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Thermally controlled silicone functionalization using selective Huisgen reactions
European Polymer Journal 69 (2015) 429–437
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European Polymer Journal journal homepage: www.elsevier.com/locate/europolj
Thermally controlled silicone functionalization using selective Huisgen reactions Mark Pascoal, Michael A. Brook ⇑, Ferdinand Gonzaga, Laura Zepeda-Velazquez Department of Chemistry and Chemical Biology, McMaster University, 1280 Main St. W., Hamilton, ON L8S 4M1, Canada
a r t i c l e
i n f o
Article history: Received 9 May 2015 Received in revised form 19 June 2015 Accepted 22 June 2015 Available online 23 June 2015 Keywords: Huisgen cyclization Silicone polymer Thermoselective Polyfunctional silicone
a b s t r a c t The thermal azide–alkyne cycloaddition using electron deficient alkynes has previously been applied to the room temperature crosslinking of polysiloxanes. However, only propiolates were used as the alkyne partner to functionalize polysiloxanes under metal-free conditions. Herein, we extend the methodology to alkynes with differing electronic demands and therefore different reactivities, which opens the possibility for selective silicone functionalization using sequential reactions simply by changing temperatures. To obtain a more thorough understanding of the effect of the alkyne electron density on the cycloaddition, differential scanning calorimetry was used to determine the temperature at which triazole formation is initiated for a variety of alkynes. The study showed acetylene dicarboxylates to have the lowest onset cycloaddition temperature of those studied, 37 °C. By contrast, propargyl esters only began to react at 101 °C, with other carbonyl-modified alkynes showing intermediate reactivity. Benzyl azide was used to demonstrate that the silicone copolymers bearing pendant propiolate alkynes could be reacted preferentially at lower temperatures, but only just, over the more electron rich terminal propiolamide alkynes. By contrast, the reaction of silicone propiolates with benzyl azide occurred nearly specifically in the presence of terminal propargyl alkynes on a polysiloxane copolymer containing both groups. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Improved synthetic methods provide a means to fine-tune polymer properties. To be of practical utility, innovative processes leading to precise structures must also involve as few steps, and as few different processes, as possible. Click chemistry provides one route that fulfills both these requirements. The Cu(I)-catalyzed azide–alkyne click reaction (CuAAC) involves the cyclization of an azide and alkyne pair into the 1,4-regioisomer of a 1,2,3-triazole. The benefits of the Cu(I)-catalyzed click reaction cannot be overemphasized, including its efficiency, mild conditions, tolerance to a wide range of solvents, its chemoselectivity in the presence of many other functional groups [1], and the formation of a single regioisomeric triazole [2]. The resilience of the CuAAC process in a wide range of reaction conditions is particularly advantageous for polymer functionalization with substrates of opposite polarity. For example, the coupling of carbohydrates onto polysiloxanes is difficult [3,4] and usually requires OH and NH protection (and difficult choices of solvent) prior to coupling. However, Halila et al. functionalized azide-containing polysiloxanes with N-propargylglycosylamines using CuAAC without the need for protection/deprotection steps [5]. Similarly, Gonzaga et al. ⇑ Corresponding author. E-mail address: [email protected] (M.A. Brook). http://dx.doi.org/10.1016/j.eurpolymj.2015.06.026 0014-3057/Ó 2015 Elsevier Ltd. All rights reserved.
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demonstrated the versatility of CuAAC by introducing a variety of small molecule substrates, ranging from alkyne-functionalized non-polar compounds to saccharides, onto azide-functionalized siloxanes and polysiloxanes without protection/deprotection [6]. The efficacy of the CuAAC click process means that it is difficult to selectively react different alkynes to create polymeric materials: multiple terminal alkynes will react competitively in the presence of a copper catalyst. The progenitor reaction, the Huisgen cyclization [7], by contrast, is less attractive at first glance in that higher temperatures are generally needed to induce [3 + 2]-cyclization, and a mixture of both regioisomers is the normal outcome of the process. Another major drawback of the Huisgen cycloaddition is the slow reaction rate: there is a 107 difference in the rate of the Huisgen when compared to an analogous CuAAC reaction at room temperature [8]. However, the efficiency of the Huisgen reaction, like the Diels–Alder reaction and other cycloadditions, is controlled by the HOMO–LUMO gap of the reaction partners [9]: if the energy gap between the azide HOMO and alkyne LUMO is reduced with the use of electron deficient alkynes, electron rich azides, or both, then the cyclization rate will be enhanced. This provides a strategy for synthetic control. The exploitation of electron-deficient alkynes in Huisgen reactions at modest temperatures has been demonstrated in a variety of situations. For example, Gonzaga et al. [7] demonstrated that room temperature crosslinking of silicones was possible using Huisgen cycloaddition of propiolate-functionalized polysiloxanes with bisazide-functionalized poly(ethylene glycol): the process was extended to the generation of dendrimers based on acetylene dicarboxylates, a functional group that is unreactive with CuAAC chemistry [10]. Perhaps the most clever utilization of the reaction with electron-deficient alkynes, however, is the use of trifluoro-substituted or ring-strained alkynes by Bertozzi et al. [11]. In a series of seminal papers, it was shown that reactions could be performed under physiological conditions, including within cells [12,13]. Reaction rates were comparable to Cu(I)-catalyzed reactions [11,14], but without the accompanying biotoxic effects of copper-based catalysts. We previously demonstrated that acetylene dicarboxylates undergo cycloaddition with azides even (albeit slowly) at room temperature [6]. It struck us that if silicones containing alkynes of sufficiently distinct reactivity could be prepared, they could be sequentially functionalized in the order desired to give a series of distinct polymers, by simply using one reaction at two temperatures. To examine this proposal, a model series of siloxanes was first prepared with different substituents at the alkyne a-position in order to establish relative thermal reactivities. Using the results from selectivity measurements, two polysiloxanes were prepared, each possessing two electronically different alkynes, by siloxane polymerization using alkyne-functionalized siloxanes. Highly preferential Huisgen modification of pendant propiolates over terminal propargyl esters, but not propiolamides, was demonstrated.
2. Experimental section 2.1. Materials 1,3-Bis(chloropropyl)tetramethyldisiloxane was obtained from ABCR. 1,3-Bis(trimethylsiloxy)methylsilane, 3-aminopro pylmethylbis(trimethylsiloxy)silane, octamethylcyclotetrasiloxane (D4), and 1,3-bis(aminopropyl)tetramethyldisiloxane were obtained from Gelest. Sodium azide (95%) was purchased from J.T. Baker. Propiolic acid (95%), triflic acid (98%), benzyl bromide (98%), sodium bicarbonate, 4-dimethylaminopyridine (99%), succinic anhydride (99%), 1-ethyl-3(3-dimethylamino propylcarbodiimide hydrochloride) (EDC) (98%), dicyclohexylcarbodiimide (DCC) (99%), allyl alcohol (98%), diethyl acetylenedicarboxylate (98%) 2,4-(trimethylsilyl)-3-butyn-2-one (98%) 7 propargyl alcohol (99%) and (2% Pt) plati num(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (Karstedt’s catalyst) in xylenes were obtained from Sigma–Aldrich. All materials were used as received. 1,3-Bis(azidopropyl)tetramethyldisiloxane 1 [6], benzyl propiolate 3 [15], benzyl propiolamide 5 [16], propargyl-terminated disiloxane 12 [17], and benzyl azide [18] were prepared according to literature procedures. 2.2. Methods 2.2.1. NMR and MS 1 H NMR and 13C NMR were recorded at room temperature on a Bruker AV-200 or AC-600 spectrometer, respectively, using deuterated solvents (CDCl3). High-resolution mass spectrometry was performed using a Hi-Res Waters/Micromass Quattro Global Ultima (Q-TOF mass spectrometer). 2.2.2. Gel permeation chromatography (GPC) analysis Number average (Mn) and weight average (Mw) molecular weights and polydispersity indexes (PDI) were determined using a Viscotek GPC system (GPCmax VE-2001) comprising of triple detectors of VE3580 RI detector, 270 dual detectors with viscometry and RALS/LALS (Right Angle Laser Light Scattering and Left Angle Laser Light Scattering), three columns of ViscoGEL I-guard-0478, ViscoGEL I-MBHMW-3078, and ViscoGEL I-MBLMW-3078 were equipped in series. Polystyrene narrow standard was used for multidetector GPC calibration. All measurements were carried out at 35 °C and at a flow rate of 1.0 mL/min, using toluene as the eluent.
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2.2.3. Differential scanning calorimetry (DSC) analysis The alkyne under study was added to a vial containing 1,3-bis(azidopropyl)tetramethyl-disiloxane (5 mg). The sample was prepared to give [C„C]:[N3] molar ratios of 1:1 with the sample size ranges between 5 and 10 mg. The sample was examined using a TA Instruments DSC 2910 in a standard aluminum pan purged with nitrogen gas. The pan was placed into the standard cell and heated at 5 °C/min over a temperature range from room temperature to 150 °C. 2.3. Syntheses 2.3.1. General procedure for propiolate ester synthesis, shown for trisiloxane 4 Dicyclohexylcarbodiimide (7.22 g, 35 mmol), dissolved in dichloromethane (5 mL), was added to a 150 mL round-bottomed flask containing propiolic acid (2.94 g, 42 mmol) in dichloromethane (10 mL) cooled to 35 °C. 3-Hydroxypropylmethylbis(trimethylsiloxy)silane 9 (4.45 g, 20 mmol) and 4-dimethylamino-pyridine (50 mg, 0.41 mmol), dissolved in dichloromethane (10 mL), were added portionwise while the reaction temperature was kept near 35 °C for 3–4 h. The reaction was then cooled to 75 °C and left overnight to warm to room temperature. Dicyclohexylurea was removed by filtration through a pad of Celite using dichloromethane as a solvent. The solvents were removed in vacuo and the crude product dissolved in diethyl ether and then refiltered. The product was purified using silica gel gravity chromatography (19:1 v/v hexane:ethyl acetate) to produce a clear colorless oil (1.67 g, yield 88%). 1 H NMR 200 MHz (CDCl3): 0.06 (s, 3H), 0.00 (s, 18H), 0.38 (m, 2H), 1.60 (m, 2H), 2.76 (s, 1H), 4.05 (t, 2H, J = 7.02 Hz) ppm. 13C NMR 200 MHz (CDCl3): 0.26, 1.95, 13.42, 22.34, 68.74, 74.49, 74.97, 152.93 ppm. 2.3.1.1. Trisiloxane amide 6. Dicyclohexylcarbodiimide (8.86 g, 42.9 mmol); propiolic acid (3 g, 42.8 mmol); 3-aminopropyl methylbis(trimethylsiloxy)silane 10 (10 g, 35.7 mmol); 4-dimethylaminopyridine (50 mg, 0.41 mmol). The product was purified with silica gel gravity chromatography (4:1 v/v hexane:ethyl acetate) to produce a viscous orange oil (6.88 g, yield 58%). 1 H NMR 200 MHz (CDCl3): 0.04 (s, 21H), 0.46 (m, 2H), 1.55 (m, 2H), 2.76 (s, 1H), 3.22 (m, 2H), 6.02 (bs, 1H) ppm. 13C NMR 200 MHz (CDCl3): 0.35, 1.81, 14.41, 22.91, 42.53, 72.98, 79.25, 152.30 ppm. HRMS: m/z [M + Na]+ calcd for C13H29O3NSi3Na: 354.1353; found: 354.1338. 2.3.1.2. Trisiloxane ester 8. Dicyclohexylcarbodiimide (1.76 g, 8.82 mmol); monopropargyl ester of butanedioic acid (1.71 g, 10.95 mmol); 3-hydroxypropylmethylbis(trimethylsiloxy)silane 9 (1.92 g, 6.85 mmol); 4-dimethylaminopyridine (50 mg, 0.41 mmol). The product was purified with silica gel gravity chromatography (4:1 v/v hexane: ethyl acetate) to produce a colorless oil (0.98 g, yield 35%). 1 H NMR 600 MHz (CDCl3): 0.05 (s, 3H), 0.07 (s, 18H), 0.43 (m, 2H), 1.62 (m, 2H), 2.45 (t, 1H, J = 4.92 Hz), 2.65 (m, 4H), 4.02 (t, 2H, J = 6.90 Hz), 4.68 (d, 2H, J = 2.52 Hz) ppm. 13C NMR 600 MHz (CDCl3): 0.10, 1.92, 2.31, 13.73, 22.70, 29.24, 52.46, 53.72, 67.51, 75.23, 77.81, 171.84, 172.34 ppm. 2.3.2. 3-Hydroxylpropylmethylbis(trimethylsiloxy)silane 9 1,3-Bis(trimethylsiloxy)methylsilane (15 g, 70 mmol) was added to a 150 mL round-bottomed flask containing allyl alcohol (4.76 g, 85 mmol) and toluene (8 mL). Karstedt’s catalyst (4 drops) was added and the reaction was flushed with nitrogen and left overnight. Decolorizing charcoal was added into the reaction and, after 30 min, filtered off. The solvent and excess allyl alcohol were evaporated in vacuo to afford a colorless oil (17.18 g, yield 90%). 1 H NMR 200 MHz (CDCl3): 0.07 (s, 21H), 0.40 (m, 2H), 1.52 (m, 2H), 3.55 (t, 2H, J = 6.72 Hz). 13C NMR 200 MHz (CDCl3): 0.23, 1.97, 13.35, 26.55, 65.60 ppm. 2.3.2.1. Disiloxane amide 11. Dicyclohexylcarbodiimide (6.03 g, 30 mmol); propiolic acid (2.60 g, 37.5 mmol); 1,3-bis(amino propyl)tetramethyldisiloxane (3.73 g, 15 mmol); 4-dimethylaminopyridine (40 mg, 0.32 mmol). The product was purified using silica gel gravity chromatography (2:1 v/v hexane:ethyl acetate) to produce a yellow solid (2.81 g, yield 64%). 1 H NMR 200 MHz (CDCl3): 0.03 (s, 12H), 0.49 (m, 4H), 1.53 (m, 4H), 2.75 (s, 2H), 3.26 (m, 4H, J = 6.36 Hz), 6.34 (bs, 2H) ppm. 13C NMR 200 MHz (CDCl3): 0.29, 15.07, 23.02, 42.81, 73.58, 77.52, 152.67 ppm. HRMS: m/z [M + H]+ calcd for C16H28O3N2Si2: 353.1717; found 353.1701. 2.3.3. Polysiloxane copolymer 13 Octamethylcyclotetrasiloxane (1.66 g, 5.6 mmol) and trisiloxane 4 (0.5 g, 1.50 mmol) were added to a 20 mL vial containing a solution of disiloxane 11 (0.60 g, 1.70 mmol) and dichloromethane (2 mL). Trifluoromethanesulfonic acid (50 lL, 0.56 mmol) was added and the reaction was left stirring for 2 d at room temperature. After the second day, dichloromethane was evaporated with a stream of nitrogen and the reaction was left stirring for an additional 2 d. Magnesium oxide (0.5 g) was added to the vial and the reaction was allowed to stir for 30 min. Hexane (15 mL) was added and the magnesium oxide was filtered off. The crude product was transferred to the Kugelrohr apparatus and the mixture was distilled at 130 °C and 0.1 Torr for 2 h to give a slightly orange, viscous oil (0.76 g, yield 24%, GPC (Mn = 2910 g/mol; Mw = 3485 g/mol, Mw/Mn = 1.197).
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1 H NMR 200 MHz (CDCl3): 0.00 (s, 302H), 0.50 (m, 15H), 1.54 (m, 6H), 1.70 (m, 6H), 2.75 (s, 2H), 2.83 (s, 2H), 3.26 (m, 5H), 4.15 (t, 4H, J = 6.72 Hz), 5.97 (bs, 2H) ppm. 13C NMR 600 MHz (CDCl3): 0.32, 0.38, 1.06, 1.31, 1.43, 1.55, 2.05, 13.47, 15.60, 22.38, 23.49, 42.95, 68.80, 73.11, 74.59, 74.82, 75.10, 77.81, 152.34, 153.05 ppm. 29Si NMR 600 MHz (CDCl3): 23.52, 22.09, 21.96, 21.67, 21.43, 21.02, 7.22, 7.37 ppm.
2.4. Following the click selectivity for the different alkynes of polysiloxane 13 using 1H NMR spectroscopy Benzyl azide (2 eq, 0.014 g, 0.0107 mmol) was added to two separate vials both containing polysiloxane 13 (1 eq, 0.2 g, 0.053 mmol) and 500 lL of CDCl3. Each vial was stirred and heated at either 35 °C or 60 °C, respectively, for one week. The 1H NMR spectrum of each sample was obtained each 2nd day and alkyne integrations were measured (Table 2, see Supporting Information) showing the formation of primarily 15 and 16 (we cannot discount the formation of small quantities of polymers with double modification under these conditions). 2.5. Alkyne selectivity measurement using a 1:1 mixture of trisiloxanes 4 and 6 using 1H NMR spectroscopy Benzyl azide (1 eq, 0.012 g, 0.09 mmol) was added to two separate vials containing approximately equal quantities of the polysiloxane 4 and 6 (0.03 g, 0.09 mmol) with 500 lL of CDCl3. The reactions was carried out over one week at 35 °C and 60 °C, respectively, and the 1H NMR spectra were obtained each day (Supporting Information). 2.6. Polysiloxane copolymer 14 Octamethylcyclotetrasiloxane (0.9 g, 3.04 mmol) was added to a 50 mL flask containing trisiloxane 4 (0.26 g, 0.81 mmol), disiloxane 12 (0.55 g, 1 mmol) and dichloromethane (2 mL). Trifluoromethanesulfonic acid (50 lL, 0.56 mmol) was added and reaction allowed to proceed for 2 d. After the second day, the reaction was placed under a gentle vacuum to remove dichloromethane and hexamethyldisiloxane that was formed in the mixture: care was taken to ensure that D4 was not readily removed over the next 2 days. Magnesium oxide (0.5 g) was added and allowed to stir for 30 min. Hexane was added and magnesium oxide was filtered off. The crude product was transferred to the Kugelrohr apparatus, distilled at 130 °C and 0.1 Torr for 2 h under high vacuum. After distillation to remove all volatile byproducts including residual D4 and hexamethyldisiloxane, the remaining polymer residue was isolated as a light orange viscous oil. (1.03 g, yield 61%, GPC (Mn = 5170 g/mol, Mw = 6720 g/mol, Mw/Mn = 1.299)). 1 H NMR 500 MHz (CDCl3): 0.07 (m, 852H), 0.52 (m, 35H), 1.38 (m, 12H), 1.63 (m, 10H), 1.70 (m, 10H), 2.45 (s, 2H), 2.66 (m, 13H), 2.82 (s, 4H), 4.07 (m, 6H), 4.11 (m, 6H), 4.68 (s, 4H) ppm. 13C NMR 600 MHz (CDCl3): 0.31, 0.42, 1.32, 1.41, 2.05, 13.60, 18.10, 19.93, 22.59, 29.03, 32.37, 52.57, 53.67, 64.94, 66.37, 67.49, 68.81, 74.61, 75.22, 153.05, 171.81, 172.38, 172.59, 172.66 ppm. 29Si NMR 600 MHz (CDCl3): 23.52, 22.26, 22.08, 21.96, 21.67, 21.42, 7.26 ppm. 2.7. Polysiloxane 17 Benzyl azide (0.031 g, 0.156 mmol) was added to a 50 mL round-bottomed flask containing polysiloxane 14 (0.3 g, 0.026 mmol) and toluene (5 mL). The reaction was heated at 70 °C with stirring. After 3 d, more benzyl azide (0.034 g, 0.25 mmol) was added and the reaction was allowed to stir for another 2 d. Excess benzyl azide was removed in vacuo using the Kugelrohr apparatus; the sample was then heated at 120 °C for 2 h under high vacuum. The product was a viscous yellow oil (0.5 g, yield 99%). After reaction, 1H NMR showed 40% conversion of the pendant propiolates giving primarily 17, and only 4% of the terminal propargyl esters (see Supporting Information). 3. Results and discussion 3.1. Effects of alkyne substituent on thermal cycloaddition temperature: model compounds A series of model alkynes was reacted with an alkylazido–silicone to better understand the thermal requirements of the Huisgen reaction with functionalized silicones. 1,3-Bis(azidopropyl)tetramethyldisiloxane 1 (Fig. 1) was chosen as a convenient model azide to characterize alkyne reactivity in the click reaction: its transformation to chromatographically separable compounds has been previously documented [6]. Commercially available organofunctional silicones are limited to a few functional groups, including monomers bearing vinyl or allyl groups, alkyl halides, alkylalcohols, alkylamines, and alkylcarboxylic acids, but not alkynes. Therefore, model alkynes were either organic, or small silicones prepared using standard protocols (Fig. 1, Table 1). The organic compounds 2, 3, 5 and 7 were either commercially available or readily prepared by standard esterification/amidation reactions. The trisiloxane model compounds 4, 6 and 8 were prepared either from hydro xypropylmethylbistrimethylsiloxysilane 9 or the commercially available aminopropylmethylbistrimethylsiloxysilane 10. Alkynes 2–8 (Table 1) were typically mixed with the model azide compound 1 in a stoichiometric ratio of functional groups ([C„C]:[N3]) = 1:1; the exceptions, benzyl propiolate and benzyl propiolamide, were mixed with the model azide compound on an equal mass basis. The efficiency of the thermal [3 + 2]-cycloaddition was examined using a differential
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A
B
C Fig. 1. Preparation of A: 1,3-bis(azidopropyl)tetramethyldisiloxane and, B: pendant functional and C: terminal functional siloxane alkynes.
scanning calorimeter: samples were heated from room temperature to 150 at 5 °C/min. The temperature of onset of cyclization for different alkynes is reported in Table 1. As can be seen from Table 1, large differences were observed in the temperature at which the Huisgen reaction started to occur. There was a clear, inverse correlation between the electronic density of the alkyne and the temperature at which the uncatalyzed cyclization began: electron-rich alkynes required much higher temperatures than electron-deficient alkynes. The efficiency of the reaction thus depends on the alkyne substituents, the reactivity of which followed the order: alkyl group < amide < ester < diester. The reactivity of the silyl-substituted alkyne 7 was low: in this case, any activation provided by the ketone is mitigated by the electronic donation, and possibly steric constraints, provided by the silyl substituent [19]. 3.1.1. Polysiloxanes: functionalization then polymerization The significant differences in thermal responsiveness between different alkynes presents an opportunity to develop generic silicone pre-elastomers that can be both crosslinked and functionalized in a variety of ways. For example, if polysiloxanes are designed to contain both reactive (e.g., propiolate esters) and less reactive (e.g., propiolamides) alkynes in different, explicit locations, it should be possible to crosslink the polysiloxane at a lower temperature (with propiolates) and perform post-cure covalent modification at a higher temperature (with propiolamides), or vice versa, to give a functional elastomer.
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Table 1 Onset cycloaddition temperatures for tested alkynes determined by DSC
. Compound number
Alkyne
Onset cycloaddition temperature (°C)
2
Diethyl acetylenedicarboxylate
37
3
Benzyl propiolate
51
4
Trisiloxane propiolate
64
5
Benzyl propiolamide
72
6
Trisiloxane propiolamide
74
7
Trimethylsilyl-3-butyn-4-one
90
8
Propargyl trisiloxane
101
Table 2 Number of alkyne units converted over time into triazoles by benzyl azide in polysiloxane 13 (based on OCH2, and NCH2 integration in 1H NMR, respectively).
a
Time (d)
Relative concentrationa
At 35 °C 0 2 6 % conversion
Pendant 2.50 2.03 1.78 32%
Terminal 2.00 1.88 1.60 19%
At 60 °C 0 2 4 6 % conversion
2.49 1.33 1.38 1.28 44%
2.00 1.29 1.23 1.18 39%
0 0.52 1.00
0.00 1.81 1.93 2.02
Normalized to 1 equiv terminal alkyne (propiolamide).
To test this hypothesis, linear silicone polymers bearing two different alkynes were prepared: the more reactive propiolate alkyne was located pendant along the polymer chain, while the less reactive alkyne was placed at the two termini of the chains. 3.1.2. Polyalkyne synthesis The direct functionalization of aminopropyl- or hydroxypropyl-silicone polymers by alkynes was problematic. Although attempts to modify commercial amino- and hydroxy-pendant polysiloxanes with propiolic acid using DCC coupling were efficient based on 1H NMR data, it was not possible to completely remove the co-product dicyclohexylurea from the polymer using silica gel chromatographic purification. Therefore, small functional siloxanes were first prepared and then incorporated into larger polymers using redistribution reactions [20].
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Activated alkynes were introduced as pendant groups to silicones by first forming trisiloxane 9 via hydrosilylation of 1 ,3-bis(trimethylsiloxy)methylsilane with allyl alcohol (Fig. 1B): the reaction was monitored by following the disappearance of the SiH signal at 4.7 ppm in the 1H NMR spectrum. The hydroxyl group was then converted into the propiolate-functionalized alkyne 4 by DCC coupling with propiolic acid, or 8 by reaction with the monopropargyl ester of butanedioic acid. The analogous amide 6 was prepared by the DCC amidation of commercial 3-aminopropylmethylbis(trime thylsiloxy)silane 10 with propiolic acid. Terminal alkynes, amides 11 and esters 12 [17], respectively, were prepared using analogous carbodiimide coupling chemistry with a, x-difunctional disiloxanes (Fig. 1C). High molecular weight silicones are frequently prepared by ring-opening polymerization under equilibrating conditions [20]. Bifunctional polymers were created from D4 and: (i) starting materials of 4 and 11 giving 13; or, (ii) 4 and 12 leading to 14, through acid-catalyzed equilibration (Fig. 2). During either reaction, two different end groups are present: the functional alkyne and AOSiMe3. In an attempt to ensure that the non-functional AOSiMe3 groups were removed from the mixture, the reaction was performed at slightly reduced pressure such that the most volatile byproduct that continuously forms during equilibration, Me3SiOSiMe3, could be removed, leaving only functional alkyne termini. According to 1H NMR polysiloxane 13, with an average Mn of about 2910 g mol 1 based on 1H NMR end group analysis and verified by GPC, possessed propiolate and propiolamide alkynes in a ratio of about 1.25:1. In spite of the reaction conditions used, however, a small quantity of SiMe3 end groups was found in the 29Si NMR. Polysiloxane 14 had a MW of about 5170 g mol 1 based on GPC and a pendant to terminal alkyne ratio of approximately 2:1. Based on 29Si NMR, only one type of end group – the propargyl ester – was detected on the polysiloxane, demonstrating that using reduced pressure to remove the byproduct Me3SiOSiMe3 was successful in this case. 3.1.3. Thermal control of network structure using click crosslinking selectivity measurements of multi-alkyne-functionalized polysiloxanes It was expected that the different alkynes would distinguish themselves in thermal reactions with azides. Based on the results in Table 1, the pendant propiolate should react at lower temperatures than either the terminal propiolamide or the propargyl ester. This proposal was initially tested using a small azide, PhCH2N3, with polysiloxane 13. Cycloadditions with an equimolar ratio of benzyl azide to the propiolate-based alkynes were carried out at two temperatures in an NMR tube and monitored by 1H NMR spectroscopy (see Supporting Information). At 35 °C over 6 days, 32% of the propiolate had reacted, and 19% of the propiolamide giving polymers such as 15 and 16 (Fig. 3A). At 60 °C, the reactivity of the two alkynes was comparable, with 44% and 39%, respectively (Table 2). Thus, the pendant propiolate was only marginally more reactive than the propiolamide: a somewhat higher level of discrimination was initially expected based on Table 1. It was recognized that greater steric accessibility of the terminal alkyne, compared to the internal propiolate, could be the origin of the outcome. To examine this proposal, a competition experiment was designed to directly pit two sterically comparable, but electronically different, alkynes against one another. An approximately equimolar mixture of trisiloxanes 4 and 6 was reacted with 1 equivalent of benzyl azide (Fig. 4) at 35 and 60 °C, respectively, and monitored by 1H NMR spectroscopy. At 35 °C, the two alkynes reacted at about the same rate, although the higher reactivity of the propiolate manifested at 60 °C (Supporting Information). Thus, the consequences of steric differences between pendant and terminal groups are minor, and the electronic differences are similarly small between the ester and amidoalkyne. Thus, a difference in onset temperature of
Fig. 2. Preparation of different pendant and terminal alkyne-functionalized polysiloxanes using acid-catalyzed equilibration polymerization.
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A
B
Fig. 3. Alkyne selectivity in Huisgen reactions with: A: Polysiloxane 13, B: Polysiloxane 14.
Fig. 4. Alkyne selectivity measurement of trisiloxane mixture.
10 °C shown in Table 1 between the amide vs ester functional alkynes is not sufficiently large to be of practical utility to give selective polymer functionalization. Higher selectivity between terminal and pendant groups could be achieved by using a significantly less reactive alkyne, such as a propargyl ester, as the low reactivity, terminal alkyne and pendant propiolates as the high reactivity alkyne. The reaction between polysiloxane 14 and benzyl azide was monitored in an NMR tube at 60 °C. Over a week, 40% of the propiolate reacted to give 17, while only 4% of the propargyl groups had reacted during this experiment. Note that the reaction is slower than those shown in Table 1 mostly because the concentrations of functional groups are much lower than in the cases of the model studies (Fig. 3B).
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The reactions described here demonstrate that the difference in reactivity of alkynes in the Huisgen cyclization can be exploited to modify silicone polymers. It is relatively straightforward to place different alkynes at either pendant, terminal, or both locations along a silicone chain. Judicious choice of alkynes and of reaction conditions permits selective modification at the pendant vs terminal sites with functional groups, or other silicones, simply by controlling the temperature and order of addition of reactants. This provides an opportunity to create several types of functional network structures from the same polymer backbone by using sequential click processes. The ability to manipulate polymer systems in a simple and generic way is clearly advantageous. We have shown that the differential reactivity between alkynes can be used to selectively, although not specifically, modify silicones containing more than one alkyne simply by controlling the temperature of the Huisgen reaction. No catalysts are needed and no byproducts are formed. While the process is described for silicones, it should be equally amenable to other polymer systems. In future work, we will demonstrate the ability to independently manipulate functionalization and crosslinking using this process. 4. Conclusion DSC studies demonstrate a large difference in reactivity in the Huisgen reaction between carbonyl-functionalized alkynes vs simple alkynes. These differences in reactivity can be used to selectively modify alkynes on multifunctional silicone polymers, with preference for reactivity, at low temperatures, of conjugated alkyne esters over propargyl groups. Standard silicone chemistry allowed the localization of the more reactive alkyne pendant along the chain, and the less reactive alkyne at the termini. The combination of these processes allows for selective functionalization with different azides at the terminal or pendant sites. Acknowledgement We gratefully acknowledge the financial support of the Natural Sciences and Engineering Council of Canada. Appendix A. Supplementary data Table showing relative reactivity for 4 and 6 for benzyl azide, 1H NMR data showing the Huisgen reaction of benzyl azide with polymers 13 and 14, respectively. Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.eurpolymj.2015.06.026. References [1] M. Meldal, Polymer, ‘‘Clicking’’ by CuAAC Reactions, Macromol Rapid Comm. 29 (12–13) (2008) 1016–1051. [2] J.E. Hein, V.V. Fokin, Copper-catalyzed azide–alkyne cycloaddition (CuAAC) and beyond: new reactivity of copper(i) acetylides, Chem Soc Rev. 39 (4) (2010) 1302–1315. [3] R. Wagner, L. Richter, B. Weiland, J. Reiners, J. Weissmuller, Silicon-modified carbohydrate surfactants.2. Siloxanyl moieties containing branched structures, Appl Organomet Chem. 10 (6) (1996) 437–450. [4] R. Wagner, L. Richter, R. Wersig, G. Schmaucks, B. Weiland, J. Weissmuller, et al, Silicon-modified carbohydrate surfactants.1. Synthesis of siloxanyl moieties containing straight-chained glycosides and amides, Appl Organomet Chem. 10 (6) (1996) 421–435. [5] S. Halila, M. Manguian, S. Fort, S. Cottaz, T. Hamaide, E. Fleury, et al, Syntheses of well-defined glyco-polyorganosiloxanes by ‘‘click’’ chemistry and their surfactant properties, Macromol Chem Phys. 209 (12) (2008) 1282–1290. [6] F. Gonzaga, G. Yu, M.A. Brook, Versatile, efficient derivatization of polysiloxanes via click technology, Chem Commun. 13 (2009) 1730–1732. [7] F. Gonzaga, G. Yu, M.A. Brook, Polysiloxane Elastomers via Room Temperature, Metal-Free Click Chemistry. Macromolecules. 42 (23) (2009) 9220–9224. [8] E.M. Sletten, C.R. Bertozzi, From Mechanism to Mouse: A Tale of Two Bioorthogonal Reactions, Accounts Chem Res. 44 (9) (2011) 666–676. [9] I. Fleming, Molecular Orbitals and Organic Chemical Reactions, Wiley, 2009. [10] F. Gonzaga, L.P. Sadowski, T. Rambarran, J. Grande, A. Adronov, M.A. Brook, Highly efficient divergent synthesis of dendrimers via metal-free ‘‘click’’ chemistry, J Polym Sci, Part A: Polym Chem. 51 (6) (2013) 1272–1277. [11] J.C. Jewett, C.R. Bertozzi, Cu-free click cycloaddition reactions in chemical biology, Chem Soc Rev. 39 (4) (2010) 1272–1279. [12] E.M. Sletten, C.R. Bertozzi, Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of Functionality, Angew Chem Int Ed. 48 (38) (2009) 6974–6998. [13] J.C. Jewett, E.M. Sletten, C.R. Bertozzi, Rapid Cu-Free Click Chemistry with Readily Synthesized Biarylazacyclooctynones, J Am Chem Soc. 132 (11) (2010) 3688–3690. [14] V. Hong, N.F. Steinmetz, M. Manchester, M.G. Finn, Labeling Live Cells by Copper-Catalyzed Alkyne Azide Click Chemistry, Bioconjugate Chem. 21 (10) (2010) 1912–1916. [15] S. Meunier, J.-M. Siaugue, M. Sawicki, F. Calbour, S. Dézard, F. Taran, et al, Modular Liquid-Phase Parallel Synthesis of a Highly Diverse Ligand Library, Journal of Combinatorial Chemistry. 5 (3) (2003) 201–204. [16] R.J. Payne, F. Peyrot, O. Kerbarh, A.D. Abell, C. Abell, Rational Design, Synthesis, and Evaluation of Nanomolar Type II Dehydroquinase Inhibitors, ChemMedChem. 2 (7) (2007) 1015–1029. [17] T. Rambarran, F. Gonzaga, M.A. Brook, Generic, Metal-Free Cross-Linking and Modification of Silicone Elastomers Using Click Ligation, Macromolecules. 45 (5) (2012) 2276–2285. [18] S. Sun, P. Wu, Mechanistic Insights into Cu(I)-Catalyzed Azide Alkyne ‘‘Click’’ Cycloaddition Monitored by Real Time Infrared Spectroscopy, The Journal of Physical Chemistry A. 114 (32) (2010) 8331–8336. [19] C. Dallaire, M.A. Brook, The Beta-effect with vinyl cations - Kinetic study of the protiodemetallation of silylalkynes, germylalkynes, and stannylalkynes, Organometallics. 12 (6) (1993) 2332–2338. [20] M.A. Brook, Chapter 9. Silicon in Organic, Organometallic, and Polymer Chemistry, John Wiley & Sons, Inc., New York, 2000, p. 256.
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European Polymer Journal journal homepage: www.elsevier.com/locate/europolj
Thermally controlled silicone functionalization using selective Huisgen reactions Mark Pascoal, Michael A. Brook ⇑, Ferdinand Gonzaga, Laura Zepeda-Velazquez Department of Chemistry and Chemical Biology, McMaster University, 1280 Main St. W., Hamilton, ON L8S 4M1, Canada
a r t i c l e
i n f o
Article history: Received 9 May 2015 Received in revised form 19 June 2015 Accepted 22 June 2015 Available online 23 June 2015 Keywords: Huisgen cyclization Silicone polymer Thermoselective Polyfunctional silicone
a b s t r a c t The thermal azide–alkyne cycloaddition using electron deficient alkynes has previously been applied to the room temperature crosslinking of polysiloxanes. However, only propiolates were used as the alkyne partner to functionalize polysiloxanes under metal-free conditions. Herein, we extend the methodology to alkynes with differing electronic demands and therefore different reactivities, which opens the possibility for selective silicone functionalization using sequential reactions simply by changing temperatures. To obtain a more thorough understanding of the effect of the alkyne electron density on the cycloaddition, differential scanning calorimetry was used to determine the temperature at which triazole formation is initiated for a variety of alkynes. The study showed acetylene dicarboxylates to have the lowest onset cycloaddition temperature of those studied, 37 °C. By contrast, propargyl esters only began to react at 101 °C, with other carbonyl-modified alkynes showing intermediate reactivity. Benzyl azide was used to demonstrate that the silicone copolymers bearing pendant propiolate alkynes could be reacted preferentially at lower temperatures, but only just, over the more electron rich terminal propiolamide alkynes. By contrast, the reaction of silicone propiolates with benzyl azide occurred nearly specifically in the presence of terminal propargyl alkynes on a polysiloxane copolymer containing both groups. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Improved synthetic methods provide a means to fine-tune polymer properties. To be of practical utility, innovative processes leading to precise structures must also involve as few steps, and as few different processes, as possible. Click chemistry provides one route that fulfills both these requirements. The Cu(I)-catalyzed azide–alkyne click reaction (CuAAC) involves the cyclization of an azide and alkyne pair into the 1,4-regioisomer of a 1,2,3-triazole. The benefits of the Cu(I)-catalyzed click reaction cannot be overemphasized, including its efficiency, mild conditions, tolerance to a wide range of solvents, its chemoselectivity in the presence of many other functional groups [1], and the formation of a single regioisomeric triazole [2]. The resilience of the CuAAC process in a wide range of reaction conditions is particularly advantageous for polymer functionalization with substrates of opposite polarity. For example, the coupling of carbohydrates onto polysiloxanes is difficult [3,4] and usually requires OH and NH protection (and difficult choices of solvent) prior to coupling. However, Halila et al. functionalized azide-containing polysiloxanes with N-propargylglycosylamines using CuAAC without the need for protection/deprotection steps [5]. Similarly, Gonzaga et al. ⇑ Corresponding author. E-mail address: [email protected] (M.A. Brook). http://dx.doi.org/10.1016/j.eurpolymj.2015.06.026 0014-3057/Ó 2015 Elsevier Ltd. All rights reserved.
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demonstrated the versatility of CuAAC by introducing a variety of small molecule substrates, ranging from alkyne-functionalized non-polar compounds to saccharides, onto azide-functionalized siloxanes and polysiloxanes without protection/deprotection [6]. The efficacy of the CuAAC click process means that it is difficult to selectively react different alkynes to create polymeric materials: multiple terminal alkynes will react competitively in the presence of a copper catalyst. The progenitor reaction, the Huisgen cyclization [7], by contrast, is less attractive at first glance in that higher temperatures are generally needed to induce [3 + 2]-cyclization, and a mixture of both regioisomers is the normal outcome of the process. Another major drawback of the Huisgen cycloaddition is the slow reaction rate: there is a 107 difference in the rate of the Huisgen when compared to an analogous CuAAC reaction at room temperature [8]. However, the efficiency of the Huisgen reaction, like the Diels–Alder reaction and other cycloadditions, is controlled by the HOMO–LUMO gap of the reaction partners [9]: if the energy gap between the azide HOMO and alkyne LUMO is reduced with the use of electron deficient alkynes, electron rich azides, or both, then the cyclization rate will be enhanced. This provides a strategy for synthetic control. The exploitation of electron-deficient alkynes in Huisgen reactions at modest temperatures has been demonstrated in a variety of situations. For example, Gonzaga et al. [7] demonstrated that room temperature crosslinking of silicones was possible using Huisgen cycloaddition of propiolate-functionalized polysiloxanes with bisazide-functionalized poly(ethylene glycol): the process was extended to the generation of dendrimers based on acetylene dicarboxylates, a functional group that is unreactive with CuAAC chemistry [10]. Perhaps the most clever utilization of the reaction with electron-deficient alkynes, however, is the use of trifluoro-substituted or ring-strained alkynes by Bertozzi et al. [11]. In a series of seminal papers, it was shown that reactions could be performed under physiological conditions, including within cells [12,13]. Reaction rates were comparable to Cu(I)-catalyzed reactions [11,14], but without the accompanying biotoxic effects of copper-based catalysts. We previously demonstrated that acetylene dicarboxylates undergo cycloaddition with azides even (albeit slowly) at room temperature [6]. It struck us that if silicones containing alkynes of sufficiently distinct reactivity could be prepared, they could be sequentially functionalized in the order desired to give a series of distinct polymers, by simply using one reaction at two temperatures. To examine this proposal, a model series of siloxanes was first prepared with different substituents at the alkyne a-position in order to establish relative thermal reactivities. Using the results from selectivity measurements, two polysiloxanes were prepared, each possessing two electronically different alkynes, by siloxane polymerization using alkyne-functionalized siloxanes. Highly preferential Huisgen modification of pendant propiolates over terminal propargyl esters, but not propiolamides, was demonstrated.
2. Experimental section 2.1. Materials 1,3-Bis(chloropropyl)tetramethyldisiloxane was obtained from ABCR. 1,3-Bis(trimethylsiloxy)methylsilane, 3-aminopro pylmethylbis(trimethylsiloxy)silane, octamethylcyclotetrasiloxane (D4), and 1,3-bis(aminopropyl)tetramethyldisiloxane were obtained from Gelest. Sodium azide (95%) was purchased from J.T. Baker. Propiolic acid (95%), triflic acid (98%), benzyl bromide (98%), sodium bicarbonate, 4-dimethylaminopyridine (99%), succinic anhydride (99%), 1-ethyl-3(3-dimethylamino propylcarbodiimide hydrochloride) (EDC) (98%), dicyclohexylcarbodiimide (DCC) (99%), allyl alcohol (98%), diethyl acetylenedicarboxylate (98%) 2,4-(trimethylsilyl)-3-butyn-2-one (98%) 7 propargyl alcohol (99%) and (2% Pt) plati num(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (Karstedt’s catalyst) in xylenes were obtained from Sigma–Aldrich. All materials were used as received. 1,3-Bis(azidopropyl)tetramethyldisiloxane 1 [6], benzyl propiolate 3 [15], benzyl propiolamide 5 [16], propargyl-terminated disiloxane 12 [17], and benzyl azide [18] were prepared according to literature procedures. 2.2. Methods 2.2.1. NMR and MS 1 H NMR and 13C NMR were recorded at room temperature on a Bruker AV-200 or AC-600 spectrometer, respectively, using deuterated solvents (CDCl3). High-resolution mass spectrometry was performed using a Hi-Res Waters/Micromass Quattro Global Ultima (Q-TOF mass spectrometer). 2.2.2. Gel permeation chromatography (GPC) analysis Number average (Mn) and weight average (Mw) molecular weights and polydispersity indexes (PDI) were determined using a Viscotek GPC system (GPCmax VE-2001) comprising of triple detectors of VE3580 RI detector, 270 dual detectors with viscometry and RALS/LALS (Right Angle Laser Light Scattering and Left Angle Laser Light Scattering), three columns of ViscoGEL I-guard-0478, ViscoGEL I-MBHMW-3078, and ViscoGEL I-MBLMW-3078 were equipped in series. Polystyrene narrow standard was used for multidetector GPC calibration. All measurements were carried out at 35 °C and at a flow rate of 1.0 mL/min, using toluene as the eluent.
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2.2.3. Differential scanning calorimetry (DSC) analysis The alkyne under study was added to a vial containing 1,3-bis(azidopropyl)tetramethyl-disiloxane (5 mg). The sample was prepared to give [C„C]:[N3] molar ratios of 1:1 with the sample size ranges between 5 and 10 mg. The sample was examined using a TA Instruments DSC 2910 in a standard aluminum pan purged with nitrogen gas. The pan was placed into the standard cell and heated at 5 °C/min over a temperature range from room temperature to 150 °C. 2.3. Syntheses 2.3.1. General procedure for propiolate ester synthesis, shown for trisiloxane 4 Dicyclohexylcarbodiimide (7.22 g, 35 mmol), dissolved in dichloromethane (5 mL), was added to a 150 mL round-bottomed flask containing propiolic acid (2.94 g, 42 mmol) in dichloromethane (10 mL) cooled to 35 °C. 3-Hydroxypropylmethylbis(trimethylsiloxy)silane 9 (4.45 g, 20 mmol) and 4-dimethylamino-pyridine (50 mg, 0.41 mmol), dissolved in dichloromethane (10 mL), were added portionwise while the reaction temperature was kept near 35 °C for 3–4 h. The reaction was then cooled to 75 °C and left overnight to warm to room temperature. Dicyclohexylurea was removed by filtration through a pad of Celite using dichloromethane as a solvent. The solvents were removed in vacuo and the crude product dissolved in diethyl ether and then refiltered. The product was purified using silica gel gravity chromatography (19:1 v/v hexane:ethyl acetate) to produce a clear colorless oil (1.67 g, yield 88%). 1 H NMR 200 MHz (CDCl3): 0.06 (s, 3H), 0.00 (s, 18H), 0.38 (m, 2H), 1.60 (m, 2H), 2.76 (s, 1H), 4.05 (t, 2H, J = 7.02 Hz) ppm. 13C NMR 200 MHz (CDCl3): 0.26, 1.95, 13.42, 22.34, 68.74, 74.49, 74.97, 152.93 ppm. 2.3.1.1. Trisiloxane amide 6. Dicyclohexylcarbodiimide (8.86 g, 42.9 mmol); propiolic acid (3 g, 42.8 mmol); 3-aminopropyl methylbis(trimethylsiloxy)silane 10 (10 g, 35.7 mmol); 4-dimethylaminopyridine (50 mg, 0.41 mmol). The product was purified with silica gel gravity chromatography (4:1 v/v hexane:ethyl acetate) to produce a viscous orange oil (6.88 g, yield 58%). 1 H NMR 200 MHz (CDCl3): 0.04 (s, 21H), 0.46 (m, 2H), 1.55 (m, 2H), 2.76 (s, 1H), 3.22 (m, 2H), 6.02 (bs, 1H) ppm. 13C NMR 200 MHz (CDCl3): 0.35, 1.81, 14.41, 22.91, 42.53, 72.98, 79.25, 152.30 ppm. HRMS: m/z [M + Na]+ calcd for C13H29O3NSi3Na: 354.1353; found: 354.1338. 2.3.1.2. Trisiloxane ester 8. Dicyclohexylcarbodiimide (1.76 g, 8.82 mmol); monopropargyl ester of butanedioic acid (1.71 g, 10.95 mmol); 3-hydroxypropylmethylbis(trimethylsiloxy)silane 9 (1.92 g, 6.85 mmol); 4-dimethylaminopyridine (50 mg, 0.41 mmol). The product was purified with silica gel gravity chromatography (4:1 v/v hexane: ethyl acetate) to produce a colorless oil (0.98 g, yield 35%). 1 H NMR 600 MHz (CDCl3): 0.05 (s, 3H), 0.07 (s, 18H), 0.43 (m, 2H), 1.62 (m, 2H), 2.45 (t, 1H, J = 4.92 Hz), 2.65 (m, 4H), 4.02 (t, 2H, J = 6.90 Hz), 4.68 (d, 2H, J = 2.52 Hz) ppm. 13C NMR 600 MHz (CDCl3): 0.10, 1.92, 2.31, 13.73, 22.70, 29.24, 52.46, 53.72, 67.51, 75.23, 77.81, 171.84, 172.34 ppm. 2.3.2. 3-Hydroxylpropylmethylbis(trimethylsiloxy)silane 9 1,3-Bis(trimethylsiloxy)methylsilane (15 g, 70 mmol) was added to a 150 mL round-bottomed flask containing allyl alcohol (4.76 g, 85 mmol) and toluene (8 mL). Karstedt’s catalyst (4 drops) was added and the reaction was flushed with nitrogen and left overnight. Decolorizing charcoal was added into the reaction and, after 30 min, filtered off. The solvent and excess allyl alcohol were evaporated in vacuo to afford a colorless oil (17.18 g, yield 90%). 1 H NMR 200 MHz (CDCl3): 0.07 (s, 21H), 0.40 (m, 2H), 1.52 (m, 2H), 3.55 (t, 2H, J = 6.72 Hz). 13C NMR 200 MHz (CDCl3): 0.23, 1.97, 13.35, 26.55, 65.60 ppm. 2.3.2.1. Disiloxane amide 11. Dicyclohexylcarbodiimide (6.03 g, 30 mmol); propiolic acid (2.60 g, 37.5 mmol); 1,3-bis(amino propyl)tetramethyldisiloxane (3.73 g, 15 mmol); 4-dimethylaminopyridine (40 mg, 0.32 mmol). The product was purified using silica gel gravity chromatography (2:1 v/v hexane:ethyl acetate) to produce a yellow solid (2.81 g, yield 64%). 1 H NMR 200 MHz (CDCl3): 0.03 (s, 12H), 0.49 (m, 4H), 1.53 (m, 4H), 2.75 (s, 2H), 3.26 (m, 4H, J = 6.36 Hz), 6.34 (bs, 2H) ppm. 13C NMR 200 MHz (CDCl3): 0.29, 15.07, 23.02, 42.81, 73.58, 77.52, 152.67 ppm. HRMS: m/z [M + H]+ calcd for C16H28O3N2Si2: 353.1717; found 353.1701. 2.3.3. Polysiloxane copolymer 13 Octamethylcyclotetrasiloxane (1.66 g, 5.6 mmol) and trisiloxane 4 (0.5 g, 1.50 mmol) were added to a 20 mL vial containing a solution of disiloxane 11 (0.60 g, 1.70 mmol) and dichloromethane (2 mL). Trifluoromethanesulfonic acid (50 lL, 0.56 mmol) was added and the reaction was left stirring for 2 d at room temperature. After the second day, dichloromethane was evaporated with a stream of nitrogen and the reaction was left stirring for an additional 2 d. Magnesium oxide (0.5 g) was added to the vial and the reaction was allowed to stir for 30 min. Hexane (15 mL) was added and the magnesium oxide was filtered off. The crude product was transferred to the Kugelrohr apparatus and the mixture was distilled at 130 °C and 0.1 Torr for 2 h to give a slightly orange, viscous oil (0.76 g, yield 24%, GPC (Mn = 2910 g/mol; Mw = 3485 g/mol, Mw/Mn = 1.197).
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1 H NMR 200 MHz (CDCl3): 0.00 (s, 302H), 0.50 (m, 15H), 1.54 (m, 6H), 1.70 (m, 6H), 2.75 (s, 2H), 2.83 (s, 2H), 3.26 (m, 5H), 4.15 (t, 4H, J = 6.72 Hz), 5.97 (bs, 2H) ppm. 13C NMR 600 MHz (CDCl3): 0.32, 0.38, 1.06, 1.31, 1.43, 1.55, 2.05, 13.47, 15.60, 22.38, 23.49, 42.95, 68.80, 73.11, 74.59, 74.82, 75.10, 77.81, 152.34, 153.05 ppm. 29Si NMR 600 MHz (CDCl3): 23.52, 22.09, 21.96, 21.67, 21.43, 21.02, 7.22, 7.37 ppm.
2.4. Following the click selectivity for the different alkynes of polysiloxane 13 using 1H NMR spectroscopy Benzyl azide (2 eq, 0.014 g, 0.0107 mmol) was added to two separate vials both containing polysiloxane 13 (1 eq, 0.2 g, 0.053 mmol) and 500 lL of CDCl3. Each vial was stirred and heated at either 35 °C or 60 °C, respectively, for one week. The 1H NMR spectrum of each sample was obtained each 2nd day and alkyne integrations were measured (Table 2, see Supporting Information) showing the formation of primarily 15 and 16 (we cannot discount the formation of small quantities of polymers with double modification under these conditions). 2.5. Alkyne selectivity measurement using a 1:1 mixture of trisiloxanes 4 and 6 using 1H NMR spectroscopy Benzyl azide (1 eq, 0.012 g, 0.09 mmol) was added to two separate vials containing approximately equal quantities of the polysiloxane 4 and 6 (0.03 g, 0.09 mmol) with 500 lL of CDCl3. The reactions was carried out over one week at 35 °C and 60 °C, respectively, and the 1H NMR spectra were obtained each day (Supporting Information). 2.6. Polysiloxane copolymer 14 Octamethylcyclotetrasiloxane (0.9 g, 3.04 mmol) was added to a 50 mL flask containing trisiloxane 4 (0.26 g, 0.81 mmol), disiloxane 12 (0.55 g, 1 mmol) and dichloromethane (2 mL). Trifluoromethanesulfonic acid (50 lL, 0.56 mmol) was added and reaction allowed to proceed for 2 d. After the second day, the reaction was placed under a gentle vacuum to remove dichloromethane and hexamethyldisiloxane that was formed in the mixture: care was taken to ensure that D4 was not readily removed over the next 2 days. Magnesium oxide (0.5 g) was added and allowed to stir for 30 min. Hexane was added and magnesium oxide was filtered off. The crude product was transferred to the Kugelrohr apparatus, distilled at 130 °C and 0.1 Torr for 2 h under high vacuum. After distillation to remove all volatile byproducts including residual D4 and hexamethyldisiloxane, the remaining polymer residue was isolated as a light orange viscous oil. (1.03 g, yield 61%, GPC (Mn = 5170 g/mol, Mw = 6720 g/mol, Mw/Mn = 1.299)). 1 H NMR 500 MHz (CDCl3): 0.07 (m, 852H), 0.52 (m, 35H), 1.38 (m, 12H), 1.63 (m, 10H), 1.70 (m, 10H), 2.45 (s, 2H), 2.66 (m, 13H), 2.82 (s, 4H), 4.07 (m, 6H), 4.11 (m, 6H), 4.68 (s, 4H) ppm. 13C NMR 600 MHz (CDCl3): 0.31, 0.42, 1.32, 1.41, 2.05, 13.60, 18.10, 19.93, 22.59, 29.03, 32.37, 52.57, 53.67, 64.94, 66.37, 67.49, 68.81, 74.61, 75.22, 153.05, 171.81, 172.38, 172.59, 172.66 ppm. 29Si NMR 600 MHz (CDCl3): 23.52, 22.26, 22.08, 21.96, 21.67, 21.42, 7.26 ppm. 2.7. Polysiloxane 17 Benzyl azide (0.031 g, 0.156 mmol) was added to a 50 mL round-bottomed flask containing polysiloxane 14 (0.3 g, 0.026 mmol) and toluene (5 mL). The reaction was heated at 70 °C with stirring. After 3 d, more benzyl azide (0.034 g, 0.25 mmol) was added and the reaction was allowed to stir for another 2 d. Excess benzyl azide was removed in vacuo using the Kugelrohr apparatus; the sample was then heated at 120 °C for 2 h under high vacuum. The product was a viscous yellow oil (0.5 g, yield 99%). After reaction, 1H NMR showed 40% conversion of the pendant propiolates giving primarily 17, and only 4% of the terminal propargyl esters (see Supporting Information). 3. Results and discussion 3.1. Effects of alkyne substituent on thermal cycloaddition temperature: model compounds A series of model alkynes was reacted with an alkylazido–silicone to better understand the thermal requirements of the Huisgen reaction with functionalized silicones. 1,3-Bis(azidopropyl)tetramethyldisiloxane 1 (Fig. 1) was chosen as a convenient model azide to characterize alkyne reactivity in the click reaction: its transformation to chromatographically separable compounds has been previously documented [6]. Commercially available organofunctional silicones are limited to a few functional groups, including monomers bearing vinyl or allyl groups, alkyl halides, alkylalcohols, alkylamines, and alkylcarboxylic acids, but not alkynes. Therefore, model alkynes were either organic, or small silicones prepared using standard protocols (Fig. 1, Table 1). The organic compounds 2, 3, 5 and 7 were either commercially available or readily prepared by standard esterification/amidation reactions. The trisiloxane model compounds 4, 6 and 8 were prepared either from hydro xypropylmethylbistrimethylsiloxysilane 9 or the commercially available aminopropylmethylbistrimethylsiloxysilane 10. Alkynes 2–8 (Table 1) were typically mixed with the model azide compound 1 in a stoichiometric ratio of functional groups ([C„C]:[N3]) = 1:1; the exceptions, benzyl propiolate and benzyl propiolamide, were mixed with the model azide compound on an equal mass basis. The efficiency of the thermal [3 + 2]-cycloaddition was examined using a differential
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A
B
C Fig. 1. Preparation of A: 1,3-bis(azidopropyl)tetramethyldisiloxane and, B: pendant functional and C: terminal functional siloxane alkynes.
scanning calorimeter: samples were heated from room temperature to 150 at 5 °C/min. The temperature of onset of cyclization for different alkynes is reported in Table 1. As can be seen from Table 1, large differences were observed in the temperature at which the Huisgen reaction started to occur. There was a clear, inverse correlation between the electronic density of the alkyne and the temperature at which the uncatalyzed cyclization began: electron-rich alkynes required much higher temperatures than electron-deficient alkynes. The efficiency of the reaction thus depends on the alkyne substituents, the reactivity of which followed the order: alkyl group < amide < ester < diester. The reactivity of the silyl-substituted alkyne 7 was low: in this case, any activation provided by the ketone is mitigated by the electronic donation, and possibly steric constraints, provided by the silyl substituent [19]. 3.1.1. Polysiloxanes: functionalization then polymerization The significant differences in thermal responsiveness between different alkynes presents an opportunity to develop generic silicone pre-elastomers that can be both crosslinked and functionalized in a variety of ways. For example, if polysiloxanes are designed to contain both reactive (e.g., propiolate esters) and less reactive (e.g., propiolamides) alkynes in different, explicit locations, it should be possible to crosslink the polysiloxane at a lower temperature (with propiolates) and perform post-cure covalent modification at a higher temperature (with propiolamides), or vice versa, to give a functional elastomer.
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Table 1 Onset cycloaddition temperatures for tested alkynes determined by DSC
. Compound number
Alkyne
Onset cycloaddition temperature (°C)
2
Diethyl acetylenedicarboxylate
37
3
Benzyl propiolate
51
4
Trisiloxane propiolate
64
5
Benzyl propiolamide
72
6
Trisiloxane propiolamide
74
7
Trimethylsilyl-3-butyn-4-one
90
8
Propargyl trisiloxane
101
Table 2 Number of alkyne units converted over time into triazoles by benzyl azide in polysiloxane 13 (based on OCH2, and NCH2 integration in 1H NMR, respectively).
a
Time (d)
Relative concentrationa
At 35 °C 0 2 6 % conversion
Pendant 2.50 2.03 1.78 32%
Terminal 2.00 1.88 1.60 19%
At 60 °C 0 2 4 6 % conversion
2.49 1.33 1.38 1.28 44%
2.00 1.29 1.23 1.18 39%
0 0.52 1.00
0.00 1.81 1.93 2.02
Normalized to 1 equiv terminal alkyne (propiolamide).
To test this hypothesis, linear silicone polymers bearing two different alkynes were prepared: the more reactive propiolate alkyne was located pendant along the polymer chain, while the less reactive alkyne was placed at the two termini of the chains. 3.1.2. Polyalkyne synthesis The direct functionalization of aminopropyl- or hydroxypropyl-silicone polymers by alkynes was problematic. Although attempts to modify commercial amino- and hydroxy-pendant polysiloxanes with propiolic acid using DCC coupling were efficient based on 1H NMR data, it was not possible to completely remove the co-product dicyclohexylurea from the polymer using silica gel chromatographic purification. Therefore, small functional siloxanes were first prepared and then incorporated into larger polymers using redistribution reactions [20].
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Activated alkynes were introduced as pendant groups to silicones by first forming trisiloxane 9 via hydrosilylation of 1 ,3-bis(trimethylsiloxy)methylsilane with allyl alcohol (Fig. 1B): the reaction was monitored by following the disappearance of the SiH signal at 4.7 ppm in the 1H NMR spectrum. The hydroxyl group was then converted into the propiolate-functionalized alkyne 4 by DCC coupling with propiolic acid, or 8 by reaction with the monopropargyl ester of butanedioic acid. The analogous amide 6 was prepared by the DCC amidation of commercial 3-aminopropylmethylbis(trime thylsiloxy)silane 10 with propiolic acid. Terminal alkynes, amides 11 and esters 12 [17], respectively, were prepared using analogous carbodiimide coupling chemistry with a, x-difunctional disiloxanes (Fig. 1C). High molecular weight silicones are frequently prepared by ring-opening polymerization under equilibrating conditions [20]. Bifunctional polymers were created from D4 and: (i) starting materials of 4 and 11 giving 13; or, (ii) 4 and 12 leading to 14, through acid-catalyzed equilibration (Fig. 2). During either reaction, two different end groups are present: the functional alkyne and AOSiMe3. In an attempt to ensure that the non-functional AOSiMe3 groups were removed from the mixture, the reaction was performed at slightly reduced pressure such that the most volatile byproduct that continuously forms during equilibration, Me3SiOSiMe3, could be removed, leaving only functional alkyne termini. According to 1H NMR polysiloxane 13, with an average Mn of about 2910 g mol 1 based on 1H NMR end group analysis and verified by GPC, possessed propiolate and propiolamide alkynes in a ratio of about 1.25:1. In spite of the reaction conditions used, however, a small quantity of SiMe3 end groups was found in the 29Si NMR. Polysiloxane 14 had a MW of about 5170 g mol 1 based on GPC and a pendant to terminal alkyne ratio of approximately 2:1. Based on 29Si NMR, only one type of end group – the propargyl ester – was detected on the polysiloxane, demonstrating that using reduced pressure to remove the byproduct Me3SiOSiMe3 was successful in this case. 3.1.3. Thermal control of network structure using click crosslinking selectivity measurements of multi-alkyne-functionalized polysiloxanes It was expected that the different alkynes would distinguish themselves in thermal reactions with azides. Based on the results in Table 1, the pendant propiolate should react at lower temperatures than either the terminal propiolamide or the propargyl ester. This proposal was initially tested using a small azide, PhCH2N3, with polysiloxane 13. Cycloadditions with an equimolar ratio of benzyl azide to the propiolate-based alkynes were carried out at two temperatures in an NMR tube and monitored by 1H NMR spectroscopy (see Supporting Information). At 35 °C over 6 days, 32% of the propiolate had reacted, and 19% of the propiolamide giving polymers such as 15 and 16 (Fig. 3A). At 60 °C, the reactivity of the two alkynes was comparable, with 44% and 39%, respectively (Table 2). Thus, the pendant propiolate was only marginally more reactive than the propiolamide: a somewhat higher level of discrimination was initially expected based on Table 1. It was recognized that greater steric accessibility of the terminal alkyne, compared to the internal propiolate, could be the origin of the outcome. To examine this proposal, a competition experiment was designed to directly pit two sterically comparable, but electronically different, alkynes against one another. An approximately equimolar mixture of trisiloxanes 4 and 6 was reacted with 1 equivalent of benzyl azide (Fig. 4) at 35 and 60 °C, respectively, and monitored by 1H NMR spectroscopy. At 35 °C, the two alkynes reacted at about the same rate, although the higher reactivity of the propiolate manifested at 60 °C (Supporting Information). Thus, the consequences of steric differences between pendant and terminal groups are minor, and the electronic differences are similarly small between the ester and amidoalkyne. Thus, a difference in onset temperature of
Fig. 2. Preparation of different pendant and terminal alkyne-functionalized polysiloxanes using acid-catalyzed equilibration polymerization.
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A
B
Fig. 3. Alkyne selectivity in Huisgen reactions with: A: Polysiloxane 13, B: Polysiloxane 14.
Fig. 4. Alkyne selectivity measurement of trisiloxane mixture.
10 °C shown in Table 1 between the amide vs ester functional alkynes is not sufficiently large to be of practical utility to give selective polymer functionalization. Higher selectivity between terminal and pendant groups could be achieved by using a significantly less reactive alkyne, such as a propargyl ester, as the low reactivity, terminal alkyne and pendant propiolates as the high reactivity alkyne. The reaction between polysiloxane 14 and benzyl azide was monitored in an NMR tube at 60 °C. Over a week, 40% of the propiolate reacted to give 17, while only 4% of the propargyl groups had reacted during this experiment. Note that the reaction is slower than those shown in Table 1 mostly because the concentrations of functional groups are much lower than in the cases of the model studies (Fig. 3B).
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The reactions described here demonstrate that the difference in reactivity of alkynes in the Huisgen cyclization can be exploited to modify silicone polymers. It is relatively straightforward to place different alkynes at either pendant, terminal, or both locations along a silicone chain. Judicious choice of alkynes and of reaction conditions permits selective modification at the pendant vs terminal sites with functional groups, or other silicones, simply by controlling the temperature and order of addition of reactants. This provides an opportunity to create several types of functional network structures from the same polymer backbone by using sequential click processes. The ability to manipulate polymer systems in a simple and generic way is clearly advantageous. We have shown that the differential reactivity between alkynes can be used to selectively, although not specifically, modify silicones containing more than one alkyne simply by controlling the temperature of the Huisgen reaction. No catalysts are needed and no byproducts are formed. While the process is described for silicones, it should be equally amenable to other polymer systems. In future work, we will demonstrate the ability to independently manipulate functionalization and crosslinking using this process. 4. Conclusion DSC studies demonstrate a large difference in reactivity in the Huisgen reaction between carbonyl-functionalized alkynes vs simple alkynes. These differences in reactivity can be used to selectively modify alkynes on multifunctional silicone polymers, with preference for reactivity, at low temperatures, of conjugated alkyne esters over propargyl groups. Standard silicone chemistry allowed the localization of the more reactive alkyne pendant along the chain, and the less reactive alkyne at the termini. The combination of these processes allows for selective functionalization with different azides at the terminal or pendant sites. Acknowledgement We gratefully acknowledge the financial support of the Natural Sciences and Engineering Council of Canada. Appendix A. Supplementary data Table showing relative reactivity for 4 and 6 for benzyl azide, 1H NMR data showing the Huisgen reaction of benzyl azide with polymers 13 and 14, respectively. Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.eurpolymj.2015.06.026. References [1] M. Meldal, Polymer, ‘‘Clicking’’ by CuAAC Reactions, Macromol Rapid Comm. 29 (12–13) (2008) 1016–1051. [2] J.E. Hein, V.V. 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