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Aminobisphosphonate Polymers via RAFT and a Multicomponent Kabachnik–Fields Reaction Patricia R. Bachler, Michael D. Schulz, Chelsea A. Sparks, Kenneth B. Wagener,* Brent S. Sumerlin*
Polyacrylamides containing pendant aminobisphosphonate groups are synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization and a multicomponent postpolymerization functionalization reaction. A Moedritzer–Irani reaction installs the phosphonic acid groups on well-defined, RAFT-generated polymers bearing a pendant amine. An alternate route to the same materials is developed utilizing a three-component Kabachnik–Fields reaction and subsequent dealkylation. Kinetics of the RAFT polymerization of the polymer precursor are studied. Successful functionalization is demonstrated by NMR and FTIR spectroscopy and elemental analysis of the final polymers.
1. Introduction Multicomponent reactions are effective tools in the synthesis of a variety of interesting and important molecules, as they often make it possible to introduce several functionalities in a single, one-pot reaction, facilitating access to multifunctional molecules. Recently, there has been renewed interest in the application of multicomponent reactions for the synthesis or derivatization of polymers.[1,2] This work has led to the creation of polymers with diverse architectures synthesized by the Passerini three-component reaction,[3–7] the Ugi four-component reaction,[8,9] and the Kabachnik–Fields three-component reaction.[10,11] Of particular interest to this work, the application of the Kabachnik–Fields reaction to polymer chemistry creates
P. R. Bachler, M. D. Schulz, C. A. Sparks, Prof. K. B. Wagener, Prof. B. S. Sumerlin George & Josephine Butler Polymer Research Laboratory Center for Macromolecular Science & Engineering Department of Chemistry University of Florida Gainesville, Florida 32611-7200, USA E-mail: [email protected]fl.edu; [email protected]fl.edu
the possibility of facilitating the synthesis of a wide range of phosphorous-containing polymers, as this reaction ligates a phosphate with an amine and an aldehyde. Phosphorous-containing materials have garnered increased attention in recent years due to their potential use in various applications, particularly as flame retardants,[12–16] but also in biomedical applications,[17–22] as fuel cell membranes,[23] as corrosion inhibiting agents,[24] and as metal chelators.[25–28] Such materials have been synthesized via a number of different approaches, depending on the intended application. In recent years, controlled radical polymerization has been used to synthesize a variety of phosphorus-containing macromolecules. In particular, reversible addition-fragmentation chain transfer (RAFT) polymerization[29,30] has been employed to synthesize phosphate-,[31] phosphonate-,[32–34] and phosphonic acidcontaining[32,35] polymers. Bisphosphonates and aminobisphosphonates (Scheme 1), also referred to as nitrogen-containing bisphosphonates, have emerged as an intriguing class of phosphorous compounds, and have found applications in metal chelation and in medicine.[36–47] One particular example of such compounds is ethylene diamine tetramethyl phosphonate (EDTMP), which is used as a metal
Macromol. Rapid Commun. 2015, DOI: 10.1002/marc.201500060
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Scheme 1. Typical structure of a bisphosphonate (A) and an aminobisphosphonate (B).
chelator in cancer therapy. Aminobisphosphonates are capable of acting as tridentate metal chelators, chelating through both phosphonate groups and the lone pair on the nitrogen atom. This multidenticity provides enhanced binding capability as compared to other phosphonate compounds. Despite considerable biological utility, there have been limited reports of polymers containing aminobisphosphonate ester moieties[48] or amino-bisphosphonic acidcontaining polymers.[22] Herein, we report the synthesis of N,N-amino-bisphosphonic acid-containing polyacrylamides via RAFT polymerization. By using a controlled polymerization method such as RAFT, we are able to control polymer architecture and molecular weight and ensure a narrow molecular weight distribution.
2. Results and Discussion
RAFT chain transfer agent (CTA), as trithiocarbonates are known to react readily with primary amines to form thiols, which could result in loss of control during the polymerization. After the polymerization was complete, the phosphonic acid groups were installed via a threecomponent reaction on the amine of each polymer side chain. Methylphosphonate groups were installed by a modified Kabachnik–Fields postpolymerization reaction.[49,50] Polymerizations were carried out with an acrylamide Boc-protected monomer (Scheme 2).[51] A variety of polymers with predetermined molecular weights were synthesized via RAFT polymerization by controlling the molar ratio of monomer to CTA and stopping the polymerizations at predetermined conversions (Table 1). For example, for a polymer with desired Mn of 16 000 g mol−1, a monomer to CTA ratio of 80:1 was chosen, and the polymerization was stopped at ≈90% conversion. Polymers exhibited good agreement between theoretical and experimental molecular weights and with narrow molecular weight distributions (Mw/Mn < 1.3), suggesting the polymerizations proceeded in a controlled manner. This controlled polymerization behavior can also be inferred from the gel permeation chromatography (GPC) traces of the final polymers, which are monomodal and narrow (Figure 1a). The controlled nature of the polymerization was further confirmed by monitoring the molecular weight at different conversions (Figure 1c). The molecular weight increased linearly with conversion, which is characteristic of a controlled, living polymerization mechanism such as RAFT. Moreover, from the GPC traces (Figure 1b), it is evident that the molecular weight increases over time, while the shape of the GPC trace changes minimally, indicating a narrow dispersity at all conversions. Initially, we focused on using the Moedritzer–Irani reaction to directly incorporate aminobisphosphonate groups. In this example of a multicomponent reaction, a primary amine can react with phosphorous acid, hydrochloric acid, and formaldehyde to yield an aminobisphosphonate (Scheme 3). Typically, formalin is used as a source of formaldehyde. However, since our polymer contained an amide group, we were concerned about possible hydrolysis under these harsh acidic conditions,
Two basic approaches to the synthesis of aminobisphosphonate-functional polymers can be envisioned: (i) direct polymerization of the aminobisphosphonate-containing monomer and (ii) polymerization of a functional precursor and postpolymerization modification to incorporate the aminobisphosphonate functionality. Of the two, the postpolymerization functionalization strategy was chosen to simplify the purification and characterization of the desired polymers. Direct polymerization of the aminobisphosphonate-containing monomers led to polymers that were hygroscopic and insoluble in organic solvents, making handling and characterization challenging. By introducing the phosphonic acid groups in the final step of the synthesis, these challenges were limited to the final material only, allowing convenient and thorough purification and characterization during each of the preceding synthetic steps. The general approach to creating N,N-amino-bisphosphonic acid-containing polyacrylamides began with the synthesis of N-Boc-2-aminoethyl acrylamide. Protection of the amine is Scheme 2. RAFT polymerization of Boc-protected amino-acrylamide. necessary to prevent aminolysis of the
2
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Aminobisphosphonate Polymers via RAFT and a Multicomponent Kabachnik–Fields Reaction
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Table 1. RAFT polymerization protocol and GPC results for P1–P4.
Entry
[Monomer] [equiv.]
[CTA] [equiv.]
[AIBN] [equiv]
Time [min]
Conversion [%]
Mn (theory) [g mol−1]
Mn (GPC) [g mol−1]
Mn/Mw
P1
78
1
0.1
90
93
16 000
21 000
1.18
P2
109
1
0.1
90
97
23 000
28 000
1.26
P3
140
1
0.1
90
97
29 000
36 000
1.29
P4
171
1
0.1
90
98
36 000
39 000
1.27
which would result in formation of acrylic acid and loss of functionality. To minimize hydrolysis, we chose paraformaldehyde as the source of formaldehyde. After 2 h, the functionalized polymers were obtained. The 1H NMR spectrum clearly showed the methylene unit introduced between the nitrogen and the phosphorous. However, due to partial peak overlap, it was difficult to calculate the degree of functionalization from the NMR integration. Complete removal of the Boc-protecting groups was confirmed by 1H NMR and FTIR spectroscopy, though this does not necessarily confirm complete functionalization and cannot exclude the possibility of deprotected amine, or acrylic acid (via hydrolysis) units along the chain. However, elemental analysis provided insight into the composition of the functionalized polymers (Table S1, Supporting Information).
To gain further insight into the degree of functionalization, we calculated the P/N ratio obtained by elemental analysis and divided it by the theoretical P/N ratio. This simplification allows us to distinguish between unfunctionalized and functionalized amine, ignoring the presence of acrylic acid. After 2 h of reaction under the Moedritzer–Irani conditions, we detected only 7.1% phosphorus by elemental analysis, which corresponds to a polymer that is approximately 28% functionalized. Moreover, we calculated the C/N ratio as evidence of possible hydrolysis of the amide, which would result in a significant increase in the C/N ratio. We found this ratio to be 3.27, which is higher than the theoretical value and therefore suggests that hydrolysis under these conditions could be a complicating factor. The presence of hydrolysis products was further evidenced by FTIR spectroscopy,
Figure 1. a) GPC traces of polymers P1–P4 (Table 1), b) GPC traces from a single RAFT polymerization of N-tert-butyloxycarbonyl-N′-acryl-1,2diaminoethane in 1,4-dioxane at 70 °C as a function of time ([Monomer]:[CTA]:[AIBN] = 225:1:0.1). c) Conversion of polymer from b) versus Mn. Line represents theoretical evolution of Mn.
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which corresponds well to the theoretical value and suggests that no significant hydrolysis takes place under these conditions.
3. Conclusion We successfully synthesized a series of amino-bisphosphonic acid-containing polymers via a multicomponent postScheme 3. Synthesis of aminobisphosphonate polymer by Moedritzer–Irani reaction. polymerization modification reaction. Due to potential cross-reactivity of the monomer, a postpolymerization method offered a facile which showed a broad peak from 2500 to 3500 cm−1. approach to these aminobisphosphonate-bearing polyIncreasing the reaction time resulted in more of these mers. RAFT polymerization of protected amine monoapparent hydrolysis products, though decreasing the mers resulted in good control over polymer molecular reaction time decreased the functionalization efficiency. weight and narrow molecular weight distributions. Both To obtain polymers with a higher degree of functionalithe Kabachnik–Fields and the Moedritzer–Irani reaction zation, we investigated a second approach that involved were employed to functionalize these amine polymers. a Kabachnik–Fields reaction followed by dealkylation While the one-step Moedritzer–Irani reaction resulted in (Scheme 4). The Kabachnik–Fields reaction is similar to partial hydrolysis of the polymer side-chain and limited the Moedritzer–Irani reaction except that it uses a phosfunctionalization efficiency, the Kabachnik–Fields reacphonate ester instead of phosphorous acid and can be tion with subsequent dealkylation proved to be a more conducted under milder conditions. We reasoned that efficient synthetic route, resulting in polymers that were eliminating the strongly acidic conditions could limit over 75% functionalized with bisphosphonic acids. These hydrolysis and allow for the reaction time to be increased. highly polar, water-soluble, tridentate materials may have After 24 h of reaction, the bisphosphonate ester funca variety of applications in fields that range from water tionalized polymer was isolated and purified by dialysis. purification to cancer therapy. To convert the phosphonate ester to the desired phosphonic acid, the polymer was reacted with TMSBr and then hydrolyzed with methanol to yield the final amino4. Experimental Section bisphosphonate functional polymer. Analysis by 1H NMR spectroscopy suggested quantitative dealkylation, as Materials and Measurements: All reagents were obtained observed by the disappearance of the peaks belonging from commercial sources and used as received, with the excepto the alkyl group attached to the phosphorous, and the tion of 1,4-dioxane, which was purified via basic alumina plug, spectrum of the final product corresponded well with and 2,2′-azobisisobutyronitrile (AIBN), which was recrystalthe polymer synthesized using the Moedritzer–Irani lized from methanol. Anhydrous solvents were obtained from reaction. Elemental analysis indicated these polymers to an anhydrous solvent system and used immediately. All 1H have 12.5% phosphorous and a P/N ratio of 1.67, which NMR (300 MHz) spectra were recorded on a Varian Mercury 300 corresponds to 75% functionalization efficiency, almost spectrometer with chemical shifts referenced to residual signals from CDCl3 (7.27 ppm). GPC was conducted in DMAC (with three times higher than that obtained by the previous 0.05 M LiCl) at 50 °C with a flow rate of 1.0 mL min−1 (Pump: method. Moreover, the C/N ratio was found to be 2.94,
Scheme 4. Kabachnik–Fields reaction on poly(N-tert-butyloxycarbonyl-N′-acryl-1,2-diaminoethane) with subsequent dealkylation to produce bisphosphonate polymer.
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Aminobisphosphonate Polymers via RAFT and a Multicomponent Kabachnik–Fields Reaction
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Agilent 1260 Infinity Isocratic Pump G1310B, Columns: Guard + two ViscoGel I-series G3078 mixed bed columns, molecular weight range 0–20 × 103 and 0–100 × 104 g mol−1). Detection consisted of a Wyatt Optilab T-rEX refractive index detector operating at 658 nm and a Wyatt miniDAWN TREOS laser light scattering detector (operating at 50 mW, 658 nm with detection angles of 49°, 90°, and 131°). Molecular weights were calculated using measured dn/dc values determined by assuming 100% mass recovery during GPC analysis (P1: 0.0561; P2: 0.0609; P3: 0.0501; P4: 0.0557 mL g−1). Synthesis of Tert-butyl-N-(2-aminoethyl)carbonate: A solution of 1,2-diaminoethane (162 g, 2.67 mol, 9 equiv.) was prepared in 1,4-dioxane (300 mL) and stirred. A second solution of ditert-butyldicarbonate (65.6 g, 0.298 mol, 1 equiv.) in 1,4-dioxane (400 mL) was added to the first solution over a 2 h period. The reaction was stirred for 22 h. 1,4-Dioxane was evaporated, and H2O (500 mL) was added to the crude reaction mixture to precipitate bis(N,N′-t-butyloxycarbonyl)-1,2-diaminoethane. Insoluble bis(N,N′-t-butyloxycarbonyl)-1,2-diaminoethane was removed by gravity filtration. The filtrate was saturated with NaCl and then extracted with CH2Cl2 (4×200 mL) and dried over MgSO4. After removing MgSO4 by filtration, the remaining solvent was removed by rotary evaporation. A colorless oil was obtained in 70% yield (32.96 g). 1H NMR: (CDCl3, 300 MHz, ppm): 5.22 (s, 1H, NHBoc), 3.06–3.07 (m, 2H, CH2NH), 2.67–2.70 (m, 2H, CH2NH2), 1.34 (s, 9H, 3CH3), 1.18 (s, 2H, NH2); 13C NMR: (CDCl3, 125 MHz, ppm): 156 (C=O), 78.5 (OCMe3), 43 (CH2NH), 41.6 (CH2NH2), 28 (CH3). Synthesis of N-tert-butyloxycarbonyl-N′-acryl-1,2-diaminoethane: A three-necked round bottom flask was placed under argon with an attached addition funnel. Tert-butyl-N-(2-aminoethyl)carbonate (33.0 g, 0.206 mol, 1 equiv.), triethylamine (100 mL), and anhydrous CH2Cl2 (350 mL) were added to the flask. The flask was cooled to −20 °C with an ice-salt bath. CH2Cl2 (200 mL) and acryloyl chloride (185 mL, 0.227 mol, 1.1 equiv.) were transferred to the addition funnel, added dropwise over a 2 h period, and the reaction mixture was left to stir for 16 h. The solution was extracted with four 250 mL portions of H2O, and the organic layer was dried with MgSO4. After removing MgSO4 by filtration, CH2Cl2 was removed by rotary evaporation. A solid white product was obtained in 86% (38.02 g) yield. The product was dissolved in ethyl acetate and passed though a silica plug for further purification. 1H NMR (CDCl3, 300 MHz, ppm): 6.62 (s, 1H, CONH), 5.1 (s, 1H, NHBoc), 6.19 (d, J = 17.00 Hz, 1H, CH2=), 5.56 (d, J = 10.24 Hz, 1H, CH2=), 6.05 (dd, J = 10.2, 17.04 Hz, CH=), 3.34–3.39 (m, 2H, CONHCH2), 3.23–3.26 (m, 2H, CH2NHBoc), 1.36 (s, 9H, C(CH3)3);13C NMR (CDCl3, 125 MHz): δ 166.4 (C=O), 157.1 (C=O, Boc), 130.9 (=CH), 126.3 (CH2=), 79.74 (t-C), 40.85 (CONHCH2), 40.08 (CH2NHBoc), 28.35 (3CH3). Synthesis of Poly(N-tert-butyloxycarbonyl-N′-acryl-1,2diaminoethane): N-Tert-butyloxycarbonyl-N′-acryl-1,2-diaminoethane was added to an 8 mL vial that was subsequently sealed with a septum and parafilm. Stock solutions of CTA and AIBN in 1,4-dioxane were prepared. Appropriate amounts of AIBN and CTA were added to the vials, depending on the intended molecular weight of the final polymer. 1,4-Dioxane was added to the vials to achieve an overall monomer concentration of 1.5 M. The vials were purged with argon for 20 min, then placed in a silicone oil bath at 70 °C until the polymerization reached ≈90% conversion. Samples were removed periodically by syringe to determine
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molecular weight and polydispersity index by SEC and monomer conversion by 1H NMR spectroscopy. After removal from the oil bath, additional 1,4-dioxane (1.0 mL) was added to the vials, and the polymer was isolated by precipitating into cold hexanes. A fluffy white solid was obtained after the solution was filtered. 1 H NMR (CDCl3, 500 MHz, ppm): 3.1–3.4 (4H, NCH2CH2N), 1.8–2.0 (3H, CH2CHCO), 1.4–1.6 (9H, C(CH3)3); 13C NMR (CDCl3, 125 MHz): δ 166.04 (C=O), 156.43 (C=O, Boc), 79.03 (t-C), 62.99 (CHCH2), 42.07 CH2CH, 40.64 (CONHCH2), 39.78 (CH2NHBoc), 28.13 (3CH3) FTIR: 3312 cm (CON–H), 1650 cm (NC=O), 1711 (Boc C=O). Functionalization of Poly(N-tert-butyloxycarbonyl-N′-acryl1,2-diaminoethane): Two synthetic methods were pursued for installing methyl phosphonate groups. For the first, H3PO3 (1.29 g, 9.32 mmol, 4 equiv.), poly(N-tert-butyloxycarbonyl-N′acryl-1,2-diaminoethane) (0.50 g, 2.3 mmol, 1 equiv.), and paraformaldehyde (0.35 g, 12 mmol, 5 equiv.) were added to a flask and placed in a silicone oil bath at 90 °C. Excess conc. HCl was added, a reflux condenser was attached, and the reaction was left to stir for 2 h. The polymer was precipitated into ethanol, filtered, and placed under vacuum to obtain an off-white hygroscopic solid. 1H NMR (D2O, 500 MHz, ppm): 3.0–3.3 (2H, NCH2P), 2.2–2.8 (4H, NCH2CH2N), 1.1–1.9 (3H, CH2CHCO). FTIR: 3310 cm (CON–H), 2500–3300 (COOH), 1650 cm (NC=O). For the second synthetic route, phosphonate esters were installed first and subsequently deprotected. Poly(N-tertbutyloxycarbonyl-N′-acryl-1,2-diaminoethane) (0.5 g, 2.33 mmol, 1 equiv.) was added to a 50 mL round-bottom flask containing anhydrous THF (10 mL). Concentrated HCl (five drops) was added, and the solution was stirred to facilitate deprotection of the Boc group. After 10 min, dimethyl phosphite (0.71 g, 5.1 mmol, 2.2 equiv.) and paraformaldehyde (0.15 g, 5.1 mmol, 2.2 equiv.) were added to the solution, and the flask was equipped with a condenser and chiller and placed in an oil bath at 60 °C. After stirring for 24 h, the remaining THF was evaporated, and the product was dissolved in MeOH and dialyzed against MeOH for two days to remove excess reagents. After two days, the solvent was evaporated and an off-white powder was obtained. For the dealkylation reaction, acetonitrile (10 mL) was added, and trimethylsilylbromide (TMSBr) (1.6 mL, 12 mmol, 10 equiv.) was added dropwise via syringe. The reaction was left to stir at room temperature for 24 h. The solvent was then removed by rotary evaporation, and a solid product was obtained. The product was dissolved in MeOH (200 mL) and allowed to stir for 24 h. Solvent was removed by rotary evaporation to give an off-white solid. 1H NMR (D O, 500 MHz, ppm): 3.0–3.3 (2H, NCH P), 2.2–2.8 (4H, 2 2 NCH2CH2N), 1.1–1.9 (3H, CH2CHCO). FTIR: 3310 cm (CON–H), 1650 cm (NC=O).
Supporting Information Supporting Information is available from the Wiley Online Library or from the author. Acknowledgements: This material is based upon work supported by the National Science Foundation under Grant Nos. DMR1203136 and DMR-0703261. The authors would also like to acknowledge “Hyundai Hope on Wheels” for funding of this project.
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Received: January 31, 2015; Revised: February 18, 2015; Published online: ; DOI: 10.1002/marc.201500060 Keywords: aminobisphosphonate; Kabachnik–Fields; Moedritzer– Irani; multicomponent reactions; postpolymerization reactions; reversible addition-fragmentation chain transfer
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Macromol. Rapid Commun. 2015, DOI: 10.1002/marc.201500060 © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communication
Aminobisphosphonate Polymers via RAFT and a Multicomponent Kabachnik–Fields Reaction Patricia R. Bachler, Michael D. Schulz, Chelsea A. Sparks, Kenneth B. Wagener,* Brent S. Sumerlin*
Polyacrylamides containing pendant aminobisphosphonate groups are synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization and a multicomponent postpolymerization functionalization reaction. A Moedritzer–Irani reaction installs the phosphonic acid groups on well-defined, RAFT-generated polymers bearing a pendant amine. An alternate route to the same materials is developed utilizing a three-component Kabachnik–Fields reaction and subsequent dealkylation. Kinetics of the RAFT polymerization of the polymer precursor are studied. Successful functionalization is demonstrated by NMR and FTIR spectroscopy and elemental analysis of the final polymers.
1. Introduction Multicomponent reactions are effective tools in the synthesis of a variety of interesting and important molecules, as they often make it possible to introduce several functionalities in a single, one-pot reaction, facilitating access to multifunctional molecules. Recently, there has been renewed interest in the application of multicomponent reactions for the synthesis or derivatization of polymers.[1,2] This work has led to the creation of polymers with diverse architectures synthesized by the Passerini three-component reaction,[3–7] the Ugi four-component reaction,[8,9] and the Kabachnik–Fields three-component reaction.[10,11] Of particular interest to this work, the application of the Kabachnik–Fields reaction to polymer chemistry creates
P. R. Bachler, M. D. Schulz, C. A. Sparks, Prof. K. B. Wagener, Prof. B. S. Sumerlin George & Josephine Butler Polymer Research Laboratory Center for Macromolecular Science & Engineering Department of Chemistry University of Florida Gainesville, Florida 32611-7200, USA E-mail: [email protected]fl.edu; [email protected]fl.edu
the possibility of facilitating the synthesis of a wide range of phosphorous-containing polymers, as this reaction ligates a phosphate with an amine and an aldehyde. Phosphorous-containing materials have garnered increased attention in recent years due to their potential use in various applications, particularly as flame retardants,[12–16] but also in biomedical applications,[17–22] as fuel cell membranes,[23] as corrosion inhibiting agents,[24] and as metal chelators.[25–28] Such materials have been synthesized via a number of different approaches, depending on the intended application. In recent years, controlled radical polymerization has been used to synthesize a variety of phosphorus-containing macromolecules. In particular, reversible addition-fragmentation chain transfer (RAFT) polymerization[29,30] has been employed to synthesize phosphate-,[31] phosphonate-,[32–34] and phosphonic acidcontaining[32,35] polymers. Bisphosphonates and aminobisphosphonates (Scheme 1), also referred to as nitrogen-containing bisphosphonates, have emerged as an intriguing class of phosphorous compounds, and have found applications in metal chelation and in medicine.[36–47] One particular example of such compounds is ethylene diamine tetramethyl phosphonate (EDTMP), which is used as a metal
Macromol. Rapid Commun. 2015, DOI: 10.1002/marc.201500060
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Scheme 1. Typical structure of a bisphosphonate (A) and an aminobisphosphonate (B).
chelator in cancer therapy. Aminobisphosphonates are capable of acting as tridentate metal chelators, chelating through both phosphonate groups and the lone pair on the nitrogen atom. This multidenticity provides enhanced binding capability as compared to other phosphonate compounds. Despite considerable biological utility, there have been limited reports of polymers containing aminobisphosphonate ester moieties[48] or amino-bisphosphonic acidcontaining polymers.[22] Herein, we report the synthesis of N,N-amino-bisphosphonic acid-containing polyacrylamides via RAFT polymerization. By using a controlled polymerization method such as RAFT, we are able to control polymer architecture and molecular weight and ensure a narrow molecular weight distribution.
2. Results and Discussion
RAFT chain transfer agent (CTA), as trithiocarbonates are known to react readily with primary amines to form thiols, which could result in loss of control during the polymerization. After the polymerization was complete, the phosphonic acid groups were installed via a threecomponent reaction on the amine of each polymer side chain. Methylphosphonate groups were installed by a modified Kabachnik–Fields postpolymerization reaction.[49,50] Polymerizations were carried out with an acrylamide Boc-protected monomer (Scheme 2).[51] A variety of polymers with predetermined molecular weights were synthesized via RAFT polymerization by controlling the molar ratio of monomer to CTA and stopping the polymerizations at predetermined conversions (Table 1). For example, for a polymer with desired Mn of 16 000 g mol−1, a monomer to CTA ratio of 80:1 was chosen, and the polymerization was stopped at ≈90% conversion. Polymers exhibited good agreement between theoretical and experimental molecular weights and with narrow molecular weight distributions (Mw/Mn < 1.3), suggesting the polymerizations proceeded in a controlled manner. This controlled polymerization behavior can also be inferred from the gel permeation chromatography (GPC) traces of the final polymers, which are monomodal and narrow (Figure 1a). The controlled nature of the polymerization was further confirmed by monitoring the molecular weight at different conversions (Figure 1c). The molecular weight increased linearly with conversion, which is characteristic of a controlled, living polymerization mechanism such as RAFT. Moreover, from the GPC traces (Figure 1b), it is evident that the molecular weight increases over time, while the shape of the GPC trace changes minimally, indicating a narrow dispersity at all conversions. Initially, we focused on using the Moedritzer–Irani reaction to directly incorporate aminobisphosphonate groups. In this example of a multicomponent reaction, a primary amine can react with phosphorous acid, hydrochloric acid, and formaldehyde to yield an aminobisphosphonate (Scheme 3). Typically, formalin is used as a source of formaldehyde. However, since our polymer contained an amide group, we were concerned about possible hydrolysis under these harsh acidic conditions,
Two basic approaches to the synthesis of aminobisphosphonate-functional polymers can be envisioned: (i) direct polymerization of the aminobisphosphonate-containing monomer and (ii) polymerization of a functional precursor and postpolymerization modification to incorporate the aminobisphosphonate functionality. Of the two, the postpolymerization functionalization strategy was chosen to simplify the purification and characterization of the desired polymers. Direct polymerization of the aminobisphosphonate-containing monomers led to polymers that were hygroscopic and insoluble in organic solvents, making handling and characterization challenging. By introducing the phosphonic acid groups in the final step of the synthesis, these challenges were limited to the final material only, allowing convenient and thorough purification and characterization during each of the preceding synthetic steps. The general approach to creating N,N-amino-bisphosphonic acid-containing polyacrylamides began with the synthesis of N-Boc-2-aminoethyl acrylamide. Protection of the amine is Scheme 2. RAFT polymerization of Boc-protected amino-acrylamide. necessary to prevent aminolysis of the
2
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Aminobisphosphonate Polymers via RAFT and a Multicomponent Kabachnik–Fields Reaction
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Table 1. RAFT polymerization protocol and GPC results for P1–P4.
Entry
[Monomer] [equiv.]
[CTA] [equiv.]
[AIBN] [equiv]
Time [min]
Conversion [%]
Mn (theory) [g mol−1]
Mn (GPC) [g mol−1]
Mn/Mw
P1
78
1
0.1
90
93
16 000
21 000
1.18
P2
109
1
0.1
90
97
23 000
28 000
1.26
P3
140
1
0.1
90
97
29 000
36 000
1.29
P4
171
1
0.1
90
98
36 000
39 000
1.27
which would result in formation of acrylic acid and loss of functionality. To minimize hydrolysis, we chose paraformaldehyde as the source of formaldehyde. After 2 h, the functionalized polymers were obtained. The 1H NMR spectrum clearly showed the methylene unit introduced between the nitrogen and the phosphorous. However, due to partial peak overlap, it was difficult to calculate the degree of functionalization from the NMR integration. Complete removal of the Boc-protecting groups was confirmed by 1H NMR and FTIR spectroscopy, though this does not necessarily confirm complete functionalization and cannot exclude the possibility of deprotected amine, or acrylic acid (via hydrolysis) units along the chain. However, elemental analysis provided insight into the composition of the functionalized polymers (Table S1, Supporting Information).
To gain further insight into the degree of functionalization, we calculated the P/N ratio obtained by elemental analysis and divided it by the theoretical P/N ratio. This simplification allows us to distinguish between unfunctionalized and functionalized amine, ignoring the presence of acrylic acid. After 2 h of reaction under the Moedritzer–Irani conditions, we detected only 7.1% phosphorus by elemental analysis, which corresponds to a polymer that is approximately 28% functionalized. Moreover, we calculated the C/N ratio as evidence of possible hydrolysis of the amide, which would result in a significant increase in the C/N ratio. We found this ratio to be 3.27, which is higher than the theoretical value and therefore suggests that hydrolysis under these conditions could be a complicating factor. The presence of hydrolysis products was further evidenced by FTIR spectroscopy,
Figure 1. a) GPC traces of polymers P1–P4 (Table 1), b) GPC traces from a single RAFT polymerization of N-tert-butyloxycarbonyl-N′-acryl-1,2diaminoethane in 1,4-dioxane at 70 °C as a function of time ([Monomer]:[CTA]:[AIBN] = 225:1:0.1). c) Conversion of polymer from b) versus Mn. Line represents theoretical evolution of Mn.
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which corresponds well to the theoretical value and suggests that no significant hydrolysis takes place under these conditions.
3. Conclusion We successfully synthesized a series of amino-bisphosphonic acid-containing polymers via a multicomponent postScheme 3. Synthesis of aminobisphosphonate polymer by Moedritzer–Irani reaction. polymerization modification reaction. Due to potential cross-reactivity of the monomer, a postpolymerization method offered a facile which showed a broad peak from 2500 to 3500 cm−1. approach to these aminobisphosphonate-bearing polyIncreasing the reaction time resulted in more of these mers. RAFT polymerization of protected amine monoapparent hydrolysis products, though decreasing the mers resulted in good control over polymer molecular reaction time decreased the functionalization efficiency. weight and narrow molecular weight distributions. Both To obtain polymers with a higher degree of functionalithe Kabachnik–Fields and the Moedritzer–Irani reaction zation, we investigated a second approach that involved were employed to functionalize these amine polymers. a Kabachnik–Fields reaction followed by dealkylation While the one-step Moedritzer–Irani reaction resulted in (Scheme 4). The Kabachnik–Fields reaction is similar to partial hydrolysis of the polymer side-chain and limited the Moedritzer–Irani reaction except that it uses a phosfunctionalization efficiency, the Kabachnik–Fields reacphonate ester instead of phosphorous acid and can be tion with subsequent dealkylation proved to be a more conducted under milder conditions. We reasoned that efficient synthetic route, resulting in polymers that were eliminating the strongly acidic conditions could limit over 75% functionalized with bisphosphonic acids. These hydrolysis and allow for the reaction time to be increased. highly polar, water-soluble, tridentate materials may have After 24 h of reaction, the bisphosphonate ester funca variety of applications in fields that range from water tionalized polymer was isolated and purified by dialysis. purification to cancer therapy. To convert the phosphonate ester to the desired phosphonic acid, the polymer was reacted with TMSBr and then hydrolyzed with methanol to yield the final amino4. Experimental Section bisphosphonate functional polymer. Analysis by 1H NMR spectroscopy suggested quantitative dealkylation, as Materials and Measurements: All reagents were obtained observed by the disappearance of the peaks belonging from commercial sources and used as received, with the excepto the alkyl group attached to the phosphorous, and the tion of 1,4-dioxane, which was purified via basic alumina plug, spectrum of the final product corresponded well with and 2,2′-azobisisobutyronitrile (AIBN), which was recrystalthe polymer synthesized using the Moedritzer–Irani lized from methanol. Anhydrous solvents were obtained from reaction. Elemental analysis indicated these polymers to an anhydrous solvent system and used immediately. All 1H have 12.5% phosphorous and a P/N ratio of 1.67, which NMR (300 MHz) spectra were recorded on a Varian Mercury 300 corresponds to 75% functionalization efficiency, almost spectrometer with chemical shifts referenced to residual signals from CDCl3 (7.27 ppm). GPC was conducted in DMAC (with three times higher than that obtained by the previous 0.05 M LiCl) at 50 °C with a flow rate of 1.0 mL min−1 (Pump: method. Moreover, the C/N ratio was found to be 2.94,
Scheme 4. Kabachnik–Fields reaction on poly(N-tert-butyloxycarbonyl-N′-acryl-1,2-diaminoethane) with subsequent dealkylation to produce bisphosphonate polymer.
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Aminobisphosphonate Polymers via RAFT and a Multicomponent Kabachnik–Fields Reaction
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Agilent 1260 Infinity Isocratic Pump G1310B, Columns: Guard + two ViscoGel I-series G3078 mixed bed columns, molecular weight range 0–20 × 103 and 0–100 × 104 g mol−1). Detection consisted of a Wyatt Optilab T-rEX refractive index detector operating at 658 nm and a Wyatt miniDAWN TREOS laser light scattering detector (operating at 50 mW, 658 nm with detection angles of 49°, 90°, and 131°). Molecular weights were calculated using measured dn/dc values determined by assuming 100% mass recovery during GPC analysis (P1: 0.0561; P2: 0.0609; P3: 0.0501; P4: 0.0557 mL g−1). Synthesis of Tert-butyl-N-(2-aminoethyl)carbonate: A solution of 1,2-diaminoethane (162 g, 2.67 mol, 9 equiv.) was prepared in 1,4-dioxane (300 mL) and stirred. A second solution of ditert-butyldicarbonate (65.6 g, 0.298 mol, 1 equiv.) in 1,4-dioxane (400 mL) was added to the first solution over a 2 h period. The reaction was stirred for 22 h. 1,4-Dioxane was evaporated, and H2O (500 mL) was added to the crude reaction mixture to precipitate bis(N,N′-t-butyloxycarbonyl)-1,2-diaminoethane. Insoluble bis(N,N′-t-butyloxycarbonyl)-1,2-diaminoethane was removed by gravity filtration. The filtrate was saturated with NaCl and then extracted with CH2Cl2 (4×200 mL) and dried over MgSO4. After removing MgSO4 by filtration, the remaining solvent was removed by rotary evaporation. A colorless oil was obtained in 70% yield (32.96 g). 1H NMR: (CDCl3, 300 MHz, ppm): 5.22 (s, 1H, NHBoc), 3.06–3.07 (m, 2H, CH2NH), 2.67–2.70 (m, 2H, CH2NH2), 1.34 (s, 9H, 3CH3), 1.18 (s, 2H, NH2); 13C NMR: (CDCl3, 125 MHz, ppm): 156 (C=O), 78.5 (OCMe3), 43 (CH2NH), 41.6 (CH2NH2), 28 (CH3). Synthesis of N-tert-butyloxycarbonyl-N′-acryl-1,2-diaminoethane: A three-necked round bottom flask was placed under argon with an attached addition funnel. Tert-butyl-N-(2-aminoethyl)carbonate (33.0 g, 0.206 mol, 1 equiv.), triethylamine (100 mL), and anhydrous CH2Cl2 (350 mL) were added to the flask. The flask was cooled to −20 °C with an ice-salt bath. CH2Cl2 (200 mL) and acryloyl chloride (185 mL, 0.227 mol, 1.1 equiv.) were transferred to the addition funnel, added dropwise over a 2 h period, and the reaction mixture was left to stir for 16 h. The solution was extracted with four 250 mL portions of H2O, and the organic layer was dried with MgSO4. After removing MgSO4 by filtration, CH2Cl2 was removed by rotary evaporation. A solid white product was obtained in 86% (38.02 g) yield. The product was dissolved in ethyl acetate and passed though a silica plug for further purification. 1H NMR (CDCl3, 300 MHz, ppm): 6.62 (s, 1H, CONH), 5.1 (s, 1H, NHBoc), 6.19 (d, J = 17.00 Hz, 1H, CH2=), 5.56 (d, J = 10.24 Hz, 1H, CH2=), 6.05 (dd, J = 10.2, 17.04 Hz, CH=), 3.34–3.39 (m, 2H, CONHCH2), 3.23–3.26 (m, 2H, CH2NHBoc), 1.36 (s, 9H, C(CH3)3);13C NMR (CDCl3, 125 MHz): δ 166.4 (C=O), 157.1 (C=O, Boc), 130.9 (=CH), 126.3 (CH2=), 79.74 (t-C), 40.85 (CONHCH2), 40.08 (CH2NHBoc), 28.35 (3CH3). Synthesis of Poly(N-tert-butyloxycarbonyl-N′-acryl-1,2diaminoethane): N-Tert-butyloxycarbonyl-N′-acryl-1,2-diaminoethane was added to an 8 mL vial that was subsequently sealed with a septum and parafilm. Stock solutions of CTA and AIBN in 1,4-dioxane were prepared. Appropriate amounts of AIBN and CTA were added to the vials, depending on the intended molecular weight of the final polymer. 1,4-Dioxane was added to the vials to achieve an overall monomer concentration of 1.5 M. The vials were purged with argon for 20 min, then placed in a silicone oil bath at 70 °C until the polymerization reached ≈90% conversion. Samples were removed periodically by syringe to determine
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molecular weight and polydispersity index by SEC and monomer conversion by 1H NMR spectroscopy. After removal from the oil bath, additional 1,4-dioxane (1.0 mL) was added to the vials, and the polymer was isolated by precipitating into cold hexanes. A fluffy white solid was obtained after the solution was filtered. 1 H NMR (CDCl3, 500 MHz, ppm): 3.1–3.4 (4H, NCH2CH2N), 1.8–2.0 (3H, CH2CHCO), 1.4–1.6 (9H, C(CH3)3); 13C NMR (CDCl3, 125 MHz): δ 166.04 (C=O), 156.43 (C=O, Boc), 79.03 (t-C), 62.99 (CHCH2), 42.07 CH2CH, 40.64 (CONHCH2), 39.78 (CH2NHBoc), 28.13 (3CH3) FTIR: 3312 cm (CON–H), 1650 cm (NC=O), 1711 (Boc C=O). Functionalization of Poly(N-tert-butyloxycarbonyl-N′-acryl1,2-diaminoethane): Two synthetic methods were pursued for installing methyl phosphonate groups. For the first, H3PO3 (1.29 g, 9.32 mmol, 4 equiv.), poly(N-tert-butyloxycarbonyl-N′acryl-1,2-diaminoethane) (0.50 g, 2.3 mmol, 1 equiv.), and paraformaldehyde (0.35 g, 12 mmol, 5 equiv.) were added to a flask and placed in a silicone oil bath at 90 °C. Excess conc. HCl was added, a reflux condenser was attached, and the reaction was left to stir for 2 h. The polymer was precipitated into ethanol, filtered, and placed under vacuum to obtain an off-white hygroscopic solid. 1H NMR (D2O, 500 MHz, ppm): 3.0–3.3 (2H, NCH2P), 2.2–2.8 (4H, NCH2CH2N), 1.1–1.9 (3H, CH2CHCO). FTIR: 3310 cm (CON–H), 2500–3300 (COOH), 1650 cm (NC=O). For the second synthetic route, phosphonate esters were installed first and subsequently deprotected. Poly(N-tertbutyloxycarbonyl-N′-acryl-1,2-diaminoethane) (0.5 g, 2.33 mmol, 1 equiv.) was added to a 50 mL round-bottom flask containing anhydrous THF (10 mL). Concentrated HCl (five drops) was added, and the solution was stirred to facilitate deprotection of the Boc group. After 10 min, dimethyl phosphite (0.71 g, 5.1 mmol, 2.2 equiv.) and paraformaldehyde (0.15 g, 5.1 mmol, 2.2 equiv.) were added to the solution, and the flask was equipped with a condenser and chiller and placed in an oil bath at 60 °C. After stirring for 24 h, the remaining THF was evaporated, and the product was dissolved in MeOH and dialyzed against MeOH for two days to remove excess reagents. After two days, the solvent was evaporated and an off-white powder was obtained. For the dealkylation reaction, acetonitrile (10 mL) was added, and trimethylsilylbromide (TMSBr) (1.6 mL, 12 mmol, 10 equiv.) was added dropwise via syringe. The reaction was left to stir at room temperature for 24 h. The solvent was then removed by rotary evaporation, and a solid product was obtained. The product was dissolved in MeOH (200 mL) and allowed to stir for 24 h. Solvent was removed by rotary evaporation to give an off-white solid. 1H NMR (D O, 500 MHz, ppm): 3.0–3.3 (2H, NCH P), 2.2–2.8 (4H, 2 2 NCH2CH2N), 1.1–1.9 (3H, CH2CHCO). FTIR: 3310 cm (CON–H), 1650 cm (NC=O).
Supporting Information Supporting Information is available from the Wiley Online Library or from the author. Acknowledgements: This material is based upon work supported by the National Science Foundation under Grant Nos. DMR1203136 and DMR-0703261. The authors would also like to acknowledge “Hyundai Hope on Wheels” for funding of this project.
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Received: January 31, 2015; Revised: February 18, 2015; Published online: ; DOI: 10.1002/marc.201500060 Keywords: aminobisphosphonate; Kabachnik–Fields; Moedritzer– Irani; multicomponent reactions; postpolymerization reactions; reversible addition-fragmentation chain transfer
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