Switch It Inside-Out: âSchizophrenicâ Behavior of All

Invited Feature Article Cite This: Langmuir XXXX, XXX, XXX−XXX

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Switch It Inside-Out: “Schizophrenic” Behavior of All Thermoresponsive UCST−LCST Diblock Copolymers Christine M. Papadakis,*,† Peter Müller-Buschbaum,*,†,‡ and Andre ́ Laschewsky*,§,∥ †

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Fachgebiet Physik weicher Materie/Lehrstuhl für Funktionelle Materialien, Physik-Department, Technische Universität München, James-Franck-Straße 1, 85748 Garching, Germany ‡ Heinz Maier-Leibnitz Zentrum (MLZ), Lichtenbergstraße 1, 85748 Garching, Germany § Institut für Chemie, Universität Potsdam, Karl-Liebknecht straße 24-25, 14476 Potsdam-Golm, Germany ∥ Fraunhofer Institute for Applied Polymer Research IAP, Geiselbergstraße 69, 14476 Potsdam-Golm, Germany ABSTRACT: This feature article reviews our recent advancements on the synthesis, phase behavior, and micellar structures of diblock copolymers consisting of oppositely thermoresponsive blocks in aqueous environments. These copolymers combine a nonionic block, which shows lower critical solution temperature (LCST) behavior, with a zwitterionic block that exhibits an upper critical solution temperature (UCST). The transition temperature of the latter class of polymers is strongly controlled by its molar mass and by the salt concentration, in contrast to the rather invariant transition of nonionic polymers with type II LCST behavior such as poly(N-isopropylacrylamide) or poly(N-isopropyl methacrylamide). This allows for implementing the sequence of the UCST and LCST transitions of the polymers at will by adjusting either molecular or, alternatively, physical parameters. Depending on the location of the transition temperatures of both blocks, different switching scenarios are realized from micelles to inverse micelles, namely via the molecularly dissolved state, the aggregated state, or directly. In addition to studies of (semi)dilute aqueous solutions, highly concentrated systems have also been explored, namely water-swollen thin films. Concerning applications, we discuss the possible use of the diblock copolymers as “smart” nanocarriers.

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INTRODUCTION Due to a complex interplay of enthalpic and entropic effects, block copolymers forged of incompatible blocks self-assemble into a wealth of nanostructured phases or colloids in bulk and at interfaces or, respectively, in solutions and thin films.1−4 Already in the simplest scenario, i.e., of a diblock copolymer in bulk, nanostructure formation is multifarious. It is regulated by a number of molecular parameters such as the interaction parameters of the individual blocks (resulting in a range of scenarios from weak to superstrong segregation regimes) or their absolute and relative sizes.5−7 The possibilities for nanostructure formation increase strongly with the complexity of the polymers, as for triblock or even multiblock copolymer systems.8−10 Similarly, block copolymers form a plethora of nanoscopic and mesoscopic colloids when dispersed in selective solvents. In the case of thin films, complexity is further increased due to the interactions at the interfaces defining the thin film geometry.11,12 A particularly interesting (not the least by virtue of the inherent link to biological systems) and versatile case is the use of water as a selective solvent for organic block copolymers. Due to the hydrophobic effect and the need for strong attractive interactions to obtain solvophilic behavior, typically via Coulomb forces or hydrogen bonding, diblock copolymers already assemble into a dazzling variety of colloidal objects.3 The © XXXX American Chemical Society

similarities of the molecular structures of amphiphilic block copolymers and low molar mass surfactants are often stressed (at least tacitly), resulting in the common use of terms for aggregates such as micelles, vesicles, and so on.1−3 Still, major differences beyond the size between the aqueous self-assembly of low molar mass and polymeric amphiphiles should be kept in mind. For instance, colloid formation of low molar mass amphiphiles mostly takes place under thermodynamic control, whereas polymeric amphiphiles tend to produce kinetically trapped, metastable structures.13−15 Also, segmental mobility and dynamics may differ substantially, not only due to the enormous difference in size but also because many hydrophobic polymer blocks are glassy or partially crystalline in the typical temperature window of aqueous self-assembly, i.e., between 0 and 100 °C. Beyond the wealth of as-prepared colloids, block copolymers offer the option of responsive self-assembly, i.e., the colloid structures change abruptly and profoundly upon relatively small changes in the system’s conditions. Preferentially, the application of a small stimulus converts solvophilic blocks into solvophobic ones or vice versa. Such a behavior that overcomes a Received: May 14, 2019 Revised: June 27, 2019

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DOI: 10.1021/acs.langmuir.9b01444 Langmuir XXXX, XXX, XXX−XXX

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Invited Feature Article

physical stimulus. The employed polymers are characterized by either an upper critical solution temperature (UCST) or a lower critical solution temperature (LCST), respectively (Scheme 1b).19 Although UCST-type behavior is typical for most real solutions, it has been rarely encountered in aqueous solutions of polymers19,20 for which thermoresponsive behavior is mostly of the LCST-type.21 Different from pH responsivity, the implementation of temperature changes is a priori noninvasive. Moreover, it represents a mild stimulus which is applicable even in biomedical environments if it is limited to a few degrees. If a polymer block with an appropriate phase diagram is chosen, this suffices to cross the consolute phase boundary, thereby switching from the soluble to the insoluble state, and vice versa. Still, as Scheme 1 illustrates, such a soluble−insoluble transition does not imply that the (micro)phase separating polymer chain becomes fully desolvated at the transition temperature. Rather, the polymer evolves more or less steeply from a strongly hydrated to a moderately hydrated state. Accordingly, the polymer coil may be considered as a nanosized gel which shrinks continuously with increasing distance from the consolute point. Various other physical and chemical stimuli have been used instead of pH or temperature changes to induce responsive behavior in polymers, including, for instance, changes of the ionic strength, electrical or magnetic fields, pressure, additives (ranging from simple cosolvents to molecular recognition units), irradiation, redox processes, or other chemical reactions.16,18 In all cases, the induced effects correspond to one of the two principles exploited by pH and temperature responsivity. Either the polymer’s inherent hydrophilicity is modified (as in the case of pH changes, see Scheme 1a), or the quality of the solvent is altered to make the system cross the consolute boundary line in the phase diagram (see Scheme 1b) but under isothermic conditions. Notwithstanding that such alternative stimuli may be the optimal choice in specific scenarios,22 responsivity is mostly more complicated to achieve than by pH or temperature changes, the effects may be rather small, and reversibility is often incomplete, in particular when using chemical reactions. Diblock copolymers with one stimulus-sensitive block, which are the simplest type of responsive polymers, have been investigated extensively.16−18,23−25 These systems with only one stimulus-responsive block may show two types of transitions, either from a fully solvent-compatible state to an amphiphilic one (corresponding to the transition I−IIa/IIb in Scheme 2) or from an amphiphilic state to a fully incompatible one (corresponding to transition IIa/IIb−III in Scheme 2). In contrast, block copolymers in which two (or even more) blocks are sensitive to stimuli have been much less explored.26−29 Already in the case of diblock copolymers with two stimulussensitive blocks, the scenarios become more complex. Such dual responsive diblock copolymers can offer four transition types that may be combined differently. This results in two fundamentally different switching sequences by either cumulating the soluble−insoluble transitions of the two blocks successively (transitions I−IIa−III and I−IIb−III in Scheme 2)30,31 or by counteracting the soluble−insoluble transitions of the individual blocks (transitions IIa−I−IIb or IIa−III−IIb in Scheme 2).32−34 For the self-assembly patterns deriving from the latter switching sequence, in which the roles of the hydrophilic and the hydrophobic blocks are interchanged, the term “schizophrenic” was coined in the seminal studies of Armes and coworkers.35,36 Apart from the fundamental interest in

purely static property profile of polymers by an interactive one has stimulated the fantasy equally of scientists, engineers, and technology scouts about most diverse applications, resulting in the catchy alternative terms as “intelligent” or “smart” polymers. Regrettably, the positive connotation and the lack of a stringent definition have resulted in an inflationary (mis)use of the attribute “stimulus-responsive”. For the sake of a meaningful discussion, we will restrict the term “responsive polymers” to scenarios in which apparently small changes of a key parameter result in marked changes of a key property. Here, this involves the compatibility or incompatibility with aqueous media and that the induced changes are a priori easily reversible.16,17 While diverse physical and chemical stimuli may induce responsive behavior in polymers, the field has been dominated since the beginning by changes of the solution pH or temperature (Scheme 1).16,18 Both stimuli excel by experimental Scheme 1. Scenarios for pH Responsive and Thermoresponsive Behaviora

a

(a) pH responsive polymers of weak polycations (upper row) and polyanions (lower row): (I) pH ≤ pKa − 2, (II) pH = pKa, (III) pH ≥ pKa + 2. (b) Suitable solution phase diagrams for thermoresponsive polymers. In both a and b, blue color indicates water-soluble, and red color indicates water-insoluble regimes.

simplicity and reversibility. Typically, pH responsivity comprises a combined physical and chemical scenario, as a pH change induces an acid−base reaction, implying the protonation or deprotonation of weak polybases and polyacids. The resulting conversion of an electrically neutral into a charged species (or vice versa) in the pH range close to the polymer’s pKa value induces marked changes of its hydrophilicity/hydrophobicity and, eventually, of its solubility in water. In practice, pH responsivity is generally realized by an invasive setup by adding acid or bases to an otherwise closed polymer solution system. A strong alteration of the number of charged groups (as e.g. from 10 to 90%) requires a pH change of 2 units across the pKa value of the acidic or basic moieties (Scheme 1a). Particularly in biomedical environments, such boundary conditions may be difficult to fulfill and/or to tolerate aside from the frequent toxicity of highly charged polymer species, in particular of polycations. Moreover, it must be kept in mind that pH changes are always associated with changes of the ionic strength. Hence, when repeated switching cycles are envisioned, the accumulating amounts of salt formed upon alternating dosages of acid and base may be problematic. These possible complications are circumvented when using thermoresponsive systems. Thermoresponsive systems mostly exploit polymers whose phase diagram in solution features a miscibility gap, either at low or at high temperature (Scheme 1b), and thus follow a purely B


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not only more complicated but also narrows the boundary conditions and risks possible interferences. A most obvious example is the superposed response to changes of pH and salinity.34,39 Therefore, the implementation of schizophrenic behavior by changing only one parameter seems attractive. Although the options are inherently limited, both dominant trigger parameters, pH and temperature, are a priori suited. For instance, weak polyacids may be combined with weak polybases, e.g. in block polyampholytes,40 or blocks that display either LCST or UCST behavior in aqueous solution may be chosen (Scheme 2). For the reasons discussed above, the use of thermosensitive systems seems particularly advantageous for model studies. Accordingly, we focused our interest in schizophrenic systems on the noninvasive, dual thermoresponsive ones. Traditionally, the synthesis of block copolymers, in particular of functional and hydrophilic block copolymers, had been most challenging. In the meantime, the significant progress made in so-called “controlled polymerization techniques” has facilitated their fabrication and enlarged their diversity considerably. Especially, the increasing maturity of reversible deactivation radical polymerization (RDRP) methods (with the main variants nitroxide-mediated polymerization (NMP), atom transfer radical polymerization (ATRP), and reversible addition−fragmentation chain transfer (RAFT) polymerization) has fertilized the field effectively and opened many novel structural options.41 When fabricating such dual thermoresponsive block copolymers, a bottleneck in the design has, up to now, been rather the selection of the block exhibiting a UCST. Against intuition, many polymers, in particular nonionic

Scheme 2. Simplified Transition Scenarios for a Diblock Copolymer in Aqueous Solution Bearing Two Independently Responsive Blocksa

a

(I) Water is a solvent for both blocks, (IIa)/(IIb) water is a selective solvent for one of the blocks, (III) water is a non-solvent for both blocks. The sequence I−IIa (or IIb)−III results in cumulative switching. The sequences IIa−I−IIb and IIa−III−IIb result in schizophrenic switching. The direct transition between scenarios IIa and IIb also occurs when simultaneous switching of both blocks is possible. Blue/cyan indicate different water-soluble segments, and red/magenta indicate different water-insoluble segments of the block copolymer.

structure formation of such polymers with variable preferences and the possible mechanisms of structure inversion, schizophrenic block copolymers have been proposed for unique uses. These comprise, e.g., smart emulsification, smart rheology control, or smart delivery of active agents, including drugs.29,37,38 The design of block copolymers with schizophrenic behavior is rather straightforward when implementing sensitivity to two different stimuli that exclusively address one or the other block, for instance changes of pH and temperature.36 Yet, the superposition of several trigger parameters renders the systems

Figure 1. Examples for dual thermoresponsive diblock copolymers exhibiting schizophrenic self-assembly which bear polysulfobetaine blocks with UCST behavior and poly(N-isopropylacrylamide] (PNIPAM) (a, b, e)32,33,37,60−63 or poly(N-isopropylmethacrylamide] (PNIPMAM) blocks (c, d, f−l) with LCST behavior.64−66 C


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Figure 2. Examples for dual thermoresponsive block copolymers reported for schizophrenic self-assembly which bear polysulfobetaine blocks with UCST behavior and alternative nonionic blocks with LCST behavior such as poly(tertiary amine methacrylate)s (a−c),67−69 poly(N,Ndiethylacrylamide)70 (d), or polyethers (e−h).46,71,72

Figure 3. Examples of dual thermoresponsive block copolymers reported for schizophrenic self-assembly which do not contain a polyzwitterion block.56−59,73

polymers, show LCST phase behavior in aqueous solution,21 while UCST behavior has been observed only rarely.19,20 Although recent efforts have produced welcome additions in the hitherto very small pool,42−47 the largest group of such polymers is polyzwitterions,48,49 mostly polysulfobetaines.50−55 Accordingly, the first reported purely thermoresponsive schizophrenic block copolymer amphiphile combined a nonionic block, namely poly(N-isopropylacrylamide) (PNIPAM) featuring a LCST transition, with a zwitterionic block, namely poly(N,Ndimethyl-N-(3-(methacrylamido)propyl)ammoniopropane sulfonate) (PSPP) featuring a UCST transition (Figure 1a).32,33 Also, the large majority of the reported block copolymers exhibiting purely thermosensitive schizophrenic self-assembly

has been based up to now on polysulfobetaines or closely related polyzwitterions (Figures 1 and 2). Alternative systems have been scarce (Figure 3)56−59 and tend to require rather unhandy boundary conditions. In particular, the ongoing search for alternative polymers with UCST behavior in aqueous solution will doubtless give rise to the implementation of other thermoresponsive blocks in the near future. Also, the structures of block copolymers aimed at purely thermosensitive schizophrenic self-assembly have recently been extended to triblock terpolymer systems (ABC type).73−75 In these systems, the additional third block is hydrophilic but not responsive, thus preventing macroscopic phase separation of the schizophrenic polymers for all possible D


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switching scenarios, including the equivalent to state III in Scheme 2 (see also ref 34). When moving from aqueous solutions to water-swollen films, we shift from the solvent-rich to the polymer-rich region of the phase diagram. This will not only affect the nanostructures formed but also their switching kinetics. In thin films, the situation becomes even more complex due to the additional interactions as well as space restrictions. Hence, it is not surprising that so far, studies on thin films of dual thermoresponsive diblock copolymers are rare. Already, the preparation of thin homogeneous films can be potentially challenging. Moreover, swelling and exchange behaviors of such films as well turned out to be highly complex.76 In this feature article, we focus on the recent advancements on the synthesis, phase behavior, and micellar structures of diblock copolymers consisting of two thermoresponsive blocks, namely a nonionic poly(N-isopropylacrylamide) or poly(N-isopropyl methacrylamide) block, which has LCST behavior, and a zwitterionic polysulfobetaine block, which has UCST behavior. Work in aqueous solutions is surveyed in the context of the existing literature, and first findings on thin films are highlighted. Synthesis/Design of the Schizophrenic Block Copolymers Investigated. Notwithstanding the examples cited above, the total number of systems reported with purely thermosensitive schizophrenic self-assembly has been small. Moreover, most reports represent singular studies in which such a behavior is studied within a focused context, or schizophrenic behavior is briefly mentioned as particular observation, without being investigated in more detail. This was the starting point for our investigations. On the one hand, we wanted to elucidate the structure of the various aggregates formed and the pathways leading to structure inversion. In particular, we intended to explore and compare the opposing scenarios in which the upper consolute boundary is positioned at lower temperature than the lower consolute boundary (Scheme 3a) and vice versa (Scheme 3b). These scenarios were recently considered in molecular simulations.77 On the other hand, we wondered whether the formal inversion of the water-soluble and the water-insoluble blocks in Schemes 2 and 3 represents merely an exchange transition between highly polar hydrophilic and rather apolar hydrophobic nanodomains without other than structural consequences, as insinuated in such a simplistic presentation. For example, transitions as from states IIa to IIb in Scheme 2 are restricted to a different arrangement of the aggregate shapes simply due to volume and packing effects, regardless of their chemical structure. Or, can we establish substantially different property profiles in the solvophobic cores and the solvophilic shells when they are either formed by the UCST-driven or LCST-driven microphase separated blocks? For instance, with respect to the uptake and release of water-insoluble active agents, it would be most exciting to be able to switch between micellar aggregates whose inverted cores enable triggercontrolled discriminating solubilization, e.g., of specific drugs or toxins, for controlled transport, delivery, and/or scavenging purposes. In our studies, we started out from the classical copolymer system PSPP-b-PNIPAM (Figure 1a) and systematically varied the absolute and relative sizes of both blocks as well as their exact chemical structure (Figure 1, Table 1). This and related block copolymers can be synthesized in a straightforward manner by RDRP methods such as RAFT.41 The selection of poly(meth)acrylamide-based systems took into account their high stability against hydrolytical degradation,78 which is desirable for long-

Scheme 3. Possible Thermoresponsive Self-Assembly of a Diblock Copolymer from a Zwitterionic Block Exhibiting UCST Behavior (Red) and a Nonionic Block Having LCST Behavior (Blue)a

a

The red dashed and the blue dash-dotted lines indicate the clearing point of the zwitterionic block, CPUCST, and the cloud point of the nonionic block, CPLCST, respectively. The resulting four regimes are denoted I, II, II′, and III. (a) CPUCST < CPLCST, (b) CPUCST > CPLCST. (c) Schematic phase behavior for electrolyte-modulated schizophrenic self-assembly, uniting scenarios a and b. Reproduced from ref 66. Copyright 2019 American Chemical Society.

Table 1. Molecular Characteristics of the Polymers Specifically Discussed block copolymer

Mna (kg mol−1)

DPn zwitterionic block

DPn nononic block

dispersity Đb

ref

PSPP430-bPNIPAM200 PSBP80-bPNIPAM100 PSPP498-bPNIPMAM144 PSBP50-bPNIPMAM155 PSBP80-bPNIPMAM115 PSBP245-bPNIPMAM105

152

430c

200e

n.d.g

62

32

80d

100e

1.5

63

210

498c

144f

1.4

65

35

50d

155f

1.3

66

32

80d

115f

1.3

63

86

245d

105f

1.4

66

a

Determined by end group analysis quantifying a dye label on the Rgroup via UV−vis spectroscopy. bBy SEC in hexafluoroisopropanol with apparent values according to calibration with poly(methyl methacrylate) standards. cSPP = 3-(N,N-dimethyl-N-(3-methacrylamidopropyl) ammonio propanesulfonate; dSBP = 3-(N,N-dimethylN-(3-methacrylamidopropyl) ammonio butanesulfonate. eNIPAM = N-isopropylacrylamide. fNIPMAM = N-isopropylmethacrylamide. g Not determined.

term studies at variable temperatures. The selected nonionic blocks poly(N-isopropylacrylamide) PNIPAM, and later on poly(N-isopropylmethacrylamide) PNIPMAM, have the advantage of showing LCST behavior of the so-called type 2 behavior with a sharp coil-to-globule collapse transition at ∼32 and ∼44 °C, respectively.79 These transitions depend only weakly on molar mass, concentration, and added electrolytes.21,80,81 The higher cloud point of PNIPMAM allows E


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The scaling behavior of the correlation length with temperature was characterized in more detail by SANS measurements on a concentrated PNIPAM solution (13 wt % in D2O).95 A large temperature range around the CPLCST was covered using a fine temperature resolution. In the one-phase state, deviations from mean-field theory were found as well, consistent with the findings in ref 93, and were attributed to hydrogen bonding of PNIPAM with water. Above the CPLCST, strong forward scattering is present, which is due to very large aggregates (beyond the resolution of the experiment) and is well-described by the Porod form factor. The specific surface, determined from its amplitude, indicates that these aggregates have sizes of at least of tens of micrometers. Thus, they are larger than the so-called mesoglobules (typical sizes few hundred nanometers) found in dilute solutions above CPLCST.94 Apart from the higher polymer concentration, also the rather low PNIPAM molar mass (25 kg/ mol) may be at the origin of the strong growth of aggregates in the two-phase region. The Ornstein−Zernike term was still present in the SANS data above the CPLCST; i.e., the aggregates contain a certain amount of D2O. The molecular origin of the counterintuitive increase of CPLCST of PNIPMAM (Figure 1c) compared to PNIPAM is still under discussion, but it seems to be related to the steric demand of the methyl group altering the chain conformation and the hydration behavior. PNIPMAM solutions were investigated intensively by turbidimetry, differential scanning calorimetry, Fourier transform infrared spectroscopy, and Raman and NMR spectroscopy.79,82,92,94,96−99 However, only one investigation addressed the chain size and structure in aqueous solution by scattering methods.84 Using light scattering, it was found that the aggregates formed above the CPLCST are more loosely packed than the ones formed by PNIPAM. We investigated a PNIPMAM195 sample in a 50 g L−1 solution in D2O. The CPLCST was found at 38.0 ± 0.5 °C,65 i.e., at a notably lower temperature than that reported in the literature. We attribute this difference to the rather hydrophobic fluorescence tag which was attached to the polymers to facilitate molar mass characterization. The SANS curves feature 3 decays at 22 and 29 °C (Figure 4). In contrast, at 39 °C, i.e. just above

separating the LCST from the UCST of the zwitterionic block, thus minimizing overlap between the two transitions. This was expected to result in a phase where the diblock copolymers are truly molecularly dissolved. Moreover, PNIPMAM shows some interesting differences from PNIPAM regarding its chain conformation and aggregation behavior.82−84 The initial choice of the zwitterionic polysulfobetaine PSPP as the block showing UCST behavior was based on the widespread occurrence of UCST behavior for polysulfobetaines in aqueous solution. This offered the opportunity to adjust the position of the consolute boundary by careful variation of their precise chemical structure (Figure 1).52−54,85 Moreover, the phase behavior of polysulfobetaines can be easily modulated by small amounts of electrolyte,50,51,54 thereby providing the option of directing the schizophrenic behavior to both scenarios of Schemes 3a and b for one given polymer. This allows for imposing the pathway for the aggregate inversion from states I to III by fine-tuning the conditions within the phase diagram (Scheme 3c, see also below). Additionally, polysulfobetaines are known to effectively incorporate charged guest molecules by virtue of their high content of ion pairs,86,87 which is in contrast to the solubilization expected by the collapsed nonionic block mainly due to lipophilic interactions. In the context of perspective uses of schizophrenic systems for biomedical applications, polysulfobetaines have the additional advantage of being highly biocompatible.88−90 Behavior of the Homopolymers. In this section, we describe the temperature-dependent solution and thin film behavior of the homopolymers which we chose for constructing our schizophrenic diblock copolymers. These are namely the nonionic PNIPAM or PNIPMAM in combination with a polysulfobetaine, namely PSPP, or poly(4-((3-methacrylamidopropyl)dimethylammonio)butane-1-sulfonate) (PSBP, Figure 1b). The Nonionic LCST Polymers PNIPAM and PNIPMAM. PNIPAM is by far the most studied thermoresponsive polymer with LCST behavior, exhibiting a sharp collapse transition at ∼32 °C.21,80,91−95 Its phase behavior was recently summarized.81 Many investigations addressed dilute or extremely dilute solutions and identified the collapse of single chains at the CPLCST and the formation of mesoglobules. These consist of a number of collapsed chains and maintain their mesoscopic size for a long time. Here, we briefly review two structural studies of semidilute aqueous solutions of PNIPAM around its CPLCST because these are the most relevant ones for understanding the behavior of the diblock copolymers based on these blocks. A comprehensive investigation on PNIPAM solutions in D2O having polymer volume fractions φ between 0.056 and 0.22 was carried out using small-angle neutron scattering (SANS) in the one-phase state.93 The correlation length of concentration fluctuations in the semidilute solution, ξ, increases with temperature and decreases with φ. ξ follows scaling behavior, ξ ∝ |Ts − T|−ν with Ts the spinodal temperature and ν the scaling exponent. The latter was found to increase from 0.42 to 0.47 for φ increasing from 0.0562 to 0.213. These values are close to, but consistently lower than the value predicted by mean field theory, ν = 0.5; however, only a few temperatures were measured at each volume fraction. The scaling behavior of ν with φ at a temperature far below Ts, ν ∝ φ−3/4, is in accordance with the behavior of a semidilute solution in a good solvent. However, for temperatures approaching Ts, the magnitude of this exponent increases, which is consistent with D2O becoming a theta solvent in this region.

Figure 4. SANS data from a 50 g L−1 PNIPMAM195 solution in at (□) 22, (◇) 29, (△) 39, and (▽) 49 °C. Adapted from ref 65. Copyright 2017 American Chemical Society.

CPLCST, the decay in intensity at low q values is more pronounced, and at 49 °C, it dominates, while the decays at high q values have nearly disappeared. The data were fitted using three terms: an Ornstein−Zernike term describing the chain correlations, a sphere form factor describing inhomogeneities at intermediate length scales (at 22 and 29 °C), and the Porod form factor to describe large aggregates (at all temperatures). The Ornstein−Zernike correlation length ξOZ increases from ca. F


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Hofmeister series,119 increasing in the order SO42− < Cl− < Br−. The salt effects are complex, though: at low salt concentrations, CPUCST increases with the amount of added salt and reaches a maximum, beyond which it continuously decreases (Figure 5b). For NaBr, the maximum is found at about 3 and 4 mM for PSPP solutions in H2O and D2O, respectively.52 Moreover, as noted for other polymers exhibiting a UCST transition in water,19 the phase transition temperature of PSPP is significantly higher in heavy water, D2O, than in normal water, H2O.52 This must be kept in mind, especially when combining data, e.g. from PSPPcontaining diblock copolymers, obtained with methods usually carried out on solutions in H2O such as turbidimetry, light scattering, fluorescence spectroscopy, or differential scanning calorimetry with data from methods such as 1H NMR or SANS where D2O is preferred or even mandatory. Although the polysulfobetaine PSBP (Figure 1d) is chemically very similar to PSPP (only the spacer group separating the ammonium and the sulfonate moieties is elongated by one methylene group in PSBP), its aqueous phase diagram is significantly altered compared to that of PSPP.53 The CPUCST of PSBP homopolymers is 60 °C or higher, i.e. markedly above the one of PSPP, and can be tuned effectively by variation of molar mass (Figure 6a). This allows shifting CPUCST above the CPLCST

2.4 nm at 22 °C to ca. 4.2 nm at 39 °C. At 49 °C, ξOZ is unchanged, but the abrupt decrease of the amplitude of this term indicates that the contributions from single chain scattering are strongly reduced above CPLCST. At 22 and 29 °C, the intermediate-scale inhomogeneities have an average sphere radius ravg = 25 ± 4 nm. Thus, in the one-phase state, the PNIPMAM195 solution features inhomogeneities at larger length scales, and very large, compact aggregates are present not only above but also below the CPLCST. These two phenomena were not observed in PNIPAM solutions. We attribute them to an enhanced hydrophobic effect due to the additional methyl groups on the polymer backbone. With respect to PNIPAM and PNIPMAM thin films, several film deposition methods were reported in the literature. Studies on PNIPAM are by far more numerous than those on PNIPMAM. Realized PNIPAM preparation methods are in particular surface grafting,100−107 dip-coating,108 spin-coating,109−111 solution casting,112,113 layer-by-layer deposition,114−116 and micelle and vesicle adsorption from solution.117 Besides such wet-chemical approaches, plasma polymerization was also reported.118 The change in temperature across the transition temperature causes a reduction of the PNIPAM film thickness due to the repellence of water molecules. Whereas for thick PNIPAM films, a bulk-like behavior is recovered, in thin films (below 100 nm), changes occur. Typically, in thin films, the transition temperature is shifted to somewhat higher temperatures as compared to the corresponding aqueous solutions. Moreover, the width of the transition is affected by the film thickness.112 The Zwitterionic UCST Polymers PSPP and PSBP. The CPUCST of PSPP is rather insensitive to the nature of the end groups but depends markedly on the molar mass (Figure 5a) and on the type and concentration of added low molar mass electrolytes (Figure 5b).52,53 The strongest effects on CPUCST were found for chaotropic anions52,53 in agreement with the

Figure 6. (a) Cloud points of PSBP homopolymers in 5 wt % aqueous solutions in D2O dependent on the degree of polymerization. The blue dash-dotted line marks the CPLCST of PNIPMAM, and the black dashed line marks the boiling point of water. (b) Cloud points of PSBP80 in 5 wt % solutions in H2O containing NaBr. All data are from ref 53.

of PNIPAM or PNIPMAM and realization of the scenario shown in Scheme 3b. Moreover, CPUCST decreases monotonously with increasing salt (sodium halide) concentration (Figure 6b); i.e., a general salting-in effect is observed, in contrast to the nonlinear behavior encountered for PSPP. The latter effect allows realization of the phase behavior sketched in Scheme 3c. Thin films of polysulfobetaines PSPP and PSBP so far have gained only very limited attention. Among the rare examples is a

Figure 5. CPUCST of PSPP dependent on number average molar mass (a) in 5 wt % aqueous solutions in H2O (□) and in D2O (■) and on salt concentration for PSSP500 in 5 wt % solutions in H2O containing (▼) NaCl and (○) NaBr (b). All data are from ref 52. G


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Figure 7. (a, b) Light transmittance of 10 g L−1 solutions of PSPP430-b-PNIPAM200 (a) and PSPP498-b-PNIPMAM144 (b) in salt-free D2O (black ■), in 6 mM NaCl (magenta ▲), and in 4 mM NaBr (green ●). The lines show CPUCST in salt-free solution (red ---), 6 mM NaCl (magenta -·-), and 4 mM NaBr in D2O (green ---) as well as CPLCST in all solutions (blue -·-). I, II, and III indicate the three regimes identified. (c, d) Concentration dependence of the cloud points of PSPP430-b-PNIPAM200 (c) in salt-free D2O (closed symbols) and in 4 mM NaBr (open symbols) and of PSPP498-bPNIPMAM144 (d) in salt-free D2O (closed symbols) and in 6 mM NaCl (open symbols): (red symbols) CPUCST, (blue symbols) CPLCST. The lines are guides to the eye.62,65 Adapted from ref 62, copyright 2016 American Chemical Society, and ref 65, copyright 2017 American Chemical Society.

study of the swelling behavior of PSPP80 thin films during exposure to an atmosphere of high humidity.55 Switching Behavior of Micellar Solutions from LCST− UCST Dual Thermoresponsive Diblock Copolymers. To realize the three patterns of phase behavior depicted in Scheme 3, we combined the nonionic LCST blocks PNIPAM or PNIPMAM (which differ in CPLCST but are rather insensitive to variation of molar mass, the choice of H2O or D2O, and salt addition) with the zwitterionic UCST blocks PSPP or PSBP, whose CPUCST can be tuned by variation of molar mass and salt concentration (see Figures 5 and 6). We started with a variation of the previously established PSPP-b-PNIPAM system,32,33,68 namely PSPP430-b-PNIPAM200, and identified the behavior shown in Scheme 3a.62 Using SANS in a wide temperature range, we found that the micellar structures in regimes I and III are very different with regards to their size, inner structure, and correlation. Addition of a small amount of NaBr (a few mM) resulted in slight structural changes. We next varied the LCST block to widen the gap between CPUCST and CPLCST and confer a larger polarity contrast. Thus, while holding onto the UCST block, we replaced PNIPAM by PNIPMAM as the LCST block and investigated PSPP498-bPNIPMAM144. In this diblock copolymer, CPUCST increases notably with the addition of few mM NaCl or NaBr; otherwise, the temperature-dependent phase behavior is rather similar with regards to the shape of the micelles in regimes I and II and the fluctuations in regime II. Small differences are consistent with the difference in block lengths and the more expanded block conformation of PNIPMAM with respect to that of PNIPAM. To realize the behavior sketched in Scheme 3b, we subsequently exchanged the PSPP block by a PSBP block that has a higher CPUCST while keeping PNIPAM or PNIPMAM as the LCST block.63,66 Initially, we designed rather symmetric

diblock copolymers, PSBP80-b-PNIPAM100 and PSBP80-bPNIPMAM115, to facilitate the interconversion of the two types of core−shell micelles in regimes I and III. In salt-free solution, indeed, schizophrenic behavior is found with a direct transition between regimes I and III without passing through regime II. This scenario is expected to occur at the point of intersection of the dashed and dash-dotted lines in Scheme 3c. In contrast, upon addition of few mM of NaBr, regime II appears for PSBP80-b-PNIPMAM115 in-between. Varying the relative block sizes of the latter system, we found that both scenarios of Schemes 3a and 3b can be deliberately addressed by the same polymer. The behavior sketched in Scheme 3c is realized by PSBP245-b-PNIPMAM105 in NaBr solution with the lower and upper consolute boundaries crossing at ∼12 mM NaBr. In the following, we describe the main findings of these investigations. Reversal of Micelles via the Molecularly Dissolved State: PSPP-b-PNIPAM and PSPP-b-PNIPMAM. The overall phase behavior of the diblock copolymers of PSPP430-b-PNIPAM200 and PSPP498-b-PNIPMAM144 was determined on rather dilute solutions using turbidimetry (10 g L−1 in D2O, Figures 7a and b). The expected three regimes I, II, and III are already visually distinguished. In regimes I and III, the diblock copolymer solutions are turbid. However, in regime III, some light is still transmitted (∼5 and ∼45% in the PSPP430-b-PNIPAM200 and PSPP498-b-PNIPMAM144 solutions, respectively), while in regime I, the transmittance of light is blocked. Moreover, the transmittance decreases sharply below CPUCST but only gradually above CPLCST. These differences suggest the presence of different self-assembled structures in the regimes I and III. In regime II, where the diblock copolymers are expected to be molecularly dissolved, the transmittance is in both cases significantly lower than 100%, pointing to significant concentration fluctuations, as known for polyelectrolytes.120 The H


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Figure 8. SANS curves from 50 g L−1 solutions of PSPP430-b-PNIPAM200 (a) and PSPP498-b-PNIPMAM144 (b) in salt-free D2O (open symbols) and in 4 mM NaBr in D2O (closed symbols) together with model fits (). The curves at different temperatures are shifted in intensity by a factor of 50 with respect to each other. Regimes I, II, and III are indicated by the blue, green, and red color, respectively.62,65 Adapted from ref 62, copyright 2016 American Chemical Society, and ref 65, copyright 2017 American Chemical Society.

∼8−12 nm in PSPP498-b-PNIPMAM144 are observed as well. They originate mainly from PNIPAM or PNIPMAM, respectively, and reflect the more expanded chain conformation of PNIPMAM compared to that of PNIPAM. Importantly, the anticipated core−shell structure was not detected. This may be due to intermixing of the two blocks: despite being no more water-soluble at the low temperature, the PSPP block is still appreciably hydrated and may incorporate PNIPAM or PNIPMAM segments into the core. This is possibly favored by the mutual attraction of the secondary amide moieties present in all blocks. The micelles are weakly correlated with each other, as evident from the shallow maximum in the SANS curves, while the forward scattering indicates the presence of large aggregates. The resulting morphology is sketched in Scheme 4.

CPUCST values increase with polymer concentration as well as with the molar mass of the PSPP block (Figures 7c and d), reflecting the behavior of the underlying PSPP homopolymers (Figure 5a and ref 52). For both diblock copolymers, CPLCST is nearly independent of polymer concentration, as expected from the behavior of the PNIPAM and PNIPMAM homopolymers (Figures 7c and d). For PSPP498-b-PNIPMAM144, we identified the three regimes in the temperature-resolved 1H NMR spectra as well.65 The peak shapes indicate that the mobilities of the two types of segments strongly differ in the three regimes: whereas in regime I, the PSPP segments are rather immobile, the PNIPMAM segments are mobile; in regime II, the segments of both blocks are mobile, and in regime III, the PSPP segments stay mobile, whereas the PNIPMAM segments become immobile. Interestingly, in regime I, the PSPP segments stay rather hydrated (presumably due to the inherent hydrophilicity of the zwitterionic side groups32). This is also, but seemingly to a lesser extent, the case for the PNIPMAM segments in regime III. Analogous observations were made for other schizophrenic zwitterionic−nonionic block copolymers displayed in Figures 1 and 232,61,64 as well as for other schizophrenic ones.57 These findings corroborate the view that the nanodomains formed by the collapsed polymer coils behave as moderately swollen hydrogels (cf. Scheme 1) rather than as oil droplets, as typically assumed for the micellar cores made of low molar mass surfactants. For both diblock copolymers, the shapes of the SANS curves measured on 50 g L−1 solutions in salt-free D2O reflect the 3 regimes identified by turbidimetry and give a wealth of structural information (Figure 8). In regime I, a smooth decay at low momentum transfers, q (named “forward scattering” hereafter), and a shallow maximum are observed. In regime II, the shallow maximum is still present, but the forward scattering is not observed any longer. In regime III, the curves decay steeply with a shallow second maximum. Differences between the two diblock copolymers are evident from the positions of the maxima and the amplitudes of the features, which are related to the structural length scales, the strength of the interactions between the micelles, and the compositions involved. Fitting of structural models enabled us to extract the micellar size, shape, and inner structure as well as their correlation. In regime I, small spherical micelles having radii of a few nanometers are present. Concentration fluctuations with correlation lengths of ∼4 nm in PSPP430-b-PNIPAM200 and

Scheme 4. Schematic Representation of the Micelle/Polymer Coils in the Three Regimes of the Salt-Free Solutions of PSPP430-b-PNIPAM200 and PSPP498-b-PNIPMAM144a

a

Red: PSPP block, blue: PNIPAM/PNIPMAM block. Red ---, CPUCST; blue -·-, CPLCST.65 Adapted from ref 65. Copyright 2017 American Chemical Society.

The SANS data in regime II comprise concentration fluctuations of the PNIPAM or PNIPMAM blocks, which are water-soluble in this temperature window, as well as those of the zwitterionic PSPP blocks. The data were successfully described by a model used previously for polyelectrolyte solutions which feature two correlation lengths.120 Correlation lengths of ∼6 and ∼50 nm are found in PSPP430-b-PNIPAM200 and ∼12−28 and ∼80−120 nm in PSPP498-b-PNIPMAM144. The smaller values may include the concentration fluctuations of the PNIPAM or PNIPMAM matrix as well, whereas the larger values mainly reflect the average distance between charged domains. This leads to the picture given in Scheme 4. I


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Figure 9. Results from PSBP80-b-PNIPMAM115 in 50 g L−1 solutions in D2O. (a) Light transmittance in salt-free D2O (black squares) and 4 mM NaBr (green triangles) in D2O. The dashed red line indicates the onset of the CPUCST in 4 mM NaBr, and the blue line indicates the CPLCST in both solutions. The three regimes are indicated by Roman letters at the top. (b) SANS data in salt-free D2O (open symbols) and in 4 mM NaBr in D2O (closed symbols). Lines: model fits. The curves are shifted vertically by a factor of 50 with respect to each other. Blue, green, and red color indicate regimes I, II, and III. (c) Schematic representation of the resulting phase diagram dependent on temperature and NaBr concentration. Red: PSBP block, blue: PNIPMAM block. Red dashed line: CPUCST of the PSBP block, blue dash-dotted line: CPLCST of the PNIPMAM block. Adapted from ref 63. Copyright 2018 American Chemical Society.

should be taken into account when designing new systems in the future. To evaluate the (slight) differences in phase behavior and structural characteristics of these two diblock copolymers, one must keep in mind that they have different block lengths, which is especially severe for the PSPP blocks, and overall copolymer compositions. Moreover, the interactions between PNIPMAM and PSPP blocks seem stronger than those between PNIPAM and PSPP blocks, presumably because the former block pair features the same (a priori more hydrophobic) backbone. Reversal of Micelles via the Aggregated State: PSBP-bPNIPMAM. In the first stage of our studies, as compiled above, we established that (i) the overall phase behavior is close to the one expected from the UCST and LCST behavior of the homopolymers, (ii) CPUCST of the zwitterionic block may be effectively manipulated via salt addition without affecting CPLCST of the nonionic block, and (iii) the micellar structures are only slightly altered by salt addition. Hence, in the following stage, we designed systems which should realize the behavior in Scheme 3b, i.e. the reversal of the micelles via the aggregated state (regime II′). To this end, we maintained PNIPAM or PNIPMAM as the nonionic LCST block but now combined them with zwitterionic blocks of PSBP. Compared to their PSPP analogues, PSBP shows much higher CPUCST values, e.g. 78 °C for PSBP80 in D2O (cf. Figure 6b) in comparison to CPUCST of about 15 °C for PSPP85.52,53 CPUCST decreases strongly and continuously with salt concentration and drops below CPLCST of, e.g., PNIPMAM (∼44 °C) at ∼10 mM of NaBr. We present here exemplarily the phase behavior and micellar structures in salt-free solution for PSBP80-b-PNIPMAM115.63 In salt-free solution, PSPB80-b-PNIPMAM115 is turbid in the entire investigated temperature range (15−65 °C) with light transmittances below 4% (Figure 9a). However, at 43 °C, a sharp decrease is observed, which reflects CPLCST of PNIPMAM. Regime II seems to be absent, but a change of structure occurs when the PNIPMAM block becomes water-insoluble. 1H NMR revealed that the signals from PNIPMAM broaden and weaken above CPLCST, as expected. In contrast, the signals from PSBP are broadest and weakest at 55−75 °C, which we attribute to a strongly attractive interaction of PSBP with the collapsed PNIPMAM, in analogy to the interaction of collapsed PSPP with PNIPMAM and PNIPAM encountered in regime I (see above).

In regime III, micelles are formed which have the expected core−shell structure (i.e., PSPP shells and PNIPAM or, respectively, PNIPMAM cores) and radii of ∼30 nm for PSPP498-b-PNIPMAM144 and ∼90 nm for PSPP430-b-PNIPAM200 (Scheme 4). The larger radius of the latter polymer’s micelles may reflect the lower volume fraction of the PSPP block. Possibly, this rather high value (compared to the contour length of the collapsed block of ca. 50 nm) is also due to clustering of the micelles. Their relatively large size is presumably at the origin of the reduced light transmittance in regime III (Figures 7a and b). As we do not observe any correlation between them, in contrast to regime I, the micelles in regimes III (mainly PSPP) and I (mainly PNIPAM or PNIPMAM) seem to have different surface compositions. To characterize the effect of electrolyte, we studied the block copolymers also after adding a few mM NaCl or NaBr, because for these conditions, the strongest effect on CPUCST (an increase by a few °C) was observed in aqueous solutions of PSPP homopolymers (Figure 5b). Also in the diblock copolymers, the CPUCST values increase upon addition of small amounts of these salts, whereas the CPLCST values are virtually unchanged at such low electrolyte concentrations (Figure 7). In the SANS data of solutions in 4 mM NaBr in D2O, the changes are most pronounced in regime I, where a significant increase of forward scattering is observed along with a change of the shape of the intensity maximum (Figure 8). Fitting reveals that, for both diblock copolymers, the spheres in regime I grow and that aggregation is enhanced compared to the salt-free solutions, presumably due to screening of ionic interactions between the zwitterionic groups. We conclude from these observations that the polysulfobetaine maintains high sensitivity to even small amounts of salt in the block copolymers, whereas the nonionic blocks do not react (yet) to this additional stimulus. Accordingly, we are able to modulate CPUCST and consequently the micellar structures in regime I by salt without affecting the behavior of the nonionic block notably. Also, it seems that, at least in regime I, the PSPP block, which is water-insoluble in this temperature range, interacts strongly with the PNIPMAM block. This implies that the responsive aggregation behavior of such schizophrenic systems is not the result of a mere superposition of the phase behavior of the underlying homopolymers. This J


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This may hamper the hydration of PSBP. Only above CPUCST of the PSBP block, the PSBP signals become narrower and more intense again. The SANS data in Figure 9b reflect the change of behavior at ∼43 °C. Model fitting revealed small spherical micelles (radius ∼14 nm) in regime I below CPLCST, which are weakly correlated, as well as concentration fluctuations characteristic of noncharged polymers. An abrupt change is observed at CPLCST, where regime III is entered directly. Here, the micelles are cylinder-shaped with cross-section radii of ∼11 nm and lengths between 25 and 54 nm. The correlation between the micelles is rather strong, which may be due to the fact that, now, the shell of the micelles consists mainly of PSBP. Moreover, the concentration fluctuations are now characteristic of polyelectrolytes, i.e. dominated by the PSBP blocks (even though these are still below their CPUCST). In contrast to the PSPP-based diblock copolymers, where the micelles had a core−shell structure in regime III, for PSBP80-b-PNIPMAM115, a core− shell structure could not be distinguished, neither in regime I nor in regime III. This may be attributed to the strong attraction between the two types of polymethacrylamide blocks, which becomes stronger with increasing hydrophobic character of the partners, i.e., from PNIPAM to PNIPMAM and from PSPP to PSBP. Addition of 4 mM NaBr reduces CPUCST of the PSBP80 homopolymer by ∼10 °C (Figure 6b) without affecting the PNIPMAM block. For the diblock copolymer PSBP80-bPNIPMAM115, addition of NaBr is accordingly expected to lead to the appearance of regime II below CPLCST, in which the polymer behaves as being double hydrophilic. This is indeed evident from the notable increase of light transmittance between ∼27 and 43 °C (Figure 9a). Further, the SANS data (Figure 9b) show that, in this temperature region, the data are of the same type as in regime II of PSPP430-b-PNIPAM200 and PSPP498-bPNIPMAM144 (Figure 8). The same model could be used for fitting the data, i.e. regime II with molecularly dissolved diblock copolymers is encountered by NaBr addition (Figure 9c). Reversal of Micelles via the Molecularly Dissolved or Aggregated State. PSBP-b-PNIPMAM in NaBr Solutions. To realize the full scenario sketched in Scheme 3c in the PSBP-bPNIPMAM system, CPUCST of the PSBP block must be raised well above CPLCST of PNIPMAM. This is readily achieved by exploiting the molar mass dependence of CPUCST of PSBP (Figure 6a). We chose a diblock copolymer with a longer PSBP block, namely PSBP245-b-PNIPMAM105. In salt-free D2O, the light transmittance is very low in the entire temperature range studied (Figure 10a). The SANS data in salt-free D2O feature 3 regimes (Figure 10b): In regime I, the data can be modeled by spherical micelles (radius 30−40 nm) that are uncorrelated, and large aggregates. Between 50 and 70 °C, spherical micelles are still observed, which have smaller radii (radius 9−19 nm) and which are correlated. We attribute this temperature range to regime II′, where the micelles form large aggregates. From 80 to 90 °C (regime III), micelles having radii of ∼12−21 nm are observed, which are weakly correlated. When NaBr is added in amounts up to 12 mM, the transmittance increases within a small temperature range below CPLCST, reminiscent of the behavior of PSBP80-bPNIPMAM115 in salt-free D2O (Figure 9a). At higher salt concentrations (16−24 mM), the transmittance gets close to 100% in a certain temperature range that becomes broader with increasing NaBr concentration. Its onset, which we attribute to CPUCST, simultaneously shifts to lower temperatures, while

Figure 10. Results from solutions of PSBP245-b-PNIPMAM105 in D2O. (a) Selected transmittance curves in a semilogarithmic representation, measured during heating for the NaBr concentrations given in the graph (polymer concentration in D2O 10 g L−1). (b) SANS data from a 50 g L−1 salt-free solution in D2O. (c) SANS data in D2O in 24 mM NaBr (symbols). In panels b and c, the symbols are the data, and the lines denote the model fits. The curves are shifted vertically for better visibility. Blue, green, purple, and red color indicate regimes I, II, II′, and III. (d) Resulting phase diagram. Red: PSBP block; blue: PNIPMAM block. The red dashed and the blue dash-dotted lines indicate the CPUCST of PSBP and the CPLCST of PNIPMAM, respectively. The four regimes are denoted I, II, II′, and III. Adapted from ref 66. Copyright 2019 American Chemical Society.

CPLCST stays constant. Thus, regime II is encountered. The SANS data in 24 mM NaBr solution (Figure 10c) resemble the ones observed for PSBP80-b-PNIPMAM115 in 4 mN NaBr. Model fitting reveals uncorrelated spherical micelles (radius ∼23 nm) and large aggregates in regime I, molecularly dissolved polymers in regime II, and correlated spherical micelles (radius 24 nm) along with aggregates in regime III. The micellar sizes are slightly increased by the presence of salt, presumably due to the screening effect. Thus, the resulting phase diagram (Figure 10d) is the one which we aimed at (cf. Scheme 3c), and the following switching scenarios are achieved: (i) micelles−molecularly dissolved polymers−inverse micelles below 12 mM NaBr, (ii) micelles− inverse micelles at 12 mM NaBr, and (iii) micelles−large aggregates−inverse micelles above 12 mM NaBr. By virtue of the specific thermo- and salt-responsive profiles of the nonionic and zwitterionic blocks, CPLCST is nearly unaffected by the small amounts of salt needed to control CPUCST. Independently of this block-specific salt response, the micellar size and shape in regimes I and III may in the future be tuned by varying the length of the nonionic PNIPAM/PNIPMAM block, exploiting their type 2 LCST phase behaviors (i.e., CPLCST hardly varies with their molar mass), while keeping the length (and thus CPUCST) of the UCST block constant. Another interesting aspect is that the compartments formed by the UCST block contain large amounts of water and differ in their polarity from the ones formed by PNIPMAM.64 The latter block increasingly dehydrates when heated toward CPLCST. This favors its K


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Scheme 5. Schematic Overview of Swelling and Exchange Experimentsa

a

(a) H2O (blue molecules) swelling followed by D2O (green molecules) exchange and (b) D2O swelling followed by H2O exchange. Different states probed in the investigation are marked: I (as prepared), II (swelling), III (swollen), IV (exchange), and V (exchanged).76 Reproduced from ref 76. Copyright 2019 American Chemical Society.

behavior in water vapor atmosphere rather than via exposure to bulk water. Accordingly, the film swelling was investigated under isothermal conditions, revealing significant differences between the swelling in H2O and D2O. Stronger film swelling with H2O (d/dini ≈ 1.65) compared to swelling with D2O (d/dini ≈ 1.48) was observed due to the incorporation of more H2O (approximately 72%) than D2O (approximately 48%) inside the films. Correspondingly, also the exchange behavior (see Scheme 5) when replacing H2O with D2O or D2O with H2O showed differences. Due to the higher affinity of the polymer film toward H2O, a faster saturation of the film with H2O was seen, and more H2O was incorporated during exchange as well. We attributed these differences to the complexity introduced by the polysulfobetaine block because block copolymers based on PNIPAM did not show such a behavior.125,126 Apparently, minor changes in the electronegativity and the dipole moment may strongly influence the H- and D-bonds of the blocks. This causes pronounced differences of the swelling and exchange behavior with H2O compared with D2O. Therefore, one can also expect that the phase transition behavior of thin PSPP-bPNIPAM films will be more complex than that of block copolymers with a single thermoresponsive block. To what extent microphase separation and nanodomain formation take place in these systems and whether schizophrenic behavior can also be implemented in thin films (and if so, at which time scale) remain open questions at present. Further investigations are under way to clarify them.

interaction with the PSBP blocks and contributes to their immobilization, which may be due to the secondary amide moieties that enable mutual hydrogen bonding. Implications for the Use of Dual Thermoresponsive Schizophrenic Block Copolymers as Nanocarriers. The various scattering investigations revealed notable differences in the micellar structures of the dual thermoresponsive block copolymers, depending on whether the UCST blocks or the LCST blocks are in the water-insoluble, collapsed state. Accordingly, the micelles formed in regimes I and III do not simply present mirror images, as the pictures in Scheme 3 may suggest, but offer different qualities of the nanodomains formed. This may be exploited, e.g., for selectively solubilizing compounds that are sparingly soluble or even insoluble in water.121−123 The possibility of distinct responsive solubilization by switching between the two aggregation regimes has been hardly addressed up to now, but the few preliminary investigations suggest that this intriguing option might be feasible. While dual thermoresponsive schizophrenic block copolymers were shown to be ineffective as solubilizers when being in the fully soluble regime II, they could solubilize hydrophobic model compounds in regime III, where the LCST blocks are collapsed.32,64 In striking contrast, the same hydrophobic model compounds are not taken up by the micelles formed in regime I or by related structures.32,46,64 However, polysulfobetaines are known to interact strongly with many charged compounds in the solid state, resulting e.g. in homogeneous blends with very high contents of such “guests”.86,87,124 Accordingly, one may speculate about schizophrenic micellar nanocarriers in which both their structure and their payload are exchanged depending on the temperature. Such systems could enable not only the controlled release of active agents but also the subsequent uptake and removal of byproducts or “waste” compounds. Thin LCST−UCST Dual Thermoresponsive Diblock Copolymer Films. In our studies on thin films, we started out from the classical copolymer system PSPP-b-PNIPAM (Figure 1a) as well and prepared homogeneous films with thicknesses below 100 nm via spin coating.76 An oxygen plasma treatment of the solid silicon substrates as well as the use of trifluoroethanol solutions instead of aqueous solutions were necessary to achieve film homogeneity. Due to the absence of chemical grafts with the substrate surface, we studied the

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SUMMARY We presented a strategy to synthesize and design schizophrenic LCST−UCST diblock copolymers which feature purely thermal orthogonal switching, the pattern of which can be additionally tuned by a secondary stimulus, namely salinity. The examples given on diblock copolymers from the polysulfobetaines PSPP or PSBP and PNIPAM or PNIPMAM demonstrate the validity of this approach. Starting from these systems, tuning of the overall molar mass, copolymer composition, chemical nature of the blocks, e.g. by copolymerization with hydrophilic/hydrophobic monomers, and architecture provide a large variety of switchable micellar solutions or (self-assembled) gels. These may qualify for a number of “smart” applications such as controlled uptake, transport, and release. Moreover, in the present examples, we found that the two types of micelles L


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present different environments. This is due to the vastly different degree of hydration, depending on which block forms the core, and to the strength of the interaction/incorporation of the other block into the core. In addition, dual responsive schizophrenic micelles may also find applications as smart emulsifiers, avoiding large-scale mass transport when switching, if aggregation/ dissolution are avoided by choosing the appropriate salt content. Though speculative yet, the realization of nanocarriers in which not only their structure but also simultaneously their payload are exchanged (in phenomenological analogy to the transport of oxygen and carbon dioxide by hemoglobin) upon small temperature changes is an exciting perspective. Nevertheless, from the fundamental point of view, many questions remain to be answered, e.g., the reason for the (in some cases) unexpected dependence of the behavior of the polysulfobetaines on salt content, the way in which the zwitterionic and nonionic blocks interact, whether this interaction may be subdued by other block chemistries, how the switching pathways are mechanistically realized at the respective transitions, and to which extent thin films will behave differently from aqueous solutions. Therefore, we can conclude that the topic of schizophrenic, in particular dual thermoresponsive block copolymers, is still far from being mature, notwithstanding the progress made hitherto. For sure, more exciting findings can be expected in the future.

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Peter Müller-Buschbaum is full professor in the Physics Department at the Technical University of Munich, Germany, heading the Chair of Functional Materials. Moreover, he is scientific director of the Munich neutron source FRM-II and scientific director of the Heinz MaierLeibnitz Zentrum MLZ. His research interests cover polymer and hybrid materials for energy and sensing applications with a special focus on thin films and nanostructures, including kinetic, in situ, and in operando experiments.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]; Phone: +49 89 289 12 447; Fax: +49 653 89 289 12 473 (C.M.P.). *E-mail: [email protected]; Phone: +49 89 289 12 451; Fax: +49 653 89 289 12 473 (P.M.B.). *E-mail: [email protected]; Phone: +49 331 997 5225; Fax: +49 331 997 5036 (A.L.). ORCID

Christine M. Papadakis: 0000-0002-7098-3458 Peter Müller-Buschbaum: 0000-0002-9566-6088 André Laschewsky: 0000-0003-2443-886X

André Laschewsky has a joint appointment as full professor (Chair for Applied Polymer Chemistry) at the Institute of Chemistry, Universität Potsdam, and as scientific director at the Fraunhofer Institute of Applied Polymer Research (Fraunhofer IAP, Potsdam, Germany). His research interests are focused on new functional monomers, polymers, and surfactants to establish structure−property relationships with focus on supramolecular systems, aqueous media, surfaces, and nanotechnology.

Notes

The authors declare no competing financial interest. Biographies

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ACKNOWLEDGMENTS We gratefully acknowledge L. P. Kreuzer, A. Meier-Koll, B.-J. Niebuur, N. S. Vishnevetskaya (all TU München), and V. Hildebrand (Universität Potsdam) for fruitful collaboration on the project. We thank A. Lieske, M. Walter (Fraunhofer IAP), M. Heydenreich, A. Krtitschka, N. M. Nizardo, D. Schanzenbach (all Universität Potsdam), J. Adelsberger, M. A. Dyakonova, A. A. Golosova, C. Herold, J.-J. Kang, C.-H. Ko, K. Kyriakos, M. Philipp, J. Puchmayr, K. N. Raftopoulos (all TU München), and S. K. Filippov (Institute of Macromolecular Chemistry, Prague) for help with experiments. The local contacts at the large-scale facilities, I. Grillo (Institut Laue-Langevin in Grenoble), L. C. Barnsley, P. Busch, Z. Di, V. Pipich, A. Radulescu (all from Jülich Centre for Neutron Science at MLZ), and J.-F. Moulin (Helmholtz-Zentrum Geesthacht at MLZ), are thanked for their help. We also appreciate stimulating discussions with S. P.

Christine M. Papadakis is a professor in the Physics Department of Technical University of Munich, Germany. Her research interests lie in experimental polymer physics. She uses scattering methods with light, X-rays, and neutrons to investigate polymers of complex architecture, responsive polymers, block copolymers, and polymers for drug delivery, often in a time-resolved manner. M


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Armes (University of Sheffield), A. H. E. Müller, H. Ringsdorf (University of Mainz), F. Plamper (TU Freiberg), H. Tenhu, and F. M. Winnik (University of Helsinki). Part of this work is based upon experiments performed at the D11 instrument at the Institut Laue-Langevin, Grenoble, France, at the KWS-1 and KWS-2 instruments operated by JCNS and at the REFSANS instrument operated by HZG at the MLZ, Garching, Germany. We acknowledge both facilities for beamtime allocation and excellent equipment. We thank Deutsche Forschungsgemeinschaft (DFG) for financial support (PA 771/14-1, MU 1487/171, LA 611/11-1).

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