Sticky Supramolecular Grafts Stretch Single Polymer Chains

May 16, 2013 - designed to fold it into a well-defined object, the SCPN. The self-assembly of these units has been investigated in great detail. Howev...
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Sticky Supramolecular Grafts Stretch Single Polymer Chains Martijn A. J. Gillissen,† Takaya Terashima,‡ E. W. Meijer,† Anja R. A. Palmans,*,† and Ilja K. Voets*,† †

Institute for Complex Molecular Systems, Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands ‡ Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan S Supporting Information *

ABSTRACT: The folding of single polymeric chains into single chain polymeric nanoparticles (SCPNs) is a unique strategy to prepare ordered structures at the nanoscopic level. Structure forming elements are attached to a polymer chain designed to fold it into a well-defined object, the SCPN. The self-assembly of these units has been investigated in great detail. However, little is known about the impact of the resulting secondary structure on the conformation of the polymer chain. Here we employ a combination of scattering methods and spectroscopy to study how pendant chiral benzene-1,3,5-tricarboxamides (BTAs) fold oligo(ethylene glycol) methyl ether methacrylate-based polymers into SCPNs. Circular dichroism spectroscopy shows that the extent of BTA self-assembly on the polymer chain in water can be fine-tuned by means of temperature and cosolvent addition (isopropanol). Small-angle neutron scattering experiments demonstrate that single polymer chains have an asymmetric shape with a constant cross section, Rcs, and variable length, L, with L > Rcs. The polymer chain extends and shortens in response to variations in temperature and solvent composition, which also influence the self-assembly of the BTA units. The SCPNs stretch upon association and shrink upon disassociation of the grafted supramolecular moieties.

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elements are either directly copolymerized with appropriate monomers or attached via postfunctionalization strategies of pendant functional groups.4−25 Here we use Ru-catalyzed living radical polymerization (LRP) of functionalized monomers to arrive at random copolymers of methacrylate monomers bearing side chains comprising either oligo(ethylene glycol) for solubilization in water or chiral benzene-1,3,5-tricarboxamide for folding into a well-defined three-dimensional (3D) structure. Resolving the 3D architecture of SCPNs is the next challenge. Direct visualization using (cryogenic) transmission electron microscopy ((cryo-)TEM) is possible, but low contrast greatly hampers the elucidation of the overall structure.9,14,16,18,25 Moreover, the interpretation of TEM and atomic force microscopy (AFM) images is ambiguous as solvent evaporation and polymer−surface contacts have a significant impact on the conformation of the polymer chain.7,11,12,14,15,20,21,24,26−28 Size exclusion chromatography (SEC) is used to circumvent these issues, allowing for the determination of the hydrodynamic volume, but it does not provide detailed information on the polymer conformation.7−10,12−18,21,23,29 Here we turn to small-angle scattering methods as these are the only label-free method to measure the

ottom-up strategies to create well-defined nanometer sized architectures gain ground as length scales smaller than tens of nanometers are not attainable with state-of-the-art top-down approaches.1−3 One highly promising route to nanometer architectures is self-assembly of small molecular building blocks, as it is a versatile, low-energy pathway that is synthetically far less demanding than other elegant chemical approaches based on e.g. foldamers and dendrimers. A recent product of this approach is so-called single-chain polymeric nanoparticles (SCPNs).4−6 These particles consist of a single polymer chain functionalized with structure forming elements designed to fold the polymer into a well-defined object by means of covalent,7−15 dynamic-covalent,16−18 or noncovalent19−25 cross-links. To date, little is known about their structural properties, but several recent papers have already convincingly demonstrated their potential as polymeric carrier systems, contrast agents, efficient catalysts, and heavy metal ion sensors.4,22,25 Here we investigate the structure of SCPNs with nonpermanent cross-links and exploit their inherent ability to respond to external stimuli as a valuable research tool. It may also prove advantageous for their application perspective in the realm of catalysis, sensing, and medicine in which structured and conformationally adaptive microenvironments enhance activity, efficacy, and efficiency. The synthesis of SCPNs comprising well-defined highly functionalized polymers typically relies on state-of-the-art controlled polymerization techniques. The structure-forming © XXXX American Chemical Society

Received: April 2, 2013 Revised: May 8, 2013

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size and shape of nanometer-sized polymer chains directly in solution. In parallel, the self-assembly of the chiral structureforming elements can readily be probed by circular dichroism (CD) spectroscopy. Hereby we recently confirmed that intrachain self-assembly of small, pendant structure-forming elements is possible; i.e., the formation of a hydrogen-bond stabilized helix within one polymer chain was corroborated.23,25 The combination of spectroscopy and small-angle scattering thus provides direct access to SCPN structure on the level of the self-assembling supramolecular motifs and the polymer chain as a whole. This allows us to tacklefor the first time the crucial question that has so far remained unanswered: to what extent does the self-assembly of the structure forming grafts alter the polymer conformation? There is no theoretical framework available to describe the conformation of heterograft copolymers with hydrophilic and hydrophobic grafts that incorporate directional attractive interactions. However, there is a solid theoretical and experimental basis to understand the conformational properties of synthetic polymer architectures in general. The dependence of polymer conformation on solvent quality, molecular weight, and temperature is well investigated for various architectures ranging from simple linear homopolymers to complex amphiphillic and charged (co)polymers.30−35 Bearing in mind the lessons learned from these studies, several scenarios may be put forward for the folding of SCPNs. Directional self-assembly of grafted structuring units could result in the formation of a “secondary structure” inducing torroidal, hairpin-like, ellipsoidal, or globular conformations depending on the shape of the secondary structure.6,36,37 Alternatively, other interactions and parameterssuch as solvophobic effects and backbone rigiditymay greatly influence the polymer conformation.38 The relative importance and interplay between these different contributions remain to be investigated. The present contribution describes the combination of scattering methods and spectroscopy to unravel how the selfassembly of pendant structure forming elements affects the conformation of single polymer chains. In addition, we elucidate the size and shape of the folded polymers and show how these sensitively depend on external factors such as temperature and solvent polarity. We focus on random copolymers of oligo(ethylene glycol) methyl ether methacrylate and benzene-1,3,5-tricarboxamide-functionalized methacrylate (poly(oEGMA-co-BTAMA)) (Scheme 1).25 The incorporation of chiral benzene-1,3,5-tricarboxamides (BTAs) allows us to monitor the self-assembly of these units with CD spectroscopy since BTAs form helical columnar aggregates stabilized by 3fold hydrogen bonding.39 The combination of methods presented here is generally applicable to study (the link between) the global chain conformation and secondary structure within foldable single polymer chains.

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Scheme 1. General Molecular Structure and Schematic Representation of Poly(oEGMA-co-BTAMA) Polymers

(Mn,NMR 52.8 kDa, Mn,SEC 34.2 kDa, PDI 1.26), contains 9 mol % BTAMA. CD Spectroscopy. Temperature-dependent circular dichroism (CD) spectroscopy was performed to monitor the intramolecular formation of helical columnar BTA aggregates during the folding of the polymers. We first evaluated the CD spectra of the copolymers in water. P0% is CD silent while a negative Cotton effect is observed for P10%. The presence of a negative Cotton effect with a minimum at λ = 225 nm is typical for 3-fold, intermolecularly hydrogen-bonded aggregates with a preferred M helical sense.39 The magnitude of the Cotton effect, expressed as the molar circular dichroism |Δε|, is a measure for the degree of aggregation of the BTA units. Upon heating the solutions, |Δε| decreased and ultimately disappeared at 90 °C (Figure S1A). This disappearance of the Cotton effect indicates that the extent of BTA self-assembly gradually diminishes and is absent at 90 °C. In less polar solvents, such as isopropanola competitive solvent for hydrogen bonding between BTAsno Cotton effect is observed, indicating the absence of BTA aggregates. We continued our studies by evaluating the CD spectra of P10% in mixtures of water and isopropanol. Increasing the volume fraction of isopropanol (ϕIPA) in the solutions results in a gradual decrease of the Cotton effect, which is fully absent at ϕIPA = 0.5 (Figure S1B). The molar circular dichroism at λ = 225 nm for P10% as a function of temperature and ϕIPA is depicted in Figure 1. When ϕIPA ≥ 0.5, the molar circular dichroism is zero at all temperatures, indicating the absence of BTA aggregates. In contrast, for ϕIPA < 0.5 the Δε decreases with decreasing temperature, indicating an increase in BTA aggregation. To summarize, the CD results show that temperature and solvent composition determine the degree of BTA aggregation in poly(oEGMA-co-BTAMA) copolymers. This allows us to control the secondary structure formation by turning “on” or “off ” the BTA aggregation in the SCPN. This control permits the investigation of the influence of local internal structure on the global conformation of the polymers.

RESULTS

Selection of Copolymers. The random copolymers investigated were prepared previously by Ru-catalyzed living radical polymerization (LRP) of benzene-1,3,5-tricarboxamidefunctionalized methacrylate (BTAMA) and oligo(ethylene glycol) methyl ether methacrylate (oEGMA, 8−9 oxyethylene units).25 We selected two copolymers with a degree of polymerization (DP) of ca. 100 that differ in the incorporation of BTAMA. The first polymer, P0%, lacks BTAMA (Mn,NMR 45.6 kDa, Mn,SEC 36.0 kDa, PDI 1.17) and the other, P10% B

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interparticle aggregation is negligible and thus unambiguously demonstrate that each P10% SCPN contains a single polymer chain only. Two independent analysis methods were subsequently employed to study the size and shape of the nanoparticles. First, the indirect Fourier transform (IFT) method was applied to convert the scattering curves into real space pair-distance distribution functions (PDDFs).40 These PDDFs allow to assess qualitatively the shape of the particle. For example, spherical objects such as polystyrene star polymers in THF or spherical micelles yield a highly symmetrically shaped PDDF, while semiflexible wormlike chains such as polystyrenesulfonate in water or CTAB micelles at high concentrations of salt give rise to asymmetrically shaped PDDFs.41−43 In addition, the size can be quantified by extracting the radius of gyration (RG) from the PDDFs according to

Figure 1. Molar circular dichroism (Δε) at λ = 225 nm as a function of T and ϕIPA for P10%, cBTA = 50 μM.

Small-Angle Neutron Scattering. To study the size, shape, and single chain character of the nanoparticles with and without internal noncovalent cross-links, we turn to small angle neutron scattering (SANS) measurements. The scattering profiles of P0% and P10% in D2O/isopropanol-d8 mixtures at 10 °C ≤ T ≤ 60 °C at a concentration of 1 mg mL−1 are given in the Supporting Information. The SANS data clearly demonstrate that the nanoparticles consist of individual polymer chains irrespective of temperature and solvent composition. This is evident from the common intercept in Figure 2 and the molecular weights of the particles extracted

Dmax

R G,IFT

1 ∫0 = 2 ∫

0

p(r )r 2 d r

Dmax

p(r ) d r

In P0%lacking the BTA unitsthe PDDFs show an asymmetric shape when ϕIPA < 1 (Figure S2). This shape is typical for elongated structures. For P10% at 25 °C, all solvent mixtures show asymmetrically shaped PDDFs (Figure S3), significantly different from that expected for a Gaussian polymer or collapsed globule. This elongated shape is also observed at all other temperatures as long as ϕIPA > 0.2. Only when the solvent is predominantly water (ϕIPA ≤ 0.2) a difference can be seen upon changing temperature. Whereas an elongated structure is still present at 10 and 25 °C, the symmetrically shaped PDDFs at 60 °C reveal the presence of globular objects. The PDDFs for the two extreme cases, in pure water and in pure IPA at 10 and 60 °C, are shown in Figure 3. Next we analyzed the effect of temperature and ϕIPA on the RG of the polymers. The polymer that is devoid of BTA units, P0%, is largest at ϕIPA = 0.5 (Figure 4A). Apparently, the mixture is a better solvent than either pure water or pure isopropanol, an effect known as cosolvency. The same effect is observed for P10%; however, at ϕIPA ≤ 0.2 a strong increase in RG is observed. The RG values show opposite temperature dependence at high and low ϕIPA. In pure water, RG is 4.2 nm at 60 °C and 6.2 nm at 10 °C. In pure isopropanol, RG is 5.4 nm at 60 °C and 4.2 nm at 10 °C (Figure 4B). The transition from an elongated to a smaller globular SCPN upon changing solvent from isopropanol to water at high

Figure 2. Ornstein−Zernike plots for P10%: (A) at ϕIPA = 0 as a function of temperature and (B) at 25 °C as a function of ϕIPA.

from the forward scattering intensity, MSANS, as summarized in Table S1. The MSANS values correspond well to those determined by NMR and GPC. These findings confirm that

Figure 3. Pair-distance distribution functions (PDDFs) for P10% at 1 mg mL−1 at 10 and 60 °C: (A) ϕIPA = 0; (B) or ϕIPA = 1. C

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from dynamic light scattering on P10% (Figures S4C and S10− S12).

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DISCUSSION Scattering experiments show that the shape of the amphiphilic polymer P10% is sensitive to solvent composition and temperature. At high ϕIPA the polymers increase in size and at the same time adopt more elongated conformations upon heating, as one would expect in a good solvent. At 60 °C the polymer is smaller and adopts a more globular shape in water than in isopropanol. This collapse can be readily understood as an amphiphilic polymer tends to bury its hydrophobic side chains in its interior when brought into water. Surprisingly, the size of the SCPN does not further decrease upon cooling at ϕIPA ≤ 0.2. Instead, the particles increase in size and elongate. The behavior of the P10% polymer appears directly coupled to the self-assembly of the pendant BTAs which we probe by CD spectroscopy: when BTA association is absent in alcohol-rich mixtures at ϕIPA ≥ 0.5, the SCPNs are fairly small, while BTA self-assembly in water-rich mixtures at ϕIPA ≤ 0.2 stretches the copolymers into larger and more elongated nanostructures at 25 °C. Overall, we see that at conditions relevant for applications of SCPNsroom temperature in pure waterthe particles are best described as elongated objects (Figure 5). We expected to obtain more compact objects of higher density by internal cross-linking of the BTA units in the interior of the SCPN, but the opposite seems to be the case. The measured specific densities of the particles at 25 °C in pure water are 1.19 and 0.93 g mL−1 for P0% and P10%, respectively (Table S1). The less dense structure of P10% could be advantageous in the envisioned SCPN applications. In catalysis, the more open structure of the particle could allow for substrates and products to enter and exit the active site of the particle more easily. The question now remains how this behavior will influence the catalytic, sensing, and other applications of these SCNP systems and how structure-forming units with a different selfassembly geometry will determine the resulting conformation of a SCPN.

Figure 4. Radius of gyration (RG) of (A) P0% and P10% as a function of ϕIPA at 25 °C and (B) P10% as a function of ϕIPA and T, as determined by IFT analysis of the SANS profiles at 1 mg mL−1.

temperature is likely caused by solvophobic interactions. This observation is in line with simulations and experimental studies on amphiphilic polymers.44−49 Interestingly, cooling down the system in waterdecreasing the solvent quality but also increasing BTA self-assemblyresults in larger more elongated SCPNs. This expansion reveals that the polymer is forced to adapt its conformation to the BTA structure that it comprises in its interior. To further quantify the dimensions in the elongated and globular states, we apply a form factor model for ellipsoidal particles (see Supporting Information for details). Here the dimensions of the particle are expressed in terms of a crosssectional radius (R) and an aspect ratio (ν). The results are summarized in Figure 5 (Figures S4−S6, Table S3). Additional

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CONCLUSION We have performed a detailed conformational study on random copolymers of methacrylate monomers bearing side chains comprising oligo(ethylene glycol) and chiral benzene-1,3,5tricarboxamide, by making use of scattering methods in combination with spectroscopy. By means of small-angle scattering, we have unambiguously shown that a SCPN of poly(oEGMA-co-BTAMA) with 10% BTA loading consists of a single polymer chain. Circular dichroism spectroscopy reveals the helical BTA structure in the interior of the SCPN. Tuning the degree of BTA self-assembly within the nanoparticles is possible by varying temperature and/or adding a competitive solvent. This local internal structure formation is clearly linked to the global conformation of the polymers. When increasing the temperaturethereby reducing the strength of the BTA hydrogen bondinga decrease in the size and the aspect ratio of the SCPN is observed. Decreasing the temperature has the opposite effect. Detailed conformational studies on SCPN systems are crucial to further develop the field. The elongation induced by (directional) secondary interactions (H-bonding, π−π interactions, and solvophobic

Figure 5. Dimensions of the P10% particles according to the ellipsoidal model: (A) cross-sectional radius (R) and ratio between the two ellipsoidal axes (ν); (B) asphericity parameter as a function of ϕIPA and T.

fits to a wormlike chain model show the same features (Figures S7−S9, Table S4). The form factor analyses reveal that the observed increase in RG is mainly caused by an increase in ν, an elongation of the particles along one axis. The cross-sectional radii stay fairly constant at 2−3 nm (Figure 5A). Finally, we calculate the asphericity parameter (αS), which is commonly used to quantify the deviation from spherical shape (Figure 5B).36 The asphericity parameter can assume any value between 0 and 1, with 0 corresponding to a perfect sphere and 1 to an infinitely long rod. For P10% we find that 0.3 ≤ αS ≤ 0.9, indicating that these SCPNs are never perfectly spherical, although they resemble globular structures at high T and ϕIPA ≤ 0.2 when αS drops below 0.5. Using the ellipsoidal model, we can now compute RH values from the obtained molecular dimensions. The computed values show the same trend as the experimentally determined values D

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effects) may prove to be highly advantageous to fine-tune the functionality of SCPNs in a variety of applications.

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ASSOCIATED CONTENT

S Supporting Information *

Experimental details; DLS data, equations used, SANS curves, and derived parameters. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail [email protected], tel 0031 40 247 4427 (I.K.V.); e-mail a. [email protected], tel 0031 40 247 3105 (A.R.A.P.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is financed by The Netherlands Organisation for Scientific Research (NWO - TOP Grant: 10007851) and NRSC-C. I.K.V. is grateful for financial support from The Netherlands Organization for Scientific research (NWO - VENI Grant: 700.10.406) and the European Union through the Marie Curie 5 Fellowship program FP7-PEOPLE-2011-CIG (Contract No. 293788). The authors thank P. A. Korevaar for his assistance during the SANS measurements and Prof. G. Fytas for helpful discussions. This work is based on experiments performed at the Swiss Spallation Neutron Source SINQ, Paul Scherrer Institute, Villigen, Switzerland. We also thank Dr. J. Kohlbrecher for his assistance.

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