Monomers for adhesive polymers, 18. Synthesis, photopolymerization and adhesive properties of polymerizable α-phosphonooxy phosphonic acids.

Four polymerizable α-phosphonooxy phosphonic acids 7a, 7b, 9 and 16 were synthesized in seven steps. They were characterized by 1H, 13C and 31P NMR spectroscopy and by high-resolution mass spectroscopy. The copolymerization of acidic monomers 7a, 7b, 9 and 16 with 2-hydroxyethyl methacrylate was studied using a differential scanning calorimeter. Due to the presence of two acidic groups, those monomers are significantly more reactive than 10-methacryloyloxydecylphosphonic acid (MDPA) and 10-methacryloyloxydecyl dihydrogen phosphate (MDP). Self-etch adhesives based on monomers 7a, 7b, 9 and 16 were formulated and used to mediate a bond between a dental composite and the dental hard tissues (dentin and enamel). These adhesives exhibit excellent performances and provide significantly higher dentin and enamel shear bond strength than adhesives based on MDP or MDPA.

Introduction

Self-etch adhesives (SEAs) are nowadays often used to achieve a bond between the dental hard tissues (dentin and enamel) and a restorative material (composite).[1-3] A SEA is an aqueous formulation containing different monomers (acidic, monofunctional and crosslinking monomers), cosolvents (ethanol, acetone, etc.) and additives (photoinitiator(s), co-initiator(s), stabilizers, fillers, etc.). Contrary to total-etch adhesives, SEAs are able to simultaneously demineralize and infiltrate the dental tissues. The acidic monomer is responsible for the etching of the tooth surface. Monomers such as polymerizable dihydrogen phosphates, carboxylic or phosphonic acids can be found in SEA formulations.[4] In SEAs, the acidic monomer should exhibit good etching properties, sufficient storage stability and a low oral toxicity.[5] It also has to show a high rate of homo- or copolymerization with the comonomers of the formulation. Van Meerbeek et al. [6-9] demonstrated that the ability of the acidic monomer to strongly interact with the calcium of hydroxyapatite (HAP) has a significant impact on the adhesive performance. Therefore, acidic monomers exhibiting strong chelating properties were synthesized and tested in SEAs. It has been demonstrated that the adhesion of SEAs can be improved when polymerizable diphosphonic acids,[10-12] β-ketophosphonic acids [13] or phosphonic acids bearing urea groups [14] are used as acidic monomer. Gem-phosphonate-phosphates were found to be potential antiatherosclerotic agents.[15] Due to the presence of both a phosphonic acid and a dihydrogen phosphate group on the same carbon, such compounds should present excellent chelating properties. To the best of our knowledge, polymerizable gem-phosphonate-phosphates have not yet been reported in the literature. In this context, we took an interest in the synthesis of polymerizable α-phosphonooxy phosphonic acids 7a, 7b, 9 and 16 (Figure 1). In this article, the synthesis, photopolymerization behavior and adhesive properties of monomers 7a, 7b, 9 and 16 are described.

Figure 1.

Structure of acidic monomers 7a, 7b, 9 and 16.

Experimental

Abbreviations

Butylated hydroxytoluene (BHT), camphorquinone (CQ), dichloromethane (DCM), double-bond conversion (DBC), N,N′-diethyl-13-bis-(acrylamido)propane (DEBAAP), diethyl ether (Et2O), 4-dimethylaminopyridine (DMAP), dimethylformamide (DMF), ethanol (EtOH), ethyl acetate (EA), ethyl 4-(dimethylamino)benzoate (EMBO), geminal (gem), Hydroxyapatite (HAP), 2-hydroxyethyl methacrylate (HEMA), Bis(2,4,6-trimethylbenzoyl)-phenylphosphineoxide (Irgacure 819), bis-(4-methoxybenzoyl)diethylgermanium (Ivocerin®), 10-methacryloyloxydecyl dihydrogen phosphate (MDP), 10-methacryloyloxydecylphosphonic acid (MDPA), methanol (MeOH), rate of polymerization (R p), room temperature (RT), shear bond strength (SBS), self-etch adhesive (SEA), tetrabutylammonium fluoride (TBAF), tetrahydrofuran (THF), tetramethylsilane (TMS), trimethylsilyl bromide (TMSBr).

Materials

DCM, THF and MeOH were dried over molecular sieves. TMSBr was distilled prior to use. 2-Isocyanatoethyl methacrylate was purchased from ABCR. tert-Butylchlorodiphenylsilane was purchased from TCI. All other reagents were purchased from Sigma–Aldrich and were used without further purification. BHT (Sigma–Aldrich), Bis-GMA (Esschem), CQ (Rahn), DEBAAP (Ivoclar-Vivadent AG), EMBO (Sigma–Aldrich), HEMA (Evonik), Ivocerin® (Ivoclar-Vivadent AG), Irgacure 819 (BASF) and MDP (Orgentis Chemical GmbH) were used in the adhesive formulations and for the photopolymerization studies. MDPA was synthesized according to a procedure reported in the literature.[16] Column chromatography were performed on Macherey-Nagel silica gel 60 (40–63 μm). Thin layer chromatography was performed on silica gel 60 F-254 plates.

Methods

1H-NMR, 13C-NMR and 31P-NMR spectra were recorded on a DPX-400 spectrometer using TMS as internal reference for 1H-NMR and 13C-NMR chemical shifts and using H3PO4 (85%) as external reference for 31P-NMR chemical shifts. Data are given in the following order: chemical shift in ppm, multiplicity (s, singlet; d, doublet; t, triplet; q, quadruplet; qt, quintuplet; m, multiplet), coupling constant in Hertz, assignment. High-resolution mass spectra (HRMS) were obtained using a Xevo G2-Xs QTof mass spectrometer (Waters).

Syntheses

Synthesis of the acidic monomer 7a

6-(tert-Butyl-diphenylsilyloxy)hexanoic acid 1a

tert-Butylchlorodiphenylsilane (58.03 g, 0.21 mol) was added, under argon atmosphere, to a solution of 6-hydroxycaproic acid (25.0 g, 0.19 mol) and imidazole (28.98 g, 0.43 mol) in DMF (180 mL). The solution was stirred for 15 h at 50 °C. The solution was poured into 400 mL of brine and the mixture was extracted with EA (3 × 500 mL). The organic layers were gathered and washed with deionized water (2 × 500 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluent = DCM/MeOH: 98/2). 46.1 g (0.12 mol) of the desired carboxylic acid 1a were isolated.

Yield: 66%. Aspect: colorless oil. 1H-NMR (400 MHz, CDCl3): δ = 1.04 (s, 9H, CH3 tBu); 1.36–1.47 (m, 2H, CH2); 1.52–1.67 (m, 4H, CH2); 2.33 (t, 3 J HH = 7.6 Hz, 2H, CH2COOH); 3.65 (t, 3 J HH = 6.4 Hz, 2H, CH2OSi); 7.34–7.45 (m, 6H, CHAr); 7.63–7.69 (m, 4H, CHAr).

6-(tert-Butyl-diphenylsilyloxy)hexanoyl chloride 2a

Oxalyl chloride (2.78 mL, 32.4 mmol) was added dropwise to a solution of carboxylic acid 1a (10.0 g, 27.0 mmol) in anhydrous toluene (100 mL). The solution was stirred for 4 h at room temperature. The solution was concentrated under reduced pressure. 10.5 g (27.0 mmol) of 2a were obtained.

Yield: 100%. Aspect: colorless oil. 1H NMR (400 MHz, CDCl3): δ = 1.05 (s, 9H, CH3 tBu); 1.37–1.48 (m, 2H, CH2); 1.51–1.61 (m, 2H, CH2); 1.69 (qt, 3 J HH = 7.6 Hz, 2H, CH2); 2.86 (t, 3 J HH = 7.4 Hz, 2H, CH2COCl); 3.66 (t, 3 J HH = 6.2 Hz, 2H, CH2OSi); 7.35–7.46 (m, 6H, CHAr); 7.62–7.69 (m, 4H, CHAr).

Diethyl 6-(tert-butyl-diphenylsilyloxy)-1-oxo-hexylphosphonate 3a

Triethyl phosphite (4.61 mL, 26.9 mmol) was added dropwise, under argon atmosphere, at 0 °C, to a solution of acyl chloride 2a (10.5 g, 26.9 mmol) in anhydrous DCM (20 mL). The solution was stirred for 1 h at room temperature. The solution was concentrated under reduced pressure. 13.1 g (26.8 mmol) of α-ketophosphonate 3a were obtained.

Yield: 100%. Aspect: slightly yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.04 (s, 9H, CH3 tBu); 1.32–1.44 (m, 2H, CH2); 1.37 (t, 3 J HH = 7.1 Hz, 6H, POCH2 CH 3); 1.50–1.67 (m, 4H, CH2); 2.83 (t, 3 J HH = 7.3 Hz, 2H, CH2COP); 3.65 (t, 3 J HH = 6.3 Hz, 2H, CH2OSi); 4.17–4.27 (m, 4H, POCH 2CH3); 7.33–7.46 (m, 6H, CHAr); 7.62–7.69 (m, 4H, CHAr). 31P NMR (162 MHz, CDCl3): δ = −2.7. 13C NMR (101 MHz, CDCl3): δ = 16.4 (d, 3 J C = 5.6 Hz, POCH2 CH3); 19.2 (SiC(CH3)3), 22.2 (d, 3 J C = 3.9 Hz, CH2CH2COP); 25.2 (CH2); 26.9 (SiC(CH3)3); 32.2 (CH2); 43.4 (d, 2 J C = 54.0 Hz, CH2COP); 63.6 (CH2OSi); 63.7 (d, 2 J C = 7.3 Hz, POCH2CH3); 127.6 (CAr); 129.6 (CAr); 134.0 (CAr); 135.6 (CAr); 211.2 (d, 1 J C = 165.2 Hz, COP).

Diethyl 6-(tert-butyl-diphenylsilyloxy)-1-diethylphosphonooxy-hexylphosphonate 4a

A solution of α-ketophosphonate 3a (13.1 g, 26.6 mmol) in Et2O (40 mL) was slowly added at 0 °C to a solution of diethyl phosphite (3.43 mL, 26.6 mmol) and diethylamine (2.75 mL, 26.6 mmol) in Et2O (60 mL). The reaction mixture was stirred for 30 min at 0 °C and for 24 h at room temperature. The solution was concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluent = EA). 12.0 g (19.1 mmol) of the compound 4a were isolated.

Yield: 72%. Aspect: slightly yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.04 (s, 9H, CH3 tBu); 1.26–1.66 (m, 18H, CH2 and POCH2 CH 3); 1.76–1.99 (m, 2H, CH2); 3.65 (t, 3 J HH = 6.4 Hz, 2H, CH2OSi); 4.05–4.25 (m, 8H, POCH 2CH3); 4.56–4.68 (m, 1H, CHP); 7.34–7.45 (m, 6H, CHAr); 7.63–7.69 (m, 4H, CHAr). 31P NMR (162 MHz, CDCl3): δ = −1.0 (d, 3 J P = 21.6 Hz, CHOP); 20.2 (d, 3 J P = 21.6 Hz, CHP). 13C NMR (101 MHz, CDCl3): δ = 16.0 (d, 3 J C = 3.4 Hz, POCH2 CH3); 16.1 (d, 3 J C = 3.2 Hz, POCH2 CH3); 16.4 (d, 3 J C = 5.6 Hz, POCH2 CH3); 16.5 (d, 3 J C = 5.6 Hz, POCH2 CH3); 19.2 (SiC(CH3)3), 25.3 (d, 3 J C = 10.5 Hz, CH2CH2CHP); 25.6 (CH2); 26.9 (SiC(CH3)3); 31.0 (CH2); 32.4 (CH2); 62.8 (d, 2 J C = 6.6 Hz, POCH2CH3); 63.8 (CH2OSi); 64.0 (d, 2 J C = 5.9 Hz, POCH2CH3); 73.2 (dd, 1 J C = 169.5 Hz, 2 J C = 7.2 Hz, CHP); 127.6 (CAr); 129.5 (CAr); 134.1 (CAr); 135.6 (CAr).

Diethyl 6-hydroxy-1-diethylphosphonooxy-hexylphosphonate 5a

A solution of TBAF (7.23 g, 23.0 mmol) in THF (25 mL) was added dropwise to a solution of compound 4a (12.0 g, 19.1 mmol) in THF (50 mL). The reaction mixture was stirred for 3 h at room temperature. A saturated solution of ammonium chloride (4 mL) was added. The solution was concentrated under reduced pressure. Deionized water (60 mL) was added and the solution was extracted with EA (3 × 60 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluent = EA/MeOH: 8/2). 6.4 g (16.4 mmol) of the desired alcohol 5a were isolated.

Yield: 86%. Aspect: slightly yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.26–1.66 (m, 18H, CH2 and POCH2 CH 3); 1.83–1.95 (m, 2H); 2.28 (ls, 1H, OH); 3.55–3.66 (m, 2H, CH2OH); 4.06–4.22 (m, 8H, POCH 2CH3); 4.57–4.68 (m, 1H, CHP). 31P NMR (162 MHz, CDCl3): δ = −1.0 (d, 3 J P = 22.1 Hz, CHOP); 20.1 (d, 3 J P = 22.1 Hz, CHP). 13C NMR (101 MHz, CDCl3): δ = 16.0 (d, 3 J C = 3.3 Hz, POCH2 CH3); 16.1 (d, 3 J C = 3.2 Hz, POCH2 CH3); 16.4 (d, 3 J C = 5.6 Hz, POCH2 CH3); 16.5 (d, 3 J C = 5.5 Hz, POCH2 CH3); 24.5 (d, 3 J C = 10.9 Hz, CH2CH2CHP); 24.8 (CH2); 30.8 (CH2); 32.3 (CH2); 62.0 (CH2OH); 62.8 (d, 2 J C = 6.2 Hz, POCH2CH3); 62.9 (d, 2 J C = 7.1 Hz, POCH2CH3); 64.1 (d, 2 J C = 5.7 Hz, POCH2CH3); 64.1 (d, 2 J C = 5.7 Hz, POCH2CH3); 72.7 (dd, 1 J C = 170.2 Hz, 2 J C = 7.2 Hz, CHP).

Diethyl 6-methacryloyloxy-1-diethylphosphonooxy-hexylphosphonate 6a

Methacrylic anhydride (1.31 mL, 8.8 mmol) was added, under argon atmosphere, to a solution of alcohol 5a (3.12 g, 8.0 mmol), DMAP (49 mg, 0.40 mmol) and triethylamine (1.23 mL, 8.8 mmol) in dry DCM (30 mL). The reaction mixture was stirred for 6 h at room temperature. The solution was concentrated under reduced pressure. EA (70 mL) was added and the solution was washed with a saturated solution of sodium bicarbonate (2 × 70 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluent = EA/MeOH: 95/5). 2.84 g (6.2 mmol) of monomer 6a were isolated.

Yield: 78%. Aspect: colorless oil. 1H NMR (400 MHz, CDCl3): δ = 1.28–1.76 (m, 18H, CH2 and POCH2 CH 3); 1.81–2.03 (m, 5H, CH2 and CH3); 4.07–4.28 (m, 10H, POCH 2CH3 and CH2OCO); 4.57–4.72 (m, 1H, CHP); 5.53–5.59 (m, 1H, CH2=C); 6.10 (ls, 1H, CH2=C). 31P NMR (162 MHz, CDCl3): δ = −1.1 (d, 3 J P = 21.8 Hz, CHOP); 19.9 (d, 3 J P = 21.8 Hz, CHP). 13C NMR (101 MHz, CDCl3): δ = 16.0 (d, 3 J C = 4.9 Hz, POCH2 CH3); 16.1 (d, 3 J C = 4.8 Hz, POCH2 CH3); 16.4 (d, 3 J C = 5.8 Hz, POCH2 CH3); 16.5 (d, 3 J C = 5.6 Hz, POCH2 CH3); 18.3 (CH3); 25.0 (d, 3 J C = 10.5 Hz, CH2CH2CHP); 25.7 (CH2); 28.4 (CH2); 30.9 (CH2); 62.8 (d, 2 J C = 6.7 Hz, POCH2CH3); 64.0 (d, 2 J C = 5.9 Hz, POCH2CH3); 64.5 (CH2OCO); 73.0 (dd, 1 J C = 169.9 Hz, 2 J C = 7.3 Hz, CHP); 125.3 (CH2=C); 136.4 (CH2=C); 167.5 (C=O).

6-Methacryloyloxy-1-phosphonooxy-hexylphosphonic acid 7a

TMSBr (4.75 mL, 36.0 mmol) was added, under argon atmosphere, to a solution of monomer 6a (2.75 g, 6.0 mmol) in anhydrous DCM (40 mL). After stirring for 5 h at 30 °C, the mixture was concentrated under reduced pressure. Methanol (40 mL) was added and the mixture was stirred for 30 min at RT. The solvent was evaporated and the product was dried to a constant weight under vacuum. 1.96 g (5.7 mmol) of the monomer 7a were isolated.

Yield: 95%. Aspect: highly viscous yellow oil. 1H NMR (400 MHz, MeOD): δ = 1.28–1.78 (m, 6H, CH2); 1.79–1.98 (m, 5H, CH2 and CH3); 4.15 (t, 3 J HH = 6.6 Hz, 2H, CH2OCO); 4.36–4.48 (m, 1H, CHP); 5.59–5.63 (m, 1H, CH2=C); 6.08 (ls, 1H, CH2=C). 31P NMR (162 MHz, MeOD): δ = 0.3 (d, 3 J P = 18.8 Hz, CHOP); 19.3 (d, 3 J P = 18.8 Hz, CHP). 13C NMR (101 MHz, MeOD): δ = 17.0 (CH3); 24.7 (d, 3 J C = 10.3 Hz, CH2CH2CHP); 25.4 (CH2); 28.1 (CH2); 30.6 (CH2); 64.4 (CH2OCO); 73.0 (dd, 1 J C = 166.1 Hz, 2 J C = 7.2 Hz, CHP); 124.6 (CH2=C); 136.5 (CH2=C); 167.5 (C=O). HRMS (m/z): calcd for C10H19O9P2, 345.0504; found, 345.0504 [M-H]−.

Synthesis of the acidic monomer 7b

10-(tert-Butyl-diphenylsilyloxy)decanoic acid 1b

10-(tert-Butyl-diphenylsilyloxy)decanoic acid 1b was synthesized, from 10-hydroxydecanoic acid (10.0 g, 53.1 mmol), according to the same procedure described for the synthesis of 6-(tert-butyl-diphenylsilyloxy)hexanoic acid 1a. 17.3 g of 1b were isolated.

Yield: 76%. Aspect: colorless oil. 1H NMR (400 MHz, CDCl3): δ = 1.05 (s, 9H, CH3 tBu); 1.20–1.40 (m, 10H, CH2); 1.50–1.69 (m, 4H, CH2); 2.35 (t, 3 J HH = 7.6 Hz, 2H, CH 2COOH); 3.65 (t, 3 J HH = 6.5 Hz, 2H, CH2OSi); 7.35–7.45 (m, 6H, CHAr); 7.65–7.70 (m, 4H, CHAr).

10-(tert-Butyl-diphenylsilyloxy)-decanoyl chloride 2b

10-(tert-Butyl-diphenylsilyloxy)-decanoyl chloride 2b was synthesized, from 10-(tert-butyl-diphenylsilyloxy)decanoic acid 1b (2.0 g, 4.7 mmol), according to the same procedure described for the synthesis of 6-(tert-butyl-diphenylsilyloxy)-hexanoyl chloride 2a. 2.1 g of 2b were isolated.

Yield: 100%. Aspect: colorless oil. 1H NMR (400 MHz, CDCl3): δ = 1.06 (s, 9H, CH3 tBu); 1.22–1.40 (m, 10H, CH2); 1.56 (qt, 3 J HH = 6.8 Hz, 2H, CH2); 1.71 (qt, 3 J HH = 7.3 Hz, 2H, CH2); 2.89 (t, 3 J HH = 7.3 Hz, 2H, CH2COCl); 3.66 (t, 3 J HH = 6.5 Hz, 2H, CH2OSi); 7.35–7.46 (m, 6H, CHAr); 7.65–7.71 (m, 4H, CHAr). 13C NMR (101 MHz, CDCl3): δ = 19.2 (SiC(CH3)3), 25.1 (CH2); 25.7 (CH2); 26.9 (CH3); 28.4 (CH2); 29.0 (CH2); 29.2 (CH2); 29.3 (CH2); 32.5 (CH2); 41.1 (CH2COCl); 64.0 (CH2OSi); 127.6 (CAr); 129.5 (CAr); 134.2 (CAr); 135.6 (CAr); 173.9 (COCl).

Diethyl 10-(tert-butyl-diphenylsilyloxy)-1-oxo-decylphosphonate 3b

Diethyl 10-(tert-butyl-diphenylsilyloxy)-1-oxo-decylphosphonate 3b was synthesized, from 10-(tert-butyl-diphenylsilyloxy)-decanoyl chloride 2b (2.0 g, 4.7 mmol), according to the same procedure described for the synthesis of diethyl 6-(tert-butyl-diphenylsilyloxy)-1-oxo-hexylphosphonate 3a. 2.4 g of 3b were isolated.

Yield: 94%. Aspect: colorless oil. 1H NMR (400 MHz, CDCl3): δ = 1.04 (s, 9H, CH3 tBu); 1.19–1.38 (m, 10H, CH2); 1.37 (t, 3 J HH = 7.1 Hz, 6H, POCH2 CH 3); 1.49–1.66 (m, 4H, CH2); 2.83 (t, 3 J HH = 7.3 Hz, 2H, CH2COP); 3.64 (t, 3 J HH = 6.5 Hz, 2H, CH2OSi); 4.17–4.27 (m, 4H, POCH 2CH3); 7.34–7.45 (m, 6H, CHAr); 7.64–7.69 (m, 4H, CHAr). 31P NMR (162 MHz, CDCl3): δ = −2.7. 13C NMR (101 MHz, CDCl3): δ = 16.4 (d, 3 J C = 5.6 Hz, POCH2 CH3); 19.2 (SiC(CH3)3); 22.4 (d, 3 J C = 3.8 Hz, CH2CH2COP); 25.8 (CH2); 26.9 (SiC(CH3)3); 28.9 (CH2); 29.2 (CH2); 29.3 (CH2); 29.4 (CH2); 32.5 (CH2); 43.4 (d, 2 J C = 53.8 Hz, CH2COP); 63.7 (d, 2 J C = 7.3 Hz, POCH2CH3); 64.0 (CH2OSi); 127.6 (CAr); 129.5 (CAr); 134.2 (CAr); 135.6 (CAr); 211.4 (d, 1 J C = 164.8 Hz, COP).

Diethyl 10-(tert-butyl-diphenylsilyloxy)-1-diethylphosphonooxy-decylphosphonate 4b

Diethyl 10-(tert-butyl-diphenylsilyloxy)-1-diethylphosphonooxy-decylphosphonate 4b was synthesized, from diethyl 10-(tert-butyl-diphenylsilyloxy)-1-oxo-decylphosphonate 3b (15.4 g, 28.2 mmol), according to the same procedure described for the synthesis of diethyl 6-(tert-butyl-diphenylsilyloxy)-1-diethylphosphonooxy-hexylphosphonate 4a. 16.1 g of 4b were isolated.

Eluent: EA. Yield: 83%. Aspect: slightly yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.04 (s, 9H, CH3 tBu); 1.19–1.66 (m, 26H, CH2 and POCH2 CH 3); 1.76–1.98 (m, 2H, CH2); 3.64 (t, 3 J HH = 6.5 Hz, 2H, CH2OSi); 4.07–4.26 (m, 8H, POCH 2CH3); 4.57–4.69 (m, 1H, CHP); 7.33–7.46 (m, 6H, CHAr); 7.63–7.70 (m, 4H, CHAr). 31P NMR (162 MHz, CDCl3): δ = −1.0 (d, 3 J P = 21.6 Hz, CHOP); 20.3 (d, 3 J P = 21.6 Hz, CHP). 13C NMR (101 MHz, CDCl3): δ = 16.0 (d, 3 J C = 4.4 Hz, POCH2 CH3); 16.1 (d, 3 J C = 4.2 Hz, POCH2 CH3); 16.4 (d, 3 J C = 5.8 Hz, POCH2 CH3); 16.5 (d, 3 J C = 5.7 Hz, POCH2 CH3); 19.2 (SiC(CH3)3); 25.4 (d, 3 J C = 10.7 Hz, CH2CH2CHP); 25.8 (CH2); 26.9 (SiC(CH3)3); 29.3 (2C, CH2); 29.4 (CH2); 29.5 (CH2); 31.0 (CH2); 32.6 (CH2); 62.8 (d, 2 J C = 6.6 Hz, POCH2CH3); 64.0 (d, 2 J C = 5.8 Hz, POCH2CH3); 64.0 (CH2OSi); 73.2 (dd, 1 J C = 169.7 Hz, 2 J C = 7.4 Hz, CHP); 127.6 (CAr); 129.5 (CAr); 134.2 (CAr); 135.6 (CAr).

Diethyl 10-hydroxy-1-diethylphosphonooxy-decylphosphonate 5b

Diethyl 10-hydroxy-1-diethylphosphonooxy-decylphosphonate 5b was synthesized, from diethyl 10-(tert-butyl-diphenylsilyloxy)-1-diethylphosphonooxy-decylphosphonate 4b (3.9 g, 5.7 mmol), according to the same procedure described for the synthesis of diethyl 6-hydroxy-1-diethylphosphonooxy-hexylphosphonate 5a. 2.35 g of 5b were isolated.

Eluent: EA/MeOH: 9/1. Yield: 93%. Aspect: colorless oil. 1H NMR (400 MHz, CDCl3): δ = 1.20–1.62 (m, 26H, CH2 and POCH2 CH 3); 1.73–1.98 (m, 3H, CH2 and OH); 3.59 (t, 3 J HH = 6.6 Hz, 2H, CH2OH); 4.05–4.22 (m, 8H, POCH 2CH3); 4.54–4.66 (m, 1H, CHP). 31P NMR (162 MHz, CDCl3): δ = −1.1 (d, 3 J P = 21.8 Hz, CHOP); 20.2 (d, 3 J P = 21.8 Hz, CHP). 13C NMR (101 MHz, CDCl3): δ = 16.0 (d, 3 J C = 4.5 Hz, POCH2 CH3); 16.1 (d, 3 J C = 4.4 Hz, POCH2 CH3); 16.4 (d, 3 J C = 5.8 Hz, POCH2 CH3); 16.5 (d, 3 J C = 5.7 Hz, POCH2 CH3); 25.3 (d, 3 J C = 10.6 Hz, CH2CH2CHP); 25.7 (CH2); 29.1 (CH2); 29.2 (CH2); 29.3 (CH2); 29.4 (CH2); 30.9 (CH2); 32.7 (CH2); 62.8 (d, 2 J C = 6.2 Hz, POCH2CH3); 62.9 (CH2OH); 64.0 (d, 2 J C = 6.1 Hz, POCH2CH3); 73.2 (dd, 1 J C = 169.8 Hz, 2 J C = 7.3 Hz, CHP).

Diethyl 10-methacryloyloxy-1-diethylphosphonooxy-decylphosphonate 6b

Diethyl 10-methacryloyloxy-1-diethylphosphonooxy-decylphosphonate 6b was synthesized, from diethyl 10-hydroxy-1-diethylphosphonooxy-decylphosphonate 5b (2.3 g, 5.1 mmol), according to the same procedure described for the synthesis of diethyl 6-methacryloyloxy-1-diethylphosphonooxy-hexylphosphonate 6a. 2.3 g of 5b were isolated.

Eluent: EA. Yield: 86%. Aspect: colorless oil. 1H NMR (400 MHz, CDCl3): δ = 1.23–1.72 (m, 26H, CH2 and POCH2 CH 3); 1.77–1.98 (m, 5H, CH2 and CH3); 4.08–4.25 (m, 10H, POCH 2CH3 and CH2OCO); 4.58–4.68 (m, 1H, CHP); 5.53–5.57 (m, 1H, CH2=C); 6.10 (ls, 1H, CH2=C). 31P NMR (162 MHz, CDCl3): δ = −1.0 (d, 3 J P = 21.7 Hz, CHOP); 20.3 (d, 3 J P = 21.7 Hz, CHP). 13C NMR (101 MHz, CDCl3): δ = 16.0 (d, 3 J C = 4.4 Hz, POCH2 CH3); 16.1 (d, 3 J C = 4.2 Hz, POCH2 CH3); 16.4 (d, 3 J C = 5.7 Hz, POCH2 CH3); 16.5 (d, 3 J C = 5.8 Hz, POCH2 CH3); 18.3 (CH3); 25.3 (d, 3 J C = 10.5 Hz, CH2CH2CHP); 26.0 (CH2); 28.6 (CH2); 29.2 (2C, CH2); 29.3 (CH2); 29.4 (CH2); 31.0 (CH2); 62.8 (d, 2 J C = 6.6 Hz, POCH2CH3); 64.0 (d, 2 J C = 5.9 Hz, POCH2CH3); 64.8 (CH2OCO); 73.2 (dd, 1 J C = 169.6 Hz, 2 J C = 7.2 Hz, CHP); 125.2 (CH2=C); 136.5 (CH2=C); 167.6 (C=O).

10-Methacryloyloxy-1-phosphonooxy-decylphosphonic acid 7b

10-Methacryloyloxy-1-phosphonooxy-decylphosphonic acid 7b was synthesized, from diethyl 10-methacryloyloxy-1-diethylphosphonooxy-decylphosphonate 6b (1.95 g, 3.8 mmol), according to the same procedure described for the synthesis of 6-methacryloyloxy-1-phosphonooxy-hexylphosphonic acid 7a. 1.52 g of 7b were isolated.

Yield: 100%. Aspect: highly viscous yellow oil. 1H NMR (400 MHz, MeOD): δ = 1.26–1.73 (m, 14H, CH2); 1.75–1.96 (m, 5H, CH2 and CH3); 4.13 (t, 3 J HH = 6.6 Hz, 2H, CH2OCO); 4.35–4.46 (m, 1H, CHP); 5.59–5.62 (m, 1H, CH2=C); 6.07 (ls, 1H, CH2=C). 31P NMR (162 MHz, MeOD): δ = 0.3 (d, 3 J P = 18.7 Hz, CHOP); 19.5 (d, 3 J P = 18.7 Hz, CHP). 13C NMR (101 MHz, MeOD): δ = 17.1 (CH3); 25.1 (d, 3 J C = 10.4 Hz, CH2CH2CHP); 25.7 (CH2); 28.3 (CH2); 28.9 (CH2); 29.0 (CH2); 29.1 (CH2); 29.2 (CH2); 30.7 (CH2); 64.6 (CH2OCO); 73.2 (dd, 1 J C = 165.9 Hz, 2 J C = 7.2 Hz, CHP); 124.7 (CH2=C); 136.5 (CH2=C); 167.5 (C=O). HRMS (m/z): calcd for C14H27O9P2, 401.1130; found, 401.1127 [M-H]−.

Synthesis of the acidic monomer 9

Diethyl 6-[2-(methacryloyloxyethylamino)carbonyloxy]-1-diethylphosphonooxy-hexylphosphonate 8

A solution of dibutyltin dilaurate (25.5 mg, 0.041 mmol) in anhydrous DCM (2.0 mL) was added, under argon atmosphere, to a solution of diethyl 6-hydroxy-1-diethylphosphonooxy-hexylphosphonate 5a (3.15 g, 8.1 mmol) in anhydrous DCM (10.0 mL). 2-Isocyanatoethyl methacrylate (1.14 mL, 8.1 mmol) was subsequently added dropwise to the mixture. The solution was stirred for 3 h at RT and concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluent: EA/MeOH: 9/1). 4.3 g of the desired compound were isolated.

Yield: 93%. Aspect: slightly yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.28–1.74 (m, 18H, CH2 and POCH2 CH 3); 1.80–1.98 (m, 5H, CH2 and CH3); 3.40–3.54 (m, 2H, CH2NH); 4.00–4.26 (m, 12H, POCH 2CH3, CH 2OCONH and CH2OCO); 4.56–4.67 (m, 1H, CHP); 5.24 (s, 1H, NH); 5.57–5.61 (m, 1H, CH2=C); 6.13 (ls, 1H, CH2=C). 31P NMR (162 MHz, CDCl3): δ = −1.1 (d, 3 J P = 22.2 Hz, CHOP); 20.1 (d, 3 J P = 22.2 Hz, CHP). 13C NMR (101 MHz, CDCl3): δ = 16.0 (d, 3 J C = 4.6 Hz, POCH2 CH3); 16.1 (d, 3 J C = 4.4 Hz, POCH2 CH3); 16.4 (d, 3 J C = 5.8 Hz, POCH2 CH3); 16.5 (d, 3 J C = 5.8 Hz, POCH2 CH3); 18.3 (CH3); 25.0 (d, 3 J C = 10.5 Hz, CH2CH2CHP); 25.7 (CH2); 28.5 (CH2); 30.8 (CH2); 40.0 (CH2NH); 62.8 (d, 2 J C = 6.1 Hz, POCH2CH3); 62.8 (d, 2 J C = 7.2 Hz, POCH2CH3); 63.8 (CH2OCO); 64.1 (d, 2 J C = 6.1 Hz, POCH2CH3); 65.0 (CH2OCO); 73.0 (dd, 1 J C = 169.9 Hz, 2 J C = 7.3 Hz, CHP); 126.0 (CH2=C); 136.0 (CH2=C); 156.7 (C=O); 167.2 (C=O).

6-[2-(Methacryloyloxyethylamino)carbonyloxy]-1-phosphonooxy-hexylphosphonic acid 9

6-[(2-Methacryloyloxyethylamino)-carbonyloxy]-1-phosphonooxy-hexylphosphonic acid 9 was synthesized, from diethyl 6-[(2-methacryloyloxyethylamino)-carbonyloxy]-1-diethylphosphonooxy-hexylphosphonate 8 (1.0 g, 1.8 mmol), according to the same procedure described for the synthesis of 6-methacryloyloxy-1-phosphonooxy-hexylphosphonic acid 7a. 750 mg of 9 were isolated.

Yield: 94%. Aspect: highly viscous yellow oil. 1H NMR (400 MHz, MeOD): δ = 1.26–1.74 (m, 6H, CH2); 1.77–1.97 (m, 5H, CH2 and CH3); 3.38 (t, 3 J HH = 5.5 Hz, 2H, CH2NH); 4.03 (t, 3 J HH = 6.5 Hz, 2H, CH2OCO); 4.17 (t, 3 J HH = 5.5 Hz, 2H, CH 2OCONH); 4.34–4.47 (m, 1H, CHP); 5.61–5.65 (m, 1H, CH2=C); 6.11 (ls, 1H, CH2=C). 31P NMR (162 MHz, MeOD): δ = 0.3 (CHOP); 19.3 (CHP). 13C NMR (101 MHz, MeOD): δ = 17.0 (CH3); 24.8 (d, 3 J C = 10.4 Hz, CH2CH2CHP); 25.3 (CH2); 28.6 (CH2); 30.6 (CH2); 39.3 (CH2NH); 63.2 (CH2OCO); 64.5 (CH2OCO); 73.0 (dd, 1 J C = 166.0 Hz, 2 J C = 7.2 Hz, CHP); 125.1 (CH2=C); 136.2 (CH2=C); 157.9 (C=O); 167.3 (C=O). HRMS (m/z): calcd for C13H24NO11P2, 432.0825; found, 432.0822 [M-H]−.

Synthesis of the acidic monomer 16

11-Phtalimido-undecanoic acid 10

A mixture of 11-aminoundecanoic acid (3.04 g, 15.1 mmol) and phthalic anhydride (2.24 g, 15.1 mmol) was heated for 1 h at 150 °C. DCM (25 mL) was added and the resulting solution was dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure. 4.9 g (14.8 mmol) of carboxylic acid 10 were obtained.

Yield: 98%. Aspect: white solid. 1H NMR (400 MHz, CDCl3): δ = 1.22–1.40 (m, 12H, CH2); 1.56–1.73 (m, 4H, CH2); 2.34 (t, 3 J HH = 7.5 Hz, 2H, CH 2COOH); 3.67 (t, 3 J HH = 7.3 Hz, 2H, CH2 N); 7.67–7.74 (m, 2H, CHAr); 7.81–7.87 (m, 2H, CHAr). 13C NMR (101 MHz, CDCl3): δ = 24.7 (CH2); 26.8 (CH2); 28.6 (CH2); 29.0 (CH2); 29.1 (CH2); 29.2 (CH2); 29.3 (CH2); 29.4 (CH2); 34.0 (CH2COOH); 38.1 (CH2 N); 123.2 (CAr); 132.2 (CAr); 133.8 (CAr); 168.5 (C=O); 179.7 (C=O).

11-Phtalimido-undecanoyl chloride 11

11-Phtalimido-undecanoyl chloride 11 was synthesized, from 11-phtalimido-undecanoic acid 10 (8.4 g, 25.3 mmol), according to the same procedure described for the synthesis of 6-(tert-butyl-diphenylsilyloxy)hexanoyl chloride 2a. 8.9 g of 11 were isolated.

Yield: 100%. Aspect: colorless oil. 1H NMR (400 MHz, CDCl3): δ = 1.22–1.39 (m, 12H, CH2); 1.58–1.77 (m, 4H, CH2); 2.87 (t, 3 J HH = 7.3 Hz, 2H, CH 2COCl); 3.67 (t, 3 J HH = 7.3 Hz, 2H, CH2 N); 7.68–7.74 (m, 2H, CHAr); 7.81–7.88 (m, 2H, CHAr).

Diethyl 11-phtalimido-1-oxo-undecylphosphonate 12

Diethyl 11-phtalimido-1-oxo-undecylphosphonate 12 was synthesized, from 11-phtalimido-undecanoyl chloride 11 (1.00 g, 2.9 mmol), according to the same procedure described for the synthesis of diethyl 6-(tert-butyl-diphenylsilyloxy)-1-oxo-hexylphosphonate 3a. 1.22 g of 12 were isolated.

Yield: 95%. Aspect: slightly yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.20–1.35 (m, 12H, CH2); 1.36 (t, 3 J HH = 7.1 Hz, 6H, POCH2 CH 3); 1.53–1.72 (m, 4H, CH2); 2.80 (t, 3 J HH = 7.3 Hz, 2H, CH2COP); 3.66 (t, 3 J HH = 7.3 Hz, 2H, CH2 N); 4.14–4.26 (m, 4H, POCH 2CH3); 7.66–7.72 (m, 2H, CHAr); 7.79–7.85 (m, 2H, CHAr). 31P NMR (162 MHz, CDCl3): δ = −2.7. 13C NMR (101 MHz, CDCl3): δ = 16.4 (d, 3 J C = 5.6 Hz, POCH2 CH3); 22.4 (d, 3 J C = 3.7 Hz, CH2CH2COP); 26.8 (CH2); 28.6 (CH2); 28.9 (CH2); 29.1 (CH2); 29.2 (CH2); 29.3 (CH2); 29.4 (CH2); 38.0 (CH2 N); 43.3 (d, 2 J C = 54.0 Hz, CH2COP); 63.7 (d, 2 J C = 7.3 Hz, POCH2CH3); 123.1 (CAr); 132.2 (CAr); 133.8 (CAr); 168.5 (CAr); 211.3 (d, 1 J C = 165.0 Hz, COP).

Diethyl 11-phtalimido-1-diethylphosphonooxy-undecylphosphonate 13

Diethyl 11-phtalimido-1-diethylphosphonooxy-undecylphosphonate 13 was synthesized, from diethyl 11-phtalimido-1-oxo-undecylphosphonate 12 (11.5 g, 25.5 mmol), according to the same procedure described for the synthesis of diethyl 6-(tert-butyl-diphenylsilyloxy)-1-diethylphosphonooxy-hexylphosphonate 4a. 10.5 g of 13 were isolated.

Eluent: EA. Yield: 70%. Aspect: slightly yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.18–1.74 (m, 28H, POCH2 CH 3 and CH2); 1.76–1.98 (m, 2H, CH2); 3.67 (t, 3 J HH = 7.2 Hz, 2H, CH2 N); 4.07–4.26 (m, 8H, POCH 2CH3); 4.57–4.68 (m, 1H, CHP); 7.68–7.73 (m, 2H, CHAr); 7.81–7.87 (m, 2H, CHAr). 31P NMR (162 MHz, CDCl3): δ = −1.0 (d, 3 J P = 21.6 Hz, CHOP); 20.3 (d, 3 J P = 21.6 Hz, CHP). 13C NMR (101 MHz, CDCl3): δ = 16.0 (d, 3 J C = 4.9 Hz, POCH2 CH3); 16.1 (d, 3 J C = 4.7 Hz, POCH2 CH3); 16.4 (d, 3 J C = 5.8 Hz, POCH2 CH3); 16.5 (d, 3 J C = 5.5 Hz, POCH2 CH3); 25.4 (d, 3 J C = 10.4 Hz, CH2CH2CHP); 26.9 (CH2); 28.6 (CH2); 29.1 (CH2); 29.2 (CH2); 29.3 (CH2); 29.4 (CH2); 31.1 (CH2); 38.0 (CH2 N); 62.7 (d, 2 J C = 6.7 Hz, POCH2CH3); 63.9 (d, 2 J C = 5.9 Hz, POCH2CH3); 73.2 (dd, 1 J C = 169.7 Hz, 2 J C = 7.4 Hz, CHP); 123.1 (CAr); 132.2 (CAr); 133.8 (CAr); 168.4 (CAr).

Diethyl 11-amino-1-diethylphosphonooxy-undecylphosphonate 14

Hydrazine monohydrate (0.13 mL, 2.54 mmol) was added to a solution of compound 13 (1.00 g, 1.70 mmol) in EtOH (10 mL). The mixture was refluxed for 2 h and the solvent removed under reduced pressure. A solution of NaOH (2 N in distilled water, 20 mL) was added and the mixture was extracted with Et2O (3 × 15 mL). The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure. 650 mg (1.41 mmol) of the desired product was isolated.

Yield: 83%. Aspect: slightly yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.20–1.66 (m, 30H, POCH2 CH 3, CH2 and NH2); 1.77–1.99 (m, 2H, CH2); 2.67 (t, 3 J HH = 6.9 Hz, 2H, CH 2NH2); 4.07–4.27 (m, 8H, POCH 2CH3); 4.56–4.69 (m, 1H, CHP). 31P NMR (162 MHz, CDCl3): δ = −1.0 (d, 3 J P = 21.8 Hz, CHOP); 20.3 (d, 3 J P = 21.8 Hz, CHP). 13C NMR (101 MHz, CDCl3): δ = 16.0 (d, 3 J C = 4.5 Hz, POCH2 CH3); 16.1 (d, 3 J C = 4.4 Hz, POCH2 CH3); 16.4 (d, 3 J C = 5.7 Hz, POCH2 CH3); 16.5 (d, 3 J C = 5.5 Hz, POCH2 CH3); 25.3 (d, 3 J C = 10.6 Hz, CH2CH2CHP); 26.9 (CH2); 29.2 (CH2); 29.3 (CH2); 29.4 (CH2); 29.5 (CH2); 31.0 (CH2); 33.8 (CH2); 40.3 (CH2 N); 62.7 (d, 2 J C = 6.3 Hz, POCH2CH3); 63.9 (d, 2 J C = 5.9 Hz, POCH2CH3); 73.2 (dd, 1 J C = 169.4 Hz, 2 J C = 7.3 Hz, CHP).

Diethyl 11-methacrylamido-1-diethylphosphonooxy-undecylphosphonate 15

Methacryloyl chloride (0.23 mL, 2.29 mmol) was added, under argon atmosphere and at 0 °C, to a solution of amine 14 (1.00 g, 2.18 mmol) and triethylamine (0.33 mL, 2.39 mmol) in dry DCM (9 mL). The reaction mixture was stirred for 6 h at RT. The solution was washed with HCl 1 N (10 mL), NaOH 1 N (10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluent = EA/MeOH: 95/5). 920 mg (1.74 mmol) of monomer 15 were isolated.

Yield: 80%. Aspect: slightly yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.19–1.64 (m, 28H, POCH2 CH 3 and CH2); 1.75–1.94 (m, 2H, CH2); 1.94 (s, 3H, CH3); 3.28 (q, 3 J HH = 6.7 Hz, 2H, CH 2 N); 4.05–4.23 (m, 8H, POCH 2CH3); 4.55–4.66 (m, 1H, CHP); 5.28 (s, 1H, C=CH2); 5.64 (s, 1H, C=CH2); 5.85 (ls, 1H, NH). 31P NMR (162 MHz, CDCl3): δ = −1.1 (d, 3 J P = 21.8 Hz, CHOP); 20.2 (d, 3 J P = 21.8 Hz, CHP). 13C NMR (101 MHz, CDCl3): δ = 16.0 (d, 3 J C = 4.5 Hz, POCH2 CH3); 16.1 (d, 3 J C = 4.4 Hz, POCH2 CH3); 16.4 (d, 3 J C = 5.8 Hz, POCH2 CH3); 16.5 (d, 3 J C = 5.7 Hz, POCH2 CH3); 18.7 (CH3); 25.3 (d, 3 J C = 10.5 Hz, CH2CH2CHP); 26.9 (CH2); 29.1 (CH2); 29.2 (CH2); 29.3 (CH2); 29.4 (CH2); 29.4 (CH2); 29.5 (CH2); 31.0 (CH2); 39.7 (CH2 N); 62.8 (d, 2 J C = 6.2 Hz, POCH2CH3); 62.9 (d, 2 J C = 7.3 Hz, POCH2CH3); 64.0 (d, 2 J C = 5.9 Hz, POCH2CH3); 73.2 (dd, 1 J C = 169.5 Hz, 2 J C = 7.2 Hz, CHP); 119.0 (C=CH2); 140.3 (C=CH2); 168.4 (C=O).

11-Methacrylamido-1-phosphonooxy-undecylphosphonic acid 16

11-Methacrylamido-1-phosphonooxy-undecylphosphonic acid 16 was synthesized, from diethyl 11-methacrylamido-1-diethylphosphonooxy-undecylphosphonate 15 (900 mg, 1.71 mmol), according to the same procedure described for the synthesis of 6-methacryloyloxy-1-phosphonooxy-hexylphosphonic acid 7a. 710 mg of 16 were isolated.

Yield: 100%. Aspect: highly viscous slightly yellow oil. 1H NMR (400 MHz, MeOD): δ = 1.15–1.59 (m, 16H, CH2); 1.65–1.87 (m, 5H, CH2 and CH3); 3.12 (t, 3 J HH = 7.2 Hz, 2H, CH 2 N); 4.25–4.35 (m, 1H, CHP); 5.25 (s, 1H, C=CH2); 5.56 (s, 1H, C=CH2). 31P NMR (162 MHz, MeOD): δ = 0.3 (d, 3 J P = 18.6 Hz, CHOP); 19.5 (d, 3 J P = 18.6 Hz, CHP). 13C NMR (101 MHz, MeOD): δ = 15.8 (CH3); 23.5 (d, 3 J C = 10.3 Hz, CH2CH2CHP); 25.0 (CH2); 27.3 (CH2); 27.4 (CH2); 27.5 (CH2); 27.6 (CH2); 27.6 (CH2); 29.1 (CH2); 37.8 (CH2 N); 71.6 (dd, 1 J C = 165.9 Hz, 2 J C = 7.2 Hz, CHP); 117.4 (C=CH2); 138.3 (C=CH2); 168.4 (C=O). HRMS (m/z): calcd for C15H30NO8P2, 414.1447; found, 414.1443 [M-H]−.

Photopolymerization procedure

Photopolymerizations were carried out on a Perkin Elmer differential scanning calorimeter (DSC), Pyris Diamond. 0.5 mol% of Ivocerin® (photoinitiator) were added to each comonomer mixture. A sample (ca. 0.8 mg) of each mixture was placed in an uncovered aluminum DSC pan. The DSC chamber was purged with nitrogen for 5 min before polymerization. One minute after the beginning of the acquisition, the samples were irradiated for 2 min at 37 °C with a LED curing light (Bluephase, Ivoclar-Vivadent AG). The incident light intensity was 20 mW cm−2. Each experiment was repeated at least three times. The heat flux was monitored as a function of time using the DSC under isothermal conditions. The DBC was calculated as the quotient of the overall enthalpy evolved [ΔH P (J g−1)] and the theoretical enthalpy obtained for 100% conversion of the mixtures [ΔH 0P (J g−1)] (Equation (1)).

ΔH 0P was calculated according to the following formula (Equation (2)):

where ΔH 0i is the theoretical enthalpy of monomer i (i = methacrylate or methacrylamide, ΔH 0i = 54.8 kJ mol−1 [17]), M i its molar mass and P i the amount used in the formulation (wt%).

The rate of polymerization (R p) was calculated according to the following formula (Equation (3)):

where Q is the heat flow per second during the reaction and m the mass of the mixture in the sample.

SBS measurement

Freshly extracted bovine mandibular incisors were embedded in unsaturated polyester resin (ViscoVoss). Flat dentinal and enamel surfaces were prepared with 120-grit and 400-grit wet silicon carbide paper on the labial side of the embedded teeth. The adhesive was first rubbed on the prepared dentin or enamel surface with a microbrush for 20 s. The adhesive layer was strongly air dried and light cured for 10 s with a LED curing light (Bluephase G2, polywave LED with a spectrum from 385 to 515 nm and 2 maxima at 410 and 470 nm, Ivoclar Vivadent AG). A poly(ethylene) mold with a central 2.38-mm diameter circular hole was fixed on the surface. A composite (Tetric EvoCeram, Ivoclar Vivadent AG) was inserted in the mold and light-cured for 20 s. The samples were finally stored in water at 37 °C for 24 h before being tested. The SBS was measured using a universal testing machine (Zwick, Germany) at a crosshead speed of 0.8 mm min−1. 10 samples were tested for each adhesive.

Results and discussion

Monomer 7a was prepared, starting from 6-hydroxycaproic acid, in seven steps (Scheme 1). The alcohol group was first protected using tert-butyldiphenylchlorosilane and imidazole in DMF. The reaction between the resulting silyl ether and oxalyl chloride provided the corresponding acyl chloride 2a in a quantitative yield. The addition of triethyl phosphite to the acyl chloride 2a resulted in the formation of α-ketophosphonate 3a. Gem-phosphonate-phosphate 4a was subsequently prepared according to conditions reported by Nguyen et al. [15]. Hence, 4a was synthesized by reacting 3a with diethyl phosphite in the presence of a stoichiometric amount of diethylamine in diethyl ether. After purification by flash column chromatography, compound 4a was isolated in 72% yield. Then, the tert-butyldiphenylsilyl protecting group was cleaved using TBAF in THF. The resulting alcohol 5a was obtained in 86% yield. Methacrylate 6a was synthesized by acylation of 5a with methacrylic anhydride in the presence of triethylamine and of a catalytic amount of DMAP. Silylation of 6a using TMSBr, followed by the methanolysis of the silyl ether, finally provided the desired acidic monomer 7a in 95% yield. Monomer 7b was prepared, from 10-hydroxydecanoic acid, according to a similar synthetic pathway (Scheme 1). It was isolated in a 47% global yield. Acidic monomer 9 was synthesized in two steps, starting from alcohol 5a (Scheme 2). Methacrylate 8 was first prepared by reacting 5a with 2-isocyanatoethyl methacrylate using dibutyltin dilaurate as a catalyst. It was obtained, after purification, in 93% yield. The dealkylation of the phosphonate and phosphate groups subsequently gave the desired monomer 9. It is well-known that the use of (meth)acrylic monomers in SEAs present some drawbacks. Indeed, SEAs being acidic aqueous solutions, such monomers tend to hydrolyse upon storage. A low acidic monomer concentration or a storage in the refrigerator are required to prevent the deterioration of the adhesive. On the other hand, (N-alkyl)(meth)acrylamides are known to be significantly more stable than (meth)acrylates in aqueous acidic medium.[11,18-23] Therefore, such monomers have been incorporated in several commercially available SEAs. In this context, we took an interest in the seven-step synthesis of methacrylamide 16 (Scheme 3). The first step consisted in reacting 11-aminoundecanoic acid with phthalic anhydride at 150 °C. This reaction led to the formation of phtalimide 10, which was obtained in 98% yield. The gem-phosphonate-phosphate 13 was then prepared in three steps, from carboxylic acid 10, according to a similar synthetic pathway than the one previously described for compounds 4a and 4b (Scheme 1). The phtalimide group was successfully cleaved using hydrazine in EtOH. The corresponding amine 14 was isolated in 83% yield. A subsequent acylation using methacryloyl chloride, followed by deprotection of both dialkyl phosphonate and phosphate groups, finally led to the targeted acidic methacrylamide 16. All new monomers were characterized by 1H-NMR, 31P-NMR and 13C-NMR spectroscopy. For example, the 1H-NMR spectrum of monomer 7b is shown in Figure 2. It is characterized by nine methylene groups at 1.26–1.73 ppm (m, 14H), 1.75–1.96 ppm (m, 2H) and 4.13 ppm (t, 2H). The signal at 4.35–4.46 ppm corresponds to the proton of the CH bearing both acidic groups. The protons of the methacrylate group are identified by the presence of signals at about 1.92 (methyl group), 5.60 and 6.07 ppm.

Figure 2.

1H-NMR spectrum of monomer 7b.

Photopolymerization in bulk

In order to study the reactivity of acidic monomers 7a, 7b, 9 and 16, their copolymerization with HEMA (acidic monomer/HEMA: 2/8, mol/mol) was investigated using photo-DSC. Each monomer mixture was polymerized under the same conditions (irradiation time: 2 min; light intensity: 20 mW cm−2). Ivocerin® (0.5 mol%) was added as photoinitiator.[24] The copolymerization of MDPA and MDP with HEMA was also studied. For each mixture, the maximum rate of polymerization (R pmax), the time to reach the maximum rate of polymerization (t Rpmax) as well as the DBC were determined (Table 1). Figure 3 shows the rate of polymerization (R p) for 7b/HEMA, MDP/HEMA, MDPA/HEMA and HEMA as a function of time. Results showed that the polymerizable α-phosphonooxy phosphonic acids 7a, 7b, 9 and 16 are significantly more reactive than MDP and MDPA. Indeed, higher R pmax and lower t Rpmax were obtained with these monomers. It can also be seen in Figure 3 that the addition of acidic monomers to HEMA results in a significant improvement of the reactivity. Contrary to MDP and MDPA, the new monomers 7a, 7b, 9 and 16 are bearing two acidic groups. It is well established that hydrogen bonding has a tremendous impact on the polymerization reactivity. Indeed, it is thought to facilitate the preorganization of the monomers, resulting in an increase of the propagation reaction rate constant (k p).[25-28] Hydrogen bonding also restricts mobility, leading to a decrease of the termination rate and consequently to an increase of the R p. The presence of two acidic groups strongly increases the ability of the monomer to form hydrogen bonds, which is probably responsible for the higher reactivity of monomers 7a, 7b, 9 and 16. This property can also explain that the polymerization of the mixtures containing α-phosphonooxy phosphonic acids 7a, 7b, 9 and 16 led to lower DBCs (75.4% < DBCs < 80.5%) than for the mixtures based on MDPA (84.2%) and MDP (85.1%). Amongst the synthesized monomers, 9 was found to be the most reactive. This result can be explained by the presence of the additional urethane group, which can also participate in hydrogen bond interactions. No significant difference was observed between the reactivity of methacrylate 7b and of the corresponding methacrylamide 16. Results obtained with 7a and 7b also showed that the spacer length has almost no influence on the polymerization rate.

Table 1.

R pmax, t Rpmax and DBC measured for different HEMA comonomer mixtures.

Mixtures (mol/mol)	tRpmax (s)	Rpmax (s−1)	DBC (%)
7a/HEMA (8/2)	4.8	0.101 ± 0.001	80.5 ± 1.0
7b/HEMA (8/2)	4.8	0.091 ± 0.001	77.1 ± 1.0
9/HEMA (8/2)	3.8	0.105 ± 0.001	79.0 ± 0.1
16/HEMA (8/2)	5.8	0.085 ± 0.001	75.4 ± 1.0
MDP/HEMA (8/2)	15.4	0.055 ± 0.001	85.1 ± 2.0
MDPA/HEMA (8/2)	14.7	0.056 ± 0.001	84.2 ± 1.0

Figure 3.

R p vs. irradiation time for the polymerization of 7b/HEMA, MDP/HEMA, MDPA/HEMA and HEMA.

Synthesis of acidic monomers 7a and 7b.

Synthesis of acidic monomer 9.

Synthesis of acidic monomer 16.

Adhesive properties

In order to evaluate the adhesive properties of monomers 7a, 7b, 9 and 16, SEAs were formulated (Table 2). Each SEA contained an acidic monomer (15 wt%), crosslinking monomers (Bis-GMA and DEBAAP), photoinitiators (CQ/EMBO and Irgacure 819), solvents (water and i-PrOH) and additives (BHT as inhibitor). SEAs based on MDPA and MDP were also prepared. These adhesives were used to mediate a bond between a composite (Tetric EvoCeram®) and dental hard tissues (dentin and enamel). The SBS was subsequently measured (Table 3). SEAs containing the new polymerizable α-phosphonooxy phosphonic acids 7a, 7b, 9 and 16 provided significantly higher dentin and enamel SBS than the adhesives based on MDPA and MDP. The results confirm that the presence of two acidic groups has a considerable influence on the adhesive properties. Excellent chelating ability as well as improved etching properties of monomers 7a, 7b, 9 and 16 are probably responsible for the outstanding performances of SEAs 1–4. These adhesives led to similar dentin and enamel SBS. Consequently, neither the spacer length nor the nature of the polymerizable group nor the presence of a carbamate group had an influence on the SBS values. It should be emphasized that MDP is one of the most frequently used acidic monomer in commercial SEAs. α-Phosphonooxy phosphonic acids are therefore excellent candidates to improve the performance of current adhesives.

Table 2.

Composition of six experimental SEAs.

Component	SEA 1 (wt%)	SEA 2 (wt%)	SEA 3 (wt%)	SEA 4 (wt%)	SEA 5 (wt%)	SEA 6 (wt%)
7a	15.00	–	–	–	–	–
7b	–	15.00	–	–	–	–
9	–	–	15.00	–	–	–
16	–	–	–	15.00	–	–
MDP	–	–	–	–	15.00	–
MDPA	–	–	–	–	–	15.00
DEBAAP	40.00	40.00	40.00	40.00	40.00	40.00
Bis-GMA	22.40	22.40	22.40	22.40	22.40	22.40
Water	15.00	15.00	15.00	15.00	15.00	15.00
i-PrOH	5.00	5.00	5.00	5.00	5.00	5.00
CQ	0.90	0.90	0.90	0.90	0.90	0.90
EMBO	0.42	0.42	0.42	0.42	0.42	0.42
Irgacure 819	1.25	1.25	1.25	1.25	1.25	1.25
BHT	0.03	0.03	0.03	0.03	0.03	0.03

Table 3.

Results of dentin and enamel SBS tests.

SEA	Acidic monomer	Dentin SBS (MPa)	Enamel SBS (MPa)
1	7a	37.3 ± 5.1	29.1 ± 4.5
2	7b	36.5 ± 4.1	25.8 ± 2.8
3	9	38.5 ± 3.8	29.8 ± 3.0
4	16	33.8 ± 3.7	27.9 ± 2.9
5	MDP	27.7 ± 4.8	22.6 ± 4.0
6	MDPA	22.0 ± 3.3	16.4 ± 2.8

Conclusion

The polymerizable α-phosphonooxy phosphonic acids 7a, 7b, 9 and 16 were successfully synthesized in seven steps. The copolymerization of these monomers as well as of MDPA and MDP with HEMA was investigated. The addition of monomers 7a, 7b, 9 and 16 to HEMA led to an acceleration of the polymerization. Acidic monomers 7a, 7b, 9 and 16 were found to be significantly more reactive than MDP and MDPA. The strong ability of these monomers to form hydrogen bonds, which can be ascribed to the presence of two acidic groups, is thought to be responsible for their high reactivity. The adhesive properties of acidic monomers 7a, 7b, 9 and 16 were also evaluated. SEAs based on these α-phosphonooxy phosphonic acids led to significantly higher dentin and enamel SBS than adhesives containing the phosphonic acid MDPA or the dihydrogen phosphate MDP. Monomers 7a, 7b, 9 and 16 are therefore excellent candidates for the formulation of high performance adhesives.

Disclosure statement

No potential conflict of interest was reported by the authors.