Polymerization of Ternary Inclusion Complexes of Interacting

The formation of ternary inclusion complexes of γ-cyclodextrin (γ-CD) with two different pairs of interacting monomers (4-vinylpyridine (4VP) with ...
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Polymerization of Ternary Inclusion Complexes of Interacting Monomer Pairs with γ‑Cyclodextrin Niels ten Brummelhuis* and Maria T. Heilmann Department of Chemistry, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany S Supporting Information *

ABSTRACT: The formation of ternary inclusion complexes of γ-cyclodextrin (γ-CD) with two different pairs of interacting monomers (4-vinylpyridine (4VP) with styrenesulfonate (SS), which can interact through attractive Coulombic interactions, and styrene (S) with 2,3,4,5,6-pentafluorostyrene (PFS), which interact through quadrupole interactions) is studied. Ternary inclusion complexes are formed for both monomer pairs, but 4VP and SS are included in the complexes in approximately the same ratio as is present in solution, whereas S and PFS are preferentially included as a pair. The influence of the ternary inclusion complexation on the copolymerization was studied. For the copolymerization of 4VP with SS no significant influence was found, whereas an enhanced tendency toward alternating copolymerization was found for the copolymerization of S and PFS in the presence of γ-CD, which is ascribed to the preferential heteroinclusion of the monomers in the γ-CD cavity.

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INTRODUCTION Controlling monomer sequence in chain-growth polymerizations is a major challenge that has not been resolved yet.1−6 Thus far, alternating copolymers are the only examples of polymers with defined monomer sequences that can readily be prepared, though a few examples exist where e.g. ABAperiodic sequences are achieved (vide inf ra). There are, generally speaking, two methods to create alternating copolymers. The first method relies on copolymerizing a large excess of a monomer that is incapable of undergoing homopropagation (and therefore homopolymerization) with a second monomer. Even when heteropropagation is not particularly favored for the second monomer (r1 = 0, r2 > 0) the large excess of the bulky monomer will nevertheless ensure incorporation of this monomer, resulting in an alternating monomer sequence. The second method is to use a monomer pair that have strongly differing electron densities. The copolymerization of maleic anhydride (MA) or maleimides with styrene (derivatives) is an example of this. The vinyl group in MA is electron-deficient, whereas the vinyl group in styrene is relatively electron-rich. This difference in electron density results in both favorable energy levels of the reactants, and thus favorable heteropropagation, and the formation of chargetransfer complexes which might preorganize the monomers and thus further enhance the formation of alternating monomer sequences. This copolymerization behavior is found in most cases where electron-rich and -deficient monomers are involved7 and also when the electron density of one of the monomers is lowered by a third moiety, e.g., by the binding of a Lewis acid to carbonyl or nitrile groups in monomers.8−10 One method of creating more complex periodic monomer sequences relies on cyclocopolymerization approaches11 or the © XXXX American Chemical Society

supramolecular equivalent thereof. Cyclopolymerizations use bifunctional (or multifunctional) monomers, the polymerizable moieties of which are all incorporated into the same polymer chain subsequently. This process results in the formation of cyclic side chains in the polymer, hence the name, and crosslinking is suppressed. Cyclocopolymerizations use multifunctional monomer together with other monomers. Cyclocopolymerization was e.g. used by Wulff and co-workers to create AAB-periodic copolymers by copolymerizing a bifunctional styrene monomer with e.g. MA.12 More recently, Sawamoto and co-workers used a trifunctional monomer consisting of two styrene moieties and a coordinated 4vinylpyridine moiety to create ABA-periodic copolymers.13 In a way the procedure described by Kamigaito and co-workers can also be considered a cyclocopolymerization, though no covalent linkers are employed.14 They described that the RAFT copolymerization of N-phenylmaleimide with e.g. limonene can, in perfluorated alcohols as solvents, result in the formation of AAB-periodic copolymers. This observation is hypothesized to result from the simultaneous interaction (through Hbonding) of a single perfluoronated alcohol with two maleimide monomers, thereby preorganizing them and promoting subsequent incorporation of two maleimides. In this paper a different adaptation of cyclocopolymerization is used to influence the monomer sequence: we use the formation of ternary inclusion complexes of two monomers in a single cyclodextrin cavity (Figure 1). Received: June 6, 2016 Revised: August 31, 2016

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H NMR spectrum is recorded. Binding constants were determined using the Benesi−Hildebrand method for 1:1 complexes. Polymer Synthesis. Copolymerization of 4VP and SS. Copolymerizations of 4-vinylpyridine and styrenesulfonate were performed using different ratios of these monomers, ranging from 7:1 to 1:7. The copolymerizations were performed in the presence and absence of 0.5 equiv of γ-cyclodextrin (compared to the total amount of monomers). 2.9 mL of D2O with 2.9 μL of 1 M HNO3 was used as a solvent, and a small amount of N,N-dimethylformamide (DMF) was used as an internal standard. The free-radical polymerization was initiated by the photochemical decomposition of α,α′-azodiisobutyramidine dihydrochloride (AAPH). Tables containing all used amounts can be found in the Supporting Information. The mixture was degassed by three freeze−pump−thaw cycles, and after drawing an aliquot for determination of the exact solution composition by 1H NMR spectroscopy the polymerization was initiated by irradiation of the solution with UV light (λ = 366 nm). Conversions around 20% are aimed for when the reactivity ratios of the copolymerization are determined. The polymers resulting from the copolymerizations with a 1:1 ratio of the two monomers were purified by dialysis in water (MWCO 2000). For the copolymerization performed in the presence of γ-CD a certain amount of sodium benzenesulfinate was added during the first few dialysis cycles in the hopes of disturbing the inclusion complex γCD might form with the polymer. The polymers were subsequently freeze-dried, yielding 17.5 mg (polymerization without γ-CD) and 23.5 mg (polymerization with γ-CD) of polymer. Copolymerization of S and PFS. Copolymerizations of styrene and 2,3,4,5,6-pentafluorostyrene were performed using different ratios of these monomers, ranging from 7:1 to 1:7. The copolymerizations were performed in the presence and absence of 0.5 equiv of γ-cyclodextrin (compared to the total amount of monomers). DMF was used as a solvent, and a small amount of N,N-dimethylacetamide (DMAc) was used as an internal standard. The free-radical polymerization was initiated using the redox reaction between N,N-dimethylaniline (DMA) and benzoyl peroxide (BPO). A table containing all used amounts can be found in the Supporting Information. γ-CD was dissolved in DMF and styrene, 2,3,4,5,6pentafluorostyrene and a small amount of N,N-dimethylacetamide (internal standard) were added as well as 100 μL of a stock solution of N,N-dimethylaniline in DMF (0.05 equiv to the total amount of monomer). The mixture was degassed by three freeze−pump−thaw cycles. 100 μL of a degassed benzoyl peroxide (0.05 equiv to the total amount of monomer) solution in DMF was added to start the polymerization under argon after drawing an aliquot for determination of the exact solution composition by 1H NMR spectroscopy. Conversions around 20% are aimed for to determine the reactivity ratios of the copolymerization. The polymers resulting from the copolymerizations with a 1:1 ratio of the two monomers were purified by dialysis in CHCl 3 (copolymerization without γ-CD) or a DMF/H2O mixture (2:1) (MWCO 2000). In the latter case a certain amount of sodium benzenesulfinate was added during the first few dialysis cycles in the hopes of disturbing the inclusion complex γ-CD might form with the polymer. The polymers were subsequently freeze-dried from 1,4dioxane, yielding 5.8 mg (polymerization without γ-CD) and 7.1 mg (polymerization with γ-CD) of polymer.

Figure 1. Schematic representation of the desired formation of ternary inclusion complexes of two monomers in cyclodextrin, resulting in an enhanced alternating copolymerization, and the chemical structure of the monomer pairs that are used in this work.

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MATERIALS AND METHODS

Materials. The following chemicals were, unless mentioned otherwise, used as received. Sodium benzenesulfinate (Acros, 97%), γ-cyclodextrin (abcr, 98%), benzoyl peroxide (Aldrich, 75% in water), N,N-dimethylaniline (abcr, 99%), α,α′-azodiisobutyramidine dihydrochloride (Sigma-Aldrich, 97%), sodium p-styrenesulfonate (Alfa Aesar, 88.6%), 4-vinylpyridine (Aldrich, 95%), 2,3,4,5,6-pentafluorostyrene (abcr, 98%), styrene (Fluka, ≥99%), DMSO-d6 (Deutero, 99.8%), D 2O (Deutero, 99.9%), CDCl3 (Deutero, 99.8%), and DMF-d7 (Deutero, 99.5%). 4-Vinylpyridine, styrene, 2,3,4,5,6-pentafluorostyrene, and DMF were passed through Alox prior to use. Benzoyl peroxide was recrystallized from chloroform. Characterization Methods. NMR Spectroscopy. NMR spectroscopic measurements were performed on a Bruker Avance III-300 spectrometer (1H NMR at 300 MHz and 13C NMR at 75 MHz) and on a Bruker Avance III-500 spectrometer (1H NMR at 500 MHz and 13 C NMR at 126 MHz) from Bruker BioSpin GmbH (Rheinstetten, Germany) at 20 °C. All chemical shifts are reported relative to residual signals of the deuterated solvents in ppm. Photochemical Initiation. A UV lamp from Kurt Migge GmbH Laborbedarf (366 nm, 6 W) was used to irradiate the polymerization solutions and start the polymerization. Size Exclusion Chromatography (SEC). SEC measurements for the 4VP/SS copolymers were performed using an aqueous 0.1 M NaNO3 solution on an Agilent Technologies (Santa Clara, CA, USA) machine with a PSS (Polymer Standards Service GmbH, Mainz, Germany) pump equipped with UV and RI detectors. MCX columns (100 000 Å, 10 μm) from PSS (Polymer Standards Service GmbH, Mainz, Germany) were used. Measurements were performed at a flow rate of 1.0 mL/min at room temperature. Poly(styrenesulfonate) standards were used for calibration. SEC measurements for the S/PFS copolymers were performed using THF as the eluent with simultaneous UV and RI detection. The measurements were performed at room temperature with a flow of 1.0 mL/min. The used column set consists of two 300 × 8 mm MZSDplus columns (PSS-Polymer Standards Service Mainz) filled with round polystyrene particles with an average diameter of 5 μm and pore sizes of 103 and 105 Å. Commercial polystyrene standards were used for calibration. 1 H NMR Titration of γ-CD with 4VP and SS. A stock solution of γ-cyclodextrin in D2O (0.2 M) was added stepwise to a solution of 4VP and SS in D2O (0.01 M of each). Before the first addition and after each successive addition an 1H NMR spectrum is recorded. Binding constants were determined using the Benesi−Hildebrand method for 1:1 complexes. 1 H NMR Titration of γ-CD with S and PFS. A stock solution of γcyclodextrin, (0.2 M), styrene (0.01 M), and 2,3,4,5,6-pentafluorostyrene (0.01 M) in DMF-d7 was added stepwise to a solution of styrene and 2,3,4,5,6-pentafluorostyrene in DMF-d7 (0.01 M of each). Before the first addition and after each successive addition an

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RESULTS AND DISCUSSION Cyclodextrins (CDs) are widely employed as cheap and environmentally friendly solubilizers:15 hydrophobic or amphiphilic molecules can be included into the hydrophobic cavity of the cyclodextrin, thereby rendering them soluble. Three CDs are commonly used: α-, β-, and γ-CD, consisting of 6, 7, and 8 glucose moieties, respectively. Though larger CDs exist and have been isolated, their cavities are typically collapsed, making them poorly suitable for the formation of inclusion complexes.16 B

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ternary heteroinclusion complexes can be formed in all cases. The solutions were oversaturated (100 mM γ-CD) so that the solutions needed to be heated to obtain clear solutions. Upon cooling, the complexes precipitated from solution were isolated by centrifugation and decantation of the supernatant, and the ratio of 4VP, SS, and γ-CD in the complexes (Table 1) was analyzed by 1H NMR spectroscopy in DMSO-d6.

In polymerization CDs have been used as solubilizers, thereby bypassing the need for organic solvents,17−20 but have also been used to influence the microstructure of polymers, e.g., by polymerizing monomers in channels built out of stacked CDs21−24 or by modifying the apparent size of the side chains.25−27 Depending on the relative sizes of the guest and the host cavity different types of inclusion complexes can be formed, the simplest of which is a 1:1 complex. Also, ternary complexes with CD:guest ratios of 2:1 or 1:2 have been found. A 2:1 ratio is found when the guest is too large to be completely enveloped in one cavity, whereas a 1:2 ratio is found when the cavity is large enough to accommodate two guest molecules. Especially this last class of inclusion complexes is also interesting when the microstructure of polymers should be influenced. Saito et al. e.g. used randomly methylated β-CD (β-RMCD) to create ternary inclusion complexes wherein two 4-vinylpyridinium are included in one CD moiety, leading to the formation of primarily heterotactic poly(4-vinylpyridine).28 CDs have, to the best of our knowledge, not been used to influence monomer sequence. In this work we propose to influence the monomer sequence using ternary heteroinclusion complexes, i.e., complexes where two different monomers are included in a CD moiety. To form such complexes, an attractive interaction between the monomers is desirable. The polymerization of such complexes should lead to an (increased) tendency of the two monomers to form alternating copolymers. Two different types, and correspondingly monomer pairs, of attractive supramolecular interactions were used: Coulombic and quadrupole interactions. The investigation of the inclusion complexes and the polymerization behavior are described in the following sections. Coulombic Interactions. Since the formation of ternary homoinclusion complex of p-styrenesulfonate (SS) in γ-CD29 and of protonated 4-vinylpyridine (4VPH+) in β-RMCD28 is known, these two monomers were selected in this work. SS carries a negatively charged sulfonate group at all but the most extremely acidic pH, whereas 4VPH+ is formed under slightly acidic conditions (pKb of 4VP ∼5.6). The opposite charges are reasoned to provide an attractive interaction between these monomers, thereby leading to the formation of inclusion complexes (ICs) that preferable incorporate one molecule of each monomer. Only γ-CD was used in this study since, from literature reports, this CD seems the most suitable to form ternary ICs. This was also confirmed in preliminary studies with β-CD where it was shown that only one monomer was included in its cavity. All studies with this monomer pair were performed at pH ∼3 (set using HNO3) to ensure that 4VP is present in its protonated, positively charged form. First, the solubility of the inclusion complexes with equimolar concentrations of γ-CD, SS, and 4VP was studied in aqueous acidic solution. Clear solutions were obtained at room temperature up to a concentration of roughly 50 mM. Since the solubility of the complexes with different ratios of SS and 4VP might be different, a γ-CD concentration of 25 mM was used for all further studies, unless mentioned otherwise. To determine how many monomers are included in the γCD cavity, and whether 4VP and SS are preferentially incorporated together, solutions with a 3-fold excess of the two monomers to γ-CD (assuming the formation of ternary inclusion complexes) were prepared while varying the ratio of the two monomers from 5:1 to 1:5, thereby providing an excess of monomers, and if preferential heteroinclusion takes place,

Table 1. Composition of the Inclusion Complexes As Determined by 1H NMR in DMSO-d6 for the Precipitate Formed after Mixing Different Feed Ratios of γ-CD, 4VP, and SS composition feed ratio (γ-CD:4VP:SS)

γ-CD

4VP

SS

4VP + SS

1:5:1 1:4:2 1:3:3 1:2:4 1:1:5

1.0 1.0 1.0 1.0 1.0

2.5 1.8 1.4 1.0 0.5

0.4 0.6 1.0 1.1 1.4

2.9 2.4 2.4 2.1 1.9

The 1H NMR spectra indicate that the total number of monomers per γ-CD molecule varies between 1.9 and 2.9. This indicates that at least two monomers are included in each γ-CD cavity. Based on literature studies, it is unlikely that more than two monomers are included in the γ-CD, so that values >2 are likely due to the coprecipitation of single monomers, e.g., as a result of Coulombic interactions. More important is the ratio of the two monomers in the precipitate, which is shown in Figure 2. These ratios indicate that compared to the feed ratio of the

Figure 2. Percentual inclusion of 4VP or SS in γ-CD with varying feed percentages of the two monomers.

monomers slightly more 4VP is included in γ-CD. Clearly, there is no tendency toward the inclusion of two different monomers, which would result in a plateau in Figure 2. To prove that inclusion complexation takes place and that coprecipitation is not the sole reason for the fact that monomers are present in the precipitate, 1H NMR studies of a 1:1:1 mixture of γ-CD, 4VP, and SS were performed. From the literature it is known that upon inclusion of a guest molecule in the cavity of a CD the 1H NMR signals of the guest, as well as signals attributed to CD protons inside the cavity, shift. The 1H NMR spectra of pure 4VP and SS as well as for mixtures of 4VP with SS and finally of the ternary mixture C

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Figure 3. 1H NMR spectra in D2O of (from bottom to top) 4VP, SS, a 1:1 mixture of 4VP and SS, and a ternary mixture of 4VP, SS, and γ-CD. Dotted lines are meant as guides to the eye to better visualize the shift of the signals.

A 1H−1H-NOESY spectrum of a 1:1:1 mixture of 4VP, SS, and γ-CD was recorded (see Supporting Information) in an attempt to confirm this proposed mode of complexation. Cross-correlation signals were observed both between the two monomers and between monomers and γ-CD. Between 4VP and SS the following cross-correlation signals were found: between the cis-H of 4VP and the trans-H of SS, between the ortho-H of 4VP and the cis-H of SS, and between the meta-Hs of 4VP and those of SS. These signals indicate the colocalization of the monomers and that the vinyl groups of the monomers are located on the same side of the complex. The inclusion complexation is proven by the cross-signals of the monomers and γ-CD, but whether or not the vinyl groups are located within the cavity of γ-CD or protrude from them is hard to determine from this spectrum. This however is shown by the much smaller shift of the vinyl-H signals (vide supra). Additionally, inclusion complexation of monomers while positioning the two vinyl groups in close proximity to each other would likely only be possible if they protrude from the wide opening of the γ-CD cavity because of steric restraints. To get a better idea of the strength of the interaction, a 1H NMR titration was performed, wherein a concentrated solution of γ-CD was added to a dilute solution of both 4VP and SS. The shift of various signals was followed with varying ratios of the components. Examples of these spectra are shown in the Supporting Information. The shifts of the cis-Hs of the monomers were used to determine the binding constants. For SS an association constant (Ka) of ∼2.0 × 103 M−1 was found, whereas for 4VP a Ka of ∼5.0 × 103 M−1 was found. These values are just a rough indication of the actual binding constants since the used method is better suited for 1:1 complexation than a ternary heterocomplexation. Nevertheless, the same trend is observed here as was found from the composition of the precipitated inclusion complexes: 4VP is more efficiently included in the γ-CD cavity, and thus more of this monomer is found in the precipitated complexes. Despite the fact that all indications point toward the conclusion that 4VPH+ and SS incorporated into the pocket of γ-CD in a random fashion, the copolymerization behavior of these monomers was studied in the absence and presence of γCD. The copolymerizations were performed in D2O with a small amount of 1 M HNO3, using the photochemical decomposition of α,α′-azodiisobutyramidine dihydrochloride (AAPH) to initiate the copolymerization at room temperature (Figure 5). A small amount of DMF was used as an internal standard to be able to determine the monomer conversion by

are shown in Figure 3, and the chemical shifts found are listed in Table 2. Table 2. Chemical Shift (δ) of the 1H NMR Signals in D2O for the Pure Substances, a 1:1 Mixture of the Two Monomers, and the Ternary Mixture of γ-CD, 4VP, and SS as Well as the Relative Shifts upon Complexation (Concentrations of 25 mM Were Used in All Cases) δ (ppm)

4VP

SS

trans-H cis-H gem-H 3-Ar-H 2-Ar-H trans-H cis-H gem-H 2-Ar-H 3-Ar-H

Δδ (ppm)

pure mon

4VP + SS

γ-CD + 4VP + SS

CIa

ICb

Δc

5.58 6.11 6.77 7.49 8.45 5.42 5.94 6.83 7.61 7.76

5.56 6.08 6.74 7.44 8.42 5.40 5.92 6.80 7.58 7.75

5.56 5.99 6.61 7.27 8.34 5.35 5.77 6.65 7.36 7.66

0.02 0.03 0.03 0.05 0.03 0.02 0.02 0.03 0.03 0.01

0.02 0.12 0.16 0.22 0.11 0.07 0.17 0.18 0.25 0.10

0.00 0.09 0.13 0.17 0.08 0.05 0.15 0.15 0.22 0.09

CI: Coulombic interaction (= δpure mon − δ4VP+SS). bIC: inclusion complexation (= δpure mon − δγ‑CD+4VP+SS). cΔ: difference between CI and IC (= δ4VP+SS − δγ‑CD+4VP+SS). a

The signals of the two monomers shift upfield slighty when they are mixed together, possibly because of Coulombic interactions between the monomers. Upon addition of γ-CD, a more dramatic upfield shift is observed for most signals, indicative of inclusion complexation. The change for the signals for 4VP and SS are in the same order of magnitude, so that it is likely that they are both included in the cavities. The precise magnitude of the shifts differs between the signals: the strongest shifts are found for the meta-protons (position relative to the vinyl group) and the vinyl signal next to the aromatic ring, indicating that the change in polarity is strongest for these protons, meaning that they are likely localized in the center of the γ-CD cavity. Smaller but still significant changes are found for the ortho-Hs and the cis-H of the vinyl group. The signal for which the smallest shift is observed is the trans-H of the vinyl group, which is likely localized outside of the cavity. This observation supports the assumption that the vinyl groups protrude from the wide opening of the γ-CD cavity and can therefore polymerize. D

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Table 3. Reactivity Ratios As Determined by Different Methods for the Copolymerization of 4VP (M1) and SS (M2) in the Absence and Presence of γ-CD no γ-CD

with γ-CD

r1 r2 r1r2 r1 r2 r1r2

CF

F−R

inv F−R

K−T

T−M

1.428 0.088 0.126 1.297 0.029 0.037

1.384 0.080 0.111 1.268 0.004 0.005

1.293 0.040 0.052 1.589 0.088 0.140

1.335 0.054 0.072 1.330 0.028 0.038

1.556 −0.011 −0.018 1.873 0.016 0.030

Though the inclusion of 2,3,4,5,6-pentafluorostyrene (PFS) is, to the best of our knowledge, not known, the size of this monomer is similar to that of S, and it is known that there is a quadrupole interaction between these two monomers, caused by the electron-rich nature of the aromatic ring in S and the electron-deficient nature of the PFS ring,34,35 which makes PFS a promising monomer to use in conjunction with S. When S and PFS (both liquids) are added to an aqueous solution of γ-CD in a 1:1:1 ratio, the formed complexes precipitate from solution, even under rather dilute conditions (e.g., 10 mM). Upon heating to 75 °C clear solutions could be obtained up to a concentration of ∼13 mM. To investigate the stoichiometry in the complexes as well as the potential formation of hetero-ICs, 6 equiv of S and PFS (in ratios ranging from 5:1 to 1:5) was added to a 12.5 mM solution of γ-CD. The solutions were heated to 75 °C until clear solutions were obtained, and the precipitate formed upon cooling was collected by centrifugation and decantation of the supernatant. The precipitate was investigated by 1H NMR spectroscopy in DMSO-d6, which gives access to the ratio of monomer/CD, which are listed in Table 4.

Figure 4. Chemical shifts with varying ratios of γ-CD to monomer as found in the 1H NMR titration of γ-CD to a solution of 4VP (open rectangles) and SS (filled rectangles). The lines display the fits to the data.

Figure 5. Schematic depiction of the copolymerization of 4VP and SS in the absence and presence of γ-CD.

Table 4. Composition of the Inclusion Complexes As Determined by 1H NMR in DMSO-d6 for the Precipitate Formed after Mixing Different Feed Ratios of γ-CD, S, and PFS

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H NMR spectroscopy. Two series of copolymerizations were performed: one without γ-CD and one with a 1:2 ratio of γ-CD to the total amount of monomers (the ratio needed for ideal ternary inclusion complexes). In both series the feed ratio of the monomers was varied from 7:1 to 1:7. After degassing of the solutions an aliquot of each copolymerization was taken to determine the exact feed ratio of the monomers. The polymerization was started by irradiation of the solutions with UV light (366 nm). After certain times aliquots were taken to determine the monomer conversion by 1H NMR spectroscopy. Conversions around 20% are used to determine the reactivity ratios. The reactivity ratios (r) were determined using a number of different methods: the curve fitting (CF), (inverted) Fineman− Ross ((inv) F−R),30 Kelen−Tüdõs (K−T),31 and Tidwell− Mortimer (TM)32 methods. The obtained reactivity ratios are shown in Table 3. In all cases reactivity ratios of r1 (= r4VP) ∼ 1.4 and r2 (= rSS) ∼ 0 are found, for the copolymerizations both with and without γ-CD, meaning that the homopropagation of 4VP is slightly preferred, whereas SS preferentially undergoes heteropropagation. The fact that γ-CD does not appear to have a significant influence on the reactivity ratios (and thereby the monomer sequence distribution) is to be expected since the two monomers are incorporated in the complexes at random, thereby not placing two different monomers in close proximity to each other. Quadrupole Interactions. The formation of ternary homo-ICs of styrene (S) in γ-CD is known from literature.33

composition feed ratio (γ-CD:S:PFS)

γ-CD

S

PFS

S + PFS

1:5:1 1:4:2 1:3:3 1:2:4 1:1:5

1.00 1.00 1.00 1.00 1.00

0.37 0.60 0.76 1.03 0.91

0.96 0.65 0.76 0.78 0.56

1.33 1.25 1.52 1.81 1.47

For each γ-CD molecule between 1.25 and 1.81 monomers are included, suggesting that both inclusion complexes in which one monomer is captured as well as ternary complexes are formed. The ratio of the two monomers is not, as for the 4VP/ SS system, almost equal to the feed ratio. Instead, the monomer of which less is present in the feed is, relatively, included more strongly in the complexes: when e.g. 20% S is present (and 80% PFS) in the feed, 28% of the included monomers are S, and when 20% PFS is present in the feed, 38% of the monomers in the complex are PFS molecules. From the fact that in all cases a monomer ratio closer to 1:1 (Figure 6) is found in the complexes it can be concluded that S and PFS, presumably because of favorable quadrupole interactions between the monomers, are preferentially included together, forming ternary hetero-ICs. E

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Figure 7. Chemical shifts with varying ratios of monomer to γ-CD as found in the 1H NMR titration of γ-CD to a solution of S (filled rectangles) and PFS (open rectangles). The lines display the fits to the data.

Figure 6. Percentual inclusion of S or PFS in γ-CD with varying feed percentages of the two monomers.

Though promising results were found that support the formation of ternary hetero-ICs, the further investigation of these complexes in aqueous solution proved impossible due to the poor solubility of the complexes in water at room temperature. This insolubility also hindered the investigation of the copolymerization behavior of these complexes in water. Heating of the solutions to 75 °C did lead to clear solutions, but when samples were drawn from the copolymerization mixture and diluted with a large excess of DMSO-d6 for 1H NMR spectroscopic investigation, signals for S and PFS were much lower than expected (also before the start of the polymerization). The reason for this behavior remains unclear but might be related to the poor solubility of the monomers in the H2O/DMSO-d6 mixture. Removal of water from this mixture to improve solvent quality was also not viable since this procedure would also have removed (some of) the monomers, making it impossible to determine the conversion of monomers. Because of these problems, DMF was used for further studies. One of the main driving forces for the binding of many guest molecules in CDs is the release of water molecules from the cavity. The decreased polarity and increased size of DMF as compared to water, as well as the fact that the unpolar monomers are much more soluble in DMF than in water, would likely lead to much lower binding constants. Therefore, the inclusion complexation of S and PFS with γ-CD in DMF was studied. All components as well as the complex were soluble in DMF up to high concentrations, thereby making it impossible to investigate the composition of precipitated complexes directly. Instead, a 1H NMR titration was performed in DMF-d7, wherein a 0.2 M solution of γ-CD is titrated to a solution with 10 mM S and 10 mM PFS. The chemical shifts of the gem-H of S and PFS were used to determine the (apparent) binding constants of the two monomers. Relative chemical shifts are shown in Figure 7. For S Ka ∼ 54 M−1 and for PFS Ka ∼ 1.0 × 102 M−1 were found. These binding constants, though rather weak, nevertheless indicate that S and PFS bind in the pocket of γ-CD. The shifts in the 1H NMR spectra (up to 0.04 ppm) are rather weak compared to the shifts found for the inclusion complexion of 4VP and SS in aqueous solution (up to 0.4 ppm). These weak shifts in DMF-d7 are likely due to the fact that the polarity of the cavity and the solvent are much more similar than the cavity

is to the aqueous solution and should not be interpreted as direct indications of the interaction strength. Additionally, NOESY experiments were performed, but no cross-correlation between CD and monomer signals was observed. To get some idea of what conformation the monomers might adopt in the ICs, a 1:1:1 mixture of S, PFS, and γ-CD was also studied in DMSO-d6, where somewhat larger chemical shifts are observed than in DMF-d7. Parts of the 1H NMR spectra for the monomers, a 1:1 mixture of the S and PFS, and the ternary mixture are shown in Figure 8. The chemical shift of the signals are tabulated in Table 5. By comparing the shifts for a 1:1 mixture of S and PFS with the 1:1:1 mixture, it can be concluded that the aromatic signals of S show larger shifts than the vinyl-Hs, indicative of a conformation where the vinyl groups face the solution. Since PFS only has protons on the vinyl group, a direct comparison with the aromatic signals is impossible. Nevertheless, it is observed that the gem-H shows the largest shift, followed by the cis-H, which correlates well with a conformation where the aromatic ring is included in the cavity while the vinyl group protrudes (partly) from the CD cavity. While it proved impossible to generate the solid complex, it remains speculative that in DMF also ternary complexes are formed, but since the size of the cavity remains identical, it is highly likely that such complexes can also be formed in DMF. The copolymerization of S and PFS is known to proceed with a tendency toward alternation,34,36,37 which can be influenced by changing a number of parameters including temperature and solvent, which strongly indicates that the quadrupole interaction between these monomers plays a role in the copolymerization behavior. The influence of hetero-ICs on the copolymerization was investigated by the copolymerization of S and PFS in the presence of 0.5 equiv of γ-CD (to the total amount of monomers) in different ratios. Additionally, this series was repeated without γ-CD. The copolymerizations were performed in DMF at room temperature using the redox reaction between N,N-dimethylaniline (DMA) and benzoyl peroxide (BPO) (Figure 9).38 Initially, the photochemical initiation using AIBN was attempted (similar to the photochemical initiation using AAPH for the 4VP/SS system), but this proved extremely slow. F

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Macromolecules

Figure 8. 1H NMR spectra in DMSO-d6 of (from bottom to top) S, PFS, a 1:1 mixture of S and PFS, and a ternary mixture of S, PFS, and γ-CD. Dotted lines are meant as guides to the eye to better visualize the shift of the signals.

Table 5. Chemical Shift (δ) of the 1H-NMR Signals in DMSO-D6 for the Pure Substances, a 1:1 Mixture of the Two Monomers and the Ternary Mixture of γ-CD, S and PFS, as Well as the Relative Shifts upon Complexation δ (ppm) S + PFS

γ-CD + S + PFS

QIa

ICb

Δc

5.256 5.830 6.736 7.269 7.345 7.464 5.810 6.014 6.637

5.246 5.816 6.719 7.257 7.332 7.445 5.811 6.016 6.637

5.258 5.827 6.729 7.271 7.347 7.467 5.824 6.033 6.662

−0.010 −0.014 −0.017 −0.012 −0.013 −0.021 0.001 0.002 0.000

0.002 −0.003 −0.007 0.002 0.002 0.003 0.014 0.019 0.025

0.012 0.011 0.010 0.014 0.015 0.022 0.013 0.017 0.025

trans-H cis-H gem-H p-Ar-H o-Ar-H m-Ar-H trans-H cis-H gem-H

S

PFS

Δδ (ppm)

pure mon

a QI: quadrupole interaction (= δpure mon − δS+PFS). bIC: inclusion complexation (= δpure mon − δγ‑CD+S+PFS). cΔ: difference between QI and IC (= δS+PFS − δγ‑CD+S+PFS).

In this case the reactivity ratios are slightly decreased by the presence of γ-CD: especially r1 (=rS) is significantly lowered when γ-CD is present (from an average over the various methods to determine the reactivity ratios of ∼0.3 to an average of ∼0.15). This effect can likely be ascribed to the fact that a preorganization of the monomers (into heterodimers) is achieved using the inclusion complexation, thereby promoting the heteropropagation. The fact that r2 (=rPFS) remains more or less unaffected might be related to the higher binding constant found for this monomer, which could correlate with the formation of homo-ICs with two PFS monomers as guests. This is supported by the observation that somewhat more PFS is incorporated in the polymers when γ-CD is present (for a 1:1 ratio of S and PFS d[S]/d[PFS] without γ-CD ∼ 0.68 after 75 h, whereas d[S]/d[PFS] without γ-CD ∼ 0.62) and the fact that inclusion in CDs is known to accelerate polymerization.29 In the purified polymers similar ratios of the monomers are found (d[S]/d[PFS] ∼ 0.75 in the presence of γ-CD and d[S]/ d[PFS] ∼ 0.55 and in the absence of γ-CD; see Supporting Information). 13 C NMR spectra of copolymers prepared in the absence and presence of γ-CD were recorded as well as spectra for poly(styrene) and poly(pentafluorostyrene) homopolymers prepared in the presence of γ-CD (see Supporting Information). Large differences are observed between the spectra obtained for the homopolymers and the copolymers, which confirms that largely alternating monomer sequences are

Figure 9. Schematic depiction of the copolymerization of S and PFS in the absence and presence of γ-CD.

Reactivity ratios for the copolymerizations in the presence and absence of γ-CD were determined and are shown in Table 6. Table 6. Reactivity Ratios As Determined by a Variety of Different Methods for the Copolymerization of S (M1) and PFS (M2) in the Absence and Presence of γ-CD no γ-CD

with γ-CD

r1 r2 r1r2 r1 r2 r1r2

CF

F−R

inv F−R

K−T

T−M

0.426 1.091 0.465 0.199 0.883 0.176

0.398 0.900 0.358 0.197 0.841 0.165

0.219 0.617 0.135 0.146 0.694 0.101

0.315 0.688 0.217 0.152 0.711 0.108

0.237 0.649 0.154 0.114 0.731 0.083 G

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Macromolecules formed for both copolymers prepared with and without γ-CD. Between the two copolymers only minor differences are observed, the most marked of which is that the signals corresponding to the para-C of the styrene aromatic ring (at ∼124 ppm) shifts downfield significantly, which could indicate a difference in the monomer sequence distribution. Another possibility is that the presence of γ-CD influences the tacticity of the copolymer, e.g., resulting in heterotactic polymers, as was observed for the polymerization of protonated 4VP in the presence of β-RMCD.28 More detailed investigations are required to be able to unequivocally distinguish between these possibilities.

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CONCLUSION It was possible to form ternary inclusion complexes of 4VP and SS with γ-CD in aqueous solution, though these monomers showed no preference for their incorporation as a pair. S and PFS, which interact through quadrupole interactions, are on the other hand included preferentially as a pair in the γ-CD cavity. Because of the poor solubility of these complexes in water, they were also studied in DMF, where all indications are that here also hetero-IC are formed, though likely with smaller binding constants than in water. The copolymerization of S and PFS in the presence of γ-CD lead to an increased tendency toward alternation due to the preorganization of heterodimers of the monomers, even with the weak binding found in DMF. For monomers that interact more strongly with for which the inclusion complexation is stronger it is likely that much larger effects can be achieved. The method that is presented here can potentially also be used to incorporate two monomers in adjacent positions in a terpolymer with a third, noncomplexing, monomer.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.6b01203. Additional information about the copolymerizations, characterization of inclusion complexes and copolymers, and the determination of the reactivity ratios (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (N.t.B.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the Chemical Industry Fund (FCI Liebigfellowship) and the German Research Foundation (DFG, project number BR 4363/3-1) for financial support. Furthermore, we thank Marlies Gräwert and Bernhard Schmidt (Max Planck Institute of Colloids and Interfaces, Potsdam, Germany) for the SEC measurements in aqueous solution.

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DOI: 10.1021/acs.macromol.6b01203 Macromolecules XXXX, XXX, XXX−XXX