Supramolecular polymerization in water harnessing both hydrophobic effects and hydrogen bond formation

Article abstract of DOI:10.1039/c3cc38949a

The formation of supramolecular polymers in water through rational design of a benzene-1,3,5-tricarboxamide (BTA) motif is presented. Intermolecular hydrogen bonding and hydrophobic effects cooperate in the self-assembly into long fibrillar aggregates. Minimal changes in molecular structure significantly affect the internal packing of the aggregates. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc38949a

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Supramolecular polymerization in water harnessing both hydrophobic
effects and hydrogen bond formation†
Christianus M. A. Leenders,a Lorenzo Albertazzi,a Tristan Mes, a Marcel. M. E. Koenigs,a Anja R. A.
Palmans,*a E. W. Meijer*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The formation of supramolecular polymers in water through
rational design of a benzene-1,3,5-tricarboxamide (BTA)
motif is presented. Intermolecular hydrogen bonding and
10 hydrophobic effects cooperate in the self-assembly into long
fibrillar aggregates. Minimal changes in molecular structure
significantly affect the internal packing of the aggregates.
Ph
a,b,c
OH
O
O
O
HO
HO
O
Br
O
O
P
O
O
O
Ph Ph
d,e
O
f
TBDMS
O
TBDMS
i,j
O
O
O
O
O
O
O
O
O
g,h
O
2
H2N
Since the first example of a hydrogenꢀbonded supramolecular
polymer,1 the field of supramolecular polymer chemistry has
15 become a distinct part of materials research.2,3 Numerous selfꢀ
assembling motifs have emerged and detailed studies showed that
hydrogen bonding, πꢀπ stacking and metal coordination are the
main driving forces for selfꢀassembly in organic solvents.4ꢀ5 In
water, however, the hydrophobic effect represents an additional
20 interaction driving selfꢀassembly processes.6 Assembly of small
molecules in water has attracted much interest for several
applications. Low molecular weight (LMW) hydrogelators, for
example, in most cases rely on the assembly of small molecules
into fibrillar structures to immobilize water. Although much
25 progress has been made in recent years, 6ꢀ9 it is still difficult if not
impossible to predict the assembly and hydrogelation properties
of a small molecule from its molecular structure.10
R1
R2
=
O
O
O
O
OH
OH
O
O
O
O
1
2
3
R1 R2
N
=
H
O
R1
R1
R2 = H
=
O
N
R2
R2
N
R1
R2
=
=
O
O
OH
O
O
O
R1
Methyl
Scheme 1 (Top) Synthetic route towards 2.(a) NaH, THF, 0 °C,
50 Benzylbromide, room temperature (RT), overnight, 58%; (b) NaH, THF,
0 °C, 1,6ꢀdibromohexane, RT, overnight, 50 %; (c) PPh3, 140 °C, 7 days,
93%; (d) imidazole, TBDMS chloride, DMF, 0 °C to RT, overnight.
quantitative; (e) DCM, O3(g), ꢀ80 °C, DMS, RT, 1 h, 91%; (f) THF, nꢀ
BuLi, ꢀ30 °C, ꢀ80 °C to RT, 3 h, 59%; (g) TBAF, THF, 0 °C to RT 4.5 h,
55 91%; (h) 1) Phthalimide, PPh3, DIAD, ether, 0 °C to RT, overnight. 2)
N2H4, ethanol, 80 °C, overnight, 81%; (i) 1,3,5ꢀbenzenetricarbonyl
trichloride, triethylamine, CHCl3, 0 °C to RT, 4 h, 77%; (j) Pd/C, H2(g),
methanol, RT, overnight, 98 %. (Bottom) Molecular structure of 1, 2 and
3.
In apolar organic solvents, N,N’,N”ꢀtrialkylꢀbenzeneꢀ1,3,5ꢀ
tricarboxamides (BTAs) selfꢀassemble in a cooperative fashion
30 into helical, oneꢀdimensional stacks via threefold hydrogen
bonding between the amides.11ꢀ13 In view of the importance of
water as a solvent for selfꢀassembly processes, we rationally
redesigned the BTA motif to become waterꢀcompatible. While
hydrogenꢀbond driven selfꢀassembly in water has been reported
35 for several systems,14ꢀ18 only a few examples of supramolecular
polymers in water based on the BTA motif have been reported.19ꢀ
60 can be probed by circular dichroism (CD) spectroscopy,
providing information on the helical order within the aggregate.24
Finally, the amides in BTA derivative 3 are methylated to assess
the contribution of intermolecular hydrogen bonding to the selfꢀ
assembly.
65
Achiral BTA derivative 1 was obtained via a straightforward
procedure using protecting group chemistry yielding the alcohol
end groups (ESI, Scheme S1). BTA derivative (S)ꢀ2 was
synthesized starting from (S)ꢀcitronellol to introduce
a
22
Here, we report on a simple molecular design using merely
stereogenic methyl side group in the aliphatic spacer (Scheme 1,
aliphatic chains to shield a central hydrogenꢀbonding unit from
the surrounding polar media, carrying hydrophilic ethylene glycol
40 motifs in the periphery to ensure solubility (Scheme 1, top). We
investigate a series of three waterꢀcompatible BTA derivatives 1ꢀ
3 (Scheme 1, bottom). BTA derivative 1 is decorated with
aliphatic spacers creating a hydrophobic pocket, and tetraethylene
glycol motifs in the periphery with alcohol end groups to provide
45 solubility in water.23 By introducing a stereogenic center in (S)ꢀ2,
the selfꢀassembly
70 top).25 After protection of the alcohol, the double bond was
cleaved by ozonolysis. Subsequently, a Wittig reaction was
performed to obtain a spacer with a stereogenic methyl group on
the third carbon and the protected tetraethylene glycol motif at the
other end. In subsequent steps the alcohol unit was deprotected
75 and converted into an amine via a Gabriel synthesis. After
coupling to the aromatic triacid trichloride, the reduction of the
double bond and deprotection of the tetraethylene glycol was
achieved in one step yielding (S)ꢀ2. Methylation of the core
amides of 1 with methyl iodide yielded 3.
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Solutions of 1 in water were prepared by heating 1 in water to
temperatures above 80 °C, upon which the mixture became hazy.
After cooling to 20 °C, a clear viscous solution was obtained (ηrel
= 1.43 at c = 3x10ꢀ4 M), suggesting that 1 indeed forms large
aggregates. (S)ꢀ2 is less soluble in water, therefore, samples were
prepared by injection from methanol into water (ESI).
5
In order to study the supramolecular polymerization in detail,
the aggregates were visualized by cryoꢀTEM (Fig, 1, ESI, Fig.
S1). Clearly, both 1 and (S)ꢀ2 form long thin fibers in the order of
10 micrometers in length with a diameter of approximately 5
nanometers. The high aspect ratio is an interesting feature of
these supramolecular polymers; recent examples of BTA
assemblies in water and BTA based hydrogelators were shown to
assemble in fibrillar or bundled structures with much larger
15 diameters.20ꢀ22 Interestingly, close inspection of the aggregates
reveals significant differences between the exact packing of the
two BTA derivatives (ESI, Fig. S1). In particular, 1 shows a
slightly larger diameter and a subtle and periodic variation in the
contrast and diameter, which is not observed in (S)ꢀ2. Such an 60 Fig. 1 CryoꢀTEM image of 1 in water, showing long very narrow fibrillar
20 effect is often observed for helical bundles or twisted ribbons7.
aggregates. Scale bar represents 100 nm.
To further elucidate the internal packing, the aggregation
C 0.3
A
20 o
30 o
40 o
50 o
60 o
70 o
C
C
C
C
C
C
0.3
0.2
0.1
0.0
behaviour of BTAs 1 and (S)ꢀ2 was studied by UVꢀvis and CD
spectroscopy. In organic solvents, a single absorption maximum
at 193 nm is indicative for BTAꢀbased helical columnar stacks
25 held together by threefold intermolecular hydrogen bonds, while
a maximum at 208 nm is representative for the molecularly
dissolved state.11 In methanol, the UV spectrum of 1 shows an
absorption maximum at 209 nm, consistent with the molecularly
dissolved state (ESI, Fig. S2). In water, at 20 °C the UV spectrum
30 of 1 shows two distinct absorption bands at 211 nm and 226 nm
(Fig. 2A). Heating the solution from 20 °C to 50 °C does not lead
to visible changes in the shape and intensity of the UV spectra. At
temperatures above 50 °C, the absorption spectrum gradually
changes, resulting in only a single band at 209 nm at 70 °C. The
35 lower critical solution temperature (LCST) of 1 is reached at
temperatures above 70 °C (ESI, Fig. S3) and presents the upper
limit for temperatureꢀdependent measurements. Interestingly, the
UV spectrum of chiral analogue (S)ꢀ2 in water at 20 °C differs
significantly from 1 and shows an absorption maximum at 192
40 nm (Fig. 2B), and a Cotton effect at 220 nm (ꢁε = ꢀ40 Mꢀ1 cmꢀ1),
similar to columnar helical stacks of (S)ꢀBTAs in organic
solvent.24 In methanol, the absorption spectrum of (S)ꢀ2 displays
an absorption maximum at 209 nm (ESI, Fig. S2) and the solution
is CD silent, which is consistent with the molecularly dissolved
45 state also observed for 1. These results suggest that both 1 and
(S)ꢀ2 selfꢀassemble in water at 20 °C. Aggregates of 1 appear to
be stable up to 50 °C and then gradually dissociate reaching a
state where all hydrogen bonds are broken at 70 °C. Above 50 °C,
also the viscosity decreases, corresponding well to the observed
50 changes in the UV absorption. For (S)ꢀ2, precipitation was
observed before a shift in the UV absorption was recorded. The
absorption spectra of 1 and (S)ꢀ2 suggest that (S)ꢀ2 adopts the
reported helical columnar packing, while 1 adopts a different
packing within the supramolecular polymer, consistent with the
55 cryoꢀTEM results. The details of the packing of 1, however,
remain unclear. This indicates that the minimal difference in the
hydrophobic chains of 1 and (S)ꢀ2 has a dramatic effect on the
packing of the monomers resulting in different fibrillar structures.
50 min
0.2
0.1
0.0
200 220 240 260 280 300 320
Wavelength / nm
200 225 250 275 300 325 350
Wavelength / nm
D100
B120
Water
0.3
0.2
0.1
0.0
-0.1
-0.2
1
2
3
80
80
40
0
60
40
20
0
-40
200 225 250 275 300 325 350
Wavelength / nm
600
650
700
750
800
Wavelength / nm
Fig. 2 (A) UVꢀVis absorption of 1 (c = 1x10ꢀ5 M) in water, as a function
of temperature, (arrow indicates the trend upon heating) (B) UVꢀVis
65 absorption (grey) and CD (black) spectra of 2 (c = 1x10ꢀ5 M) in water. (C)
Evolution of UVꢀVis absorption of 1 (c = 1x10ꢀ5 M) in water (arrow
indicates trend in time). (D) Nile Red fluorescence in pure water (black),
solution of 1 (dark grey), 2 (grey) or 3 (light grey) (c = 1x10ꢀ5 M).
Intrigued by the difference in packing between aggregates of 1
70 and 2, the aggregation of 1 was studied as a function of time (Fig.
2C). A small volume of a concentrated solution of 1 in methanol
was injected into water (final concentration c = 1x10ꢀ5 M) and the
UV absorption spectrum was recorded at set intervals. Directly
after injection the absorption spectrum displays a maximum at
75 192 nm, as was observed for (S)ꢀ2. In time, however, the
absorption spectrum undergoes a red shift via an isosbestic point.
The absorption maximum at 192 nm suggests that initially helical,
columnar, oneꢀdimensional stacks are formed that subsequently
convert into the structures observed by cryoꢀTEM. In contrast, for
80 solutions of (S)ꢀ2 in water, no transition occurs in time after
injection from methanol, which suggests that (S)ꢀ2 is in the
thermodynamically stable state. Possibly, the stereogenic methyl
side group in (S)ꢀ2 preorganizes the molecules resulting in a
preference for a columnar packing.
2
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These observations stress the importance of a careful design of
the formation of these fibrillar aggregates. These results highlight
the aliphatic spacers. However, the contribution of intermolecular 60 the potential of combining hydrogen bonding and hydrophobic
hydrogen bonds to the stabilisation of the aggregates remains
unclear. Therefore, we assessed the presence of hydrogen
bonding in the aggregates of 1 in water by the addition of
hexafluoroisopropanol (HFIP), a denaturant that is capable of
interfering with intermolecular hydrogen bonds.16 Upon addition
of small aliquots of HFIP to a solution of 1 in water (ESI, Fig. S4)
the absorption maximum gradually shifts to lower wavelengths,
10 indicating depolymerization of the aggregates. The changes in the
UV spectra upon addition of HFIP are comparable to those
observed upon raising the temperature. As such, it is likely that
hydrogen bonds play an important role in the stabilisation of the
aggregates of 1 and (S)ꢀ2.
effects for the formation of supramolecular polymers in water and
contribute to the development of general guidelines for the
rational formation of oneꢀdimensional assemblies in water.
5
Notes and references
65 a Institute for Complex Molecular Systems, Eindhoven University of
Technology, P.O. Box 513, 5600 MB Eindhoven, The Netherlands.
Eꢀmail: e.w.meijer@tue.nl, a.palmans@tue.nl;
Fax: +31 (0)40 2451036; Tel: +31 (0)40 2473101
† Electronic Supplementary Information (ESI) available: [Experimental
70 details, characterization by UV and fluorescence spectroscopy and cryoꢀ
TEM.]. See DOI: 10.1039/b000000x/
15
Additional proof for the importance of the hydrogen bonds in
the aggregate formation was obtained by methylation of the BTA
amide groups in 3. As a result, 3 cannot form intermolecular
hydrogen bonds26 and the potential aggregation of 3 can only be
the result of its amphiphilic nature. The aggregation behaviour of
1
C. Fouquey, J.ꢀM. Lehn and A.ꢀM. Levelut, Adv. Mater., 1990, 2,
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75
80
85
90
2
3
4
5
20 3 in water and methanol was studied by UVꢀvis spectroscopy.
The UV spectrum of 3 does not change upon changing the solvent
from water to methanol (ESI, Fig. S6). These results show that 3
does not form supramolecular polymers in either one of the
solvents at the applied concentration, indicating the importance of
25 hydrogen bonding for aggregate stabilization.
6
7
8
9
After studying the significance of intermolecular hydrogen
bond formation, the contribution of hydrophobic effects to the
selfꢀassembly process was selectively assayed by probing the
polarity of the hydropobic pocket using the solvatochromic dye
30 Nile Red. In pure water Nile Red displays low fluorescence
intensity, which increases in more apolar solvents. Furthermore,
the fluorescence wavelength depends on the polarity of the
environment. This tool has been widely used to probe the
formation of selfꢀassembled structures with a hydrophobic core.27
35 Selfꢀassembly of BTA molecules in water will result in a strong
enhancement of fluorescent intensity due to probe encapsulation
and the emission wavelength will provide information about the
polarity of the hydrophobic pocket.16 Compared to pure water, the
fluorescence intensity of Nile Red in a solution of 1 increases two
40 orders of magnitude and a large blue shift is observed (Fig. 2D).
Interestingly, in a solution of (S)ꢀ2, the blue shift is smaller and
the fluorescence intensity is lower. Furthermore, compound 3
shows almost no difference with pure water, and only at higher
concentration (c = 5x10ꢀ5 M) a blue shift and increase in intensity
45 is observed (ESI, Fig. S7), indicating that the initial concentration
is below the critical aggregation concentration. The difference in
fluorescence wavelength and intensity confirms that 1 and (S)ꢀ2
adopt a different packing within the aggregates. The packing of 1
results in the formation of a more apolar hydrophobic domain,
50 even though it has fewer carbons in the spacer. The low
fluorescence increase of 3 further supports the importance of
stabilization of the aggregates by hydrogen bonding.
10 J. H. van Esch, Langmuir, 2009, 25, 8392ꢀ8394.
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In summary, we have rationally designed several waterꢀsoluble
BTA derivatives and studied their selfꢀassembly in water. These
55 molecules selfꢀassemble into supramolecular polymers,
micrometers in length and only a few nanometers in diameter.
UVꢀVis and fluorescence spectroscopy support that both
hydrophobic effects and hydrogen bonding play a crucial role in
120 25 E. J. Lenardao, G. V. Botteselle, F. de Azambuja, G. Perin and R. G.
Jacob, Tetrahedron, 2007, 63, 6671ꢀ6712.
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This journal is © The Royal Society of Chemistry [year]
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Supramolecular polymerization in water harnessing both hydrophobic
effects and hydrogen bond formation†
5
Christianus M. A. Leenders,a Lorenzo Albertazzi,a Tristan Mes, a Marcel. M. E. Koenigs,a Anja R. A.
Palmans,*a E. W. Meijer*a
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]