Triggered self-assembly of simple dynamic covalent surfactants

Article abstract of DOI:10.1021/ja902808q

(Figure Presented) A prototype surfactant system was developed with the unique feature that it can be switched between an aggregated, amphiphilic state and a nonaggregated, nonamphiphilic state using external stimuli. This switchable surfactant system uses the reversible formation of a dynamic covalent bond for pH- and temperature-triggered on/off self-assembly of micellar aggregates by reversible displacement of the equilibrium between nonamphiphilic building blocks and their amphiphilic counterparts. The potential for application in controlled-release systems is shown by reversible uptake and release of an organic dye in aqueous media.

Full text of DOI:10.1021/ja902808q

Published on Web 07/23/2009
Triggered Self-Assembly of Simple Dynamic Covalent Surfactants
Christophe B. Minkenberg, Louw Florusse, Rienk Eelkema, Ger J. M. Koper, and Jan H. van Esch*
Delft UniVersity of Technology, DelftChemTech, Julianalaan 136, 2628 BL Delft, The Netherlands
Received April 16, 2009; E-mail: j.h.vanesch@tudelft.nl
Surfactants continue to attract widespread industrial and scientific
attention, ranging from applications in detergent formulation to self-
assembly of protocells and controlled drug delivery. Control of
surfactant self-assembly using environmental stimuli is critical in
many of these applications and could provide a breakthrough in
the construction of artificial biomimetic architectures. Several
surfactant systems in which a change in aggregate morphology is
triggered by external stimuli have been reported.1-6 However,
systems in which the on/off assembly and disassembly of am-
phiphiles can be triggered remain largely unexplored. Dynamic
combinatorial chemistry (DCC)7-9 is a powerful tool for the
construction of supramolecular architectures because of its reversible
molecular recognition properties and has already led to the
controlled formation and amplification of macrocycles,10,11 gels,12,13
and polymers.14-16 Recently, it has been shown that the formation
and dissociation of dynamic covalent surfactants17 based on
insoluble precursors lead to autocatalytic micelle formation18 and
transformation into vesicles and oil droplets,19 respectively.
Here we report a prototype surfactant system that can be switched
between an aggregated, amphiphilic state and a nonaggregated,
nonamphiphilic state by a change in pH or temperature. This
switchable surfactant system is formed from simple nonamphiphilic,
water-soluble precursors through the formation of a dynamic
covalent bond. The reversible character of this bond allows control
over the surfactant concentration, which can be used to trigger self-
assembly, simply by displacing the equilibrium away from the
water-soluble nonamphiphilic precursors by changing the pH and
temperature. To this end, we mixed a polar aldehyde-functionalized
headgroup fragment20 and an apolar primary-amine-functionalized
chain extender, forming amphiphiles in situ through the formation
of covalent imine bonds (Scheme 1). The advantage of using imine
chemistry is that both the aldehyde and amine building blocks have
only one active functionality for directional dynamic bond forma-
tion, which prevents the formation of nonamphiphilic compounds.7
We chose to combine an aromatic aldehyde with several aliphatic
amines (Scheme 1)20 because in general the equilibrium constant
for imine formation is largest using this combination.21
time scale. However, at higher concentrations the imine peak
gradually shifts upfield, indicating that association into micellar
structures involves an equilibrium that is fast on NMR time scale.
The concentration from which the imine signals significantly shift
upfield (∆δ > 0.05 ppm) was taken as the critical micelle
concentration (CMC) (see Table 1, Figure 1B, and Figure S3 in
the Supporting Information). This phenomenon was investigated
in more detail by drop-volume surface tension and dynamic light
scattering (DLS) measurements. The surface tension studies clearly
showed that the formed imines are surface-active, with surface
tensions of 37 mN/m at surfactant concentrations above the CMC
(Figure S6).
The CMC values determined with surface tension match nicely
with the 1H NMR results and, as expected, decrease with increasing
chain length of the surfactant (see Table 1 and Table S1). The
hydrodynamic diameters measured by DLS were ∼5 nm, which is
a typical size for micelles formed from single-chain surfactants (see
Table 1 and Table S2).
Table 1. CMCs and Hydrodynamic Diameters for Micelles of 1a
surfactant system
CMCald (mM)b
CMCim (mM)c
Dh (nm)d
C4OHIM
C5IM
C6IM
C7IM
C8IM
-
-
10.7
6.7
3.8
0.9
-
22.7
13.5
5.5
3.8 ( 0.8
4.4 ( 1.2
5.5 ( 1.1
6.0 ( 1.6
1.8
a All measurements were performed in pH 11.8 phosphate buffer at
25 °C. b Determined using 1H NMR, expressed in terms of the initial
c
1
aldehyde concentration. Determined using H NMR, expressed in terms
of the equilibrium imine concentration. d Determined using DLS.
Neither the aldehyde nor the amine building blocks are surface-
active under the mentioned conditions. Additionally, the control
system C4OHIM, which was composed of 1 and the polar chain
extender 4-amino-1-butanol, did not show amphiphilic behavior or
micelle formation either (Figure 1B and Figures S3 and S6).
From a constitutional point of view, it is anticipated that micelle
formation should lead to imine stabilization.18 We investigated this
by measuring imine conversion curves for C4OHIM and micelle-
forming C5IM, C6IM, C7IM, and C8IM at thermodynamic equi-
librium20 and observed that above their CMCs, C7IM and C8IM
clearly deviate from the other investigated systems. The slopes of
the sigmoidal C7IM and C8IM curves are significantly steeper than
those for the C4OHIM, C5IM and C6IM systems. The situation
below the CMC was described by fitting the C4OHIM data with a
simple one-binding-site model; this gave an equilibrium constant
for imine formation of 1050 ( 35 M-1, which is of the same order
of magnitude as those reported for similar systems (see Figure 1A
and Figure S2).21 We can conclude from these results that in
contrast to C4OHIM, C5IM, and C6IM, micelle association for
C7IM and C8IM is more cooperative, resulting in additional imine
stabilization. These NMR studies point out that the imine self-
assembly equilibrium, which is fast on the NMR time scale, is
Scheme 1. Dynamic Formation of Imine Amphiphilesa
a In pH 11.8 phosphate buffer at 25 °C.
1
Imine formation was observed by H NMR spectroscopy, even
at millimolar concentrations, after mixing equimolar amounts of
both building blocks in an aqueous buffer solution (pH 11.8) at 25
°C. The observation of separate peaks for the aldehyde and imine
indicates that the imine formation equilibrium is slow on the NMR
9
11274 J. AM. CHEM. SOC. 2009, 131, 11274–11275
10.1021/ja902808q CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
coupled to the imine formation equilibrium, which is slow on NMR
time scale. In contrast with similar systems,18,19 the precursors are
not surface-active and remain soluble at low surfactant concentra-
tions, which makes this system fully reversible. These properties
make these systems ideal smart-surfactant assemblies, in which a
displacement of the imine equilibrium by, for example, pH or
temperature can be used to trigger self-assembly.
The pH-triggered demicellization of a C7IM solution was examined
using fluorescence emission spectroscopy, with Nile Red as a
hydrophobic probe.22 Nile Red emission was observed at 654 nm in
buffer, but addition of C7IM at concentrations above its CMCim was
accompanied by a blue shift of the Nile Red emission to 645 ( 2 nm,
indicating the incorporation of the Nile Red probe molecules into the
hydrophobic microenvironment of the C7IM micelles. The imine
micelles dissociated upon titration of a concentrated C7IM mi-
celle solution with acid, and this was accompanied by a red shift in
the emission due to the release of Nile Red from the hydrophobic
micelle core (Figure 2A).
was observed in both samples upon heating from 25 to 75 °C (see
Figure S9). Simultaneously, the position of the imine peak for I
underwent a downfield shift until a plateau was reached at 55 °C.
However, this peak position for II remained constant across the entire
temperature range. These results show that a downfield shift of the
imine peak accompanies the dissociation of the micellar aggregates
with increasing temperature for I. A constant chemical shift was
observed for I at temperatures of 55 °C and higher, indicating complete
micelle dissociation. The total imine concentration at 55 °C was
calculated to be 3.3 mM, which corresponds quite well with the CMCim
of C7IM at room temperature (3.8 mM) at pH 11.8. These observations
indicate that the micelle dissociation is due to imine dissociation instead
of a more general dependence of the CMC on temperature, as found
for more common surfactants.23
In conclusion, this study represents a new approach for pH- and
temperature-triggered on/off self-assembly of micellar aggregates by
reversible displacement of the equilibrium between nonamphiphilic
building blocks and their amphiphilic counterparts. The dynamic nature
of the system and the use of nonamphiphilic starting materials provides
facile entry into a variety of complex aggregates after just simple
mixing using a library approach.7,9 The potential for drug delivery
was shown by reversible uptake and release of an organic dye in
aqueous media. The stabilization of the dynamic covalent imine bonds
by self-aggregation and their associated dynamic constitutional response
to changes in pH and temperature make these structures highly
interesting candidates for future smart drug-delivery vehicles and for
the switchable formation of bilayers and polyelectrolytes.
Acknowledgment. This work was supported by The Netherlands
Organization for Scientific Research (NWO) and STW/Nanoned.
Figure 1. (A) Imine conversion curves for C4OHIM (O), C5IM (4), C6IM
(0), C7IM (2), and C8IM (b) as functions of initial aldehyde concentration.
(B) Imine CHdN chemical shifts of C7IM (2) and C4OHIM (O) as
functions of initial aldehyde concentration, obtained from 1H NMR
measurements in pH 11.8 phosphate buffer at 25 °C.
Supporting Information Available: Synthetic procedures and
results of surface tension and 1H NMR titration experiments. This
material is available free of charge via the Internet at http://pubs.acs.org.
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