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

Abstract 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][2][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][7][8][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][11][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.

Diethyl
6-hydroxy-1-diethylphosphonooxyhexylphosphonate 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.

6-Methacr yloylox y-1-phosphono ox yhexylphosphonic 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.

Diethyl 11-amino-1-diethylphosphonooxyundecylphosphonate 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 Et 2 O (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.
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.

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)).
(1) DBC = ΔH P ∕ΔH 0P 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 1 H-NMR, 31 P-NMR and 13 C-NMR spectroscopy. For example, the 1 H-NMR spectrum of monomer 7b is shown in Figure 2

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 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][19][20][21][22][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 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][26][27][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
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.
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.

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.