Synthesis and evaluations of bisphosphonate-containing monomers for dental materials

Article abstract of DOI:10.1002/pola.26305

Two new bismethacrylamide (1, 2) and two new methacrylamide (3, 4) dental monomers were synthesized. In each group, one monomer contains a bisphosphonate group, the other a bisphosphonic acid group. Monomer 1 and 3 were synthesized by amidation of 2-(2-chlorocarbonyl-allyloxymethyl)-acryloylchloride and methacryloyl chloride with tetraethyl aminomethyl-bis(phosphonate) and converted to the bisphosphonic acid monomers 2 and 4 by hydrolysis with trimethylsilyl bromide. Monomer 1 (m.p.: 71-72 °C), monomer 3 (33-34 °C), and monomer 4 (no m.p.) were obtained as white solids and monomer 2 a viscous liquid, soluble in water. Homopolymerization of 1 gave crosslinked polymers, indicating its low cyclization tendency. The photopolymerization studies indicated that its copolymerizability with 2,2-bis[4-(2-hydroxy-3-methacryloyloxy propyloxy) phenyl] propane and 2-hydroxyethyl methacrylate (HEMA) without changing their rates and conversions significantly means that it could be used as a biocompatible crosslinker. Although monomer 2 showed low polymerizability, because of its good performance in terms of solubility, hydrolytic stability, hydroxyapatite interaction, acidity, and copolymerizability with HEMA, it shows potential to be used in self-etching dental adhesives. The thermal polymerization of 3 resulted in soluble polymers and evaluation of monomer 4 in terms of solubility, acidity, and copolymerizability with HEMA indicated its potential as an adhesive monomer.

Full text of DOI:10.1002/pola.26305

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Synthesis and Evaluations of Bisphosphonate-Containing
Monomers for Dental Materials
Burcin Akgun, Duygu Avci
Department of Chemistry, Bogazici University, 34342 Bebek, Istanbul, Turkey
Correspondence to: D. Avci (E-mail: avcid@boun.edu.tr)
Received 6 July 2012; accepted 30 July 2012; published online
DOI: 10.1002/pola.26305
ABSTRACT: Two new bismethacrylamide (1, 2) and two new
methacrylamide (3, 4) dental monomers were synthesized. In
each group, one monomer contains a bisphosphonate group,
methacrylate (HEMA) without changing their rates and con-
versions significantly means that it could be used as a bio-
compatible crosslinker. Although monomer
2 showed low
the other
a
bisphosphonic acid group. Monomer
1
and
3
polymerizability, because of its good performance in terms of
solubility, hydrolytic stability, hydroxyapatite interaction, acid-
ity, and copolymerizability with HEMA, it shows potential to be
used in self-etching dental adhesives. The thermal polymeriza-
tion of 3 resulted in soluble polymers and evaluation of mono-
mer 4 in terms of solubility, acidity, and copolymerizability
were synthesized by amidation of 2-(2-chlorocarbonyl-allyloxy-
methyl)-acryloylchloride and methacryloyl chloride with tetra-
ethyl aminomethyl-bis(phosphonate) and converted to the
bisphosphonic acid monomers 2 and 4 by hydrolysis with tri-
methylsilyl bromide. Monomer 1 (m.p.: 71–72 ꢀC), monomer 3
(33–34 ꢀC), and monomer 4 (no m.p.) were obtained as white
solids and monomer 2 a viscous liquid, soluble in water. Homo-
polymerization of 1 gave crosslinked polymers, indicating its
low cyclization tendency. The photopolymerization studies indi-
cated that its copolymerizability with 2,2-bis[4-(2-hydroxy-3-metha-
cryloyloxy propyloxy) phenyl] propane and 2-hydroxyethyl
with HEMA indicated its potential as an adhesive monomer.
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KEYWORDS: adhesives; bisphosphonic acids; cyclopolymerization;
dental adhesives; photopolymerization; radical polymerization
INTRODUCTION Dental composites and ‘‘self-etching’’ enamel-
dentin adhesives based on mixtures of monofunctional and
multifunctional monomers, are important components in den-
tistry. The main problems of dental composites are their
shrinkage upon polymerization, mechanical wear, breakdown
due to hydrolysis in the oral environment, and insufficient ad-
hesion to tooth tissue.1,2 The main approach to solve the last
problem is the use of dental adhesives. The modern ‘‘self-etch-
ing’’ dental adhesives are based on acidic monomers contain-
ing monohydrogenphosphate or dihydrogenphosphate, phos-
phonic, sulfonic, or carboxylic acid groups and used to
achieve a strong bond between dental filling composites and
dental tissues.3,4 They solubilize the smear layer, demineralize
the dentin, and form a thin hybrid layer, providing the desired
adhesion. Besides this micromechanical interlocking through
hybridization, Inoue et al. reported that the long-term durabil-
ity of adhesive-dentin bonds depends on the hydrolytic stabil-
ity of the functional monomer and its chemical interaction
potential with the dental tissue.5 Therefore, extensive research
has been conducted to develop new monomers with acidic
functional groups, which may strongly bond to HAp.
Bisphosphonates, structural analogues of naturally existing
pyrophosphate with increased chemical and enzymatic stabil-
ity, have strong affinity for HAp.6 Moreover, it was also
reported that bisphosphonates can inhibit enzymes (metallo-
proteinases) which degrade the collagen network.7–9 Recently,
bisphosphonate-containing monomers were investigated for
self-etching dental adhesive applications.10–12 They facilitate
adhesion of dental restoratives and orthodontic appliances to
dental tissue.
The most common problems of self-etching adhesives are
their hydrolysis in the aqueous environment because water
is an important ingredient in these systems. In recent years,
self-etching adhesive monomers and filling composites con-
taining hydrolytically stable ether and amide linkages were
synthesized to overcome the problem of hydrolysis.10–27
In this study, we designed two groups of novel dental mono-
mers with improved properties such as hydrolytic stability,
ability to form bonds with the tooth material and high rate
of copolymerization with dental monomers (Fig. 1). The first
group monomers are bismethacrylamides based on ether
dimers of alkyl a-hydroxymethyl acrylates (RHMA), with
bisphosphonate or bisphosphonic acid functional groups. The
second group monomers are methacrylamides based on
methacryloyl chloride, with same functional groups.
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FIGURE 1 Structures of synthesized monomers.
Monomers of both groups are expected to be hydrolytically
stable since they contain amide and ether linkages instead of
instable ester bonds. The presence of bisphosphonate/
bisphosphonic acid group will improve the monomers’ capa-
bility of etching enamel and dentin and their interaction
with HAp.
Monomer Synthesis
Synthesis of Monomer 1
To a solution of tetraethyl aminomethyl-bis(phosphonate)
(0.716 g; 2.36 mmol) and anhydrous pyridine (0.188 g;
2.36 mmol) in 2 mL of dry dichloromethane, 2-(2-chloro-
carbonyl-allyloxymethyl)-acryloylchloride (0.239 g; 1.072
mmol) in 2.52 mL of dry dichloromethane was added
dropwise in an ice bath under N2. After stirring overnight
at room temperature, 20 mL of chloroform was added and
the solution was extracted with distilled water (3 ꢁ 8
mL), 2M cold HCl (3 ꢁ 12 mL), 2M cold NaOH (3 ꢁ 8
mL), and brine (1 ꢁ 8 mL). After drying the organic phase
with anhydrous Na2SO4, the solvent was evaporated. The
crude product was purified by reversed-phase flash chro-
matography on C18, eluting with H2O:MeOH (50:50) to
give monomer 1 as a white solid with a melting point of
71–72 ꢀC in 20% yield.
EXPERIMENTAL
Materials
Tetraethyl aminomethyl-bis(phosphonate), 2-(2-carboxy-ally-
loxymethyl)-acrylic acid, and 2-(2-chlorocarbonyl-allyloxy-
methyl)-acryloylchloride were prepared according to litera-
ture procedures.28–30 Methacryloyl chloride, triethyl amine,
2-hydroxyethyl methacrylate (HEMA), 2,2-bis[4-(2-hydroxy-
3-methacryloyloxypropyloxy) phenyl] propane (Bis-GMA),
hydroxyapatite (HAp), and Na2SO4 were purchased from
Aldrich and used as received. Trimethylsilyl bromide
(TMSBr) (Aldrich, Taufkirchen, Germany) was distilled before
use. The thermal initiators 2,20-azobis(isobutyronitrile)
(AIBN) and 2,20-azobis(N, N-amidinopropane) dihydrochlor-
ide (V-50) and the photoinitiators 2,20-dimethoxy-2-phenyl
acetophenone (DMPA) and bis(2,4,6-trimethylbenzoyl)phe-
nylphosphine oxide (BAPO) were obtained from Aldrich and
used without further purification. Dichloromethane (CH2Cl2)
was dried over molecular sieves. All other solvents and start-
ing materials were obtained from Aldrich and used as
received.
1H NMR (CDCl3): 1.29 (qt, 24H, CH3), 4.06–4.21 (m, 16H,
CH2AOAP), 4.27 (s, 4H, OACH2), 5.08 (d of t, 2H, CHAP),
5.69, 6.10 (s, 4H, C¼¼CH2), 7.29 (d, 2H, NH) ppm.
13C NMR (CDCl3): 16.62 (CH3), 42.09, 43.55, 45.01 (CHAP),
63.54 (OACH2ACH3), 69.79 (OACH2AC), 124.63 (C¼¼CH2),
138.28 (C¼¼CH2), 165.58 (C¼¼O) ppm. 31P NMR (CDCl3):
16.06 ppm. FTIR: 3468, 3246 (NAH), 2983, 2908 (CAH),
1672 (C¼¼O), 1628 (C¼¼C), 1517 (NH), 1254 (P¼¼O), 1014
and 967 (PAOAEt) cmꢂ1
.
ELEM. ANAL, Calcd. for
C26H52N2P4O15: C, 41.27%; H, 6.93%; N, 3.70%; P, 16.38%; O
Characterization
31.72%. Found: C, 40.85%; H, 7.17%; N, 3.70%.
1H NMR, 13C NMR, and 31P NMR spectroscopy (Varian
Gemini 400 MHz) and Fourier transform infrared (FTIR)
spectroscopy (T380) were used for monomer characteriza-
tion. The photopolymerizations were performed on a TA
Instruments Q100 differential photocalorimeter. Thermogra-
vimetric analysis (TGA) was done with a TA Instrument Q50.
Elemental analyses were obtained from Thermo Electron SpA
FlashEA 1112 elemental analyzer (CHNS separation column,
PTFE; 2 m; 6 ꢁ 5 mm). Combi Flash Companion Teledyne
ISCO Flash Chromatography was used for purification of
monomers. Gel permeation chromatography (Viscotek) was
carried out with THF solvent using polystyrene standards.
Synthesis of Monomer 2
TMSBr (0.904 g; 5.906 mmol) was added dropwise to a solu-
tion of monomer 1 (0.372 g; 0.4921 mmol) in 2.12 mL dry
dichloromethane in an ice bath and under N2. After stirring
for 4 h at 40 ꢀC, the volatile components were removed
under vacuum. Methanol (6.5 mL) was added and the mix-
ture was stirred at room temperature overnight. After re-
moval of the solvent, the crude product was purified by
reversed-phase flash chromatography on C18, eluting with
H2O to give monomer 2 as a clear, colorless viscous oil in
58% yield.
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1H NMR (MeOD:D2O 1:1 v/v): 4.19, 4.26 (d, 4H, OACH2),
4.80 (2H, CHAP), 5.73, 5.81, 5.89, 6.02 (s, 4H, C¼¼CH2) ppm.
13C NMR (MeOD:D2O 1:1 v/v): 29.29, 29.85, 30.45 (CHAP),
69.76 (CH2AO), 123.92, 125.39 (C¼¼CH2), 138.48, 141.11
(C¼¼CH2), 168.19 (C¼¼O) ppm. 31P NMR (D2O): 13.53 ppm.
FTIR: 3306 (NAH), 3000–2600 (OH), 2914 (CAH), 1652
(C¼¼O), 1610 (C¼¼C), 1522 (NH), 1140 (P¼¼O), 998 and 915
initiator. The homopolymer was not soluble. The copoly-
merization was done in two different ratios, TBEED:1,
90:10 and 80:20 mol %. The copolymers were purified
by precipitation into methanol:water (5:1) mixture where
both monomers are soluble.
ii. The copolymerization of monomer 2 (18 mg and 0.0338
mmol) with acrylamide (AAm, 45.8 mg, and 0.6445
(PAO) cmꢂ1
.
ꢀ
mmol) was carried out in 0.06 mL of water at 65 C with
V-50 (0.64 mg and 0.0023 mmol). The resulting cross-
linked polymer was washed several times with water to
remove unreacted monomers and dried under vacuum.
iii. The copolymerization of monomer 2 (22 mg and 0.0413
mmol) with HEMA (48.4 mg and 0.372 mmol) was car-
ried out in 0.03 mL of ethanol at 50 ꢀC with AIBN (6.7
mg and 0.034 mmol). The resulting crosslinked polymer
was washed several times with ethanol and dried under
vacuum.
iv. The homopolymerization of monomer 3 was carried out
in bulk at 65 ꢀC with 2 mol % AIBN as initiator. The
polymer was purified by precipitation into hexane with a
few drops of ether.
Synthesis of Monomer 3
To a solution of tetraethyl aminomethyl-bis(phosphonate)
(0.303 g; 1.00 mmol) and triethylamine (0.21 mL; 1.50
mmol) in anhydrous dichloromethane (2.8 mL) was added
methacryloyl chloride (0.16 mL; 1.65 mmol) in anhydrous
ꢀ
dichloromethane (1.63 mL) at 0 C, under N2 and the result-
ing mixture was stirred at room temperature for 2 h. The
reaction was stopped by addition of distilled water (1.63
mL). The organic layer was washed with distilled H2O (1 ꢁ
5 mL), 2M HCl (1 ꢁ 5 mL), saturated NaHCO3 (1 ꢁ 5 mL),
and distilled H2O (1 ꢁ 5 mL) and dried over anhydrous
Na2SO4 and filtered. After removal of the solvent, the crude
product was purified by reversed-phase flash chromatogra-
phy on C18, eluting with H2O:MeOH (50:50) to give mono-
mer 3 as a white solid with a melting point of 33–34 ꢀC in
36% yield.
Photopolymerization
The photopolymerizations were carried out using a DSC
equipped with a mercury arc lamp. The samples (3–4 mg)
containing 2.0 mol % initiator were irradiated for 10 min ꢂa2t
1H NMR (CDCl3): 1.33 (q, 12H, OCH2CH3), 1.98 (s, 3H, CH3),
4.17 (m, 8H, CH2AOAP), 5.10 (d of t, 1H, CHAP), 5.42, 5.74
(s, 2H, C¼¼CH2), 6.45, 6.47 (d, 1H, NH) ppm. 13C NMR
(CDCl3): 16.28 (OCH2CH3), 18.57 (CH3), 42.17, 43.63, 45.09
(CHAP), 63.53, 63.69 (CH2AOAP), 120.66 (C¼¼CH2), 139.21
(C¼¼CH2), 167.42 (C¼¼O) ppm. 31P NMR (CDCl3): 16.42 ppm.
FTIR: 3471, 3256 (NAH), 2984, 2933 (CAH), 1668 (C¼¼O),
1626 (C¼¼C), 1518 (NH), 1250 (P¼¼O), 1014 and 971
ꢀ
40 and 72 C with an incident light density of 20 mW cm
under a nitrogen flow of 20 mLminꢂ1. Rates of polymeriza-
tion were calculated according to the following formula:
ðQ=sÞM
Rate ¼
nDHpm
(PAOAEt) cmꢂ1
.
where Q/s is the heat flow per second, M the molar mass of
the monomer, n the number of double bonds per monomer
molecule, DHp the heat released per mole of double bonds
reacted, and m the mass of monomer in the sample. The the-
oretical value used for DHp was 13.12 kcalmolꢂ1 for metha-
crylamide double bonds.31,32
Synthesis of Monomer 4
TMSBr (0.742 g; 4.848 mmol) was added dropwise to a solu-
tion of monomer 3 (0.3 g; 0.808 mmol) in 3.5 mL dry
dichloromethane in an ice bath and under N2. After stirring
for 2 h at 40 ꢀC, the volatile components were removed
under vacuum. Methanol (11 mL) was added and the mix-
ture was stirred at room temperature overnight. After
removal of the solvent, the crude product was purified by
reversed-phase flash chromatography on C18, eluting with
H2O to give monomer 4 as a white solid in 95% yield.
Hydrolytic Stability
The hydrolytic stability of the monomers was investigated by
1H NMR measurements of 2 wt % solutions of the mono-
mers in methanol-d6/D2O (1:1 v/v) after storage at 37 ꢀC
for 1 month.
1H NMR (D2O): 1.87 (s, 3H, CH3), 4.66 (t, 1H, CHAP), 5.43,
5.67 (s, 2H, CH2¼¼C) ppm. 13C NMR (D2O): 17.47 (CH3),
46.57 (CHAP), 121.70 (C¼¼CH2), 138.54 (C¼¼CH2), 170.85
(C¼¼O) ppm. FTIR: 3338 (NAH), 3000–2600 (OH), 2920
(CAH), 1651 (C¼¼O), 1610 (C¼¼C), 1533 (NH), 1118 (P¼¼O),
RESULTS AND DISCUSSION
Synthesis and Characterization of Monomers
The new bisphosphonate-containing bis(methacrylamide) (1)
was synthesized in four steps: (i) synthesis of tert-butyl a-
hydroxymethacrylate-ether derivative (TBEED) from the
reaction of tert-butyl acrylate and paraformaldehyde in the
presence of 1,4-diazabicyclooctane (DABCO) as catalyst, (ii)
conversion to a carboxylic acid by cleavage of tert-butyl
groups using trifluoroacetic acid, (iii) conversion to an acid
chloride by using oxalyl chloride, and (iv) reaction of the
acid chloride and tetraethyl aminomethyl-bis(phosphonate)
(Fig. 2). After purification by flash chromatography, this
954 and 922 (PAO) cmꢂ1
.
Thermal Polymerizations
The thermal homopolymerizations and copolymerizations
were carried out with standard freeze-evacuate-thaw
procedures:
i. The homopolymerization and copolymeriꢀzation of mono-
mer 1 was carried out in solution at 80 C with AIBN as
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FIGURE 2 Synthesis of monomers 1 and 2.
monomer was isolated in 20% yield, as a white solid (m.p.
71–72 C), which is soluble in polar organic solvents such as
methylene chloride, acetone, ether, ethanol, and THF and in
water (Table 1).
The silylation of monomer 1 with TMSBr and methanolysis
of the silyl ester groups provided the new bisphosphonic
acid-containing bis(methacrylamide) (2). This monomer was
obtained as clear viscous oil in 58% yield after purification
by C18 reversed-phase flash chromatography. Monomer 2
dissolves very well in water, which is very important for
dental adhesive applications (Table 1). The FTIR spectrum of
monomer 2 shows broad peaks in the region of 3000–2600
cmꢂ1 and 2300–2100 cmꢂ1 due to OH stretching, 1670–
1600 cmꢂ1 due to OH bending and strong peaks at 1652,
1610, and 1522 cmꢂ1 due to C¼¼O, C¼¼C, and NH stretching,
respectively. Also the strong bands at 998 and 915 cmꢂ1 cor-
respond to the symmetric and asymmetric vibration of PAO.
1H NMR spectrum of monomer 2 shows the complete disap-
pearance of bisphosphonic ester peaks at 1.29 and 4.06–4.21
ppm (Fig. 5). Monomer 2 also showed two sets of double
bond and methylene peaks due to different resonance forms
of the amide linkage and one form is strengthened after
hydrolysis.
ꢀ
The characterization of this monomer was carried out by
1
FTIR, H NMR, 13C NMR, and 31P NMR spectroscopy, as well
as elemental analysis. The spectral data are in agreement
with the expected structure of the monomer. For example,
the single bisphosphonate proton is supported by the pres-
ence of a doublet of triplet at 5.08 ppm. Other characteristic
peaks of this monomer were methyl protons at 1.29 ppm,
methylene protons adjacent to oxygen at 4.06–4.21 and 4.27
ppm and double bond hydrogen at 5.69 and 6.10 ppm (Fig.
3). The peak at 7.29 ppm is typical for the NH peak of car-
bamide group. In the 13C NMR spectrum, the triplet seen at
42.09, 43.55, and 45.01 ppm is due to methine carbon
attached to two phosphorus (Fig. 4). The peak of the phos-
phorus atom at 16.06 ppm in the 31P NMR spectrum is char-
acteristic for the phosphonate group. In the FTIR spectra,
this monomer showed characteristic peaks at 3400–3300
cmꢂ1 (amide V region), 1672 cmꢂ1 (amide I region), and
1517 cmꢂ1 (amide II region). Monomer 1 also showed
absorption peaks of C¼¼C, P¼¼O, and PAO peaks at 1628,
The new bisphosphonate-containing methacrylamide (3) was
synthesized in one step by the reaction of methacryloyl chlo-
ride and tetraethyl aminomethyl-bis(phosphonate) in the
presence of triethylamine (Fig. 6). This monomer was
obtained as a white solid with a melting point of 33–34 ꢀC
in 36% yield after purification by flash chromatography. It is
well soluble in common organic solvents such as hexane,
methylene chloride, acetone, ether, ethanol, THF, and in
water (Table 1). The structure of monomer 3 was proved by
FTIR, 1H NMR, 13C NMR, and 31P NMR spectroscopy. In the
1H NMR spectrum, the single bisphosphonate proton is pres-
ent as a doublet of triplet at 5.10 ppm (Fig. 7). Besides, the
structure of this monomer is supported by the presence of
methyl protons at 1.33 and 1.98 ppm, methylene protons at
4.17 ppm and double bond hydrogens’ at 5.42 and 5.74
1254, 1014, and 967 cmꢂ1
.
TABLE 1 Solubility of Monomers 1–4
H2O
Ethanol
THF
Acetone
Diethyl ether
CH2Cl2
1
2
3
4
þ
þ
þ
þ
þ
þ
þ
þ
þ
ꢂ
þ
ꢂ
þ
ꢂ
þ
ꢂ
þ
ꢂ
þ
ꢂ
þ
ꢂ
þ
ꢂ
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FIGURE 3 1H NMR spectrum of monomer 1.
ppm. In the 31P NMR spectrum, one peak at 16.42 ppm con-
firmed the purity of this monomer. Satisfactory microanalysis
results were obtained for this monomer.
triplet at 4.66 ppm stands for the methine attached to the
two phosphorus atoms.
Acidity, Interactions with HAP, and Stability of Acid
Monomers
Monomer 3 was converted to the new bisphosphonic acid
containing methacrylamide, monomer 4, by the reaction with
TMSBr (Fig. 6). After purification by flash chromatography,
monomer 4 was isolated with excellent yield (95%) as a
white solid, soluble in water. Upon heating to 250 ꢀC, no
melting point was observed. In the 1H NMR, the disappear-
ance of the characteristic peaks of the ethyl groups of the
phosphonates at 1.33 and 4.17 ppm shows that the depro-
tection is complete (Fig. 8). The double bond protons are
characterized as two singlets at 5.43 and 5.67 ppm. The
The pH value of aqueous solution of monomer 2 (5 wt %)
and 4 (2 wt %) was found to be 1.10 and 1.21, indicating
their enamel etching ability. The addition of 15, 30, and 60
mg HAp, a model compound for dentin and enamel, to the
solutions of monomer 2 resulted in increases in the pH val-
ues to 1.65, 1.90, and 3.34, respectively.
We expected that monomers 2 and 4 would be more hydro-
lytically stable compared with commercial dentin adhesives
FIGURE 4 13C NMR spectrum of monomer 1.
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FIGURE 5 1H NMR spectrum of monomer 2.
such as 2-(methacryloyloxy)-ethyl dihydrogen phosphate
(MEP) or 10-(methacryloyloxy)-decyl dihydrogen phosphate
(MDP) due to the presence of amide linkages instead of ester
linkages, since it is known that amides are more hydrolyti-
cally stable than esters under acidic conditions due to lower
reactivity of amide carbonyl. However, it was difficult to pre-
dict the stability of monomers 2 and 4, which contain acid
groups within the same structure. Therefore, hydrolytic sta-
bility of the acid monomer 2 was investigated by recording
1H NMR spectroscopy of their 2 wt % solutions in methanol-
sterically inhibit intermolecular addition and increase cycli-
zation efficiency. In addition, cyclization efficiency increases
at high temperatures and dilute conditions. Moszner et al.
and our group prepared bis(methacrylamide)s from TBEED
using propyl amine, diethyl 2-aminoethylphosphonate, and
diethyl 1-aminomethylphosphonate and found high crosslink-
ing tendency of these monomers.27,33
Thermal solution homopolymerizations and copolymeriza-
tions of monomer 1 were conducted under the same condi-
tions as TBEED to see the effect of bisphosphonate substitu-
ꢀ
d6/D2O (1:1) after storage at 37 C. After 30 days of storage,
ent (Table 2). Monomer
1 gave crosslinked polymers,
the 1H NMR spectrum showed no decrease of the peaks
assigned to monomer 2, showing its stability for at least one
month.
indicating its low cyclization efficiency. Our efforts to
decrease polymerization time to obtain soluble polymers
were not successful, giving just milky solutions. However,
TBEED gave soluble or crosslinked polymers under similar
conditions. Although crosslinked polymers of TBEED were
obtained as clear gels, crosslinked polymers of monomer 1
were white solid powders. The labile hydrogen between two
phosphonate groups in monomer 1 probably results in chain
transfer reaction, giving unexpectedly high crosslinking
Thermal Polymerizations
In general, polymerization of ether dimers of a-hydroxyme-
thacrylates, which have 1,6-heptadiene structure gives solu-
ble or crosslinked polymers depending on monomer struc-
ture and polymerization conditions.29 It was observed that
bulky ester groups such as tert-butyl and adamantyl
FIGURE 6 Synthesis of monomers 3 and 4.
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FIGURE 7 1H NMR spectra of monomer 3 and poly-3.
tendency despite a bulky bisphosphonate substituent and
low molecular weight crosslinked polymers. To check the
possibility of hydrogen abstraction, the photopolymerization
of this monomer in the presence of benzophenone (BP) was
tried. Although no polymerization was observed without BP,
utilization of BP (2 mol %) resulted in 33% conversion,
indicating presence of the labile hydrogens under our photo-
polymerization conditions.
of one of the copolymers, TBEED:1 (80:20 mol %), with a
peak at 1018 cmꢂ1 due to PAO stretching supported the
incorporation of monomer 1 into the copolymer. However, it
was difficult to calculate copolymer composition using 1H
NMR due to overlapping peaks. The lower number average
molecular weight (Mn) of the copolymers (around 20,000)
than that of homopolymer of TBEED indicated the impor-
tance of chain transfer reactions.
Monomer 1 was copolymerized with TBEED so that we
could obtain soluble polymers. The copolymers showed simi-
lar solubility with poly-TBEED except they were insoluble in
hexane where poly-TBEED was soluble. The FTIR spectrum
The thermal stability of polꢂy-11 was investigated by TGA
under nitrogen at 10 ꢀC min and compared with that of
poly-TBEED. Poly-TBEED started to lose weight (40%)
around 200 ꢀC due to decomposition of tert-butyl ester
FIGURE 8 1H NMR spectrum of monomer 4.
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TABLE 2 Thermal Polymerization Results of Monomers 1, 3, TBEED, and TBEED:1 (90:10 mol %)
Monomer
[M]
Temperature (ꢀC)
[AIBN]
Solvent
Time (min)
Conversion (%)
Mn
TBEED
1.26
1.31
1.30
1.26
1.26
1.30
1.30
1.30
–
80
80
80
80
80
80
80
80
65
65
0.0350
0.0380
0.0380
0.0350
0.0350
0.0380
0.0380
0.0380
2 mol %
2 mol %
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
–
6
Crosslinked
–
TBEED
35
21
180
120
21
28
45
10
13
38
49,118
TBEED
Crosslinked
–
–
1
Crosslinked
1
No polymer
TBEED:1 (90:10 mol %)
Crosslinked
–
TBEED:1 (90:10 mol %)
54
43
40
21
22,450
26,650
32,000
–
TBEED:1 (90:10 mol %)
3
3
–
–
group and then degraded (40%) at around 375 ꢀC. Poly-1
was found to be more stable than poly-TBEED, starting to
decompose around 225 ꢀC and then degraded gradually to
give higher char yield of 53.42% compared with poly-TBEED
(11.83%) at 575 ꢀC. This high char yield is probably due to
the formation of bisphosphonic acid, which causes crosslink-
ing reactions during degradation.
Photopolymerization
The polymerizability of monomer 1 was found to be similar
to TBEED with the maximum rates of polymerizations of
0.0508 and 0.0554 sꢂ1 and conversions of 87 and 82% for 1
and TBEED. At maximum rate of polymerizations, 47 and 24
mol % of the double bonds were reacted for monomers
TBEED and 1. The reason for lower conversion at maximum
rate for monomer 1 indicates earlier gelation due to higher
crosslinking tendency of this monomer compared with
TBEED.
Thermal bulk homopolymerization of monomer 3 with AIBN
gave soluble polymers in 10 min at 40% conversion, indicat-
ing its high reactivity (Table 2). The polymer was soluble in
dichloromethane, acetone, ether, and water but insoluble in
hexane. 1H NMR spectrum of this polymer indicated com-
plete disappearance of the double bond peaks at 5.42 and
5.74 ppm after polymerization (Fig. 7). The number average
molecular weight (Mn) for this polymer was around 32,000
as estimated by gel permeation chromatography. The DSC
analysis for this polymer showed no glass-transition temper-
To test the use of monomer 1 as reactive diluent in filling
composites and also crosslinking monomer in dental adhe-
sives, we investigated its copolymerization with Bis-GMA and
HEMA. The results (Fig. 9 and Table 3) show that the poly-
merization rate of monomer 1 is lower than Bis-GMA but
slightly higher than HEMA. The conversions follow the order:
HEMA> 1> Bis-GMA. Addition of 10 mol % of monomer 1
to Bis-GMA slightly decreased its rate without changing its
conversion. However, addition of 10 mol % of monomer 1 to
HEMA did not change its rate but decreased its conversion
due to crosslinking.
ꢀ
ature from 0 to 160 C.
To test the potential of monomer 2 to be used in dental
adhesives, the copolymerization kinetics of this monomer
with HEMA using a water-soluble initiator BAPO were inves-
tigated. Various formulations consisting of mixtures of HEMA
and water (60:40 wt %); HEMA, 2 and water (at different
ratios) were photopolymerized. Figure 10 shows that addi-
tion of 5–20 wt % of 2 to HEMA resulted to gradual
decreases in both conversion and rate of polymerization.
TABLE 3 Photopolymerization results of HEMA, Bis-GMA, 1,
Bis-GMA:1 (90:10 mol %), and HEMA:1 (90:10 mol %) at 728C
Monomer
Rp (sꢂ1
)
Conversion (%)
1
0.051
0.099
0.045
0.083
0.046
84
67
92
65
77
Bis-GMA
HEMA
FIGURE 9 Rate-time and conversion-time curves in the homo-
polymerization and copolymerizations of 1 with HEMA and Bis-
GMA at 72ꢀC.
Bis-GMA:1 (90:10 mol %)
HEMA:1 (90:10 mol %)
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FIGURE 10 Rate-time and conversion-time curves in the
copolymerizations of 2 with HEMA using BAPO at 40ꢀC.
In addition, slight shift in the peak maximum indicated
incorporation of monomer 2 into copolymers.
FIGURE 12 Rate-time and conversion-time curves during
copolymerizations of 4 with HEMA using BAPO at 72ꢀC.
Homopolymerizations and copolymerization behavior of
monomer 3 with HEMA were also investigated with photo-
differential scanning calorimetry using DMPA as photoinitia-
tor (Fig. 11). The rate of polymerizations for monomer 3 fea-
tures a lower maximum (0.013 sꢂ1), which however keeps
flat for a long time, in contrast to the narrow peaks for
HEMA or the HEMA-3 mixture (maximum 0.034 sꢂ1). This
results in total conversion of 3 that is not significantly less
than HEMA or the HEMA-3 mixture (64 vs. 82%). The lower
compared with HEMA may possibly be explained due to
steric effect of the bulky bisphosphonate group. Addition of
10 mol % of monomer 3 to HEMA, decreased its rate with-
out changing its conversion significantly.
Monomer 4 was also copolymerized with HEMA using a
water soluble initiator BAPO to observe its performance as
dental adhesive monomer. The formulations consisting of
mixtures of HEMA and water (60:40 wt %); HEMA, 4 and
water (50:10:40 wt %), and HEMA, 4 and water (57:3:40 wt
%) were photopolymerized. Addition of 3 and 10 wt % of
monomer 4 to HEMA resulted in slight improvements in the
rate of polymerization w.r.t. pure HEMA, without changing its
conversion (Fig. 12).
maximum rate of photopolymerization of monomer
3
Thermal Copolymerizations of Monomer 2
Thermal homopolymerization of monomer 2 was not investi-
gated due to its very low photopolymerization rate. However,
to check the incorporation of monomer 2 into the copolymers,
its thermal solution copolymerizations with AAm and HEMA
were investigated. Monomer 2 was copolymerized with AAm
(5:95 mol %) in water at 65 ꢀC with V-50 as initiator.
Although AAm homopolymerizes in 4 min to give soluble
polymers, its copolymerization with 2 took more than 12 h.
Crosslinked copolymers precipitated as white solid powders
which indicate the incorporation of monomer 2. Monomer 2
was also copolymerized with HEMA (10:90 mol %) in ethanol
ꢀ
at 50 C with AIBN as initiator. The addition of monomer 2 to
HEMA decreased its polymerization rate: HEMA homopoly-
merize in 45 min giving clear gels, but the copolymer formed
in more than 12 h giving a white solid crosslinked polymer.
FTIR spectrum of one of the copolymers (after removal of re-
sidual monomers) indicated OH, C¼¼O peaks of HEMA at
FIGURE 11 Rate-time and conversion-time curves during poly-
merizations of 3, HEMA and HEMA:3 (90:10 mol %) at 40ꢀC.
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3309 and 1720 cmꢂ1 and additional peaks due to C¼¼O and
NAH peaks of monomer 2 at 1657 and 1530 cmꢂ1, which
proved its incorporation into the copolymer.
9 Boissier, S.; Ferreras, M.; Peyruchaud, O.; Magnetto, S.; Ebe-
ꢀ
ꢀ
tino, F. H.; Colombel, M.; Delmas, P.; Delaisse, J.-M.; Clezardin,
P. Cancer Res. 2000, 60, 2949–2954.
10 Bala, J. L. F.; Kashemirov, B. A.; McKenna, C. E. Synth.
Commun. 2010, 40, 3577–3584.
CONCLUSION
11 Abuelyaman, A. S.; Boardman, G. S.; Shukla, B. A.; Aasen,
S. M.; Mitra, S. B.; Mikulla, M.; Cinader, D. K. (3M Innovative
Properties Company). U.S. Patent 0,206,932 A1, 2004.
We have successfully synthesized four novel monomers at
high purity. The first two are bismethacrylamides, and the
second group is methacrylamides, in each group one mono-
mer containing a bisphosphonate and the other a bisphos-
phonic acid functional group.
12 Catel, Y.; Besse, V.; Zulauf, A.; Marchat, D.; Pfund, E.; Pham,
T.-N.; Bernache-Assolant, D.; Degrange, M.; Lequeux, T.;
Madec, P.-J.; Pluart, L. L. Eur. Polym. J. 2012, 48, 318–330.
13 Moszner, N.; Zeuner, F.; Rheinberger, V. (Ivoclar Vivadent
AG). U.S. Patent 6,172,131 B1, 2001.
The polymerization studies of the bisphosphonate-containing
bismethacrylamide indicated high reactivity, crosslinking and
chain transfer tendency. The photopolymerization reactivity
of this monomer was comparable to TBEED. The copolymer-
ization results with Bis-GMA and HEMA indicated that this
highly reactive monomer might possess potential as reactive
diluent for dental composites. The bisphosphonate-contain-
ing methacrylamide was also found to be highly reactive but
gave soluble polymers.
14 Moszner, N.; Pavlinec, J.; Lamparth, I.; Zeuner, F.; Anger-
mann, J. Macromol. Rapid Commun. 2006, 27, 1115–1120.
15 Catel, Y.; Degrange, M.; Pluart, L. L.; Madec, P.; Pham, T.;
Picton, L. J. Polym. Sci. Part A: Polym. Chem. 2008, 46, 7074–7090.
16 Klee, J. E.; Lehmann, U. Beilstein J. Org. Chem. 2009, 5,
1–9.
17 Pavlinec, J.; Zeuner, F.; Angermann, J. Macromol. Chem.
Phys. 2005, 206, 1878–1886.
18 Klee, J. E.; Walz, U. (Dentsply DeTrey GmbH). U.S. Patent
6,812,266, 2004.
The bisphosphonic acid-containing monomers showed good
performance in terms of solubility, acidity, and copolymeriz-
ability with HEMA. Hydrolytic stability was found to be good
for the bismethacrylamide, and conjectured to be so for the
methacrylamide, since the former has two bisphosphonic
acid groups. The first monomer, as representative of both
bisphosphonic acid-containing monomers, was also found to
interact with HAp, which serves as representative of dental
tissue.
19 Salz, U.; Mucke, A.; Zimmerman, J.; Moszner, N.; Zeuner, F.;
Rheinberger V. (Ivoclar Vivadent AG). U.S. Patent 0,130,701 A1,
2006.
20 Erdmann, C.; Ziegler, S.; Neffgen, S.; Bolln, C.; Muhlbauer,
W.; Luck, R. (Ernst Muhlbauer GmbH&Co). U.S. Patent
6,902,608, 2005.
21 Moszner, N.; Zeuner, F.; Pfeiffer, S.; Schurte, I.; Rheinberge,
V.; Drache, M. Macromol. Mater. Eng. 2001, 286, 225–231.
22 Salz, U.; Zimmermann, J.; Zeuner, F.; Moszner, N. J. Adhes.
Dent. 2005, 7, 107–116.
We conclude that the shelf life and bonding reliability of
dental monomers can be increased by utilizing these four
monomers.
23 Sahin, G.; Albayrak A. Z.; Bilgici, Z. S.; Avci, D. J. Polym.
Sci. Part A: Polym. Chem. 2009, 47, 1953–1965.
24 Albayrak, A. Z.; Saraylı, Z.; Avci, D. Macromol. React. Eng.
2007, 1, 537–546.
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10
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