8
[Mꢀ(3H+6NH3)+Na]2ꢀ
,
936.5 [Mꢀ(3H+6NH3)]3ꢀ
; )
ICP-MS (GdIII
FTIR (ATR): n˜ =3288, 2942, 2521, 1728, 1635, 1543, 1403, 1203 cmꢀ1
(H+9HCl)]ꢀ: 1548.6; found:
;
calcd: 16.2 wt%; found: 10.2 wt%.
ESI-MS (negative mode): m/z calcd for [Mꢀ
ACHTUNGTRENNUNG
1548.6; elemental analysis calcd (%) for C63H96N12O33·9HCl: C 40.30, H
5.64, N 8.95; found: C 41.11, H 5.93, N 8.87.
3b: Compound 17 (50.0 mg, 19.2 mmol) was dissolved in ultra-pure water
(30 mL) and the pH was adjusted to 7 by adding aliquots of 0.1 N
NH4OH. The yttrium complex was prepared by adding the amount of Y-
1a: Compound 7 (50.7 mg, 27.0 mmol) was dissolved in water (5 mL) and
the pH was adjusted to 7 by adding aliquots of a 2m ammonia solution.
AHCTUNTGREG(NNUN OAc)3·xH2O (58 mmol) predetermined by UV titration. The solution was
stirred vigorously overnight at room temperature at a pH of 7. After
freeze-drying, 3b was obtained as a white fluffy powder (46.6 mg, quanti-
tative yield). 1H NMR [66.4% 10 mm d6-succinic acid buffer in H2O/D2O
90:10 (pH 6.0) + 33.6% [D6]DMSO]: d=10.31 (s, 3H), 8.91 (m, 3H),
8.55 (s, 3H), 8.22 (s, 3H), 7.79 (6H, d, J=9.5 Hz), 7.58 (6H, d, J=
9.5 Hz), 7.4–7.2 (m, 15H), 3.6–3.0 (m, 45H), 2.8–2.5 (m, 18H), 1.8–
1.2 ppm (m, 18H) ppm; FTIR (ATR): n˜ =3261, 1599, 1539, 1506, 1440,
1408, 1319, 1257, 1185, 1091 cmꢀ1; ESI-MS (negative mode): m/z calcd
The gadolinium complex was prepared by adding GdACTHNUTRGNE(UNG OAc)3·xH2O
(33.3 mg, 81 mmol) as predetermined by UV titration.[50,51] The solution
was stirred vigorously for 6 h at room temperature at pH 7. After lyophi-
lization of the reaction mixture overnight, the crude product was dis-
solved in water (1 mL) and precipitated in ethanol (10 mL). Filtration of
the precipitate under a flow of argon yielded the title compound 1a as an
off-white hygroscopic solid (36.6 mg, 64%). FTIR (ATR): n˜ =3145, 3040,
2868, 1575, 1435, 1401, 1323, 1087 cmꢀ1; ESI-MS (negative mode): m/z
for [Mꢀ(2H+6NH3)]2ꢀ
:
1301.3; found: 1302.3 [Mꢀ(2H+6NH3)]2ꢀ
,
calcd for [Mꢀ(2H+6NH3)]2ꢀ: 1005.3; found: 1005.1; ICP-MS (GdIII
)
1313.3 [Mꢀ(3H+6NH3)+Na]2ꢀ
,
867.9 [Mꢀ(3H+6NH3)]3ꢀ
; ICP-MS
calcd: 21.9 wt%; found: 20.1 wt%.
(YIII) calcd: 9.9 wt%; found: 8.3 wt%.
11: A 4m HCl–dioxane solution (6.5 mL) was added dropwise to a solu-
tion of 10 (181 mg, 63 mmol) in chloroform (6.5 mL). After 2 h at room
temperature, the reaction mixture was concentrated in vacuo at 408C
and the concentrate was redissolved in a 2m aqueous HCl solution
(26 mL). After 44 h, the reaction mixture was freeze-dried for three days,
resulting in the off-white hygroscopic solid 11 (152 mg, quantitative
Acknowledgements
1
yield). H NMR (D2O, 363 K): d=8.09 (s, 3H), 7.31 (m, 15H), 4.77 (3H),
3.94 (s, 24H), 3.62 (b, 3H), 3.4–3.2 (m, 36H), 1.8–1.3 ppm (m, 18H);
FTIR (ATR): n˜ =3303, 2977, 2933, 2867, 1726, 1658, 1538, 1456, 1392,
1368, 1250, 1219, 1150 cmꢀ1; ESI-MS (negative mode): m/z calcd for
[Mꢀ(2H+9HCl)]2ꢀ: 994.4; found: 994.0; elemental analysis calcd (%)
for C90H123N15O36·9HCl: C 45.19, H 5.65, N 8.78; found: C 45.64, H 5.85,
N 8.45.
We thank the NWO (K.P.H.), IBOS (Project 053.63.310), and Marie
Curie Actions FP7 (SahnMat, PIEF-GA-2009-235914) (P.B.), BSIK (proj-
ect 03033) (T.M.H.) for funding, Dr. Maarten Smulders for fitting some
of the temperature-dependent CD profiles, Marko Nieuwenhuizen for
discussions, Dr. Koen Pieterse for the 3D modeling and artwork, Dr.
Xianwen Lou for MALDI-TOF MS measurements, Joost van Dongen
and Ralf Bovee for chiral HPLC analyses, Henk Eding for elemental
analyses, and Dr. Erik Sanders, Dr. Gustav Strijkers, and Prof. Klaas Ni-
kolay for access to and help with relaxation time measurements. We also
thank Dr. Sander Langereis and Jeanette Smulders (MiPlaza Materials
Analysis laboratories, Philips Research Europe) for carrying out ICP-MS
measurements of the final compounds, Tristan Mes, Dr. Michel van Hou-
2a: Compound 11 (60.0 mg, 25.8 mmol) was dissolved in ultra-pure water
(95 mL) and the pH was adjusted to 7 by adding aliquots of 0.1 N
NH4OH. The gadolinium complex was prepared by adding GdCl3·6H2O
(78 mmol) as predetermined by UV titration. The solution was stirred vig-
orously for 6 h at room temperature at a pH of 7. After freeze-drying, 2a
was obtained as a white hygroscopic solid (66.4 mg, quantitative yield).
Chem. Eur. J. 2011, 17, 5193 – 5203
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5201

E. W. Meijer et al.
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 5193 – 5203

Controlled Supramolecular Oligomerization
FULL PAPER
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downfield, but to a lesser extent than expected. We hypothesise that
this can be explained by two competing processes that contribute to
the chemical shift of these protons. The first one is the aromatic ring
current effect. Stacking of the aromatic groups would result in an
Received: October 15, 2010
Published online: March 22, 2011
Chem. Eur. J. 2011, 17, 5193 – 5203
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