The influence of ethylene glycol chains on the thermodynamics of hydrogen-bonded supramolecular assemblies in apolar solvents

Article abstract of DOI:10.1039/b806506c

Substitution of hydrogen bond directed supramolecular assemblies with ethylene glycol chains leads to a reduction in the association constant in apolar solvents, where the reduction of the association constant is dependent on the length of the aliphatic spacer connecting the hydrogen bonds and the ethylene glycol chain. The Royal Society of Chemistry.

Full text of DOI:10.1039/b806506c

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The influence of ethylene glycol chains on the thermodynamics
of hydrogen-bonded supramolecular assemblies in apolar solventsw
Tom F. A. de Greef, Marko M. L. Nieuwenhuizen, Patrick J. M. Stals,
´
Carel F. C. Fitie, Anja R. A. Palmans, Rint P. Sijbesma and E. W. Meijer*
Received (in Cambridge, UK) 16th April 2008, Accepted 27th May 2008
First published as an Advance Article on the web 16th July 2008
DOI: 10.1039/b806506c
Substitution of hydrogen bond directed supramolecular assem-
blies with ethylene glycol chains leads to a reduction in the
association constant in apolar solvents, where the reduction of
the association constant is dependent on the length of the
aliphatic spacer connecting the hydrogen bonds and the ethylene
glycol chain.
ization constant (Kdim = 6 ꢀ 107 Mꢁ1 in CHCl3) has been
measured.4b Remarkably, the 1H-NMR spectrum of tri-EG
monomethyl ether substituted UPy 1a (in which the EG chain
is connected via a C2 spacer) in dry CDCl3 shows two signals
at a concentration of 0.1 mM at d = 5.82 and 5.86 ppm. This
is in contrast to the butyl substituted UPy where only a signal
at d = 5.82 ppm is observed at this concentration.3a Dilution
experiments (Fig. 2) reveal that at high concentrations only a
single signal is present at d = 5.82 ppm, indicating that the
additional signal at d = 5.86 ppm at low concentrations
originates from monomeric ureido-pyrimidinone species.
DOSY NMR on a solution of 1a (0.5 mM in CDCl3) indeed
confirms that the second signal at d = 5.86 ppm belongs to a
faster diffusing species (Fig. 2, inset). Based on the ratio of the
two diffusion constants, a molecular weight ratio of 1.85 was
calculated, in close agreement with the fact that the additional
signals originate from the 6[1H]-pyrimidinone monomeric
form. Furthermore, concentration dependent infrared (IR)
measurements performed on a solution of 1c in CDCl3 re-
vealed significant changes in the amide I and amide II regions,
indicative of a rearrangement of the hydrogen bond array.
Based on the integral ratio between the monomeric and
dimeric signals in the 1H-NMR spectrum, a Kdim of 3
(ꢂ 0.5) ꢀ 104 Mꢁ1 for 1a was calculated. This value of Kdim
is approximately 1000 times lower than the dimerization
constant of an aliphatic substituted ureido-pyrimidinone.3b
Recently, the effect of short ethylene glycol (EG) monomethyl
ether chains on two distinct supramolecular assemblies has
been independently reported by Bouteiller et al.1 and Araki
et al.2 In both cases, the dominant secondary interaction
responsible for the formation of the non-covalent assembly
is hydrogen bonding. In the first report, Bouteiller discusses
the influence of EG tails on the supramolecular polymeriza-
tion of EG substituted bis-ureas in polar and apolar solvents,
while in the second example Araki discusses the influence of
EG tails on the formation of giant supramolecular vesicles
composed of hydrogen-bonded sheet structures of guanosine
derivatives. These two examples have in common that the
microscopic (formation of vesicles) and macroscopic proper-
ties (viscosity) of the thermodynamically formed supramole-
cular assembly are highly dependent on the creation of a
hydrophobic pocket that shields the hydrogen bonds3 from
the EG moiety.
This communication aims to generalize the findings re-
ported by Bouteiller and Araki by further evaluating the effect
of short ethylene glycol monomethyl ether (EG) groups on the
self-assembly of two frequently used supramolecular motifs,
the ureido-pyrimidinone (UPy) unit and the benzene-1,3,5-
tricarboxamide (BTA) unit. Aliphatic derivatives of both
systems have been studied in detail by our group.4,5 We here
rationalize the behavior of the EG functionalized self-
assembling units and discuss the implications of these findings
for design rules of novel synthetic supramolecular assemblies
in which short EG units are indispensable to impart solubility
in polar and apolar solvents.
The UPy motif forms a self-complementary quadruple
hydrogen bonded (Fig. 1) motif for which a very high dimer-
Laboratory of Macromolecular and Organic Chemistry, Eindhoven
University of Technology, P. O. Box 513, 5600 MB Eindhoven, The
Netherlands. E-mail: e.w.meijer@tue.nl; Fax: +31 (0)40 2451036;
Tel: +31 (0)40 2473101
w Electronic supplementary information (ESI) available: Synthesis
and characterization of 1a–c and 2a,b. Experimental data of 1H-
NMR, CD, IR and DOSY measurements. Extended list of references.
See DOI: 10.1039/b806506c
Fig. 1 Equilibrium of triethylene glycol substituted UPy 1a, 1b and
1c in their 4[1H] dimeric and 6[1H] monomeric forms.
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Fig. 4 (a) CD spectra of compound 2a in decalin at c = 48.0 mM, c =
7.7 mM and c = 0.6 mM. The spectra were measured in a 0.01 mm,
0.1 mm and 1 mm cuvette, respectively. (b) Development of the
normalized gvalue as a function of chiral 2a added (c = 48 mM in
decalin).
Fig. 2 1H-NMR spectra at various concentrations of 1a in CDCl3.
The spectrum shows the region where the alkylidene protons resonate.
DOSY spectrum of a 0.5 mM solution of 1a in CDCl3 (inset).
either the loss of helical stacking within the columns (loss of
directionality of the intermolecular hydrogen bonds) or from a
significantly reduced Kass of 2a in alkane solution.
To estimate the Kass in 2a, we used the Havinga model
which has previously allowed us to estimate the Kass in similar
systems.5a,9 In this model, chiral and achiral derivatives are
mixed in different ratios (the ‘‘sergeants-and-soldiers’’ experi-
ment) and the chiroptical response is measured by CD spectro-
scopy as a function of the enantiomeric excess (ee). If
amplification of chirality is present, a non-linear relationship
is observed between the chiroptical response and the ee.
Comparing the data to values predicted by the Havinga model
allows for a rough estimation of Kass. We performed the
‘‘sergeants-and-soldiers’’ experiment on compound 2a and
achiral derivative 2b at a concentration of 48 mM in decalin.
Fig. 4b clearly shows the non-linearity when the normalized
gvalue (= De/e) is plotted as a function of the amount of 2a
added to a solution of achiral 2b. The solid line represents the
predicted values using a Kass of 21 Mꢁ1, a significantly lower
value than previously found for the trialkyl substituted
BTAs.5a
In sharp contrast, ureido-pyrimidinone 1b in which a hydro-
phobic hexyl spacer ‘protects’ the hydrogen bonding array
from the polar EG chain does not show any evidence of a
diminished dimerization constant (see ESIw).
We then extended our investigations to the effect of short EG
chains on the hydrogen bond induced supramolecular polymer-
ization of N,N0,N00-trialkylbenzene-1,3,5-tricarboxamides in
apolar solvents. Symmetric trialkyl substituted BTA’s are well
known to self assemble in one dimensional stacks in alkane
solution as a result of threefold, a-helix type intermolecular
hydrogen bonding between the amide moieties of neighbor
molecules.6,7 Circular dichroism (CD) measurements of a chiral
derivative based on (R)-3,7-dimethyloctyl chains showed a
pronounced CD-effect (De = 44 Mꢁ1 cmꢁ1) in heptane at a
concentration of 6.5 ꢀ 10ꢁ5 M and the association constant
.
(Kass) was around 5 ꢀ 108 Mꢁ1 5a We desymmetrized the BTA
motif by replacing one alkyl chain by an oligoEG chain
affording compounds 2a,b (Fig. 3). No CD-effect was observed
for chiral 2a at 6.5 ꢀ 10ꢁ5 M in heptane and the UV spectrum
showed a lmax at 208 nm which is typical for molecularly
dissolved BTA species.5b,7 Increasing the concentration of 2a
to c = 0.6 mM, c = 7.7 mM and c = 48 mM finally resulted in
a CD-effect (De = 37 Mꢁ1 cmꢁ1 at l = 225 nm) at the highest
concentration (Fig. 4a).8 The CD-effect is similar in size and
shape when compared to the chiral derivative based on three
(R)-3,7-dimethyloctyl chains suggesting that helical order is
present in the columns at high concentrations. In addition,
the IR spectrum of the 48 mM solution confirmed the presence
of threefold intermolecular hydrogen bonding (see ESIw). The
loss of the CD-effect at lower concentrations can originate from
The presence of a single oligoEG chain has a dramatic effect
on the stability of both the UPy dimerization and the forma-
tion of BTA stacks. The large conformational space of an
oligoEG chain and the stabilizing effect of intramolecular10,11
and intermolecular12 hydrogen bonding on different confor-
mations of the EG chain has lead to unexpected results in
supramolecular self-assembling systems before.13,14 The 1000
fold decrease in Kdim for UPy dimerization is most probably
the result of stabilization of the 6[1H] monomeric form by
backfolding of the triEG chain. Previously, Kaifer and Sun
reported a generation dependent decrease in Kdim in a series of
ureido-pyrimidinones substituted with Newkome type dendri-
mers.15 In their case, the decrease in Kdim was mainly attrib-
uted to an increase in steric crowding upon increasing the
dendrimer generation. However, in our case steric issues are
unlikely to have a pronounced effect on the value of Kdim. For
the BTA stacks, competition between the intermolecular hy-
drogen bonds between neighboring molecules and intramole-
cular hydrogen bonds with the EG chains results in an even
higher decrease in the Kass. This competition decreases the
cohesive energy between molecules in the stacks which results
16
in a lower Kass
.
As the field of supramolecular chemistry is making the
transition to the development of supramolecular assemblies
that can display structure and properties in water,17–19 the
Fig. 3 Chemical structures of BTAs 2 and the threefold intermole-
cular hydrogen bonds formed upon stacking, resulting in a helical
packing of the molecules.
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findings reported in this paper are important to design novel
synthetic supramolecular assemblies in which short oligoEG
units are used to impart aqueous solubility. Although in water
backfolding of the EG chain will not occur due to the
preference of the hydrated random coil ‘‘helical’’ structure
(gauche–trans–gauche) of the EG chain,20 the presence of a
hydrophobic spacer of sufficient length is necessary to increase
the association constant by providing an apolar microenvir-
onment that prevents hydrogen bonding between water
and the hydrogen bonds that constitute the supramolecular
assembly.1,2
3 For the use of hydrogen bonding for supramolecular structures,
see: R. Custelcean, Chem. Commun., 2008, 295–307.
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7 A reference compound with 2 n-octyl chains and one (R)-3,7-
dimethyloctyl chain showed an identical CD effect to the com-
pound with 3 (R)-3,7-dimethyloctyl chains showing that one chiral
chain suffices to induce chirality in the BTA stacks.
8 Decalin was selected for the measurements at higher concentra-
tions since the solubility of 2a,b was not sufficient in heptane.
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The striking effect of intramolecular shielding of hydrogen
bonding patterns found here, may also be responsible for low
association constants in other supramolecular systems in
apolar solvents after introducing oligoEG chains. More im-
portantly, the results obtained can be generalized; it is most
likely that other functional groups containing hydrogen bond
donors (amides, ureas and carbamates moieties) or acceptors
(esters, ureas, amides or carbamates) will influence the ther-
modynamics of hydrogen-bond based self-assemblies if the
linker connecting the functional groups to the hydrogen bond
array is not sufficiently long. The result of the proposed
intramolecular competition between hydrogen bond accepting
and donating groups in the side chain with the intermolecular
hydrogen bonds of any supramolecular assembly will be
reflected in significant changes in both microscopic and macro-
scopic properties compared to their aliphatic derivatives.
Funding by NWO is gratefully acknowledged.
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Notes and references
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