Letter pubs.acs.org/macroletters
Organic Reaction as a Stimulus for Polymer Phase Separation Masami Naya,† Yoshimi Hamano,† Kenta Kokado,*,†,‡ and Kazuki Sada*,†,‡ †
Graduate School of Chemical Sciences and Engineering and ‡Faculty of Science, Hokkaido University, Kita10 Nishi8, Kita-ku, Sapporo, 060-0810, Japan S Supporting Information *
ABSTRACT: Molecular design of stimuli-sensitive polymers has been attracting considerable interest of chemists because of their latent ability to achieve smart materials. Heat, light, pH, and chemicals have been often utilized as a stimuliinducing polymer phase transition from solution to aggregation and vice versa. In this report, as a new trigger for lower critical solution temperature (LCST)-type polymer phase transition, we introduce organic reaction of small organic molecules, not to the polymer chain itself. The addition of the reactant for the “effector”, which can interact with the polymer chain for increasing the compatibility of the polymer chain with the media, caused a polymer phase separation, due to reduction of the solvation ability of the effector to the polymer chain. In other words, decrease of the “effector” concentration induced the polymer phase separation. Within our knowledge, this is the first report to connect a polymer phase separation with organic reaction dynamics. This process will be the first step for the development of artificial allosteric enzyme mimics from a combination of a simple synthetic polymer and a product or reactant in organic reactions.
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respectively. Otherwise, specific chemicals cleave or convert the functional moieties on polymer chain, resulting in chemosensitivity.29−31 More recently, polymer phase separation in response to a reductant or an oxidant was prepared by introduction of mild redox sites.32−34 On another front, new molecular design of LCST-type thermoresponsive polymers has been reported, which is based on control of the desolvation process. Ritter et al. reported that a polymer bearing adamantyl moieties showed LCST-type thermoresponsivity in the presence of methylated β-cyclo dextrin (β-CD) in water owing to the dissociation of β-CD from the adamantyl group on the polymer chain by heating.35,36 More recently, our group demonstrated two examples of thermosensitive polymers with LCST-type phase transition. A polymer bearing urea units, poly(3-(3-butylureido)propyl acrylate) (PBPU), is shown in Figure 1, which exhibited LCST behavior based on hydrogen bond between the urea unit in the polymer chain and an alcohol as an “effector” for controlling the polymer solubility.37 At the elevated temperature, thermal cleavage of hydrogen bonds between the polymer chains and the effectors induces deposition and aggregation of the polymer chains. Similar LCST behavior was observed by utilization of charge transfer interaction between the pyrene group in poly((1-pyrene)methyl acrylate) and electron-accepting molecules.38,39 Dissociation of charge transfer complexes triggers drastic change of solubility upon heating. These results clearly indicated that dissociation of supramolecular complexes between the polymer chain and the
timuli-sensitive polymers that exhibit a drastic change of solubility or volume in the solution or gel phase induced by little environmental change have been widely investigated,1−4 directing the application for the smart materials.5−8 The most important and common strategy for designing stimuli-sensitive polymers is utilization of lower critical solution temperature (LCST)-type thermoresponsive polymers which show a sharp polymer phase transition in a narrow temperature range.2,3 The thermosensitivity is originated from desolvation of the polymer chains, thus release of solvent molecules from the polymer chain, followed by aggregation of the polymer chains.9 Amphiphilic polymers such as poly(ethylene glycol) (PEG) or poly(ethylene oxide) (PEO), poly(N-isopropylacrylamide) (PNIPAM), 10−12 poly(vinyl ether)s, 13,14 and poly(2oxazoline)s15,16 in water can exhibit LCST-type phase separation and were used as the important starting materials for stimuli-sensitive polymers or gels, via partial introduction of them as a sensing and responding functional group.1−4 The structural change of the stimuli-responsive group modulates the phase transition temperature (Tc), which allows us to design and control the stimuli sensitivity. For example, photosensitive copolymers have been synthesized by mainly equipping them with a photoreactive group undergoing photoisomerization for structural and polarity change.17−22 For pH-sensitive polymers, acidic or basic groups such as carboxylic acids and amines are found in the polymer chain as protonating or deprotonating sites according to the pH variation.23−25 For chemosensitive polymers, a molecular receptor was equipped for formation of a molecular complex with a specific guest compound as a stimulus.26−28 As typical examples, polymers tethering boronic acid,26 cyclodextrin,27 and crown ether28 provided the chemosensitivity for sugar, aromatic compounds, and metal ions, © XXXX American Chemical Society
Received: April 26, 2017 Accepted: July 28, 2017
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DOI: 10.1021/acsmacrolett.7b00315 ACS Macro Lett. 2017, 6, 898−902
Letter
ACS Macro Letters
hydroxyl group was chosen for protection of the hydrogen bonding functional group due to the high reactivity, mild conditions, and high selectivity, compared to the reaction of the hydroxyl and isocyanate group. Three conventional silylation reagents, trimethylsilyl cyanide (TMSCN), trimethylsilyl imidazole (TMSIm), and trimethylsilyl chloride (TMSCl), were examined for induction of phase separation of PBPU. The silylation reagent (0.51 equiv for 1-hexanol) to the effector was rapidly added to the clear solution of PBPU ([PBPU] = 25 mg/L, [urea unit] = 0.11 M) and 1-hexanol ([1-hexanol] = 0.87 M, 8.0 equiv/urea unit) in DCE. The change of PBPU solubility was monitored by transmittance at 800 nm. Around 10 min after the addition of TMSCN, the solution became turbid, and the transmittance of the solution decreased as shown in Figure 2 (see also Movie 1). This change indicated
Figure 1. Schematic drawing for phase separation of polymer induced by organic reaction of an effector.
effector by heating triggers the LCST behavior. These findings inspired us to explore a new class of stimuli-sensitive polymer system driven by chemical changes of the effector. As the first example, in this report, we demonstrate that loss of the solvation abilities of an effector induced by organic reaction triggers a polymer phase separation. This demonstration should be the first example of stimuli-sensitive polymers triggered by progress of chemical reaction between small molecules other than the polymer chain itself. Our strategy is based on the LCST or UCST behavior of PBPU in the presence of suitable effectors with hydrogen bonding functional groups.37 The effector ability should disappear by treatment with other reactants for the hydrogen bonding functional group on the effector, resulting in polymer phase separation, due to decreasing the concentration of the effector. For screening of the effectors, we first investigated effector ability of some organic substances (6 to 8 carbon atoms) with various functional groups to PBPU in 1,2-dichloroethane (DCE), as listed in Table S1. Small molecules with a strong hydrogen bonding donor such as alcohol, carboxylic acid, primary or secondary amide, and urea acted as an effector that induces LCST or UCST polymer phase separation as we found in the previous report.37 Indeed, 1-hexanol exhibited a thermoresponsivity at around room temperature (Table S1). On the other hand, most of the compounds with weak or no hydrogen bonding groups, such as alkane, ester, ether, silyl ether, ketone, aldehyde, thiol, and nitrile, did not change apparent solubility of PBPU upon heating in DCE. Organic bases including primary, secondary, and tertiary amines also did not. For other examples than the compounds listed in Table S1, triethylamine hydrochloride and pyridine hydrochloride did not act as an effector in DCE due to low solubility. However, trihexylamine hydrochloride and tetra(n-butyl)ammonium chloride with much improved solubility exhibited UCST polymer phase separation because of the strong hydrogen bonding ability of the chloride anion, which is consistent with previously reported results.37 These results indicated that protection of a hydrogen bonding group of effectors is suitable for polymer phase transition induced by chemical reaction. From this point of view, 1-hexanol was selected as the effector undergoing a chemical reaction, and silylation of the
Figure 2. Transmittance change of the solution of PBPU in the presence of 1-hexanol and TMSCN in 1,2-dichloroethane (DCE) including their photo images. Transmittance was recorded at 800 nm and 25 °C. [PBPU] = 25 mg/mL ([urea unit] = 0.11 M), [1-hexanol] = 0.87 M (8.0 equiv/urea unit).
that the addition of TMSCN induced the polymer phase transition of PBPU. Appearance of aggregate after 10 min was also confirmed by dynamic light scattering (DLS) measurement (Figure S1). Then, addition of the same amount of 1-hexanol to this turbid solution recovered the solution to clear again, meaning dissolution of PBPU with an increase of 1-hexanol concentration and consequent solvation (see also Movie 2). This is clear evidence for controlling the polymer phase separation via organic reaction of the effector. Moreover, some additional cycles of alternative addition of 1-hexanol and TMSCN induced the repeating change of the turbidity of PBPU solution. In order to clarify the relation between the chemical reaction of the effector and polymer phase separation, the silylation was monitored by 1H NMR in DCE-d4, as shown in Figure 3. At the time of the phase separation (∼10 min) of PBPU, the conversion of TMSCN was observed to be around 60% from the integral ratio of TMSCN and 1-hexyl-OTMS. After 20 min, the conversion of 1-hexanol became more than 90%. The fast silylation reaction occurred to convert the effector to noneffector, inducing the phase separation. This result suggests that the polymer precipitated after addition of TMSCN, and the silyl ether of 1-hexanol as a main product of this reaction was generated in the solution. Hydrogen cyanide was generated as a byproduct but did not work as an effector. Therefore, the 899
DOI: 10.1021/acsmacrolett.7b00315 ACS Macro Lett. 2017, 6, 898−902
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ACS Macro Letters
Figure 4. LCST-type phase transition of the solution of PBPU and 1hexanol in 1,2-dichloroethane (DCE) after the silylation reaction with various portions of TMSCN. [PBPU] = 25 mg/mL ([urea unit] = 0.11 M), [1-hexanol] = 0.87 M (8.0 equiv/urea unit), [TMSCN] = 0 M (0 equiv/1-hexanol), 0.056 M (0.065 equiv), 0.11 M (0.13 equiv), 0.17 M (0.19 equiv), 0.23 M (0.26 equiv), 0.28 M (0.32 equiv), 0.34 M (0.39 equiv), 0.39 M (0.45 equiv), and 0.46 M (0.52 equiv). Solid line: heating; dashed line: cooling.
transition induced by the organic reaction of the effector and control Tc. For other silylating reagents such as TMSIm and TMSCl, they did not provide clear evidence for the polymer phase separation. Under the same conditions of TMSCN, the addition of TMSIm did not induce formation of the precipitation (Figure S6a). The prolonged reaction time or excess amount of the TMSIm never induced the polymer phase separation. Monitoring the reaction of 1-hexanol with TMSIm by 1H NMR, the conversion rate was estimated to be 82% on the basis of integral ratios of the peaks of TMS ether and imidazole from the spectrum of the reaction mixture after 10 min (Figure S6b). This conversion rate should be enough to decrease induction of the polymer phase separation of PBPU compared to the result of TMSCN. Therefore, imidazole should act as an effector by formation of hydrogen bonding to the urea group and increase solubility of PBPU. When equimolar TMSCl to the effector was used as the silylation reagent of 1-hexanol, no precipitation of PBPU occurred (Figure S7a). The 1H NMR spectrum illustrated that the conversion remained only 28% without a suitable base (Figure S7b). Since progress of the silylation reaction was slow, it could not induce polymer phase separation. In the presence of triethylamine or pyridine as a quencher of hydrogen chloride, the byproduct of silylation, corresponding hydrochloride was precipitated by addition of TMSCl, and PBPU did not exhibit polymer phase separation (Table S2 and Figure S8). In the case of trihexylamine as the base, both hydrochloride salt and PBPU were not precipitated, which indicates that the hydrochloride salt acted as the effector for PBPU. In particular, the resulting chloride ion interacted with the urea group in the polymer chain (vide supra). From these observations, addition of both TMSCl and TMSIm did not induce the polymer phase separation of PBPU via silylation of the OH group of the effector, 1-hexanol. This feature is attributed to the effector ability of the byproducts of the silylation reaction. Hydrogen cyanide from TMSCN has less hydrogen bonding ability for the urea groups in the polymer chain. Therefore, elaborate design of the main product by protecting the hydroxyl group as well as its byproduct should be requisite for the polymer phase separation induced by chemical reaction as a stimulus. Weak
Figure 3. (a) Time course change of the 1H NMR spectrum after addition of TMSCN into the solution of PBPU and 1-hexanol in 1,2dichloroethane-d4 (DCE-d4). [PBPU] = 25 mg/mL ([urea unit] = 0.11 M), [1-hexanol] = 0.87 M (8.0 equiv/urea unit), [TMSCN] = 0.39 M (0.46 equiv/1-hexanol). (b) The conversion plot of TMSCN calculated from the integral ratio of TMSCN and 1-hexyl-OTMS.
silylation induced the phase separation of the PBPU. Additionally, the precipitation of PBPU caused a significant upfield shift of the hydroxy proton of 1-hexanol, due to loss of the hydrogen bond with PBPU. After isolation of the precipitation by filtration, the yield of PBPU was recovered with nearly 90% yield. The 1H NMR spectrum of the recovered polymer indicates no chemical transformation of PBPU while contaminated with a small amount of 1-hexyl-OTMS (Figure S2). In the reference experiment, no solubilization of PBPU in DCE-d4 was observed by treatment with an excess amount of TMSCN at room temperature (Figure S3). These results indicated that TMSCN selectively reacted with the hydroxyl group of 1-hexanol, and this chemical reaction reduced the concentration of the effector and subsequently induced the phase separation. Since PBPU in DCE exhibited LCST-type phase transition depending on the concentration of 1-hexanol as the effector (Figure S4), we investigated the phase separation of PBPU by the addition of TMSCN (0−0.52 equiv to 1-hexanol) as shown in Figure 4. In all cases, the solution exhibited LCST-type phase separation, and Tc decreased from 72 to 19 °C with increasing the amount of TMSCN. To lower the Tc to room temperature, ∼0.50 equiv of TMSCN was required. Moreover, the high Tc could be roughly recovered by addition of 0.095 M 1-hexanol as shown in Figure S5. In other words, increase of the effector concentration required high temperature for desolvation of the effector from the polymer chain. These results clearly indicated that strict control of the effector concentration by nearly quantitative organic reaction realized the polymer phase 900
DOI: 10.1021/acsmacrolett.7b00315 ACS Macro Lett. 2017, 6, 898−902
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ACS Macro Letters
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hydrogen bonding ability of hydrogen cyanide as the byproduct plays a key role for this polymer phase separation. In this report, we demonstrated organic-reaction-induced polymer phase separation as a new class of stimuli-sensitive polymer solution, on the basis of the LCST behavior of polymer in the presence of the effector and a reactant for it. Blocking the hydrogen bond functional groups of the effectors by the TMS silylation reduced the concentration of the effector and induced the polymer phase separation. Addition of the effector recovered the solubility of the polymer to transparent solution. Moreover, the cloud point of PBPU could be controlled by the amount of the reactant. Therefore, coupling of the organic reaction of the effector with the phase separation of the polymer in solution was achieved. To our surprise, this is the first example for conjugation of polymer phase separation with organic reaction involved with a solvating small molecule. This is a good contrast to the enormous number of examples that demonstrate the organic or acid−base reactions for the polymer-chain-induced phase separation because our system can provide a stable and unperturbed state due to the inertness of the polymer to the trigger and basically irreversible organic reaction. Incorporation of catalytic sites for exploration for allosteric enzyme mimics is currently being investigated.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.7b00315. Experimental details, solubility summary, 1H NMR spectra after addition of silylation reagents, LCST-type phase transition after addition of TMSCN and 1-hexanol (PDF) Movie for phase transition of PBPU solubility after the addition of TMSCN (MOV) Movie for phase transition of PBPU solubility after the addition of 1-hexanol (MOV)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Kenta Kokado: 0000-0003-3880-9094 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors acknowledge financial support from JSPS KAKENHI JP26102502, JP26288054, JP15H01077, and Inamori foundation.
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REFERENCES
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