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Core–shell inversion by pH modulation in dynamic covalent micelles† R. Nguyen,‡a N. Jouault,§b S. Zanirati,a M. Rawiso,a L. Allouche,c G. Fuks,a E. Buhler*b and N. Giuseppone*a Dynamic covalent surfactants have been obtained by the reversible condensation of a hydrophobic aldehyde (ended by an ionic tip) with various neutral polyethylene glycol based hydrophilic amines. In water, the duality between the two hydrophilic domains (charged and neutral) leads to their segregation when the surfactants are self-assembled within micelles. Depending on the number of polyethylene glycol units, a core–shell inversion leading to a switching orientation of the ionic tips from the inside to

Received 12th January 2014 Accepted 28th February 2014

the outside of the micelles has been demonstrated by a combination of scattering techniques. In competition experiments, when several amines of different pKas and hydrophilic polyethylene glycol

DOI: 10.1039/c4sm00072b www.rsc.org/softmatter

chains are competing for the same aldehyde, it becomes possible to trigger this core–shell inversion by pH modulation and associated dynamic constitutional reorganization.

Introduction Dynamic covalent (or constitutional) chemistry (DCC)1 rests on the design and synthesis of molecules – or macromolecules – being produced by the reversible covalent (or non-covalent) associations of their fragments. In mixtures, when using competing sets of building blocks, this approach leads to dynamic combinatorial libraries (DCLs) in which the (macro) molecular composition is thermodynamically driven and can adapt its composition to internal or external parameters, ideally by selecting the best tted components.2 Several elds of investigation have taken advantage of this dynamic of constitution, going from inhibitor synthesis to coordination chemistry, catalysis, template synthesis, self-replicating systems, logic gates, etc.3–9 In addition, by implementing the basic concepts of dynamic combinatorial chemistry in materials science, researchers have recently opened new approaches for the design of responsive functional adaptive systems and materials.10,11 Chemical or physical stimuli such as pH,12 metal a

Institut Charles Sadron, CNRS, University of Strasbourg, 23 rue du Loess, BP 84047, 67034 Strasbourg Cedex 2, France. E-mail: [email protected] Mati`ere et Syst`emes Complexes (MSC) Laboratory, University of Paris Diderot – Sorbonne Paris Cit´e, Paris VII, UMR 7057, Bˆ atiment Condorcet, 75205 Paris Cedex 13, France. E-mail: [email protected]

b

c Institut de Chimie, Service de RMN, Universit´e de Strasbourg, 1 Rue Blaise Pascal, 67000 Strasbourg, France

† Electronic supplementary information (ESI) available: Synthetic pathways and procedures, characterization of organic molecules, and analytical ts of SAXS and SANS data. See DOI: 10.1039/c4sm00072b ‡ Current address: Centre de recherche de l'UTC, rue Personne de Roberval, 60200, Compi` egne, France. § Current address: Sorbonne Universit´ es, UPMC Univ Paris 06, CNRS, UMR 8234, 75005 Paris, France.

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ion concentration,13 temperature,14 shearing,15 or even electric eld16 are some external parameters which have been used to reversibly modify the molecular composition of these systems. In some particular cases, these dynamic molecular components can aggregate into larger self-assemblies which themselves display an intrinsic supramolecular reversibility of formation. This hierarchical dynamics1e existing between the molecular and supramolecular levels, i.e. linking both length scales and characteristic time scales of exchanges, is of interest for the design of new responsive materials. Within this framework, the design of dynamic surfactants and block copolymers is promising for the development of new responsive mesophases17 which can be tuned in both their composition and structures by external effectors. In a series of recent studies, it has been shown that the design of dynamic amphiphilic block copolymers (dynablocks), in which a hydrophobic block is reversibly linked to a hydrophilic one, can lead to tunable dynamic selfassemblies. This approach can be used for the controlled release of entrapped substances in micelles or vesicles by hydrolyzing their dynamic surfactants.18 Other interests concern the dynamics of constitutional reorganization between various mesophases when several dynablocks are competing in the system, possibly generating self-replicating behaviours.19 Such an implementation of dynablocks in systems chemistry20 is enriched by the possibility of using external triggers to perturb the structuring of the responsive self-assemblies by molecular redistribution. This kind of control is particularly attractive as it confers a new dimension of constitution in phase diagram which can change a number of properties in these materials. Herein, we study an original type of supramolecular self-assembly obtained from more complex dynablocks in which the hydrophilic block is reversibly linked by an imine

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bond to a hydrophobic block, which itself ends with a water soluble ionic tip. Assuming a spontaneous segregation of the two hydrophilic domains, the corresponding supra-molecular structures can in principle exhibit two different kinds of selfassembly depending on the orientation of the dynablocks, i.e. the charges pointing at the inner or at the outer surface of the nanostructure. Because of the imine bond, and by tuning amines' pKas, the molecular composition of such systems can also be modied by pH modulation. Thus, by modifying the size of the condensed hydrophilic moiety, one might expect to trigger structural transition by core–shell inversion depending on the molecular constitution and on the related orientation of the unimers within the nanostructure (Fig. 1). In addition, such micellar systems, depending on their surface interactions (charged or neutral), can aggregate at a third level of organization to produce ordered mesophases and thus to couple to a third layer of structural dynamics in the system.

Results and discussion

Soft Matter

Fig. 2 Imine condensation between diammonium aldehyde A and a set of amines (B–K) in D2O. Individual charged amphiphilic dynablocks (AB–AK) are subsequently able to self-assemble in well-defined micellar structures with characteristic sizes, shapes, and thermodynamic stabilities.

Conception and preparation of the samples To conceive the charged dynablocks, an aliphatic chain was functionalized at one end by a diammonium, and at the other end by an aromatic aldehyde to produce compound A (Fig. 2) (see ESI for synthetic pathways and experimental details†). The latter were coupled by imine condensation to hydrophilic amines based on neutral polyethylene glycol (PEG) blocks with different lengths (n ¼ 2 to 25 PEG units). The nucleophilicities and basicities of these hydrophilic moieties were modulated by using various amines (aromatic, benzylic, aliphatic, and oximes) (compounds B to J). Hydrophobic butylamine K was also synthesized and used as a reference in the following study. The reversibility of dynablocks AB–AK is ensured by the hydrolysis of the imine bond in the presence of water. As the availability of an amine to condense into an imine can be modulated by pH,12b,21 the reactivity of each hydrophilic block could be controlled upon the protonation/deprotonation

process. When combined together, hydrophobic and hydrophilic blocks lead to an amphiphilic dynablock which displays dual hydrophilic parts, i.e. one charged and one neutral, which can in principle determine vesicular or micellar structures depending mainly on the nature of the building blocks and on their volume ratio.22,23 Also, the formation of charged micelles having bis-ammonium tips in their external corona should display a characteristic repulsive peak in the scattering pattern. Imine condensations were performed at room temperature directly in water by mixing aldehyde A (with a referential concentration of 50 mM) and amines B–K (at a concentration 100 mM to shi the equilibrium toward imine formation, excepted for amines H, I, J and K (50 mM)). As demonstrated previously, the micellar structuring strongly inuences the imine condensation in water,19a and although this coupling is reversible with equilibrium shiing towards opening in water, the supramolecular structure stabilises the imine bond and most of the dynablocks, thus formed, are stable in water. Condensation values were determined by 1H NMR and are reported in Table 1. Structural parameters of dynablock self-assemblies

Fig. 1 General principle of the core–shell inversion in charged dynablocks. Two different neutral hydrophilic blocks (red) compete for one hydrophobic block (blue) with a hydrophilic ionic tip (green). In water, the two expressed dynablocks can adopt different supramolecular structures depending on the segregation and location of the charged tips. At a third level of thermodynamic equilibrium, depending on the surface interaction between micelles, those can or cannot aggregate in larger ordered mesophases.

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Reference structures with charges pointing to their external part: compounds A and AK. The self-assembled amphiphilic systems were analyzed in water solutions by small-angle neutron scattering (SANS), small angle X-ray scattering (SAXS), dynamic light scattering (DLS) and static light scattering (SLS), while the corresponding molecular compositions were determined by 1H NMR coupled with diffusion ordered spectroscopy (DOSY) NMR. To understand the formation of charged selfassemblies, reference compounds were analyzed rst. Aldehyde A possesses surfactant properties (that is without further imine condensation) due to the presence of a bis-ammonium tip, and thus forms charged micelles in water as conrmed by DOSY NMR24 (Fig. 3). Indeed, two diffusion coefficients were

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Table 1 Conversion values for imine condensation at equilibrium in deuterated water (determined by 1H NMR)

Imine

Aa vs. amine ratio

Conversion (%)

Concentration (mM)

AB AC AD AE AF AG AH AI AJ AK

1:2 1:2 1:2 1:2 1:2 1:2 1:1 1:1 1:1 1:1

92 90 82 73 70 96 64 98 97 68

46 45 41 36.5 35 48 32 49 48.5 34

a

[A] ¼ 50 mM for all experiments.

determined: the rst one corresponds to the Brownian motion of micelles made of aldehyde A (73 mm2 s1), whereas the second one is associated with the motion of the tosylate counter ions, which diffuse with a faster rate (305 mm2 s1). Using the Stokes–Einstein relationship25 (ESI†), one obtains a hydrodynamic radius of 2.7 nm and of 0.7 nm for the micelles and the counter-ions, respectively. More detailed insight into the structure of these supramolecular ionic self-assemblies has been obtained by SANS and SAXS. A major advantage of small-angle scattering is its ability to provide information across a broad range of length scales varying from 1 to 30 nm. The combination of SANS and SAXS has already proved its high potential to determine the structural parameters and exchange behavior of dynablocks.26 The micelles in D2O appear to be homogeneous for neutron scattering. In contrast, due to the high electronic density of the aromatic hydrophobic block, the SAXS signal is dominated by the scattering of the hydrophobic core. By setting apart the scattering length densities (SLDs) that depend on the used technique, SANS and SAXS spectra have been tted with the same structural parameter values. The characteristic parameters of dynablocks (AB–AK) such as the weight average molecular weight Mw, the concentration C, the density d (determined from the scattered intensity at zero-wave vector of the monomer

Fig. 3

DOSY NMR of aldehyde A in D2O (50 mM).

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solutions), the volume fraction F, and SANS and SAXS scattering length densities (rSANS and rSAXS) are listed in Table 2. Fig. 4a shows the variations of the scattered intensity I with the magnitude of the wave-vector q, obtained from SANS (blue circles) and SAXS (red squares) for aldehyde A. The high-q data with the oscillations associated with the form factor of the micelles are satisfactorily tted using a polydisperse spherical core–shell model whose parameters are the overall radius R of the micellar aggregates, the variance in size s, and the thickness of the shell, e (see ESI† for details and for the core–shell model description). From the best ts (black dashed and continuous lines), one obtains R ¼ 2.8 nm  0.5 nm with s ¼ 0.17 and e ¼ 0.9 nm. The extrapolation of the tted data at zero-wave vector, q / 0 (calculated Guinier plateau), gives an estimation of the micelle aggregation number of 45 (solvatation being not taken into account). One can also note that a smooth increase associated with a few larger micelles is observed at very low-q. In addition, in the intermediate range of q, a peak attributed to the repulsive interactions between the charged micelles is found at ˚ 1 (the structure factor contribution is not qmax ¼ 0.046 A included in the t of the data shown in Fig. 4). This conrms the presence of the bis-ammonium tips in the corona of the micelles and the peak position gives the average distance between objects that is D ¼ 2p/qmax ¼ 13.7 nm. Scattering patterns of aldehyde A were then compared with data obtained for reference dynablock AK resulting from the condensation between charged aldehyde A with non-hydrophilic butylamine K (Fig. 4b). The SANS (blue circles) and SAXS (red squares) data are very close to those obtained for aldehyde A, but display more pronounced oscillations in the intermediate q-range coming from the higher density of the core which is in agreement with a higher length of the hydrophobic part of the surfactant (made of butylamine). Again, spectra have been tted satisfactorily with a spherical core–shell model (black dashed and continuous lines) giving a radius of 3.6 nm and a thickness of 0.9 nm. From the extrapolation of the intensity at q / 0 we determined an aggregation number of 101. The presence of this repulsive peak in the intermediate range of q, observed for both experiments (SANS and SAXS) is the signature that the charges of the aldehyde are located in the external corona of the micelles, and will be used as a diagnostic in the following. Its position qmax is slightly shied towards the low-q values ˚ 1), giving a characteristic distance of D ¼ 34 nm and (0.035 A suggesting that the size of the charged micelles AK is larger. This is also conrmed by the position of the rst oscillation shied towards the low-q values. Table 3 summarizes the results obtained from the SAS experiments which were also in agreement with DOSY NMR giving a hydrodynamic radius of 3.1 nm for the AK micelles (diffusing at 64 mm2 s1 and containing the non-condensed aldehyde). To summarize this rst part, the formation of charged micelles displaying bis-ammonium tips in the external corona leads to (i) the apparition of a repulsive peak in the intermediate q-range, and (ii) to well-dened oscillations mostly associated with the hydrophobic dense core (less solvated than the ionic shell of the micelles) in the high q-range. This overall behaviour is used as a qualitative diagnostic tool in the following study.

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Table 2

Soft Matter Characteristic parameters of dynablocks AB–AK

Component

Mw (g mol1)

C (mM)

d (g cm3)

F

rSANS (1010 cm2)

rSAXS (1010 cm2)

A AB AC AD AE AF AG AH AI AJ AK

847 979 1155 1331 1551 1947 949 1239 1079 1475 793

50 46 45 41 36.5 35 48 32 49 48.5 34

1.165 1.141 1.127 1.132 1.127 1.124 1.147 1.143 1.148 1.138 1.107

0.036 0.039 0.046 0.048 0.050 0.061 0.040 0.035 0.046 0.063 0.024

1.014 0.946 0.890 0.860 0.826 0.785 0.945 0.762 0.810 0.761 0.757

10.622 10.415 10.302 10.354 10.321 10.296 10.478 10.483 10.515 10.434 10.170

Structural parameters obtained from SANS and SAXS for aldehyde A and dynablock AK

Table 3

Componenta

Rb (nm)

ec (nm)

Rcd (nm)

Nagge

Df (nm)

A AK

2.8  0.5 3.6  0.5

0.9 0.9

1.7  0.5 2.5  0.5

45  2 101  5

13.7 34

a Concentration of 50 mM. b Radius of the micelles. c Thickness of the shell. d Radius of the core. e Number of aggregated unimers obtained from the zero-q scattered intensity. f Characteristic distance between micelles: D ¼ 2p/qmax, where qmax is the position of the repulsive peak.

two samples (Fig. 5). The scattering patterns of these samples are quite different from those obtained for A and AK. The scattering curve of AJ (16 PEG units) displays a Guinier plateau in the low q-range associated with nite size objects and thus indicates that aggregation doesn't occur. At higher q, a power law with an exponent close to 4 is followed by a constant ˚ 1. Such a evolution of the intensity with a crossover q*  0.2 A sequence is reminiscent of star-like or spherical comb-like macromolecules.27,28 If the number of arms, f, is larger than 6, it is usual to consider the model developed by Daoud and Cotton,29 which takes into account repulsive interactions between arms. In this model, each arm is represented by a series of blobs of size x(r, f) that increases with the distance to the star centre, r, and decreases with the functionality f (at a

SANS (blue circles) and SAXS (red squares) scattering intensities as a function of q for (a) aldehyde A and (b) dynablock AK. The black dashed and continuous lines are the best fits using a core–shell spherical form factor (see ESI for details†).

Fig. 4

Structures with charges in the micellar core: AI and AJ. We subsequently investigated the structural behaviour – which by nature depends on the unimer orientation – of imines involving additional hydrophilic PEG blocks. Dynablocks AI and AJ, resulting from the condensation of charged aldehyde A with alkoxy-amines I (7 PEG units) and J (16 PEG units), were studied by the same techniques. For these two compounds, the poorly reversible oxime bond was formed with more than 90% of condensation and SAXS experiments were performed on these

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Fig. 5 SAXS scattering intensities of dynablocks AI (7 PEG units) (red circles) and AJ (16 PEG units) (blue squares).

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distance r, we have f blobs of size x(r, f) and the stretching of the arms becomes more marked with an increase of f). The compact stacking condition of these blobs leads to x(r, f) ¼ r  f1/2. The model depends on three characteristic lengths: the radius of the star-like micelle, R, the size of the larger blob x(R, f) that is the outer blob of the corona, and the statistical unit b. These lengths dene the three q-domains observed in Fig. 5 (and later in the paper): the Guinier regime q < R1; R1 < q < x(R)1 and x(R)1 < q < b1. In the intermediate regime two successive power laws with exponents 2/n and 1/n (Gaussian arms, n ¼ 0.5; arms with excluded volume, n ¼ 0.588) with a crossover value at q* ¼ 1/x(R) are predicted for 1 < qR < f1/2 and f1/2 < qR, respectively. We can estimate the average functionality by using the ratios of intensities at qR  1 and q*R ¼ f1/2 as I1(q ¼ 0)/ I2(q*) gives f3/2. One obtains x ¼ 0.4 nm, f ¼ 17.6, and the radius of the objects R ¼ xf1/2 ¼ 1.64 nm for AI and AJ. Also in rst approximation we can consider that R ¼ Rg if f  10, where Rg is the radius of gyration determined at low-q. For AI and AJ the scattered level is pretty low over the whole investigated q-range, indicating that the aggregation number (or f) is also low. As a consequence the second power law at a high q cannot be precisely determined. Interestingly, at a high q, an oscillation is slightly visible indicating that the core of the star cannot be reduced to one point, but this oscillation is not well-pronounced suggesting that the core is less dense than that of A and AK micelles. The formation of this charged core-swollen by the solvent-probably prevents the formation of spherical comb-like micelles with a large aggregation number (or f). AI and AJ display the same characteristic behaviour at intermediate and high q, namely a strong decrease followed by a constant variation in the scattered intensity. In the case of dynablock AI (7 PEG units), the increase of the scattered intensity at very low q comes from a colloidal aggregation of the branched objects that can only occur for structures with external PEGs.30,31 This suggests that the corona is composed of the PEG gras for dynablocks with more than 7 PEG units. In addition, relatively short external PEG chains favour the aggregation of the spherical branched objects leading to a supplementary mesophase in the system, while this phenomenon is unfavoured for longer hydrophilic PEG chains which stabilize single branched objects.30 Core–shell inversion: effect of the PEG length. Following the Israelaschvili approach, we have also hypothesized that, depending on the volume ratio occupied by the neutral hydrophilic chains in comparison with the charged ionic tips, an inversion of the core–shell structure would be observed in such dynablocks. To fully investigate the inuence of the PEG length on the nanostructures, aromatic and benzylic charged dynablock AB–AG self-assemblies (from 2 to 25 PEG units) were synthesized, analyzed by SANS, and compared together with aldehyde A. Fig. 6a shows the SANS results. For clarity, the data have been shied by one log unit (or two for AD) along the y-axis. As described above, compound A exhibits a repulsive peak in the intermediate range of q (indicated by a black arrow in the gure) due to the external orientation of the ionic tips (i.e. outside the corona). For smaller PEG sizes, and in particular for AB (n ¼ 3),

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Fig. 6 (a) SANS profiles of Dynablocks AB–AF. For clarity the data have been shifted by one log unit (or two for AD) along the y-axis. The black arrows indicate the repulsive peak positions and the dashed line the position of the oscillation associated with the form factor of the dense core. (b) Evolution of I/f at qR < 1 (low q plateau) as a function of n; n corresponds to the length of the PEG unit.

the overall behaviour of the SANS pattern (blue squares) is similar to that of A and AK and is satisfactorily described with the core–shell model (the latter being described in the ESI†). At ˚ 1 higher q, we observe a well-dened oscillation at q  0.25 A (marked by a dashed line in Fig. 6a) associated with the shapedependent form factor of the relatively dense core made of PEG units and less solvated than its hydrophilic ionic counterparts. At low q, the system exhibits a Guinier regime with a plateau of higher magnitude than that of A, which indicates a larger average nite size of the AB micelles. This plateau is followed by a slight upturn at very low-q probably associated with the presence of few larger micelles. Finally, the scattering prole of AB displays a peak slightly shied towards the lower q values suggesting also that the micelles are larger than those made of A, but still with external charges. This behavior was conrmed by DOSY NMR analysis (Fig. 7) shows micellar objects diffusing at 61 mm2 s1 (RH ¼ 3.3 nm) with non-condensed aldehyde also inserted in the structures, and counter ions diffusing at 293 mm2 s1. This is corroborated by DLS experiments displaying a diffusive mode with RH ¼ 3.4 nm. Let us rst discuss the SANS proles of compounds AD, AE and AF having PEG lengths of 11, 16, and 25 units, respectively.

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Soft Matter Structural parameters for dynabock (AB–AF) micelles obtained using core–shell and branched models

Table 4

Component

n

f/Nagga

Rb (nm)

Rgc (nm)

AB AD AE AF

3 11 16 25

18/26 6.5/6.6 5.7/5.8 7.4/7.5

2.80 1.40 1.34 1.82

1.9 1.4 1.4 1.8

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a

Number of arms or aggregation number obtained using the star-like model and the zero-q scattered intensity, respectively. b Radius. c Radius of gyration obtained from a Guinier analysis in the low qrange. It corresponds to that obtained using the ratio R/Rg calculated by Grest and coworkers.28 Fig. 7 DOSY NMR of dynablock AB in D2O ([A] ¼ 50 mM).

According to the previous data obtained for AI and AJ, the external corona of the micellar objects is made of PEG parts if n, the number of PEG units, is larger than 7. The overall behaviour of the SANS curves is reminiscent of star-like macromolecules. We also observe the complete disappearance of the correlation peak in the intermediate q-range. The core–shell transition in Fig. 6b is followed by plotting of the ratio I/f calculated at qR < 1 (low q plateau) as a function of the number of PEG units n. Indeed, I/f is directly proportional to the molecular weight, Mw, and thus to the aggregation number of the scattering objects. From n ¼ 0 (A) to n ¼ 3 (AB), the ratio I/f increases strongly indicating a signicant increase of the mass of the objects, while for n ¼ 11 (AD), 16 (AE) and 25 (AF) I/f decreases to a value close to 40 cm1. These changes in micellar mass for n  7 are corroborated with the disappearance of the repulsive peak and are attributed to the structural transition from spherical core– shell micelles to star-like objects composed of PEG arms. The low functionality of the star-like objects, f, is due to the swelling of the electrostatically charged core by water (lower amphiphilic character of the unimers). The latter cannot be reduced here to one point and its swelling generates a decrease of f. For the same reason the oscillation(s) associated with the form factor of the core are (is) not visible in the SANS spectra. For the aromatic imine series, this transition (core–shell inversion) occurs at n ¼ ˚ f ¼ 18.3, R ¼ 2.8 nm 7. For compound AB, we obtained x ¼ 5 A, and Rg ¼ 2.2 nm using the star-like analysis. The difference observed for AB between values of f and Nagg conrms that the branched object model is not adapted for AB (a micelle displaying a dense core and a large aggregation number cannot be visualized as a star). For the other samples, the zero-q scattered intensity (extrapolation of the plateau) gives aggregation numbers in good agreement with the f values obtained with the branched structure (star-like) model. Structural characteristics such as aggregation number, f, R, and Rg are summarized in Table 4. One should note that solvation is not included in our tting models and thus aggregation numbers/f are underestimated. Micelles with a PEG core were also observed for compound AG (2 PEG units with a benzylic group), which forms spherical micelles with a highly dense core due to the presence of benzylic groups that increase the hydrophobic environment of the imine bond. Using the core–shell model and the value of I0, we

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deduced an aggregation number of 54, a radius of 2.7 nm and a polydispersity of 0.15. This core–shell inversion can be explained by a hydrophilic inversion. As described above, each dynablock is composed of one charged tip, one PEG chain, both hydrophilic, and one intermediate hydrophobic alkane chain. For n ¼ 0, or small PEGs, the hydrophilicity of the molecule comes from the charged tips. When n increases the dominating hydrophilic part becomes the PEG chain leading to an inversion of the micelle. As a consequence the charged tips located inside the core of the micelles and, due to the electrostatic repulsion between the positive tips, prevent the formation of inverse micelles with a large aggregation number Nagg. However, the presence of the counter ions inside the core stabilizes the micelles at a low Nagg. In the same time, the “charged core”, swollen by the solvent is less dense, leading to the weakness of the oscillations at high q in the SANS curves. Finally, for oxime AI, one observes an upturn of the scattered intensity at very low q associated with an aggregation process of the micelles. This low-q upturn is also observed for AD, AE, and AF, but not for AJ. Interestingly, this shows that such a kinetically driven aggregation phenomenon depends not only on the PEG length in the corona, but also on the nature of the imine bond. It appears that the rigidity of the backbone is enhanced with aromatic imines (due to p–p stacking interactions19a) and the presence of larger aromatic hydrophobic part leads to objects with smaller f/Nagg (less than 10) and to an aggregation, even for long PEG chains, showing that the real parameter to consider is the PEG density in the corona, instead of the PEG chain length itself. Such aggregates were also observed by TEM microscopy for aromatic dynablocks (Fig. 8). Aer several days this aggregation process leads to a macroscopic phase separation, which can shi the equilibrium toward imine formation. This kind of supplementary coupling of these systems with a phase transition phenomenon can be of interest for original selection pathways in various dynamic combinatorial approaches. To summarize, for long PEG gras, the corona of the micelles is composed of the PEG chains and we observe a low-q increase of the scattered intensity associated with the aggregation of the micelles leading to a macroscopic phase separation. These neutral micelles do not display a characteristic peak in

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Scheme 1

TEM image of dynablock AE. The aggregate size is around 30 nm in diameter. The TEM images were obtained five days after imine formation. Fig. 8

the intermediate q-range nor well pronounced oscillations in the high q-range. Exchanges and competition between dynablocks. Regarding the structural properties determined above, one can postulate that in competition experiments by providing proper mixtures of scrambling dynablocks, the molecular composition could be modulated through a variation of pH which would subsequently produce a core–shell inversion at the supramolecular level (Fig. 2). To study this kind of pH triggered micellar inversion, we have studied two models of competition experiments involving AE with AG on one hand, and AD with AK (exchange b) on the other hand. The choice of these competition experiments was motivated by the fact that, for each of them, pKas of amines are involved as well as hydrophilicities of the amine chains are clearly differentiated. The competition experiments were formed by mixing A (50 mM) with the corresponding set of amines. In exchange a, amines E and G were used at a concentration of 75 mM each; while in exchange b, amines D and K were both added at 50 mM. Deuterated triuoroacetic acid and triethylamine were used to modify the pD of the solutions. For each pD value, the molecular composition of the mixtures was determined by 1H NMR and coupled with scattering measurements. Let us rst consider the structures of the mesophases adopted by dynablocks AE and AG alone in solution (Scheme 1). Fig. 9a displays SANS patterns. For AE, the intermediate and high q-ranges exhibit an overall behaviour characteristic of starlike objects with f ¼ 6. The low-q increase of the scattered intensity is associated with the formation of aggregates larger than 30 nm (i.e. aggregates of branched objects involving intermicellar PEG interactions). Conversely, AG (2 PEG units with a benzylic group), forms spherical micelles with a dense PEG core due to the presence of a benzylic group that increases the hydrophobic environment of the imine bond. This is illustrated by the fact that the data can be tted satisfactorily with a core–shell model leading to an overall radius of 2.7 nm (with a size polydispersity of 0.15). The presence of a low q plateau associated with the nite size of the objects shows that the micelles do not aggregate. This is also corroborated by the slightly visible repulsive peak at intermediate q that originates from the external orientation of the charged tips. From the value of I0, we deduced an aggregation number of 54.

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Exchange reaction between AE and AG modulated by pD

variations.

Fig. 9 (a) SANS scattering pattern for AG (black circles) and AE (blue squares). (b) Normalized distribution of the scattered intensity as a function of the hydrodynamic radius obtained by applying the Contin procedure to our DLS data at a scattering angle of 90 for AG and AE.

As SANS get only access to local and internal structures, it was necessary to turn to DLS measurements on both samples and Fig. 9b shows the normalized distribution of scattered intensity as a function of the size by applying the Contin method to our data for AG and AE. As expected, the size distribution is monomodal for AG that leads to the formation of a single micellar population of 4.9 nm (larger than the geometrical radius and thus conrming the formation of dense micellar objects), whereas the distribution is bimodal for AE: the average size of the rst population (fast mode) is around 3.8 nm, whereas the second population, much polydisperse, has an average RH of 65.8 nm. These results are consistent with SANS measurements which show that AG arranges into nite-size

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spherical micelles with PEG as a core while AE forms branched objects (with PEG as a corona) in coexistence with larger aggregates driven by inter-micellar PEG interactions.30,31 Let's now focus on the structural behavior during competition between amines E and G for the association with aldehyde A. The evolution of dynablock concentrations and corresponding SANS scattering curves are shown in Fig. 10 for various pDs. The two dynablocks have a clear inversed evolution in concentration, and good selections are obtained for each extrema (aromatic dynablock AE at low pD (82%) and benzylic dynablock AG at high pD (74%)) with an isoselectivity point corresponding to the pKa of the benzylic amine (pD z 9.1), as expected. Concomitantly, the progressive evolution of scattering patterns indicates the continuous growth of the mesophases from AE to AG as an outcome triggered by the molecular modulation. For intermediate pD values, micelles having internal PEG and external ionic tips (similar to AG) coexist with star-like objects (similar to AE) showing a colloidal aggregation. For this complex system composed of a mixture of too many different species, no accurate model exists and no quantitative structural information can be obtained about each constituent of the DCC. We can however observe qualitatively that at low pD, the mixture is quite similar to pure AE and, as the pD increases, the curves tend to reach the pure AG spectrum, but still express a majority of branched objects. At intermediate q the scattering intensity level increases indicating the increase of the mass of the objects. Also, the apparition of a structural pic at intermediate q for high pD is characteristic of the presence of external

Fig. 10 (a) Molecular composition of the system: concentration of benzylic dynablock AG (black circles) and aromatic dynablock AE (blue squares) as a function of pD obtained from 1H NMR data. (b) Corresponding SANS profiles as a function of similar pD values.

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micellar charges. At low pD the proportion of AE dynablock provides a large amount of PEG in the corona that maintains a preferential star-like structure, but as the pD increases, selectivity for AG dynablock increases and the amount of PEG in the corona is not sufficient anymore, leading to some core–shell inversion and to the apparition of external charges in the corona. This exchange experiment was performed with aromatic amine D (11 PEG units) and butylamine K that are competing to condense with aldehyde A (Scheme 2). SAXS and SANS scattering patterns of pure dynablocks AD (a) and AK (b) in D2O are shown in Fig. 11 (see also Tables 3 and 4 for structural parameters). The SAS curves display the two characteristic behaviors of the dynamic micelles. First, AK self-assembles in charged micelles with external ionic tips. The corresponding SAXS and SANS curves clearly show (i) the presence of a correlation peak at intermediate q resulting from the electrostatic repulsion between the objects (note that there is no increase at low q suggesting the good dispersion of these micelles in solution) and (ii) well-dened oscillations associated with the form factor of the micelles (the SAXS signal being dominated by the dense core) at higher q. Second, AD arranges in micelles with internal charges. Indeed, in that case, there is no correlation peak at intermediate q and we observe a clear increase at low q indicating the aggregation of the micelles due to the short external PEG chains. In contrast, AD displays the characteristic behaviour of external PEG micelles, namely an upturn of the scattered intensity at low q associated with the previously described aggregation behaviour, and non-well-pronounced high-q oscillations. The molecular composition of the system as a function of pD is plotted in Fig. 12. As expected, the aliphatic dynablock AK is favoured (71% from total imines) at high pD (more basic aliphatic amine), while a selectivity is obtained in favour of aromatic dynablock AD (83%) at low pD. The opening of the imine bonds is also observed at low pD (40%) according to the decrease of the nucleophilicity of the amines. As expected, the isoselectivity point occurs close to the pKa of the butylamine at pD z 10.1. SANS and SAXS experiments were performed for each pD value and the corresponding curves are reported in Fig. 13. As

Scheme 2

Exchange reaction between AD and AK modulated by pD

variations.

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Fig. 11 SANS (blue) and SAXS (red) scattering patterns for dynablocks AD (a) and AK (b).

Molecular composition of the system determined by 1H NMR: concentration of aldehyde A (green triangle), dynablock AK (black circles) and dynablock AD (blue squares) as a function of pD. Fig. 12

for the former exchange, no tting model can describe this complex mixture and only qualitative structural data were extracted. At low pD, the scattering pattern of the mixture is close to that obtained for pure AD. The structure evolves slowly through that of AK with an increase of the average size of the objects, as shown by the shi towards the low q values of the oscillation in the SAXS spectra. Also, another modication is found with the oscillation, which is more pronounced at high pD suggesting the densication of the core, a characteristic of micelles with internal PEG chains. A star-like analysis shows an increase of the functionality (from 12 to 17) and of the radius when the pD varies from 6 to 11.4. In particular, the radius increases from 2 to 2.3 nm at a pD  10.3 close to the pKa of the butylamine, showing a small structural break due to the presence of a larger amount of AK unimers in the system at this pD.

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SAXS (a) and SANS (b) scattering curves obtained for the exchange system between AD and AK at different pD values. The curve at pD ¼ 8 superimposes with pD ¼ 6 and is not plotted for the sake of clarity.

Fig. 13

The investigated pD range is however not wide enough to nd a behaviour similar to that of pure AK. Finally, the kinetics of such structural transition was investigated by SAXS experiments upon pD modications. Two initial solutions Sa (acid) and Sb (basic) were prepared at pD ¼ 6 and 12, respectively. Triethylamine was added to acidic solution Sa and triuoroacetic acid to the basic solution Sb to reach a pD value of 11.5 and 6, respectively. The SAXS were monitored as a function of time and the scattering curves are shown in Fig. 14. Let us rst recall that the available SAXS q-range gives only access to the internal structure of these large micellar aggregates. Aer pH modication at t ¼ 0 (t ¼ 0 refers to the mixture before pH modication), the patterns of Sa and Sb are quite different. For Sa the curve shows a clear oscillation at high q and a slightly lower intensity at low q. The increase at very low q is the signature of the larger aggregates. Sb presents a Guinier regime at low q with higher intensity indicating that the aggregation number or size object is higher for Sb whereas, at high q, no clear oscillations are visible. Thus at t ¼ 0 local structures are different. When the time increases Sa evolves towards Sb (and inversely) with an increase of I(q) at low q and slightly less visible oscillation at high q. At innite time (around 4 hours), both curves are very similar and well superimposed in the whole q-range suggesting that micellar aggregates adopt the same local structure. This experiment shows that an addition of an acid or base induces a clear structural change, which can be kinetically followed by SAXS. Through pD modication, the

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Experimental section

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Small-angle neutron scattering (SANS)

Fig. 14 SAXS scattering curves obtained for Sa (black squares) and Sb

(red circles) as a function of time. The last curve represents the system at infinite time (around 4 hours).

system evolves in 4 hours towards an intermediate structure compared to the reference ones. Note that at t ¼ 0 (modication of pD), the scattering patterns of Sa and Sb are different from those measured at the corresponding pD. This is due to an instant effect of the acidic and basic solution used to modulate the pD.

Conclusion In this paper we have shown the possibility to build a new kind of dynamic covalent micellar objects incorporating concomitantly both neutral and charged hydrophilic moieties. The segregation between these functions around the hydrophobic moiety leads to the formation of micelles in water which display either an inner or an outer orientation of their ionic tips. This orientation depends on the length of the PEG chains, but also, to some extent, on the nature of the imine itself. For a number of PEG units inferior to 7, one can obtain spherical micelles with a dense core lled with neutral PEG units and a corona constituted with charged tips which gives rise to a clear scattering repulsive peak. In this series, the size of the core increases with the length of the PEG chain (AB > AG > A) and the number of aggregations (and the overall size) increases with the hydrophobicity of the core (AK > AG > AB). Above 7 units of PEG, one can obtain small branched objects lled with the ionic tips and having the PEG chains oriented toward the outside of the micelle. In this case, the size of the object is less dependent on the size of the PEG chain but, interestingly, the size of the PEG can inuence the colloidal aggregation of the micelles. Going further, in competition experiments, a qualitative interpretation of these behaviors shows that it is possible to drive exchanges of blocks of different lengths and to induce a core– shell inversion in these objects. This kind of dynamic transition controlled by constitutional changes in so materials is of interest to implement new parameters in phase diagrams and to produce complex chemical systems capable of responding to changes in their environment by adapting their structure and chemical constitution.

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SANS measurements were performed on a PACE spectrometer at the Laboratoire L´ eon Brillouin (LLB, CEA Saclay) and on the D22 instrument at the Institut Laue-Langevin (ILL, Grenoble). On PACE three congurations were used: the rst with a sample to ˚ and a collimation detector distance of 5 m, a wavelength of 13 A ˚ distance of 5.00 m, the second at 3 m and 7 A and the last at 1 m ˚ with a collimation distance of 2.50 m, providing a large and 7 A ˚ 1. The neutron accessible q-range from 3  103 to 0.3 A wavelength distribution Dl/l was 0.11. Data treatment was done with a homemade program (Pasinet) following standard procedures. To get the cross-section per volume in absolute units (cm1), the incoherent scattering cross-section of H2O was used as a calibration. It was estimated from a measurement of the attenuator strength and of the direct beam with the same ˚ attenuator. On D22 two congurations were used: 1.5 m at 8 A ˚ giving an experimental q-range from 0.0028 A ˚ 1 and 17 m at 8 A ˚ 1. In order to enhance the contrast and reduce the to 0.45 A incoherent background D2O was used as the solvent. Aer standard corrections and normalizations the intensities are corrected from the incoherent scattering of the solvent D2O. Small-angle X-ray scattering (SAXS) SAXS experiments were performed with two setups: an Elexience spectrometer with a sample to detector distance of 1.5 m, a ˚ and a Nanostar spectrometer (Brukerwavelength of 1.54 A Anton Paar) that operates with a pinhole collimator and a wire ˚ proportional gas detector. A monochromatic (l ¼ 1.54 A,  CuKa1) and almost parallel beam (divergence ¼ 0.03 ) is obtained through two Gobel crossed mirrors. The size of the incident beam on the sample is close to 300 mm. The sample-to˚ 1 < q < 1 A ˚ 1), and the q detector distance was set at 1 m (0.06 A 1 ˚ resolution was 0.005 A . The SAXS experiments were also performed at the ESRF (Grenoble, France) on the ID-02 instrument using a pinhole camera at the energy of 12.46 keV at two sample-to-detector distances (1 m and 8 m) corresponding to a ˚ 1 and 0.57 A ˚ 1. The absolute q-range varying between 0.0011 A units are obtained by normalization with respect to water (high q-range) or lupolen (low q-range) standard. Static and dynamic light scattering (SLS and DLS) SLS and DLS measurements were carried out using a 3D DLS spectrometer (LS Instruments, Fribourg, Switzerland) equipped with a 25 mW HeNe laser (JDS uniphase) operating at l ¼ 632.8 nm, a two channel multiple tau correlator (1088 channels in autocorrelation), a variable-angle detection system, and a temperature-controlled index matching vat (LS Instruments). The scattering spectrum was measured using two single mode bre detections and two high sensitivity APD detectors (Perkin Elmer, model SPCM-AQR-13-FC). Solutions were directly ltered through a 0.22 mm Millipore lter into the scattering cell. In DLS, the experimental signal is the normalized time autocorrelation function of the scattered intensity g(2)(q, t).32 In our experiments cooperative mechanisms, with characteristic

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times inversely proportioned to q2 were observed. We have applied the classical Contin analysis based on the Laplace transform of the correlation function to determine the distribution of cooperative diffusion coefficients, D.32 The latter are related to the average apparent hydrodynamic radius of the species, RH, through the Stokes–Einstein relationship.25

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RH ¼

kT 6phs D

Where k is the Boltzmann constant, hs the solvent viscosity, and T the absolute temperature. Diffusion ordered spectroscopy NMR (DOSY NMR) 1

H NMR spectra were recorded at room temperature on a Bruker Avance spectrometer at 500.13 MHz from the NMR service of Institut de Chimie de Strasbourg. The spectra were internally referenced to the residual proton solvent signal. Residual solvent peaks were taken as reference (D2O: 4.79 ppm). The NMR probe is an inverse 1H-X equipped with a Z gradient coil, able to generate pulse eld gradients of 55 Gauss cm1 with a power amplier of 10 A. Self-diffusion NMR data were acquired using a Stimulated Echo pulse sequence with bipolar z gradients. Limited Eddy current Delay was xed to 5 ms. A recycling delay of 3 s was respected between scans. Diffusion datasets were acquired with an array of 30 gradients steps from 2.5 to 50 Gauss cm1, linearly incremented. The diffusion time was xed to 250 ms. Processing was performed by the DOSY module of the soware NMRNotebook, using Inverse Laplace Transform (ILT) driven by maximum entropy, to build the diffusion dimension. An exponential line broadening apodization of 1 Hz was applied to the spectral axis and the baseline offset was corrected before DOSY calculation. Intensities of selected NMR peaks were processed by ILT. The nal DOSY spectra were obtained with 128 points in the diffusion dimension and 1000 MaxEnt iterations. Transmission electronic microscopy (TEM) The cryo TEM images were obtained at the Institut Charles Sadron, using a Tecnai G2 FEI microscope under “low dose” conditions of observations. The images were taken with a low scan 2k camera Eagle Fei. For the sample preparation, 5 mL of the solution were deposited on a hydrophilic grid.

Acknowledgements The research leading to these results has received funding from the European Research Council under the European Community's Seventh Framework Program (FP7/2007-2013)/ERC Starting Grant agreement no. 257099 (N.G.). We wish to thank the CNRS, the icFRC, the LabEx CSC, the University of Strasbourg, the University of Paris Diderot-Paris 7, and the Institut Universitaire de France (IUF). R.N. thanks the Region Alsace for a doctoral fellowship. We are grateful to the Laboratoire L´ eon Brilloin (LLB, CEA, Saclay, France) as well as to the European Synchrotron Radiation Facility (ESRF, Grenoble, France) for beamtime allocation. This work was supported by a post-

3936 | Soft Matter, 2014, 10, 3926–3937

doctoral fellowship (N.J.) from the Agence Nationale de la Recherche (ANR-09-BLAN-034-02).

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