WO2022178444A1 - Dental adhesives formulated with secondary methacrylamides - Google Patents

Dental adhesives formulated with secondary methacrylamides Download PDF

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WO2022178444A1
WO2022178444A1 PCT/US2022/017365 US2022017365W WO2022178444A1 WO 2022178444 A1 WO2022178444 A1 WO 2022178444A1 US 2022017365 W US2022017365 W US 2022017365W WO 2022178444 A1 WO2022178444 A1 WO 2022178444A1
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hemam
methyl
group
hema
dental adhesive
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PCT/US2022/017365
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French (fr)
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Carmem PFIEFER
Oscar Navarro Fernandez
Ana Paula Piovezan Fugolin
Jack FERRACANE
Matthew LOGAN
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Oregon Health & Science University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/60—Preparations for dentistry comprising organic or organo-metallic additives
    • A61K6/62—Photochemical radical initiators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/30—Compositions for temporarily or permanently fixing teeth or palates, e.g. primers for dental adhesives

Definitions

  • the present invention concerns amine ⁇ terminated and methacrylate/methacrylamide monomers for dental adhesive applications.
  • STATEMENT OF GOVERNMENT SUPPORT This invention was made with government support under 1U01 ⁇ DE023756, 1R01 ⁇ DE026113, K02 ⁇ DE025280; R01 ⁇ DE028757; and R35 ⁇ DE029083 awarded by NIH ⁇ NIDCR. The government has certain rights in the invention. BACKGROUND OF THE INVENTION Dental adhesive interfaces with reduced susceptibility to degradation could lead to dental restorations with extended clinical lifetimes.
  • Degradation is the result of two factors: (1) collagen degradation by endogenous proteases [ Mazzoni et al., Endodontic Topics. 2009;21:19 ⁇ 40], [ Tjäderhane et al., Dent Mater. 2013;29:116 ⁇ 35], and (2) polymer hydrolysis.
  • the hydrolysis of dental adhesives – specifically the ester functionality within the polymer – is catalyzed by acid (low pH) as well as bacterial/salivary esterases [Santerre et al., Critical Reviews in Oral Biology & Medicine. 2001;12:136 ⁇ 51], [Tay et al., Journal of Dentistry.
  • This sterically derived hydrolytic stability factor is approximately the same for both ester and amide hydrolysis.
  • additional hydrolytic stability could be imparted to the material both at the ester and the amide groups by the synthetic inclusion of chemically inert methyl groups.
  • One important point to consider is that the same factors that make amide bonds more stable than acrylate bonds also affect polymerization rate (Scheme 2 in supplemental materials). Neat methacrylamides tend to have slower polymerization kinetics compared to methacrylates [Barcelos et al., Dental Materials.
  • methacrylamide ⁇ methacrylate co ⁇ polymerizations can lead to significant gains in dentin bond strength stability, while only marginally affecting polymerization rate [Fugolin et al., Dental Materials. 2019;35:686 ⁇ 96]. It is currently unclear how methylation as mentioned above affects the polymerization kinetics and the final material properties and there remains a need for more stable dental adhesives. SUMMARY OF THE INVENTION Ester ⁇ free monomers have been suggested as more stable alternatives for dental adhesives. Specifically, alpha and beta ⁇ carbon substitutions have been shown to slow down degradation of polymeric networks.
  • the new class of monomers described here comprises systematic variations of mono and hybrid difunctional methacrylate/methacrylamides with alkyl chains being used as substitutions on the alpha or beta positions in relation to the polymerizable group.
  • Monofunctional monomers are shown in Figure 1 and hybrid monomers are shown in Figure 2. All monomers have been synthesized, and selected monomers have been evaluated in terms of kinetics of polymerization and long ⁇ term microtensile bond strength as part of the formulation of dental adhesives.
  • One embodiment herein provides a dental adhesive composition
  • a dental adhesive composition comprising one or more of: a) a hydroxyl ⁇ terminated methacrylamide compound selected from the group of: b) a hydroxyl ⁇ terminated methacrylate compound selected from the group of: ; or c) an amino ⁇ terminated methacrylate compound selected from the group of: ; or d) a di ⁇ functional methacrylamide/methacrylate compound selected from the group of: .
  • FIGURE 1 presents a bar graph of the percentage degree of conversion for three tested monomers.
  • FIGURE 2 presents a line graph representing kinetics of polymerization curves (average of three curves) for six tested monomers.
  • FIGURE 3 presents a line graph representing kinetics of polymerization results at 50 °C for HEMA, HEMAM and 2 ⁇ methyl HEMAM.
  • FIGURE 4 presents a bar graph representing the shear storage modulus values determined for the hybrids HEMAM Hy and 2dMM Hy.
  • FIGURE 5 presents a table of half ⁇ lives for monomers in acidic aqueous conditions at 37°C (data were fit to an exponential decay model).
  • FIGURE 6 depicts steric interactions of ⁇ carbon alkyl substituents have been shown to cause 2° and 3° amides to twist about the C ⁇ N bond.
  • FIGURE 7 presents bar graphs comparing water sorption and solubility determined for tested monomers.
  • FIGURE 8 presents images of comparative cracking in tested polymers.
  • FIGURE 9 presents line graphs representing the kinetics curves profiles of HEMA, HEMAM and HEMAM Hy.
  • FIGURE 10 presents a table of %DC at inflection of a deceleration curve for HEMA, HEMAM, and HEMAN Hy.
  • compositions comprising a compound selected from groups a) ⁇ d) above and one or more comonomers selected from the group of bisphenol A diglycidyl ether dimethacrylate (BisGMA), triethylene glycol dimethacrylate (TEGDMA), urethane dimethacrylate (UDMA), ethylene glycol dimethylacrylate (EGDMA), ethane ⁇ 1,2 ⁇ diyl bis(2 ⁇ methylacrylate) (PEGDMA), ethoxylated bisphenol A dimethacrylate (EBPADMA), ethylene glycoldi(meth)acrylate, hexanediol di(meth)acrylate, tripropylene glycol di(meth)acrylate, butanediol di(meth)acrylate, neopentyl glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate
  • the co ⁇ monomer or co ⁇ monomers selected from this group comprises from about 55% to 65% of the composition, by weight. Still other embodiments provide such compositions comprising at least one monomer and one co ⁇ monomer, as described herein, and further comprising a polymerization initiator, such as one selected from the group of camphorquinone (CQ); trimethylbenzoyl ⁇ diphenyl ⁇ phosphine oxide (TPO); Ethyl ⁇ 4 ⁇ dimethylamino benzoate (EDMAB); 2,2 ⁇ Dimethoxy ⁇ 2 ⁇ phenylacetophenone (DMPA); Bisacylphosphine oxide (BAPO); 1 ⁇ Phenyl ⁇ 1,2 ⁇ propanedione (PPD); phosphine oxide compounds, including naphthacene (APO), 9 ⁇ anthracene (APO), and bisacylphosphine oxide (BAPO); 1 ⁇ phenyl ⁇ 1,2 ⁇ propanedione (PPD); thioxanthone (CQ); tri
  • the polymerization initiator is a combination of initiators, such as those selected from the group of camphorquinone/ethyl ⁇ 4 ⁇ (dimethylamino)benzoate (EDMAB), camphorquinone/2 ⁇ (dimethylamino)ethyl methacrylate (DMAEMA)), DMPA/DPI ⁇ PF6, CQ/PPD, CQ/DMAEMA, CQ/EDMAB, CQ/DMAEMA/PDIHP, or CQ/EDMAB/DPIHP.
  • the polymerization initiator one or both of the group DMPA and DPI ⁇ PF.
  • the polymerization initiator comprises from about 0.05% to about 0.6% of the composition, by weight.
  • the composition also comprises a chemical inhibitor (also referred to as a stabilizer or free radical scavengers ), such as one selected from the group of butylated hydroxytoluene (BHT), hydroquinone, 2,5 ⁇ di ⁇ tert ⁇ butyl hydroquinone, monomethyl ether hydroquinone (MEHQ), and 2,5 ⁇ di ⁇ tertiary butyl ⁇ 4 ⁇ methylphenol, 3,5 ⁇ di ⁇ tert ⁇ butyl ⁇ 4 ⁇ hydroxyanisole (2,6 ⁇ di ⁇ tert ⁇ butyl ⁇ 4 ⁇ ethoxyphenol), 2,6 ⁇ di ⁇ tert ⁇ butyl ⁇ 4 ⁇ (dimethylamino)methylphenol or 2 ⁇ (2′ ⁇ hydroxy ⁇ 5′ ⁇ methylphenyl) ⁇ 2H ⁇ benzotriazole, 2 ⁇ (2′ ⁇ hydroxy ⁇ 5′ ⁇ t ⁇ octylphenyl) ⁇ 2H ⁇ benzotriazole, 2 ⁇ (2′ ⁇ hydroxy ⁇ 4′,6′ ⁇ di ⁇ tert ⁇ pent
  • BHT
  • compositions may also comprise an ultraviolet light (UV) absorber, such as 2 ⁇ hydroxy ⁇ 4 ⁇ methoxybenzophenone (UV ⁇ 9), 2 ⁇ (2 ⁇ Hydroxy ⁇ 5 ⁇ octylphenyl) ⁇ benzotriazole (UV ⁇ 5411), salicylic acid phenyl ester, 3 ⁇ (2′ ⁇ hydroxy ⁇ 5′ ⁇ methylphenyl)benzotriazole, and 2 ⁇ (2' ⁇ hydroxy ⁇ 5' ⁇ methylphenyl) ⁇ benzotriazole.
  • UV absorber may be present in the composition at from about 0.001% to about 0.5%, by weight.
  • the chemical inhibitor is incorporated into the composition at a concentration of from about 0.01% to about 0.5%, by weight.
  • the chemical inhibitor is present in the composition at from about 0.05% to about 0.3%, by weight. In still other embodiments, the chemical inhibitor is present in the composition at from about 0.05% to about 0.2%, by weight. In additional embodiments, the chemical inhibitor is present in the composition at from about 0.05% to about 0.15%, by weight. It is understood that the compositions herein may include further elements, such as a fluorescent agent, a fluoride releasing agent, a radiopaque agent, a flavoring agent, and an antimicrobial agent. Purpose/aim: Ester ⁇ free monomers have been suggested as more stable alternatives for dental adhesives. Specifically, alpha and beta ⁇ carbon substitutions have been shown to slow down degradation of polymeric networks.
  • the aim of this study was to evaluate kinetics of polymerization and long ⁇ term microtensile bond strength of dental adhesives formulated with novel secondary methacrylamides.
  • Materials and methods Secondary methacrylamides with different carbon substitutions (alpha ⁇ 2MM, beta ⁇ 3MM and no substitution ⁇ HEMAM) were copolymerized with UDMA at 40/60 mass ratio. 0.2 wt% DMPA and 0.4 wt% DPI ⁇ PF6 were used as photoinitiators. Polymerization kinetics was followed with near ⁇ IR in real ⁇ time (6165 ⁇ 6135 cm ⁇ 1 ) for 300s at 800 mW/cm 2 (320–500 nm).
  • the dental adhesive compositions herein may include one or more photoinitiator agents.
  • initiator or “polymerization initiator” herein refers to thermal initiating, redox ⁇ initiating, and/or photoinitiating compounds capable of inducing polymerization throughout a significant depth of composite material, such as camphorquinone (CQ); trimethylbenzoyl ⁇ diphenyl ⁇ phosphine oxide (TPO); Ethyl ⁇ 4 ⁇ dimethylamino benzoate (EDMAB); 2,2 ⁇ Dimethoxy ⁇ 2 ⁇ phenylacetophenone (DMPA); Bisacylphosphine oxide (BAPO); 1 ⁇ Phenyl ⁇ 1,2 ⁇ propanedione (PPD); phosphine oxide compounds, including naphthacene (APO), 9 ⁇ anthracene (APO), and bisacylphosphine oxide (BAPO); 1 ⁇ phenyl ⁇ 1,2 ⁇ propanedione (PPD); thioxanthone (TX) and its derivatives; dibenzoyl germanium derivatives, such as be
  • one initiator material may be used or 2 or more may be used, such as the combination of camphorquinone with a co ⁇ initiator, such as a tertiary amine initiator (such as ethyl ⁇ 4 ⁇ (dimethylamino) benzoate (EDMAB) and/or 2 ⁇ (dimethylamino)ethyl methacrylate (DMAEMA)), or a combination of DMPA/DPI ⁇ PF6, CQ/PPD, CQ/DMAEMA, CQ/EDMAB, CQ/DMAEMA/PDIHP, or CQ/EDMAB/DPIHP.
  • a co ⁇ initiator such as a tertiary amine initiator (such as ethyl ⁇ 4 ⁇ (dimethylamino) benzoate (EDMAB) and/or 2 ⁇ (dimethylamino)ethyl methacrylate (DMAEMA)
  • EDMAB tertiary amine initiator
  • photoinitiators for use with the present compositions include monoacylphoshine oxide (MAPO, available from Lucirin TPO, BASF), bisacylphosphine oxide (BAPO, Irgacure 819, Ciba Geigy), phenylpropanedione (PPD, Aldrich), and camphorquinone (CQ, Aldrich).
  • MAPO monoacylphoshine oxide
  • BAPO bisacylphosphine oxide
  • PPD phenylpropanedione
  • CQ camphorquinone
  • Tested Co ⁇ monomers The commercially ⁇ available monomers used in this study were purchased from Sigma Aldrich (Milwaukee, WI, USA) at 95% or greater purity, and used as received: 2 ⁇ hydroxyethyl methacrylate – HEMA, 2 ⁇ hydroxyethyl methacrylamide – HEMAM, 2 ⁇ hydroxy ⁇ 2 ⁇ methylethyl methacrylamide – 2 ⁇ methyl HEMAM. Hydroxypropyl methacrylate was obtained as a mixture of isomers consisting of the ⁇ substituted 2 ⁇ hydroxy ⁇ 1 ⁇ methylethyl methacrylate – 1 ⁇ methyl HEMA, and ⁇ substituted 2 ⁇ hydroxy ⁇ 2 ⁇ methylethyl methacrylamide – 2 ⁇ methyl HEMA.
  • composition of the mixture was determined by 1 H NMR spectroscopy to be 72% 2 ⁇ methyl HEMA and 28% 1 ⁇ methyl HEMA, consistent with the distributer's analysis.
  • the hydroxypropyl methacrylate isomeric mixture was used as received due to facile isomerization equilibrium (discussed later).
  • 2 ⁇ hydroxy ⁇ 1 ⁇ methylethyl methacrylamide – 1 ⁇ methyl HEMAM was synthesized de novo (see supplementary information). The structures of all monomers used in this study are shown below.
  • the monomers above may be copolymerized with monomers, particularly dental resin monomers (UDMA, BisGMA, etc.), in dental adhesive compositions.
  • UDMA dental resin monomers
  • UDMA dental resin monomers
  • BisGMA BisGMA
  • AEMA aminoethyl methacrylate
  • Spectra were collected for 330 s, with 2 scans per spectrum at 4 cm ⁇ 1 resolution. The light was kept on for the duration of the experiment to provide isothermal conditions, and avoid overestimation of conversion due to potential IR pathlength reduction (had the light been turned off during the experiment, causing shrinkage of the specimen). The followed peaks were 6165 and 6135 cm ⁇ 1 for methacrylates and methacrylamides, respectively.
  • the maximum rate of polymerization (RP MAX ) was calculated as the first derivative of the degree of conversion vs. time curve, and the final degree of conversion (Final DC) was based on the change in area of the vinyl overtone peaks.
  • the degree of conversion at the maximum rate of polymerization (DC at RP MAX ) was used as a proxy for the onset of vitrification. Since the ⁇ substituted secondary methacrylamide 2 ⁇ methyl AEMA was not soluble in the organic matrix at room temperature, the mixture was heated on a hot plate to 50 °C and the kinetics tested immediately at the same conditions described above. For an appropriate comparison, the methacrylamide and methacrylate controls – HEMAM and HEMA, were also tested at 50 ⁇ C, as controls. Formulations that did not cure or cured very slowly were not subjected to dentin microtensile bond strength or monomer hydrolysis kinetics.
  • Dentin microtensile bond strength Sound human dentin from extracted third molars was used as the substrate for microtensile bond strength ( ⁇ TBS) (project approved by Oregon Health & Science University – IRB #00012056). Ethanol was added at 40 vol% to the selected monomer compositions. Briefly, enamel was removed to expose a flat surface of mid ⁇ coronal dentin. A smear layer was created on this surface using 600 grit sandpaper for 30 s followed by etching with 35% phosphoric acid (3M ESPE, St. Paul, MN, USA) for 15 s and rinsing for 10 s.
  • 3M ESPE 35% phosphoric acid
  • a capillary tube was filled with a 50 mM solution of tetramethylammonium bromide dissolved in D 2 O and flame sealed. The capillary tube was placed at the bottom of the NMR tube to allow the locking of the magnet on the instrument onto the deuterium of the inner ⁇ tube with the ammonium acting as an internal standard.
  • 1 H NMR spectra were obtained using a water suppression by excitation sculpting experiment [Mobarhan et al., Analytical and Bioanalytical Chemistry. 2017;409:5043 ⁇ 55]. After the initial reading, the NMR tubes were flame sealed and incubated at 37 °C.
  • the methacrylamides, HEMAM and 1 ⁇ methyl HEMAM presented intermediate RP MAX values: 13.0 and 13.3%.s ⁇ 1 , respectively.
  • the DC at RP MAX ranged between 35.1% and 16.7%.
  • OH ⁇ terminated methacrylates showed the highest values (35.1% and 31.6% for HEMA and HEMA ⁇ , ⁇ CH 3 mixture, respectively), followed by the methacrylamides (22.2% and 24.3% for HEMAM and 1 ⁇ methyl HEMAM, respectively).
  • the NH 2 ⁇ terminated 1 ⁇ methyl and 2 ⁇ methyl AEMA presented the lowest values: 15.7% and 16.7%, respectively.
  • the unsubstituted methacrylamide, HEMAM experienced the least degradation with 89.1 ⁇ 0.01% of the monomer remaining intact after 17 days of incubation.
  • the substituted methacrylamides, 2 ⁇ methyl HEMAM and 1 ⁇ methyl HEMAM both exhibited more degradation than HEMAM, with 83.5 ⁇ 0.5% and 65.4 ⁇ 1.3% intact monomer remaining.
  • the two methacrylate monomers exhibited similar degradation amounts, HEMA with 25.2 ⁇ 0.1% intact monomer after 19 days incubation and the ⁇ , ⁇ CH 3 HEMA mixture with 31.9 ⁇ 0.4% intact monomer after 17 days incubation.
  • HEMA methylated derivative is only available as a mixture of isomers. This isomerization is very likely occurring via a low ⁇ energy transesterification mechanism [33].
  • the ⁇ substituted 1 ⁇ methyl HEMA is particularly susceptible to this isomerization.
  • the terminal hydroxyl group participates in a transesterification resulting in a dimethacrylate and propane ⁇ 1,2 ⁇ diol (Scheme 3 in supplemental materials).
  • Another transesterification occurs resulting in two monomethacrylates.
  • the secondary alcohol of the diol would need to participate in the transesterification while the more nucleophilic primary alcohol results in 2 ⁇ methyl HEMA.
  • the terminal hydroxyl group participates in a transesterification resulting in a dimethacrylate and propane ⁇ 1,2 ⁇ diol (Scheme 3 in supplemental materials). Another transesterification occurs resulting in two monomethacrylates. In order to return to the original monomethacrylate, the secondary alcohol of the diol would need to participate in the transesterification while the more nucleophilic primary alcohol results in 2 ⁇ methyl HEMA. This difference in nucleophilicity explains why an eventual equilibrium of a 3:1 ratio of 2 ⁇ methyl HEMA to 1 ⁇ methyl HEMA is reached in commercial HEMA ⁇ , ⁇ CH 3 . This transesterification will not result in an isomerization in unsubstituted monomers, like HEMA, though the dynamic behavior is likely still occurring.
  • the OH ⁇ terminated methacrylate HEMA (control) presented the highest values of DC at RP MAX and final DC when polymerized at 50 °C, with HEMAM and 2 ⁇ methyl HEMAM being similar to each other. This was expected due to the differences in molecular weight, viscosity and reactivity among the compounds, as discussed above.
  • the similarity of RP MAX among HEMA and the secondary methacrylamides was also observed for the polymerization kinetics evaluated at room temperature in this study and previously reported [Fugolin et al., Dental Materials. 2019;35:686 ⁇ 96].
  • HEMA has low molecular weight and viscosity (130 g/mol and 0.007 Pa.s), which increases the overall mobility within the comonomer system. This allows for a rapid increase in the rates of propagation and termination at the beginning of the polymerization reaction, until the formation of high molecular weight species severely hamper diffusion [Odian G. Principles of polymerization: John Wiley & Sons; 2004]. Despite methacrylates having higher reactivity than methacrylamides, the observed RP MAX values were similar. This observation reinforces that the methacrylamide ⁇ methacrylate blend ratio used in this study provides good properties without a significant loss of polymerization reactivity.
  • the low ⁇ TBS of the HEMA ⁇ , ⁇ CH 3 mix stands in contrast to the excellent polymerization kinetics observed. It is possible that the high polymerization rates and side ⁇ group substitutions at the ⁇ and ⁇ carbons might have resulted in a poorly packed polymer network with compromised mechanical properties [Pfeifer et al., European Polymer Journal. 2011;47:162 ⁇ 70].
  • the ⁇ substituted 2 ⁇ methyl HEMAM showed a statistically equivalent ⁇ TBS to the other secondary methacrylamides (HEMAM and 1 ⁇ methyl HEMAM), though lower than Single Bond.
  • HEMAM and 1 ⁇ methyl HEMAM maintained the highest bond strengths
  • 2 ⁇ methyl HEMAM showed intermediate results
  • the experimental methacrylates HEMA and HEMA ⁇ , ⁇ CH 3 mix the lowest bonds, which once again highlights the degradation resistance of the methacrylamides.
  • the reduction in ⁇ TBS over time ranged between 37.5% for the methacrylate control, HEMA, and 5.7% for the ⁇ substituted secondary methacrylamide, 1 ⁇ methyl HEMAM, which can be explained by the increased resistance to hydrolysis of the methacrylamides compared to their methacrylate counterparts.
  • HEMA and HEMA ⁇ , ⁇ CH 3 had a half ⁇ life of 9.52 days (linear regression), while the worst performing methacrylamide, 1 ⁇ methyl HEMAM, had a half ⁇ life of 27.7 days.
  • the HEMA ⁇ , ⁇ CH 3 mixture of isomers was mostly composed of the ⁇ substituted 2 ⁇ methyl HEMA (3:1), but this appeared to have no benefit or detriment to the stability to acid ⁇ catalyzed hydrolysis compared to HEMA.
  • the hydrolysis results confirmed the expected increased resistance to hydrolysis, as all methacrylate monomers showed significantly more degradation in acidic aqueous conditions than the methacrylamide monomers.
  • the HEMA ⁇ , ⁇ CH 3 mixture of isomers was mostly composed of the ⁇ substituted 2 ⁇ methyl HEMA (3:1), but this appeared to have no benefit or detriment to the stability to acid ⁇ catalyzed hydrolysis compared to HEMA. Interestingly, the addition of a ⁇ or ⁇ CH 3 groups had a detrimental effect (i.e., increased hydrolysis rate).
  • the ⁇ , ⁇ CH 3 methacrylamides (1 ⁇ methyl and 2 ⁇ methyl HEMAM) showed higher degradation rates (half ⁇ lives of 68.8 and 27.7 days, respectively) compared to unsubstituted HEMAM (half ⁇ life of 101 days).
  • Scheme 1 represents steric influence of side ⁇ chain functionality on the relative rates of base catalyzed ester hydrolysis and amide hydrolysis (Charton 1978). Note that ⁇ Me substituents have a maximum effect of ⁇ 1.5 ⁇ 1.8 times slower hydrolysis.
  • Scheme 2 below provides a) General reaction scheme for amide and ester polymerization and subsequent hydrolysis. b) Resonance structures for the radical polymerization intermediate showing propagating and non ⁇ propagating resonance differences between esters and amides.
  • X O minor resonance form
  • X NH major resonance form
  • Scheme 3 depicts 1 ⁇ methyl HEMA as an example of isomerization through transesterification of substituted hydroxyl ⁇ terminated methacrylates towards thermodynamic equilibrium resulting in a mixture of isomers.
  • Figure 6 provides names and abbreviations of the evaluated monomers along with the associated transesterification and degradation products.
  • Synthesis and characterization of 1 ⁇ methyl HEMAM N ⁇ (1 ⁇ hydroxypropan ⁇ 2 ⁇ yl)methacrylamide (1 ⁇ methyl HEMAM) Freshly distilled methacryloyl chloride (60.0 mmol, 1 equiv.) in anhydrous DCM (20 mL) was added dropwise to a stirred solution of 2 ⁇ aminopropanol (63.0 mmol, 1.05 equiv.), trimethylamine (60.0 mmol, 1 equiv.) and 5 mg of 4 ⁇ methoxyphenol in anhydrous DCM (30 mL) at ⁇ 5 °C.
  • the crude product was purified using a Buchi Reveleris X2 flash chromatography system (mobile phase A was hexanes and mobile phase B (MPB) was EtOAc, with a gradient program of 11% MPB for 1 min, 11% MPB to 47% MPB over 14.3 min and hold at 47% for 7.2 min). The fractions were collected and concentrated under reduced pressure, yielding the final product as an off ⁇ white solid (25.9 mmol, 43.2% yield).
  • Methacryloyl chloride (54.1 mmol, 1.2 equiv) was added and stirred for 2 hours. A sweep of N 2 gas was bubbled into a saturated sodium bicarbonate aqueous solution to trap the resulting HCl gas. After cooling to 40 °C, 12 mL of THF was added and the resulting solution was added dropwise to 100 mL of diethyl ether, precipitating a white solid (21.8 mmol, 48.3% yield).
  • the alcohol of 2 ⁇ methyl HEMAM is much less nucleophilic as a secondary alcohol and would have a much slower re ⁇ esterification reaction back to 1 ⁇ methyl AEMA, resulting in an equilibrium with mostly transesterification product and very little 1 ⁇ methyl AEMA.
  • the unsubstituted version resulted in very little of the transesterification product HEMAM. This could possibly suggest that transesterification occurs through both an intermolecular mechanism and an intramolecular mechanism.
  • the addition of steric bulk in the form of methyl substituents would be expected to favor intramolecular transesterification due to the Thorpe ⁇ Ingold effect and could explain why there is more transesterification products in the 1 ⁇ methyl and 2 ⁇ methyl AEMA samples.
  • HEMAM secondary methacrylamide N ⁇ hydroxyethyl methacrylamide
  • Triethyleneglycol dimethacrylate (TEGDMA) was tested as difunctional methacrylate control to provide a comparison with the difunctional methacrylamide ⁇ methacrylate hybrid monomers.
  • the partition coefficient (log P) for each monomer was calculated using the software package Chem Draw Ultra 14.1 (Perkin Elmer, San Jose, CA, USA). Tested formulations and photocuring conditions The monomers shown in Figure 1 were mixed at 40 mass% with bisphenol A ⁇ glycidyl methacrylate (bisGMA).
  • Butylated hydroxytoluene (BHT) was added at 0.1 mass% to each formulation as a free ⁇ radical inhibitor.
  • the degree of conversion at the maximum rate of polymerization was used to estimate the time point in conversion at which diffusional limitations lead to deceleration.
  • WS and SL were calculated in ⁇ g/mm 3 according the following equations, where V is the volume of the disc in mm 3 :
  • the dentin surface was etched for 15 s with 37% phosphoric acid (3M ESPE), rinsed and dried with the aid of gentle air stream for about 10 s.
  • Two layers of the adhesive were applied and, after solvent evaporation, the second layer was photocured for 60 s at 630 mW/cm 2 by the mercury arc lamp.
  • Restorative procedures consisted of a block of Filtek Supreme (shade A2 ⁇ 3M ESPE) built in 2 increments of 2 mm each, photoactived with the light guide directly over the surface for 20 s at 1200 mW/cm 2 with an Elipar TM DeepCure ⁇ S LED (3M ESPE).
  • the monofunctional HEMA and HEMAM showed the highest values (89.0 and 83.2%, respectively) and the hybrid versions HEMAM Hy, 2EM Hy and 2dMM Hy the lowest (63.5, 63.3, and 59.4%, respectively).
  • the alpha ⁇ substituted methacrylamides 2EM and 2dMM showed lower values than the monofunctional methacrylate control HEMA (73.6, 76.7 and 89.0%, respectively).
  • the WS values ranged between 33.4 ⁇ 3.2 and 183.0 ⁇ 5.7 ⁇ g/mm 3 with the highest value being for the methacrylamide HEMAM, followed by 2EM, HEMA and 2dMM (101.3 ⁇ 1.5, 93.9 ⁇ 4.8, and 79.1 ⁇ 0.9 ⁇ g/mm 3 , respectively).
  • TEGDMA and the hybrids were similar (35.5 ⁇ 1.8, 38.7 ⁇ 1.8, 44.0 ⁇ 0.8, and 33.4 ⁇ 3.2 ⁇ g/mm 3 , respectively).
  • the results ranged between ⁇ 12.7 ⁇ 1.6 and 6.4 ⁇ 2.2 ⁇ g/mm 3 for HEMA and 2EM/2dMM, respectively.
  • the hybrids HEMAM Hy, 2EM Hy and 2dMM Hy were statistically similar to TEGDMA ( ⁇ 1.6 ⁇ 0.0, 0.0 ⁇ 0.0, ⁇ 0.5 ⁇ 2.4, and ⁇ 4.2 ⁇ 6.0 ⁇ g/mm 3 , respectively).
  • the shear storage modulus, G’ values ranged between 160.7 ⁇ 8.0 and 115.7 ⁇ 7.0 MPa for the hybrids HEMAM Hy and 2dMM Hy, respectively ( Figure 4).
  • the groups were statistically similar and significant difference was only observed between HEMAM Hy versus TEGDMA, 2EM and 2dMM Hy. Dentin ⁇ TBS results are shown in Figure 5.
  • HEMAM Hy all hybrid versions showed reactivity (RP MAX ) similar to the methacrylate controls (TEGDMA and HEMA).
  • RP MAX methacrylate controls
  • HEMAM was expected to present the highest reactivity due to the absence of bulky substituents. The absence of substituents, in theory, would facilitate the access of the amine radicals to the vinyl groups. Albeit not statistically significant, the opposite was actually observed: the non ⁇ substituted HEMAM showed 45% lower RP MAX than the alpha ⁇ substituted versions. Steric interactions of substituents near amide bonds have been shown to cause slight rotation about the amide C ⁇ N bond [Wang et al., Journal of the American Chemical Society.
  • the resulting “distorted” amides have less pi ⁇ orbital overlap resulting in lengthened C ⁇ N bonds and less electron donation of the lone pair into the conjugated system of the amide [16].
  • the reduced electron donation and resulting reduction in radical stabilization is being used as a possible explanation for the reduced reactivity and rate of polymerization between non ⁇ substituted monomers and monomers with one or more ⁇ carbon substituents.
  • One additional explanation is based on the electron ⁇ donating nature of the alkyl chains, which may have created a partial negative charge on the alpha ⁇ carbon in 2EM and 2dMM [Bruice PY. Essential organic chemistry2016].
  • the methacrylamides are markedly less reactive than the methacrylates due to the strong resonance stabilization of the vinyl group provided by the nitrogen atom [Miyake et al., Macromolecules. 2009;42:1462 ⁇ 71].
  • the amide functionality is more stabilized than the ester due to the fact that the nitrogen atom is less electronegative than the oxygen and, consequently, is a better donor of nonbonding electrons [Kucharski et al., Journal of Applied Polymer Science. 1997;64:1259 ⁇ 65]. Therefore, it can be postulated that the more reactive methacrylate reacted first, further decreasing the reactivity of the already stable methacrylamide functionality.
  • the decrease in viscosity promoted by the incorporation of HEMA, HEMAM and HEMAM Hy into the formulations may increase the mobility of the system, which may have caused the polymerization of the more reactive bisGMA to take place more or less independently, at a faster rate and with earlier vitrification compared with the other co ⁇ monomers [[Pfeifer et al., Journal of Polymer Science Part A: Polymer Chemistry. 2014;52:1796 ⁇ 806].
  • the polymerization of the diluent ⁇ rich phase is hypothesized to have taken place at a slower rate, with delayed gelation and vitrification.
  • HEMAM non ⁇ substituted HEMAM showed statistically higher final degree of conversion than the alpha ⁇ substituted versions 2dMM and 2EM.
  • the increase in final double bond conversion showed by HEMAM may be associated with the relative lower viscosity of this compound, which likely played a role in preserving sufficient mobility in the system up to much higher levels in conversion [Odian G. Principles of polymerization: John Wiley & Sons; 2004].
  • Methacrylamides have hydrogen ⁇ bond acceptor (O ⁇ H dipole) and hydrogen ⁇ bond donor (N ⁇ H dipole) capabilities, which favors their interaction with water [DeRuiter et al., Principles of Drug Action. 2005;1:1 ⁇ 16].
  • methacrylate functionality on the secondary methacrylamides was to reduce the latter’s hydrophilicity.
  • the methacrylate ⁇ methacrylamide hybrids (HEMAM Hy, 2EM Hy, and 2dMM Hy) showed dramatic reduction in water sorption in comparison to their methacrylamide versions (HEMAM, 2EM, and 2dMM) ( Figure 7), with methacrylate hybrids showing 3 to 6 ⁇ fold greater log P values. This means they are a lot more hydrophobic than the methacrylamide analogs.
  • HEMAM Hy showed the highest values and 2dMM Hy and TEGDMA the lowest ones, which indicates that the molecular packing and the intermolecular interactions are playing key roles. It is known for co ⁇ polymerizations between TEGDMA and bisGMA that heterogeneous and poorly ⁇ packed polymer networks result, due to TEGDMA’s tendency to cyclization, as well as bisGMA’s rigidity [Pfeifer et al., Eur Polym J. 2011;47:162 ⁇ 70].
  • Cyclization is likely in difunctional molecules with flexible backbones, ultimately leading to the formation of a network with reduced cross ⁇ linking density and glass transition temperature, despite the high levels of final degree of conversion [Anhseth et al., Chemical Engineering Science. 1994;49:2207 ⁇ 17; Elliot et al., Dental Materials. 2001;17:221 ⁇ 9; and Boots et al., Polymer Bulletin. 1984;11:415 ⁇ 20].
  • the flexibility of the pendant groups and crosslinks make the TEGDMA molecule susceptible to rotational motion and with tendency to occupy more space, which compromises the packing efficiency and increases the free volume [Pfeifer et al., Eur Polym J. 2011;47:162 ⁇ 70].
  • HEMAM Hy does not contain any substituents, and its polymerization reaction took place at slow rates which, in tandem with the potential phase separation indicated by the double ⁇ staged kinetic profile, may have led to toughening of the material, as previously demonstrated [Naficy et al., Journal of Applied Polymer Science. 2013;130:2504 ⁇ 13].
  • bars were prepared for dynamic mechanical analysis test, but the experiment was not conducted because, after the post ⁇ curing heat processing necessary prior to the DMA test (16 hours at 180°C), the bars of HEMAM Hy, 2EM and 2dMM groups became too brittle and showed evidence of significant internal cracking (Figure 8).
  • Embodiment 1 provides a dental adhesive composition comprising one or more monomer compounds selected from the group of:
  • Embodiment 2 provides a dental adhesive composition comprising one or more monomer compounds selected from the group of:
  • Embodiment 3 provides a dental adhesive composition comprising one or more monomer compounds selected from the group of:
  • Embodiment 4 provides a dental adhesive composition comprising one or more monomer compounds selected from the group of:
  • Embodiment 5 provides a dental adhesive composition comprising one or more monomer compounds selected from the group of: .
  • Embodiment 21 comprises the dental adhesive composition of any of Embodiments 1 through 20, further comprising a co ⁇ monomer compound selected from the group of bisphenol A diglycidyl ether dimethacrylate (BisGMA), triethylene glycol dimethacrylate (TEGDMA), urethane dimethacrylate (UDMA), ethylene glycol dimethylacrylate (EGDMA), ethane ⁇ 1,2 ⁇ diyl bis(2 ⁇ methylacrylate) (PEGDMA), ethoxylated bisphenol A dimethacrylate (EBPADMA), ethylene glycoldi(meth)acrylate, hexanediol di(meth)acrylate, tripropylene glycol di(meth)acrylate, butanediol di(meth)acrylate, neopentyl glycol di(meth)acrylate, diethylene glycoldi(meth)acrylate, diethylene glycoldi(meth)acrylate, hexanediol di
  • Embodiment 22 comprises the dental adhesive composition of Embodiment 21, wherein the co ⁇ monomer compound is BisGMA.
  • Embodiment 23 comprises the dental adhesive composition of Embodiment 21, wherein the co ⁇ monomer compound is TEGDMA.
  • Embodiment 24 comprises the dental adhesive composition of Embodiment 21, wherein the co ⁇ monomer compound is UDMA.
  • Embodiment 25 comprises the dental adhesive composition of Embodiment 21, wherein the co ⁇ monomer compound is EGDMA.
  • Embodiment 26 comprises the dental adhesive composition of Embodiment 21, wherein the co ⁇ monomer compound is PEGDMA.
  • Embodiment 27 comprises the dental adhesive composition of any of Embodiments 21 through 26, wherein: a) the relevant one or more monomers indicated in Embodiments 1 through 20 comprise from about 35% to about 45%, by weight, of the dental adhesive composition; and b) the relevant co ⁇ monomer compound indicated in Embodiments 21 through 26 comprises from about 55% to about 65%, by weight, of the composition.
  • Embodiment 28 comprises the dental adhesive composition of any of Embodiments 21 through 26, wherein: a) the relevant one or more monomers indicated in Embodiments 1 through 20 comprise from about 37% to about 43%, by weight, of the dental adhesive composition; and b) the relevant co ⁇ monomer compound indicated in Embodiments 21 through 26 comprises from about 57% to about 63%, by weight, of the composition.
  • Embodiment 29 comprises the dental adhesive composition of any of Embodiments 1 through 28, wherein the dental adhesive composition further comprises a photoinitiator.
  • Embodiment 30 comprises the dental adhesive composition of Embodiments 29, wherein the photoinitiator or polymerization initiator is selected from the group of camphorquinone (CQ); trimethylbenzoyl ⁇ diphenyl ⁇ phosphine oxide (TPO); Ethyl ⁇ 4 ⁇ dimethylamino benzoate (EDMAB); 2,2 ⁇ Dimethoxy ⁇ 2 ⁇ phenylacetophenone (DMPA); Bisacylphosphine oxide (BAPO); 1 ⁇ Phenyl ⁇ 1,2 ⁇ propanedione (PPD); phosphine oxide compounds, including naphthacene (APO), 9 ⁇ anthracene (APO), and; 1 ⁇ phenyl ⁇ 1,2 ⁇ propanedione (PPD); thioxanthone (TX) and its derivatives; dibenzoyl germanium derivatives, such as benzoyltrimethylgermane (BTG) and dibenzoyldiethylgermane; hexaarylbiimi
  • Embodiment 31 comprises the dental adhesive composition of any of Embodiments 29 and 30, wherein the photoinitiator or polymerization initiator is selected from the group of 2,2 ⁇ Dimethoxy ⁇ 2 ⁇ phenylacetophenone (DMPA), diphenyliodonium hexafluorophosphate, and (diethylgermanediyl)bis((4 ⁇ methoxyphenyl)methanone) (Ivocerin), or a combination thereof.
  • DMPA 2,2 ⁇ Dimethoxy ⁇ 2 ⁇ phenylacetophenone
  • Ivocerin diethylgermanediyl
  • Embodiment 32 comprises the dental adhesive composition of any of Embodiments 29, 30, and 31, wherein the photoinitiator or polymerization initiator is selected from the group of 2,2 ⁇ Dimethoxy ⁇ 2 ⁇ phenylacetophenone (DMPA) and diphenyliodonium hexafluorophosphate, or a combination thereof.
  • DMPA 2,2 ⁇ Dimethoxy ⁇ 2 ⁇ phenylacetophenone
  • diphenyliodonium hexafluorophosphate or a combination thereof.
  • Embodiment 33 comprises the dental adhesive composition of any of Embodiments 29, 30, 31, and 32, wherein the composition further comprises a chemical inhibitor/stabilizer/free radical scavenger selected from the group of butylated hydroxytoluene (BHT), hydroquinone, 2,5 ⁇ di ⁇ tert ⁇ butyl hydroquinone, monomethyl ether hydroquinone (MEHQ), and 2,5 ⁇ di ⁇ tertiary butyl ⁇ 4 ⁇ methylphenol, 3,5 ⁇ di ⁇ tert ⁇ butyl ⁇ 4 ⁇ hydroxyanisole (2,6 ⁇ di ⁇ tert ⁇ butyl ⁇ 4 ⁇ ethoxyphenol), 2,6 ⁇ di ⁇ tert ⁇ butyl ⁇ 4 ⁇ (dimethylamino)methylphenol or 2 ⁇ (2′ ⁇ hydroxy ⁇ 5′ ⁇ methylphenyl) ⁇ 2H ⁇ benzotriazole, 2 ⁇ (2′ ⁇ hydroxy ⁇ 5′ ⁇ t ⁇ octylphenyl) ⁇ 2H ⁇ benzotriazole, 2 ⁇ (2′ ⁇ hydroxy ⁇ 4′,6′ ⁇
  • Embodiment 34 comprises the dental adhesive composition of Embodiment 33, wherein the composition comprises a chemical inhibitor/stabilizer/free radical scavenger at a concentration of from about 0.01% to about 0.5%, by weight.
  • Embodiment 35 comprises the dental adhesive composition of any of Embodiments 33 and 34, wherein the composition comprises a chemical inhibitor/stabilizer/free radical scavenger at a concentration of from about 0.05% to about 0.3%, by weight.
  • Embodiment 36 comprises the dental adhesive composition of any of Embodiments 33, 34, and 35, wherein the composition comprises a chemical inhibitor/stabilizer/free radical scavenger at a concentration of from about 0.05% to about 0.2%, by weight.
  • Embodiment 37 comprises the dental adhesive composition of any of Embodiments 33, 34, 35, and 36, wherein the composition comprises a chemical inhibitor/stabilizer/free radical scavenger is butylated hydroxytoluene (BHT).
  • Embodiment 38 comprises the dental adhesive composition of any of Embodiments 1 through 37, wherein the dental adhesive composition further comprises a self ⁇ etching agent.
  • Embodiment 39 comprises the dental adhesive composition of Embodiment 38, wherein the self ⁇ etching agent comprises a carboxylic acid, phosphonic acid, or phosphate groups
  • Embodiment 40 comprises the dental adhesive agent of any of Embodiments 38 and 39, wherein the self ⁇ etching agent is selected from the group of 10 ⁇ methacryloyloxydecyl dihydrogen phosphate (10 ⁇ MDP or MDP, CAS Reg. No.

Abstract

The present invention concerns amine-terminated and methacrylate/methacrylamide monomers for dental applications, particularly including dental adhesives. Some embodiments comprise photocurable compositions.

Description

DENTAL ADHESIVES FORMULATED WITH SECONDARY METHACRYLAMIDES  FIELD OF THE INVENTION  The present invention concerns amine‐terminated and methacrylate/methacrylamide monomers  for dental adhesive applications.  STATEMENT OF GOVERNMENT SUPPORT  This invention was made with government support under 1U01‐DE023756, 1R01‐DE026113, K02‐ DE025280; R01‐DE028757; and R35‐DE029083 awarded by NIH‐NIDCR. The government has certain rights  in the invention.  BACKGROUND OF THE INVENTION  Dental adhesive interfaces with reduced susceptibility to degradation could lead to dental  restorations with extended clinical lifetimes. Degradation is the result of two factors: (1) collagen  degradation by endogenous proteases [ Mazzoni et al., Endodontic Topics. 2009;21:19‐40], [ Tjäderhane  et al., Dent Mater. 2013;29:116‐35], and (2) polymer hydrolysis. The hydrolysis of dental adhesives –  specifically the ester functionality within the polymer – is catalyzed by acid (low pH) as well as  bacterial/salivary esterases [Santerre et al., Critical Reviews in Oral Biology & Medicine. 2001;12:136‐ 51], [Tay et al., Journal of Dentistry. 2004;32:611‐21], [ Finer et al., Journal of Biomaterials Science,  Polymer Edition. 2003;14:837‐49], [Huang et al., Acta Biomaterialia. 2018;71:330‐8]. A host of strategies  have been suggested to achieve a more stable dental adhesive interface to promote longer clinical  lifetimes, including the use of compounds shown to reduce the activity of the metalloproteinases and  cysteine cathepsins responsible for the proteolysis of collagen fibrils [Loguercio et al., European journal  of oral sciences. 2009;117:587‐96], [Gendron et al.,  Clin Diagn Lab Immunol. 1999;6:437‐9], [Scaffa et  al., Journal of dental research. 2012;91:420‐5], [Perchyonok T, Grobler SR, Zhang S, Olivier A, Oberholzer  T. Insights into chitosan hydrogels on dentine bond strength and cytotoxicity. 2013], [Carrilho et al.,  Journal of dental research. 2007;86:529‐33]. One common example is chlorhexidine digluconate, but  this compound shows cytotoxicity, high water solubility, low substantivity and only short‐term   effects [Karpiński et al., Eur Rev Med Pharmacol Sci. 2015;19:1321‐6], [Frassetto et al., Dental Materials.  2016;32:e41‐e53], [Hashimoto et al., Journal of Dental Research. 2000;79:1385‐91], [ Komori et al.,  Operative Dentistry. 2009;34:157‐65], [ Ricci et al., European Journal of Oral Sciences. 2010;118:411‐6].  Another strategy relies on the dentin biomodification by flavonoid‐type polyphenolics (such  as proanthocyanidins, quercetin, and curcumin) or 1‐Ethyl‐3‐(3‐dimethylamino‐propyl) carbodiimide  (EDC), which may function as collagen cross‐linking agents and inhibit the activity of the  endopeptidases [ Frassetto et al., Dental Materials. 2016;32:e41‐e53], [Porto et al., European Journal of  Oral Sciences. 2018;126:146‐58], [Betancourt et al., Int J Biomater. 2019;2019:5268342‐], [Hass et al.,  Dental Materials. 2016;32:732‐41], [Seseogullari‐Dirihan et al., Dental Materials. 2016;32:423‐ 32], [Bedran‐Russo et al., Journal of Biomedical Materials Research Part B: Applied Biomaterials: An  Official Journal of The Society for Biomaterials, The Japanese Society for Biomaterials, and The  Australian Society for Biomaterials and the Korean Society for Biomaterials. 2007;80:268‐72]. The  undesirable effects of staining dentin along with the uncertain longevity of the benefits make the clinical  feasibility of this approach questionable.  Another recent strategy to improve dental adhesive performance is the use of hydrolysis‐ resistant compounds. After more than 60 years using purely methacrylate‐based compositions,  researchers have concentrated their efforts on the inclusion of more hydrolytically stable compounds as  co‐monomers for dental adhesives. Methacrylamide‐methacrylate blends have emerged as materials  with significantly improved properties [Fugolin et al., Dental Materials. 2019;35:686‐96], [Rodrigues et  al., Dental Materials. 2018;34:1634‐44], [Salz et al., J Adhes Dent. 2005;7:107‐16], [Moszner et al.,  Macromolecular Materials and Engineering. 2016;301:750‐9]. The replacement of the oxygen atom in  the ester group of hydroxyethylmethacrylate (HEMA) by an NH (amide group) resulted in formulations  with markedly higher bond stability, which was mainly attributed to the replacement of ester bonds  with amide bonds, making the polymers more resistant to hydrolysis [Nishiyama et al., Journal of Dental  Research. 2001;80:855‐9]. Methacrylamide‐based polymer performance is highly dependent on  the chemical structure localized about the amide functional group. For example, α‐substituted  secondary methacrylamides (40% weight blend in methacrylates) lead to materials with more stable  mechanical adhesion after 6 months than unsubstituted secondary methacrylamides [Fugolin et al.,  Dental Materials. 2019;35:686‐96]. However, the degree to which the side‐group substituents  affect polymerization kinetics and subsequent polymer stability (hydrolysis kinetics) is not well  understood for methacrylamides, especially in comparison with methacrylates. Further, the effects that  α‐ and β‐carbon substituents have on hydrolysis in materials remain unexplored.  Based on homogenous chemical model systems, the maximum expected effect of the  substitution on the hydrolysis rates of amides is ten times slower (i.e., ten times longer lifetime)  compared to esters [Bender et al., Journal of the American Chemical Society. 1958;80:1044‐8], and a  maximum factor of ∼2.5 slower hydrolysis is expected for sterically imposing side‐chains [Charton et al.,  Journal of Organic Chemistry. 1978;43:3995‐4001] – see Scheme 1 in supplemental materials. This  sterically derived hydrolytic stability factor is approximately the same for both ester and amide  hydrolysis. Thus, additional hydrolytic stability could be imparted to the material both at the ester and  the amide groups by the synthetic inclusion of chemically inert methyl groups.  Based on homogenous chemical model systems, the maximum expected effect of the  substitution on the hydrolysis rates of amides is ten times slower (i.e., ten times longer lifetime)  compared to esters [Bender et al., Journal of the American Chemical Society. 1958;80:1044‐8], and a  maximum factor of ∼2.5 slower hydrolysis is expected for sterically imposing side‐chains [Charton et al.,  Journal of Organic Chemistry. 1978;43:3995‐4001] – see Scheme 1 in supplemental materials. This  sterically derived hydrolytic stability factor is approximately the same for both ester and amide  hydrolysis. Thus, additional hydrolytic stability could be imparted to the material both at the ester and  the amide groups by the synthetic inclusion of chemically inert methyl groups.  One important point to consider is that the same factors that make amide bonds more stable  than acrylate bonds also affect polymerization rate (Scheme 2 in supplemental materials). Neat  methacrylamides tend to have slower polymerization kinetics compared to methacrylates [Barcelos et  al., Dental Materials. 2020;36:468‐77] because the vinyl radical that is generated during the  polymerization is better resonance stabilized by the amide nitrogen in a non‐propagating form (Scheme  2 in supplemental materials) than an analogous ester oxygen. The difference in resonance forms makes  the vinyl amide radical more stable and subsequently, less reactive than the less stable and more  reactive methacrylate radical. In addition, (meth)acrylamides are more prone to water sorption, and  therefore, are expected to lead to a reduction in bulk mechanical properties after exposure to the oral  environment [Fugolin et al., Dental Materials. 2019;35:1378‐87]. To overcome these limitations,  methacrylamide‐methacrylate co‐polymerizations can lead to significant gains in dentin bond strength  stability, while only marginally affecting polymerization rate [Fugolin et al., Dental Materials.  2019;35:686‐96].  It is currently unclear how methylation as mentioned above affects the polymerization kinetics  and the final material properties and there remains a need for more stable dental adhesives.    SUMMARY OF THE INVENTION      Ester‐free  monomers  have  been  suggested  as  more  stable  alternatives  for  dental  adhesives.  Specifically, alpha and beta‐carbon substitutions have been shown to slow down degradation of polymeric  networks. The new class of monomers described here comprises systematic variations of mono and hybrid  difunctional methacrylate/methacrylamides with alkyl chains being used as substitutions on the alpha or  beta positions in relation to the polymerizable group. Monofunctional monomers are shown in Figure 1  and  hybrid  monomers  are  shown  in  Figure  2.  All  monomers  have  been  synthesized,  and  selected  monomers have been evaluated in terms of kinetics of polymerization and long‐term microtensile bond  strength as part of the formulation of dental adhesives.    One embodiment herein provides a dental adhesive composition comprising one or more of:  a) a hydroxyl‐terminated methacrylamide compound selected from the group of: 
Figure imgf000006_0001
b) a hydroxyl‐terminated methacrylate compound selected from the group of: 
Figure imgf000006_0004
; or  c) an amino‐terminated methacrylate compound selected from the group of: 
Figure imgf000006_0002
; or  d) a di‐functional methacrylamide/methacrylate compound selected from the group of: 
Figure imgf000006_0003
 
Figure imgf000007_0001
.  BRIEF DESCRIPTION OF THE DRAWINGS    FIGURE 1 presents a bar graph of the percentage degree of conversion for three tested monomers.    FIGURE 2 presents a line graph representing kinetics of polymerization curves (average of three  curves) for six tested monomers.    FIGURE 3 presents a line graph representing kinetics of polymerization results at 50 °C for HEMA,  HEMAM and 2‐methyl HEMAM.    FIGURE 4 presents a bar graph representing the shear storage modulus values determined for the  hybrids HEMAM Hy and 2dMM Hy.    FIGURE 5 presents a table of half‐lives for monomers in acidic aqueous conditions at 37°C (data were  fit to an exponential decay model).    FIGURE 6 depicts steric interactions of α‐carbon alkyl substituents have been shown to cause 2° and  3° amides to twist about the C‐N bond.    FIGURE 7 presents bar graphs comparing water sorption and solubility determined for tested  monomers.    FIGURE 8 presents images of comparative cracking in tested polymers.     FIGURE 9 presents line graphs representing the kinetics curves profiles of HEMA, HEMAM and  HEMAM Hy.    FIGURE 10 presents a table of %DC at inflection of a deceleration curve for HEMA, HEMAM, and  HEMAN Hy.      DETAILED DESCRIPTION OF THE INVENTION    Other embodiments, provide a composition comprising a compound selected from groups a)‐d)  above and one or more comonomers selected from the group of bisphenol A diglycidyl ether  dimethacrylate (BisGMA), triethylene glycol dimethacrylate (TEGDMA), urethane dimethacrylate  (UDMA), ethylene glycol dimethylacrylate (EGDMA), ethane‐1,2‐diyl bis(2‐methylacrylate) (PEGDMA),  ethoxylated bisphenol A dimethacrylate (EBPADMA), ethylene glycoldi(meth)acrylate, hexanediol  di(meth)acrylate, tripropylene glycol di(meth)acrylate, butanediol di(meth)acrylate, neopentyl glycol  di(meth)acrylate, diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, dipropylene  glycol di(meth)acrylate, allyl (meth)acrylate, 1,6‐hexanediol dimethacrylate (HEDMA), 1,6‐ hexamethylene glycol dimethacrylate (HGDMA), divinyl benzene and derivatives thereof.  In some  embodiments, the co‐monomer or co‐monomers selected from this group comprises from about 55% to  65% of the composition, by weight.    Still other embodiments provide such compositions comprising at least one monomer and one  co‐monomer, as described herein, and further comprising a polymerization initiator, such as one  selected from the group of camphorquinone (CQ); trimethylbenzoyl‐diphenyl‐phosphine oxide (TPO);  Ethyl‐4‐dimethylamino benzoate (EDMAB); 2,2‐Dimethoxy‐2‐phenylacetophenone (DMPA);  Bisacylphosphine oxide (BAPO); 1‐Phenyl‐1,2‐propanedione (PPD); phosphine oxide compounds,  including naphthacene (APO), 9‐anthracene (APO), and bisacylphosphine oxide (BAPO); 1‐phenyl‐1,2‐ propanedione (PPD); thioxanthone (TX) and its derivatives; a dibenzoyl germanium derivative,  benzoyltrimethylgermane (BTG), dibenzoyldiethylgermane; hexaarylbiimidazole derivatives; a silane  based derivative; (diethylgermanediyl)bis((4‐methoxyphenyl)methanone); benzenesulfinic acid sodium  salt (BS); a diaryliodonium salt, diphenyliodonium chloride or iodonium salt [diphenyliodonium  hexafluorophosphate (DPIHP or DPI‐PF6))], bromide, iodide, or hexafluorophosphate; benzoyl peroxide  (BPO), and ethyl 4‐N,N‐dimethaminobenzoate.  In further embodiments, the polymerization initiator is a  combination of initiators, such as those selected from the group of camphorquinone/ethyl‐4‐ (dimethylamino)benzoate (EDMAB), camphorquinone/2‐(dimethylamino)ethyl methacrylate  (DMAEMA)), DMPA/DPI‐PF6, CQ/PPD, CQ/DMAEMA, CQ/EDMAB, CQ/DMAEMA/PDIHP, or  CQ/EDMAB/DPIHP.   In some embodiments, the polymerization initiator one or both of the group DMPA  and DPI‐PF.  In some embodiments, the polymerization initiator comprises from about 0.05% to about  0.6% of the composition, by weight.  In some embodiments, the composition also comprises a chemical inhibitor (also referred to as  a stabilizer or free radical scavengers ), such as one selected from the group of butylated  hydroxytoluene (BHT), hydroquinone, 2,5‐di‐tert‐butyl hydroquinone, monomethyl ether hydroquinone  (MEHQ), and 2,5‐di‐tertiary butyl‐4‐methylphenol, 3,5‐di‐tert‐butyl‐4‐hydroxyanisole (2,6‐di‐tert‐butyl‐ 4‐ethoxyphenol), 2,6‐di‐tert‐butyl‐4‐(dimethylamino)methylphenol or 2‐(2′‐hydroxy‐5′‐methylphenyl)‐ 2H‐benzotriazole, 2‐(2′‐hydroxy‐5′‐t‐octylphenyl)‐2H‐benzotriazole, 2‐(2′‐hydroxy‐4′,6′‐di‐tert‐ pentylphenyl)‐2H‐benzotriazole, 2‐hydroxy‐4‐n‐octoxybenzophenone, 2‐(2′‐hydroxy‐5′‐methacryloxy‐ ethylphenyl)‐2H‐benzotriazole, phenothiazine, and HALS (hindered amine light stabilizers).     The compositions may also comprise an ultraviolet light (UV) absorber, such as 2‐hydroxy‐4‐ methoxybenzophenone (UV‐9), 2‐(2‐Hydroxy‐5‐octylphenyl)‐benzotriazole (UV‐5411), salicylic acid  phenyl ester, 3‐(2′‐hydroxy‐5′‐methylphenyl)benzotriazole, and 2‐(2'‐hydroxy‐5'‐methylphenyl)‐ benzotriazole.  The UV absorber may be present in the composition at from about 0.001% to about  0.5%, by weight.  In some embodiments the chemical inhibitor is incorporated into the composition at a  concentration of from about 0.01% to about 0.5%, by weight.  In other embodiments, the chemical  inhibitor is present in the composition at from about 0.05% to about 0.3%, by weight.  In still other  embodiments, the chemical inhibitor is present in the composition at from about 0.05% to about 0.2%,  by weight.  In additional embodiments, the chemical inhibitor is present in the composition at from  about 0.05% to about 0.15%, by weight.   It is understood that the compositions herein may include further elements, such as a  fluorescent agent, a fluoride releasing agent, a radiopaque agent, a flavoring agent, and an antimicrobial  agent.  Purpose/aim: Ester‐free monomers have been suggested as more stable alternatives for dental adhesives.  Specifically, alpha and beta‐carbon substitutions have been shown to slow down degradation of polymeric  networks. The aim of this study was to evaluate kinetics of polymerization and long‐term microtensile  bond strength of dental adhesives formulated with novel secondary methacrylamides.  Materials and methods:  Secondary methacrylamides with different carbon substitutions (alpha ‐ 2MM,  beta ‐ 3MM and no substitution ‐ HEMAM) were copolymerized with UDMA at 40/60 mass ratio. 0.2 wt%  DMPA and 0.4 wt% DPI‐PF6 were used as photoinitiators. Polymerization kinetics was followed with near‐ IR  in  real‐time  (6165‐6135 cm−1)  for  300s  at  800 mW/cm2  (320–500 nm).  Solvated  adhesives  (40 vol%  ethanol) were used to bond composite (Filtek Supreme) to flat human dentin surfaces, and compared  with Adper Single Bond (3M). Dentin microtensile bond strength (µTBS) was measured on sticks (1mm2)  after 24 h and 6 months storage in water at 37 °C. Results were analyzed with one‐way ANOVA/Tukey's  test (α=0.05).  Results: Chemical structures, degree of conversion (DC, grey line) (%) and µTBS (MPa) are shown in Fig. 1.  DC was similar for HEMAM and 2MM (89.9% and 86.6%, respectively) and higher than 3MM (66.0%), likely  due to higher viscosity of 3MM, which forms a gel‐like mixture with UDMA at room temperature. At 24h,  µTBS was similar for all groups (p = 0.063). After 6‐months, 2MM showed the highest and 3MM the lowest  values (42.9 and 33.0 MPa, respectively).   The  dental  adhesive  compositions  herein may  include  one  or more  photoinitiator  agents.    The  term  “initiator”  or  “polymerization  initiator”  herein  refers  to  thermal  initiating,  redox‐initiating,  and/or  photoinitiating compounds capable of inducing polymerization throughout a significant depth of  composite material,  such  as  camphorquinone  (CQ);  trimethylbenzoyl‐diphenyl‐phosphine oxide  (TPO);  Ethyl‐4‐dimethylamino  benzoate  (EDMAB);  2,2‐Dimethoxy‐2‐phenylacetophenone  (DMPA);  Bisacylphosphine  oxide  (BAPO);  1‐Phenyl‐1,2‐propanedione  (PPD);  phosphine  oxide  compounds,  including  naphthacene  (APO),  9‐anthracene  (APO),  and  bisacylphosphine  oxide  (BAPO);  1‐phenyl‐1,2‐ propanedione  (PPD);  thioxanthone  (TX)  and  its  derivatives;  dibenzoyl  germanium derivatives,  such  as  benzoyltrimethylgermane  (BTG)  and  dibenzoyldiethylgermane;  hexaarylbiimidazole  derivatives;  silane  based  derivatives;  (diethylgermanediyl)bis((4‐methoxyphenyl)methanone)  (Ivocerin);  benzenesulfinic  acid  sodium  salt  (BS);  diaryliodonium  salts  (such  as  diphenyliodonium  chloride  or  iodonium  salt  [diphenyliodonium  hexafluorophosphate  (DPIHP,  DPI‐PF6,  or  DPI‐PF6))],  bromide,  iodide,  or  hexafluorophosphate; and benzoyl peroxide (BPO). It is understood that in the compositions herein, one  initiator material may be used or 2 or more may be used, such as the combination of camphorquinone  with a co‐initiator, such as a tertiary amine initiator (such as ethyl‐4‐(dimethylamino) benzoate (EDMAB)  and/or 2‐(dimethylamino)ethyl methacrylate (DMAEMA)), or a combination of DMPA/DPI‐PF6, CQ/PPD,  CQ/DMAEMA,  CQ/EDMAB,  CQ/DMAEMA/PDIHP,  or  CQ/EDMAB/DPIHP.    Commercially  available  photoinitiators for use with the present compositions include monoacylphoshine oxide (MAPO, available  from Lucirin TPO, BASF), bisacylphosphine oxide (BAPO, Irgacure 819, Ciba Geigy), phenylpropanedione  (PPD, Aldrich), and camphorquinone (CQ, Aldrich).  Tested Co‐monomers  The commercially‐available monomers used in this study were purchased from Sigma Aldrich  (Milwaukee, WI, USA) at 95% or greater purity, and used as received: 2‐hydroxyethyl methacrylate –  HEMA, 2‐hydroxyethyl methacrylamide – HEMAM, 2‐hydroxy‐2‐methylethyl methacrylamide – 2‐methyl  HEMAM. Hydroxypropyl methacrylate was obtained as a mixture of isomers consisting of the α‐ substituted 2‐hydroxy‐1‐methylethyl methacrylate – 1‐methyl HEMA, and β‐substituted 2‐hydroxy‐2‐ methylethyl methacrylamide – 2‐methyl HEMA. The composition of the mixture was determined by 1H  NMR spectroscopy to be 72% 2‐methyl HEMA and 28% 1‐methyl HEMA, consistent with the distributer's  analysis. The hydroxypropyl methacrylate isomeric mixture was used as received due to facile  isomerization equilibrium (discussed later). 2‐hydroxy‐1‐methylethyl methacrylamide – 1‐methyl  HEMAM was synthesized de novo (see supplementary information). The structures of all monomers  used in this study are shown below.    Hydroxyl‐Terminated Methacrylamides 
Figure imgf000011_0001
    Hydroxyl‐Terminated Methacrylates 
Figure imgf000011_0002
  Amino‐Terminated Methacrylates 
Figure imgf000011_0003
  The monomers above may be copolymerized with monomers, particularly dental resin  monomers (UDMA, BisGMA, etc.), in dental adhesive compositions.  The NH2‐terminated methacrylate used in this study (2‐aminoethyl methacrylate (AEMA) was  obtained as a hydrochloride salt. The α‐substituted, 2‐amino‐1‐methylethyl methacrylate – 1‐methyl  AEMA, and the β‐substituted, 2‐amino‐2‐methylethyl methacrylate – 2‐methyl AEMA, amino‐terminated  monomers were synthesized as hydrochloride salts following procedures adapted from a previous  report [31]. Detailed information can be found in the supplementary information. In order to prevent  the confounding variable of the presence of a salt in the polymer formulations, the hydrochloride salts  were neutralized prior to formulation of the tested materials.  Formulations and photocuring conditions  The co‐monomers were mixed at 40 wt% with UDMA (urethane dimethacrylate, purchased from  ESSTECH, Essington, PA, USA). The mixtures were made polymerizable by the addition of 0.2 wt% DMPA  (2,2‐dimethoxy‐2‐phenyl acetophenone) and 0.4 wt% DPI‐PF6 (diphenyliodonium hexafluorophosphate).  BHT (butylated hydroxytoluene) was incorporated at 0.1 wt% into the formulations as an inhibitor. All  photocuring procedures were carried out with a mercury arc lamp (Acticure 4000, 320–500 nm filtered)  at 630 mW/cm2 measured directly on the surface of the samples using a power meter (PowerMax 5200,  Molectron Detector Inc., Portland, OR, USA).    Kinetics of polymerization  Polymerization kinetics were followed with real time by near‐IR spectroscopy. Discs of 6 mm diameter  and 0.8 mm thickness were sandwiched between glass slides and photoactivated for 300 s with the tip  of the light guide placed 4 cm away and perpendicular to the glass surface, delivering 630 mW/cm2 at  the sample surface (n = 3). Spectra were collected for 330 s, with 2 scans per spectrum at  4 cm−1 resolution. The light was kept on for the duration of the experiment to provide isothermal  conditions, and avoid overestimation of conversion due to potential IR pathlength reduction (had the  light been turned off during the experiment, causing shrinkage of the specimen). The followed peaks  were 6165 and 6135 cm−1 for methacrylates and methacrylamides, respectively. The maximum rate of  polymerization (RPMAX) was calculated as the first derivative of the degree of conversion vs. time curve,  and the final degree of conversion (Final DC) was based on the change in area of the vinyl overtone  peaks. The degree of conversion at the maximum rate of polymerization (DC at RPMAX) was used as a  proxy for the onset of vitrification.  Since the β‐substituted secondary methacrylamide 2‐methyl AEMA was not soluble in the organic matrix  at room temperature, the mixture was heated on a hot plate to 50 °C and the kinetics tested  immediately at the same conditions described above. For an appropriate comparison, the  methacrylamide and methacrylate controls – HEMAM and HEMA, were also tested at 50˚C, as controls.  Formulations that did not cure or cured very slowly were not subjected to dentin microtensile bond  strength or monomer hydrolysis kinetics.  Dentin microtensile bond strength  Sound human dentin from extracted third molars was used as the substrate for microtensile bond  strength (μTBS) (project approved by Oregon Health & Science University – IRB #00012056). Ethanol was  added at 40 vol% to the selected monomer compositions. Briefly, enamel was removed to expose a flat  surface of mid‐coronal dentin. A smear layer was created on this surface using 600 grit sandpaper for 30  s followed by etching with 35% phosphoric acid (3M ESPE, St. Paul, MN, USA) for 15 s and rinsing for  10 s. After blotting the surface dry, two consecutive coats of the experimental adhesives were applied  and solvent evaporated using a gentle air spray for 10 s. The second coat of the adhesive was  photoactivated for 60 s with the light guide 4 cm away from the surface delivering 630 mW/cm2. The  restorative procedures consisted of a composite block (Filtek Supreme, A2 – 3M ESPE, St. Paul, MN,  USA) built in 2 increments of 2 mm thickness, photoactivated for 30 s each at 1100 mW/cm2 (Elipar  DeepCure‐S, 3M ESPE, St. Paul, MN, USA). Adper Single Bond (composed of dimethacrylates and HEMA,  3M ESPE, St. Paul, MN, USA) was tested as commercial control and used as described previously except  for the photoactivation of the second coat, carried out for 20 s using Elipar (Mono‐wave LED, 3M‐ESPE)  at 1100 mW/cm2 placed directly over the dentin surface (n = 6). All experimental adhesives, including  the experimental control, were photoactivated with light parameters that were optimized for the type  and concentration of initiator (DMPA/DPI = PF6, λmax = 365 nm), as determined in a preliminary study.  The commercial control was included as an external benchmark, and photoactivated according to  manufacturer's instructions using a commercially available light source. After 24 h, the teeth were cut  on a slow speed diamond saw to obtain 1 mm2 transversal section area sticks, which were stored for an  additional 24 h or 6 months in distilled water at 37 °C. At the end of the storage time, sticks were fixed  to a custom‐made metal jig (Odeme Equipment, Luzerna, SC, Brazil) using super glue (Zapit, Dental  Ventures of America Inc, Corona, CA, US), attached to a universal testing machine (Criterion MTS, Eden  Prairie, MN, USA), and tested until failure at 0.5 mm/min.  Monomer hydrolysis kinetics  An aqueous solution (H2O, pH = 1) was prepared using HPLC grade water and adjusted using 1.0 M HCl.  A 50 mM solution of each monomer (n = 3) was prepared using 1.0 mL of the acidic aqueous solution. A  capillary tube was filled with a 50 mM solution of tetramethylammonium bromide dissolved in D2O and  flame sealed. The capillary tube was placed at the bottom of the NMR tube to allow the locking of the  magnet on the instrument onto the deuterium of the inner‐tube with the ammonium acting as an  internal standard. 1H NMR spectra were obtained using a water suppression by excitation sculpting  experiment [Mobarhan et al., Analytical and Bioanalytical Chemistry. 2017;409:5043‐55]. After the initial  reading, the NMR tubes were flame sealed and incubated at 37 °C. At 4, 9, and 17 days (4, 7, 12, and 19  days for HEMA), the samples were removed from incubation to obtain water suppressed 1H NMR  spectra. To determine the amount of monomer degradation, spectra were first aligned using the ITSD  singlet peak and then an integration region unique to vinyl protons of the monomer, methacrylic acid,  and transesterification product (if applicable) were compared to calculate the percentage of intact  monomer. To determine the rate constant and half‐lives for the hydrolysis of each monomer, data were  fit to a pseudo‐first order exponential decay function (Eq. (1)) where A is the percentage of intact  monomer, A0 is the initial monomer purity (>99%), and t is time in days.     (1) A=A0e−kt    Statistical analysis  Data were statistically analyzed with one‐way ANOVA and Tukey's test (α = 0.05), after normality and  homoscedasticity tests. Student's T‐test was carried out to analyze the effect of the storage time on the  μTBS (α = 0.05).  Polymerization kinetics  Kinetics of polymerization results for the groups tested at room temperature are shown in Fig.  2 and Table 1. The OH‐terminated methacrylate, HEMA α‐,β‐CH3 mixture showed the highest RPMAX,  20.2%∙s−1, and the NH2‐terminated 1‐methyl and 2‐methyl AEMA the lowest at 5.3%∙s−1. The  methacrylamides, HEMAM and 1‐methyl HEMAM, presented intermediate RPMAX values: 13.0 and  13.3%.s−1, respectively. The DC at RPMAX ranged between 35.1% and 16.7%. In general, OH‐ terminated methacrylates showed the highest values (35.1% and 31.6% for HEMA and HEMA α‐,β‐ CH3 mixture, respectively), followed by the methacrylamides (22.2% and 24.3% for HEMAM and 1‐ methyl HEMAM, respectively). The NH2‐terminated 1‐methyl and 2‐methyl AEMA presented the lowest  values: 15.7% and 16.7%, respectively. Final DC values ranged between 94.0% and 79.0%, with HEMA  and 2‐methyl AEMA presenting the highest and the lowest values, respectively. All other groups were  statistically similar to each other. The non‐substituted NH2‐terminated AEMA did not polymerize.  Fig. 2. Depicts degree of conversion (%) as a function of time (s), and polymerization rate (%∙s−1)  as a function of the degree of conversion (%) for all tested copolymers containing UDMA as base  monomer. The kinetics of polymerization was followed at room temperaure in real time by near‐IR  spectroscopy during photopolymerization for 300 s at 630 mW/cm2.  Table 1. Average (standard deviation) for maximum rate of polymerization (RPMAX – %∙s−1), degree of  conversion at the maximum rate of polymerization (DC at (RPMAX – %) and final degree of conversion  (Final DC – %) for all tested copolymers. Values followed by different letters indicate significant  differences among the tested groups (p < 0.05). 
Figure imgf000015_0001
Kinetics of polymerization results at 50 °C for HEMA, HEMAM and 2‐methyl HEMAM are presented  in Fig. 3 and Table 2. While there was no statistical difference among the tested groups in terms of  RPMAX (values ranged between 16.1 and 18.1%∙s−1), the methacrylate control HEMA showed the highest  values, 41.7% and 92.0%, for DC at RPMAX and final DC, respectively, and the non‐substituted HEMAM  and the β‐substituted 2‐methyl HEMAM methacrylamides presented the lowest values of DC at RPMAX,  29.6% and 31.3%, respectively, and final DC, 86.3% and 86.6%, respectively.    Fig. 3. Depicts degree of conversion (%) as a function of the time (s) and polymerization rate (%∙s−1) as a  function of the degree of conversion (%) for the OH‐ terminated methacrylate control HEMA, and the  non‐substituted HEMAM and the β‐substituted 2‐methyl HEMAM methacrylamides heated at 50 °C. The  kinetics of polymerization was followed in real time by near‐IR spectroscopy during the  photopolymerization for 300 s at 630 mW/cm2.  Table 2. Maximum rate of polymerization (RPMAX – %∙s−1), degree of conversion at the maximum rate of  polymerization (DC at (RPMAX – %) and final degree of conversion (Final DC – %) for the methacrylate and  methacrylamide controls, and the β‐substituted methacrylamide 2‐methyl HEMAM. Values followed by  different letters indicate significant difference among the tested groups (p < 0.05). 
Figure imgf000016_0001
Dentin microtensile bond strength  Dentin μTBS for the selected groups after 24 h and 6 months storage time are shown in Fig. 4. At 24 h,  the commercial control Single Bond and the methacrylamides, HEMAM and the α‐substituted 1‐methyl  HEMAM, showed the highest values (53.4 ± 9.8, 40.4 ± 5.9, and 45.5 ± 6.4 MPa, respectively), whereas  HEMA α‐,β‐CH3 mixture presented the lowest bond strength (23.2 ± 6.8 MPa). After 6 months, Single  Bond and 1‐methyl HEMAM presented the highest results (43.3 ± 5.3 and 42.9 ± 7.2 MPa, respectively).  The methacrylates HEMA and HEMA α‐,β‐CH3 mixture presented the lowest values: 21.9 ± 5.2 MPa and  12.7 ± 3.2 MPa, respectively. The reduction in μTBS over time was statistically significant only for the  HEMA α‐,β‐CH3 mixture, but all groups showed a numeric reduction ranging between 37.5% and 5.7%  for HEMA and 1‐methyl HEMAM, respectively.    Fig. 4. represents dentin microtensile bond strength after 24 h and 6 months aging for the selected  groups. Different uppercase letters indicate significant difference among the groups at the same storage  condition (p < 0.05), and different lowercase letters indicate significant difference between the storage  conditions within the composition (p < 0.05).  Monomer hydrolysis kinetics  All tested monomers showed a measurable amount of degradation after 4 days or less exposure to  acidic aqueous conditions (H
Figure imgf000017_0001
 pH = 1) (Fig. 5). The unsubstituted methacrylamide, HEMAM,  experienced the least degradation with 89.1 ± 0.01% of the monomer remaining intact after 17 days of  incubation. The substituted methacrylamides, 2‐methyl HEMAM and 1‐methyl HEMAM, both exhibited  more degradation than HEMAM, with 83.5 ± 0.5% and 65.4 ± 1.3% intact monomer remaining. The two  methacrylate monomers exhibited similar degradation amounts, HEMA with 25.2 ± 0.1% intact  monomer after 19 days incubation and the α,β‐CH3 HEMA mixture with 31.9 ± 0.4% intact monomer  after 17 days incubation. The half‐life results from fitting to an exponential decay model and a  transformed linear regression showed that HEMAM had the greatest half life at 104 days, nearly 10×  longer than the α,β‐CH3 HEMA mixture (Figure 5). Additionally, transesterification products were  observed in the methacrylamide groups. NMR spectra and further analysis can be found in the  supplementary information.    Fig. 5. Represents degradation of monomer over time in acid aqueous conditions (H2O, pH = 1) at 37  °C. NMR spectroscopy was used to determine the amount of remaining monomer compared to  degradation products (and transesterification products where applicable). Error bars are too small to be  seen. Data were fit to a pseudo‐first order exponential decay curve to determine monomer half‐life.  Table 3. Half‐lives for monomers in acidic aqueous conditions at 37°C. Data were fit to an  exponential decay model (Fig. 5) as well as linear regression using a natural logarithmic  transformation. 
Figure imgf000018_0001
Dynamic isomeric transesterification equilibrium  The degradation of the adhesive interface is believed to be one of the most important causes of the  reduced clinical lifetime of adhesive dental restorations. In addition to the collagen degradation, the  hydrolysis of the polymeric constituents play a crucial role on the adhesive interface  instability [3], [4], [5], [6], leading to the development of more degradation resistant monomers. The  original experiment was designed to systematically evaluate the effect of the carbon substitutions on  monomer reactivity and stability, in which alpha and beta‐substituted HEMA monomers would be tested  individually. However, the systematic evaluation of the effect of the methyl substitutions for the HEMA  derivatives was not possible due to the facile susceptibility to α and β‐CH3 isomerization. In fact, even  the commercially available HEMA methylated derivative is only available as a mixture of isomers. This  isomerization is very likely occurring via a low‐energy transesterification mechanism [33]. For example,  the β‐substituted 1‐methyl HEMA is particularly susceptible to this isomerization. The terminal hydroxyl  group participates in a transesterification resulting in a dimethacrylate and propane‐1,2‐diol (Scheme 3  in supplemental materials). Another transesterification occurs resulting in two monomethacrylates. In  order to return to the original monomethacrylate, the secondary alcohol of the diol would need to  participate in the transesterification while the more nucleophilic primary alcohol results in 2‐methyl  HEMA. This difference in nucleophilicity explains why an eventual equilibrium of a 3:1 ratio of 2‐methyl  HEMA to 1‐methyl HEMA is reached in commercial HEMA α‐,β‐CH3. This transesterification will not  result in an isomerization in unsubstituted monomers, like HEMA, though the dynamic behavior is likely  still occurring. This mechanism explains the observation that the common impurities in commercial  HEMA are dimethacrylate and ethylene glycol [34].     The degradation of the adhesive interface is believed to be one of the most important causes of the  reduced clinical lifetime of adhesive dental restorations. In addition to the collagen degradation, the  hydrolysis of the polymeric constituents play a crucial role on the adhesive interface  instability [3], [4], [5], [6], leading to the development of more degradation resistant monomers. The  original experiment was designed to systematically evaluate the effect of the carbon substitutions on  monomer reactivity and stability, in which alpha and beta‐substituted HEMA monomers would be tested  individually. However, the systematic evaluation of the effect of the methyl substitutions for the HEMA  derivatives was not possible due to the facile susceptibility to α and β‐CH3 isomerization. In fact, even  the commercially available HEMA methylated derivative is only available as a mixture of isomers. This  isomerization is very likely occurring via a low‐energy transesterification mechanism [33]. For example,  the β‐substituted 1‐methyl HEMA is shown as an example in Fig. 6 and is particularly susceptible to this  isomerization. The terminal hydroxyl group participates in a transesterification resulting in a  dimethacrylate and propane‐1,2‐diol (Scheme 3 in supplemental materials). Another transesterification  occurs resulting in two monomethacrylates. In order to return to the original monomethacrylate, the  secondary alcohol of the diol would need to participate in the transesterification while the more  nucleophilic primary alcohol results in 2‐methyl HEMA. This difference in nucleophilicity explains why an  eventual equilibrium of a 3:1 ratio of 2‐methyl HEMA to 1‐methyl HEMA is reached in commercial HEMA  α‐,β‐CH3. This transesterification will not result in an isomerization in unsubstituted monomers, like  HEMA, though the dynamic behavior is likely still occurring. This mechanism explains the observation  that the common impurities in commercial HEMA are dimethacrylate and ethylene glycol [34]. A  detailed exploration of this phenomenon is beyond the scope of this paper.    Amino‐terminated methacrylates (AEMA, 1‐methyl AEMA, and 2‐methyl AEMA) were obtained or  synthesized as hydrochloride salts and did not form isomers like their hydroxyl‐terminated counterparts.  However, when the hydrochloride salts were free‐based before being incorporated into the  formulations, they rapidly formed amides from the primary amine, acting as a nucleophile, resulting in a  mixture of methacrylates and methacrylamides (and likely hybrid methacrylate‐methacrylamide)  monomers. Additional details are discussed in the supplementary information.  Polymerization kinetics  The reactivity rates as observed from the polymerization kinetics experiments ranked as follows: NH2‐ terminated methacrylates < OH‐terminated methacrylamides < OH‐terminated methacrylates.    The NH2‐terminated methacrylates (AEMA, 1‐methyl AEMA and 2‐methyl AEMA) resulted in a  copolymerization characterized by markedly low values of RPMAX and DC at RPMAX (Fig. 2 and Table 1).  One possible explanation is potential phase‐separation, as the final polymer presented a nacre‐like  structure. While one may expect the slow kinetics for these monomers would result in low final DC  values, the final DCs were actually comparable or only slightly lower as compared to the other  monomers. This was likely due to the long period of photoactivation which compensated for the slow  curing kinetics. However, the low reactivity and phase‐separation make the NH2‐terminated monomers  unsuitable for dental material compositions and, therefore were not subjected to further tests.    For the remaining compounds, in general, OH‐terminated methacrylates showed higher values of  RPMAX and DC at RPMAX than the secondary methacrylamides. This was expected since the tested  methacrylates show lower molecular weight and viscosity than the methacrylamides, which likely  increased the molecular mobility [Odian G. Principles of polymerization: John Wiley & Sons; 2004]. In  addition, due to the known strong resonance stabilization of the carbonyl with the lone pair of electrons  from the nitrogen, amide functionalities show significantly lower reactivity than methacrylates [Kovács  et al., Molecules. 2018;23:2859].    The side‐group substitution played no significant role in the monomer reactivity, especially for the  methacrylamides. It had previously been shown that the incorporation of ethyl or methyl side‐group  substituents on the α carbon of secondary methacrylamides resulted in marginally increased  polymerization reactivity and, subsequently, increased bonding performance [Fugolin et al., Dental  Materials. 2019;35:686‐96]. An increase in polymerization kinetics of a methacrylamide monomer with  side‐chain substitution can likely be attributed to amide twisting (a twisting of the amide C(O)–NH  bond), which changes the geometry, reducing the contribution from the non‐propagating resonance  form (Scheme 2 in supplemental materials) due to de‐conjugation of the nitrogen lone pair with the  carbonyl π‐system [Wang et al., Journal of the American Chemical Society. 1991;113:5757‐65]. In this  study, the lack of an observable effect is likely due to the small steric profile of the methyl substitutions.  The side‐group substitution played no significant role in the monomer reactivity, especially for  the methacrylamides. It had previously been shown that the incorporation of ethyl or methyl side‐group  substituents on the α carbon of secondary methacrylamides resulted in marginally increased  polymerization reactivity and, subsequently, increased bonding performance [Fugolin et al., Dental  Materials. 2019;35:686‐96]. An increase in polymerization kinetics of a methacrylamide monomer with  side‐chain substitution can likely be attributed to amide twisting (a twisting of the amide C(O)–NH  bond), which changes the geometry, reducing the contribution from the non‐propagating resonance  form (Scheme 2 in supplemental materials) due to de‐conjugation of the nitrogen lone pair with the  carbonyl π‐system [ Wang et al., Journal of the American Chemical Society. 1991;113:5757‐65]. In this  study, the lack of an observable effect is likely due to the small steric profile of the methyl substitutions.    The OH‐terminated methacrylate HEMA (control) presented the highest values of DC at  RPMAX and final DC when polymerized at 50 °C, with HEMAM and 2‐methyl HEMAM being similar to each  other. This was expected due to the differences in molecular weight, viscosity and reactivity among the  compounds, as discussed above. The similarity of RPMAX among HEMA and the secondary  methacrylamides was also observed for the polymerization kinetics evaluated at room temperature in  this study and previously reported [Fugolin et al., Dental Materials. 2019;35:686‐96]. As mentioned  above, HEMA has low molecular weight and viscosity (130 g/mol and 0.007 Pa.s), which increases the  overall mobility within the comonomer system. This allows for a rapid increase in the rates of  propagation and termination at the beginning of the polymerization reaction, until the formation of high  molecular weight species severely hamper diffusion [Odian G. Principles of polymerization: John Wiley &  Sons; 2004]. Despite methacrylates having higher reactivity than methacrylamides, the observed  RPMAX values were similar. This observation reinforces that the methacrylamide‐methacrylate blend ratio  used in this study provides good properties without a significant loss of polymerization reactivity.  Another interesting finding is that the polymerization kinetics was less affected than expected  when the polymerization was carried out at 50 °C, compared with room temperature. The increase in  RPMAX was similar for HEMA and HEMAM (22% and 24%, respectively, and the DC at RPMAX increased by  19% for HEMA and 33% for HEMAM. The increase in and final DC was negligible. The effect on DC at  RPMAX observed for HEMAM was expected based both on the increased mobility and on the decrease in  activation energy at higher temperatures [Odian G. Principles of polymerization: John Wiley & Sons;  2004], mainly because of its greater hydrogen bonding potential and viscosity at room  temperature [Daronch et al., Journal of Dental Research. 2005;84:663‐7], [Nie et al., Acta Polymerica.  1998;49:145‐61], [Bausch et al., Journal of Oral Rehabilitation. 1981;8:309‐17]. The absence of  significant effects on final DC is likley due to the fact that the materials were polymerized at a relatively  high intensity, for a relatively long time (300 s at 630 mW/cm2).  Dentin microtensile bond strength  The similarity of the μTBS (after 24 h) for commercial control Single Bond and the experimental  secondary methacrylamides (HEMAM and 1‐methyl HEMAM formulations) suggests that the  methacrylamides may be useful candidates as co‐monomers for improved dental adhesive formulations.  The low μTBS of the HEMA α‐,β‐CH3 mix stands in contrast to the excellent polymerization kinetics  observed. It is possible that the high polymerization rates and side‐group substitutions at the α‐
Figure imgf000022_0001
and β‐ carbons might have resulted in a poorly packed polymer network with compromised mechanical  properties [Pfeifer et al., European Polymer Journal. 2011;47:162‐70]. The β‐substituted 2‐methyl  HEMAM showed a statistically equivalent μTBS to the other secondary methacrylamides (HEMAM and  1‐methyl HEMAM), though lower than Single Bond. A previous study has shown that the performance of  the (meth)acrylamide copolymers is highly dependent on the chemical structure localized about the  amide, as well as the blending monomer [Fugolin et al., Dental Materials. 2019;35:686‐96].    As mentioned previously, 2‐methyl HEMAM is a powder and, even after the addition of solvent for the  adhesive formulation, still led to a product with noticeably higher viscosity compared with the remaining  monomers. Even though viscosity was not measured in this study, it can be speculated that this affected  the quality of the hybridization of the collagen substrate in the 2‐methyl HEMAM group. At 6 months,  while Single Bond, HEMAM and 1‐methyl HEMAM maintained the highest bond strengths, 2‐methyl  HEMAM showed intermediate results, and the experimental methacrylates HEMA and HEMA α‐, β‐ CH3 mix the lowest bonds, which once again highlights the degradation resistance of the  methacrylamides. Finally, the reduction in μTBS over time ranged between 37.5% for the methacrylate  control, HEMA, and 5.7% for the α‐substituted secondary methacrylamide, 1‐methyl HEMAM, which can  be explained by the increased resistance to hydrolysis of the methacrylamides compared to their  methacrylate counterparts.  Monomer hydrolysis kinetics  The hydrolysis results confirmed the expected increased resistance to hydrolysis, as all methacrylate  monomers showed significantly more degradation in acidic aqueous conditions than the  methacrylamide monomers. Notably, the hydrolysis rates of the amides vs esters were in agreement  with simple chemical models which predict a factor of ten difference ([28], Scheme 1 in supplemental  materials). The unsubstituted methacrylate, HEMA, and mixture of isomers, HEMA α‐,β‐CH3, performed  similarly to each other and poorly in comparison to the methacrylamides in the degradation experiment.  Both HEMA and HEMA α‐,β‐CH3 had a half‐life of 9.52 days (linear regression), while the worst  performing methacrylamide, 1‐methyl HEMAM, had a half‐life of 27.7 days. The HEMA α‐,β‐CH3 mixture  of isomers was mostly composed of the β‐substituted 2‐methyl HEMA (3:1), but this appeared to have  no benefit or detriment to the stability to acid‐catalyzed hydrolysis compared to HEMA.  The hydrolysis results confirmed the expected increased resistance to hydrolysis, as all methacrylate  monomers showed significantly more degradation in acidic aqueous conditions than the  methacrylamide monomers. Notably, the hydrolysis rates of the amides vs esters were in agreement  with simple chemical models which predict a factor of ten difference ([Charton et al., Journal of Organic  Chemistry. 1978;43:3995‐4001], Scheme 1 in supplemental materials). The unsubstituted methacrylate,  HEMA, and mixture of isomers, HEMA α‐,β‐CH3, performed similarly to each other and poorly in  comparison to the methacrylamides in the degradation experiment. Both HEMA and HEMA α‐,β‐CH3 had  a half‐life of 9.52 days (linear regression), while the worst performing methacrylamide, 1‐methyl  HEMAM, had a half‐life of 27.7 days. The HEMA α‐,β‐CH3 mixture of isomers was mostly composed of  the β‐substituted 2‐methyl HEMA (3:1), but this appeared to have no benefit or detriment to the  stability to acid‐catalyzed hydrolysis compared to HEMA.   Interestingly, the addition of a α‐ or β‐CH3 groups had a detrimental effect (i.e., increased  hydrolysis rate). The α‐,β‐CH3 methacrylamides (1‐methyl and 2‐methyl HEMAM) showed higher  degradation rates (half‐lives of 68.8 and 27.7 days, respectively) compared to unsubstituted HEMAM  (half‐life of 101 days). The α‐CH3 substituted 1‐methyl HEMAM was hydrolyzed about 3.5 times faster  than HEMAM, with the the β‐CH3 substituted 2‐methyl HEMAM being hydrolyzed about 1.5 times faster  than HEMAM. This trend is the opposite of what was expected from a simple chemical steric model for  base‐assisted hydrolysis (Scheme 1 in supplemental materials). Notably, the magnitude of the effect is  approximately the same. These observations suggest that for the acid catalyzed hydrolysis reaction,  increased steric influence accelerates the leaving group (X‐R in Scheme 1 in supplemental materials).  This would be the case, for example, if protonation of the heteroatom (O for ester, NH for amide) were  the rate‐limiting step instead of the H2O nucleophilic attack of the carbonyl, which also tracks with the  basicity of the heteroatom increasing in the order (e.g., HEMAM < 1‐methyl HEMAM < 2‐methyl  HEMAM).  Interestingly, the addition of a α‐ or β‐CH3 groups had a detrimental effect (i.e., increased  hydrolysis rate). The α‐,β‐CH3 methacrylamides (1‐methyl and 2‐methyl HEMAM) showed higher  degradation rates (half‐lives of 68.8 and 27.7 days, respectively) compared to unsubstituted HEMAM  (half‐life of 101 days). The α‐CH3 substituted 1‐methyl HEMAM was hydrolyzed about 3.5 times faster  than HEMAM, with the the β‐CH3 substituted 2‐methyl HEMAM being hydrolyzed about 1.5 times faster  than HEMAM. This trend is the opposite of what was expected from a simple chemical steric model for  base‐assisted hydrolysis (Scheme 1 in supplemental materials). Notably, the magnitude of the effect is  approximately the same. These observations suggest that for the acid catalyzed hydrolysis reaction,  increased steric influence accelerates the leaving group (X‐R in Scheme 1 in supplemental materials).  This would be the case, for example, if protonation of the heteroatom (O for ester, NH for amide) were  the rate‐limiting step instead of the H2O nucleophilic attack of the carbonyl, which also tracks with the  basicity of the heteroatom increasing in the order (e.g., HEMAM < 1‐methyl HEMAM < 2‐methyl  HEMAM).  During the hydrolysis experiment, transesterification products were observed for the  methacrylamide monomers. Acid and base catalyzed transesterification of monomers like HEMA have  been reported under concentrated conditions, such as hydrogels [Lee et al., Journal of Polymer Science,  Part A: Polymer Chemistry. 2002;40:1858‐67]; however, this was an unexpected chemical equilibrium at  the dilute aqueous conditions of the experiment. 1‐methyl HEMAM exhibited the most  transesterification product after 17 days, making up 9.0%. While this number may seem small, only  34.6% of the monomer hydrolyzed at this time point meaning 26.0% of the 2‐aminopropan‐1‐ol  degradation product re‐esterified into the methacrylate transesterification product, 2‐methyl AEMA.  During the hydrolysis experiment, transesterification products were observed for the  methacrylamide monomers. Acid and base catalyzed transesterification of monomers like HEMA have  been reported under concentrated conditions, such as hydrogels [[Lee et al., Journal of Polymer Science,  Part A: Polymer Chemistry. 2002;40:1858‐67]; however, this was an unexpected chemical equilibrium at  the dilute aqueous conditions of the experiment. 1‐methyl HEMAM exhibited the most  transesterification product after 17 days, making up 9.0%. While this number may seem small, only  34.6% of the monomer hydrolyzed at this time point meaning 26.0% of the 2‐aminopropan‐1‐ol  degradation product re‐esterified into the methacrylate transesterification product, 2‐methyl AEMA.  The re‐esterification likely occurred due to the low pH of the aqueous environment. At pH = 1, the  amino group is more than 9 units below its pKa and the population of water molecules is essentially  all hydronium ions, leaving the alcohol as the best available nucleophile for the transesterification  reaction. This concept is consistent in the other methacrylamide groups, HEMAM and 2‐methyl HEMAM.  In the case of HEMAM, there is very little monomer hydrolysis, only 10.9%, but 36.3% of the less  sterically hindered degradation product, aminoethanol, re‐esterifies to form AEMA. Of the 16.51% of  hydrolyzed 2‐methyl AEMA, only 22.8% re‐esterifies into the transesterification product, 1‐methyl  AEMA.  The re‐esterification likely occurred due to the low pH of the aqueous environment. At pH = 1,  the amino group is more than 9 units below its pKa and the population of water molecules is essentially  all hydronium ions, leaving the alcohol as the best available nucleophile for the transesterification  reaction. This concept is consistent in the other methacrylamide groups, HEMAM  and 2‐methyl  HEMAM. In the case of HEMAM, there is very little monomer hydrolysis, only 10.9%, but 36.3% of the  less sterically hindered degradation product, aminoethanol, re‐esterifies to form AEMA. Of the 16.51%  of hydrolyzed 2‐methyl AEMA, only 22.8% re‐esterifies into the transesterification product, 1‐methyl  AEMA (see Figs. 6 and 7).  The secondary alcohol of the 1‐aminopropan‐2‐ol is less nucleophilic than the primary alcohol of  2‐aminopropan‐1‐ol and aminoethanol, resulting in less re‐esterification of the degradation products.  The fact that weak nucleophiles such as secondary alcohols are able to participate in this  transesterification suggests that the activated carbonyls of methacrylates and methacrylamides are very  prone to transesterification. In the case of HEMA, much like in the discussion of amino‐terminated  monomers, this transesterification can go unnoticed as ethylene glycol can only re‐esterify into HEMA.  This would mean that the HEMA molecule is breaking and reforming, which makes the degradation of  HEMA appear artificially slow compared to the methacrylamide groups where the amine is protonated  and unable to participate in re‐esterification of the original monomer. More importantly, this evidence  of transesterification would suggest that more care should be used when analyzing degradation  products of dental materials as the degradation product mixtures have potential to be more complex  than simply primary degradation products.  Conclusions  The blend of methacrylamides (40 wt%) in methacrylates produced good bond strengths and  excellent hydrolytic stability, while retaining acceptable polymerization kinetics. α‐and β‐CH3 derivatives  had a non‐measurable effect on polymerization kinetics, suggesting that the methyl moiety is not  sufficiently sterically hindering to affect the reactivity as previously seen with larger ethyl groups. NH2‐ terminated monomers had unacceptable polymerization rates, making these non‐starters for dental  materials. Even the fast polymerization kinetics of HEMA α‐β‐CH3 mixture along with the side‐group  substitutions compromised bond strength.  Amide monomers were approximately ten times more stable to hydrolysis than the analogous  methacrylates. The addition of a α
Figure imgf000026_0001
 or β‐CH3 groups increased the rate of hydrolysis. The magnitude of  the effect was approximately the same as a model system (base‐catalyzed hydrolysis of esters or  amides) but opposite in influence.  The α‐CH3 substituted secondary methacrylamide, 1‐methyl HEMAM,  showed the most stable adhesive interface.  Finally, a side reaction was observed with transesterification of the monomers studied under  ambient conditions. Transesterifications of this nature typically occur under much harsher reaction  conditions, and it is not clear why the transesterification of the diol moiety is so facile for methacrylates  compared to simple esters.  Scheme 1 below represents steric  influence of side‐chain  functionality on  the relative rates of  base catalyzed ester hydrolysis and amide hydrolysis (Charton 1978). Note that α‐Me substituents have a  maximum effect of ~1.5‐1.8 times slower hydrolysis. 
Figure imgf000026_0002
  Scheme 2 below provides a) General reaction scheme for amide and ester polymerization and  subsequent  hydrolysis.  b)  Resonance  structures  for  the  radical  polymerization  intermediate  showing  propagating and non‐propagating resonance differences between esters and amides. 
Figure imgf000027_0002
X = O minor resonance form X = NH major resonance form   Scheme  3  below  depicts  1‐methyl  HEMA  as  an  example  of  isomerization  through  transesterification  of  substituted  hydroxyl‐terminated  methacrylates  towards  thermodynamic  equilibrium resulting in a mixture of isomers. 
Figure imgf000027_0001
  Figure 6 provides names and abbreviations of the evaluated monomers along with the  associated transesterification and degradation products.  Synthesis and characterization of 1‐methyl HEMAM 
Figure imgf000027_0003
  N‐(1‐hydroxypropan‐2‐yl)methacrylamide (1‐methyl HEMAM): Freshly distilled methacryloyl chloride  (60.0 mmol, 1 equiv.) in anhydrous DCM (20 mL) was added dropwise to a stirred solution of 2‐ aminopropanol (63.0 mmol, 1.05 equiv.), trimethylamine (60.0 mmol, 1 equiv.) and 5 mg of 4‐ methoxyphenol in anhydrous DCM (30 mL) at ‐5 °C. The temperature was maintained after the addition  for 2 hours before adding a catalytic amount of 4‐dimethylaminopyridine (3.0 mmol, 0.05 equiv.). The  mixture was allowed to stir at room temperature for 36 before filtration. The organic filtrate was  washed with 20 mL of 0.1 M NaOH solution and saturated brine. The organic layer was dried over  Na2SO4, filtered, and concentrated under reduced pressure to give the crude product as a pale yellow  oil. The crude product was purified using a Buchi Reveleris X2 flash chromatography system (mobile  phase A was hexanes and mobile phase B (MPB) was EtOAc, with a gradient program of 11% MPB for 1  min, 11% MPB to 47% MPB over 14.3 min and hold at 47% for 7.2 min). The fractions were collected and  concentrated under reduced pressure, yielding the final product as an off‐white solid (25.9 mmol, 43.2%  yield). 1H NMR (400 MHz, Deuterium Oxide) δ 5.63 – 5.51 (m, 1H), 5.42 – 5.26 (m, 1H), 3.96 (h, J = 6.8 Hz,  1H), 3.53 (dd, J = 11.5, 4.9 Hz, 1H), 3.46 (dd, J = 11.4, 6.7 Hz, 1H), 1.84 (s, 3H), 1.07 (d, J = 6.8 Hz, 3H).  13C{1H} NMR (101 MHz, Chloroform‐d) δ 168.98, 139.79, 119.90, 66.24, 47.61, 18.59, 16.97.  Synthesis and characterization of amine hydrochloride salt terminated monomers  
Figure imgf000028_0001
  1‐aminoprop‐2‐yl methacrylate hydrochloride (1‐methyl AEMA•HCl): 1‐aminopropan‐2‐ol  (45.1  mmol) was added dropwise to stirring solution of conc. HCl (45.1 mmol) aqueous solution at 0 °C. The  solution was stirred and temperature maintained for 20 minutes followed by distillation under reduced  pressure at 60 °C to remove excess HCl. The remaining aqueous solution was lyophilized resulting in white  solid hydrochloride salt. 4‐methoxyphenol (1.0 mol%) was added to the hydrochloride salt and heated to  85 °C. Methacryloyl chloride (54.1 mmol, 1.2 equiv) was added and stirred for 2 hours. A sweep of N2 gas  was bubbled into a saturated sodium bicarbonate aqueous solution to trap the resulting HCl gas. After  cooling to 40 °C, 12 mL of THF was added and the resulting solution was added dropwise to 100 mL of  diethyl ether, precipitating a white solid (21.8 mmol, 48.3% yield). 1H NMR (400 MHz, Deuterium Oxide)  δ 6.27 – 6.12 (m, 1H), 5.85 – 5.71 (m, 1H), 5.31 – 5.10 (m, 1H), 3.38 – 3.18 (m, 2H), 1.95 (s, 3H), 1.37 (d, J  = 6.5 Hz, 3H). 
Figure imgf000029_0001
  2‐aminopropyl  methacrylate  hydrochloride  (2‐methyl  AEMA•HCl):  2‐aminopropan‐1‐ol  (57.5  mmol) was added dropwise to stirring solution of conc. HCl (57.5 mmol) aqueous solution at 0 °C. The  solution was stirred and temperature maintained for 20 minutes followed by distillation under reduced  pressure at 60 °C to remove excess HCl. The remaining aqueous solution was lyophilized resulting in white  solid hydrochloride salt. 4‐methoxyphenol (1.0 mol%) was added to the hydrochloride salt and heated to  85 °C. Methacryloyl chloride (69.0 mmol, 1.2 equiv) was added and stirred for 2 hours. A sweep of N2 gas  was bubbled into a saturated sodium bicarbonate aqueous solution to trap the resulting HCl gas. After  cooling to 40 °C, 15 mL of THF was added and the resulting solution was added dropwise to 100 mL of  diethyl ether, precipitating a white solid (33.6 mmol, 58.4% yield). 1H NMR (400 MHz, Deuterium Oxide)  δ 6.26 – 6.18 (m, 1H), 5.83 – 5.76 (m, 1H), 4.41 (dd, J = 12.3, 3.4 Hz, 1H), 4.26 (dd, J = 12.3, 7.0 Hz, 1H),  3.85 – 3.72 (m, 1H), 1.96 (s, 3H), 1.39 (d, J = 6.8 Hz, 3H).     Neutralization of amine terminated monomers  General Procedure: 2‐aminoethyl methacrylate hydrochloride salt  (2‐AEMA•HCl; CAS# 2420‐94‐2) was  obtained from Sigma Aldrich. 1‐aminoprop‐2‐yl methacrylate hydrochloride (1‐methyl AEMA•HCl) and 2‐ aminopropyl methacrylate hydrochloride (2‐methyl AEMA•HCl) were synthesized as described above. The  hydrochloride salts (10.0 mmol) were neutralized by slurrying the solids in 25 mL dichloromethane (DCM)  and an excess of triethylamine (15.0 mmol) for 1 hour. After filtration, the filtrate was concentrated under  reduced pressure at 25 °C. Due to the limited solubility of TEA•HCl salt in DCM, some salts remained after  removal of solvent. The oil was dissolved in 10 mL acetone, filtered, and concentrated to an oil under  reduced pressure. All compounds were observed as slightly yellow oil and were stored under N2 gas until  use in formulations.  General Characterization Considerations: 1H NMR spectra of the resulting products in CDCl3. Upon  neutralization, a transesterification resulting in a methacrylamide compound occurred in all cases. This  transesterification can be observed by NMR spectroscopy:  the vinyl proton peaks around 5.7 and 5.3 ppm  (actual ppm vary for each compound) are upfield from the methacrylate vinyl proton peaks around 6.1  and  5.6  ppm.  Additionally,  there  is  a  set  of methacrylate  vinyl  proton  peaks  that  are  likely  from  the  presence of methacrylic acid (presumably from the hydrolysis of the product compounds). Anhydrous TEA  would be likely avoid methacrylic acid formation.   Attempts  to  characterize  the  complex  mixtures  resulting  from  the  neutralization  of  each  compound  can  be  found  in  the  figures  below.  Further  purification  is  needed  for  a  complete  characterization  of  the  resulting  mixture;  however,  this  falls  outside  of  the  scope  of  this  paper.  Nonetheless, understanding the reaction paradigm can be established using the observational data as is.  When 1‐methyl AEMA hydrochloride salt is neutralized, the resulting mixture of compounds is almost all  (~93%) the transesterication product, 2‐methyl HEMAM, which has secondary alcohol. In contrast, when  2‐methyl AEMA hydrochloride salt is neutralized, the resulting mixture is more evenly distributed between  the neutralized 2‐methyl AEMA, the transesterification product 1‐methyl HEMAM, and methacrylic acid.  This  difference  could  be  explained  by  the  difference  in  nucleophilicity  of  the  pendant  alcohol  in  the  transesterification product, where 1‐methyl HEMAM has a primary alcohol and 2‐methyl HEMAM has a  secondary alcohol. The primary alcohol of 1‐methyl HEMAM is able to participate in a transesterification  reaction back  to  the  intended compound 2‐methyl AEMA, pushing  the equilibrium to  lie between the  intended  product  and  the  transesterification  product.  The  alcohol  of  2‐methyl  HEMAM  is  much  less  nucleophilic as a secondary alcohol and would have a much slower re‐esterification reaction back to 1‐ methyl AEMA, resulting in an equilibrium with mostly transesterification product and very little 1‐methyl  AEMA. Interestingly, the unsubstituted version, resulted in very little of the transesterification product  HEMAM.  This  could  possibly  suggest  that  transesterification  occurs  through  both  an  intermolecular  mechanism  and  an  intramolecular  mechanism.  The  addition  of  steric  bulk  in  the  form  of  methyl  substituents  would  be  expected  to  favor  intramolecular  transesterification  due  to  the  Thorpe‐Ingold  effect  and  could explain why  there  is more  transesterification products  in  the 1‐methyl  and 2‐methyl  AEMA samples. Additional investigation into this product mixtures is needed to determine the presence  of any other compounds important to better understanding the dynamics of the neutralization reaction,  such  as  methacrylate‐methacrylamide  hybrid  monomers  and  oxazoline  byproducts  that  could  have  formed.  The  instability  of  the  amino‐terminated  monomers  in  neutralized  form  prevents  a  clear  understanding of the effects of methyl substituent placement as this cannot be observed in the complex  mixture that forms after neutralization. Additionally, while the hydrochloride salt forms are stable and  able to be purified, they cannot included in the systematic evaluation due to large changes in properties  (hydrophilicity, water absorption) that would occur from including a salt in formulation and due to the  likely transesterification that would occur upon exposure to bases present in co‐monomers or initiators  during formulation.  
Figure imgf000031_0001
  1‐methacrylamido‐2‐methylpropan‐2‐yl methacrylate (2dMM Hybrid): colorless oil.  IR (neat) νmax 3341,  3086, 2978, 2959, 2927, 2849, 1720, 1664, 1626, 1528, 1477, 1455, 1405, 1393, 1367, 1321, 1298, 1251,  1166, 1021, 989, 940, 813 cm‐1. 1H NMR (400 MHz, Chloroform‐d) δ 6.10 – 6.03 (m, 1H), 6.03 – 5.95 (br,  1H), 5.60 – 5.48 (m, 2H), 5.27 – 5.17 (m, 1H), 4.22 (s, 2H), 1.91 – 1.87 (m, 3H), 1.88 – 1.83 (m, 3H), 1.37 (s,  6H). 13C NMR (101 MHz, Chloroform‐d) δ 168.15, 167.34, 140.90, 135.98, 125.93, 118.89, 69.59, 53.62,  23.79, 18.62, 18.24.   
Figure imgf000031_0002
  2‐methacrylamidobutyl methacrylate (2EM Hybrid): slight yellow oil. IR (neat) νmax 3319, 3806, 3050, 2968,  2930, 2879, 2740, 1721, 1656, 1620, 1532, 1456, 1404, 1377, 1323, 1297, 1206, 1169, 1042, 1013, 983,  939, 814, 784 cm‐1. 1
Figure imgf000031_0003
NMR (400 MHz, Chloroform‐d) δ 6.10 – 6.04 (m, 1H), 6.03 – 5.96 (m, 1H), 5.63 –  5.56 (br, 1H), 5.55 – 5.49 (m, 1H), 5.29 – 5.21 (m, 1H), 4.26 – 4.02 (m, 3H), 1.89 (s, 3H), 1.88 (s, 3H), 1.66  – 1.42 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, Chloroform‐d) δ 168.30, 167.50, 140.18, 135.95,  126.07, 119.33, 65.73, 50.10, 24.67, 18.66, 18.29, 10.33. 
Figure imgf000031_0004
  2‐methacrylamidoethyl methacrylate (HEMAM Hybrid): yellow oil. IR (neat) νmax 3342, 3807, 2981, 2957,  2928, 2851, 1744, 1720, 1659, 1622, 1531, 1453, 1377, 1403, 1320, 1296, 1250, 1204, 1167, 1121, 1108,  1082, 1037, 1011, 941, 814 cm‐1. 1H NMR (400 MHz, DMSO‐d6) δ 8.16 – 7.95 (br, 1H), 6.24 – 5.96 (m, 1H),  5.92 – 5.65 (m, 1H), 5.65 – 5.60 (m, 1H), 5.39 – 5.27 (m, 1H), 4.13 (t, J = 5.8 Hz, 2H), 3.39 (q, J = 5.6 Hz, 2H),  1.94 – 1.85 (m, 3H), 1.84 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 168.22, 166.98, 140.30, 136.31, 126.28,  119.54, 63.23, 38.36, 19.04, 18.43.    Materials and Methods  Tested monomers and synthesis procedures    The  tested  monomers  are  shown  in  Figure  1.  All  commercially‐available  monomers  were  purchased from Sigma‐Aldrich (Milwaukee, WI, USA) at 97% purity and used as received. The chemical  structure of the secondary methacrylamide N‐hydroxyethyl methacrylamide (HEMAM) was modified with  ethyl and methyl substituents on the first  (alpha) carbon (2EM and 2dMM, respectively), as described  previously [Fugolin et al., Dental Materials. 2019;35:686‐96]. The hybrid versions of these monomers were  isolated via chromatography, as described in the supporting information.  NMR and IR spectral data can  also be found in the supporting information.    N‐hydroxyethyl  methacrylate  (HEMA)  was  tested  as  monofunctional  methacrylate  control.  Triethyleneglycol dimethacrylate (TEGDMA) was tested as difunctional methacrylate control to provide a  comparison  with  the  difunctional  methacrylamide‐methacrylate  hybrid  monomers.    The  partition  coefficient (log P) for each monomer was calculated using the software package Chem Draw Ultra 14.1  (Perkin Elmer, San Jose, CA, USA).  Tested formulations and photocuring conditions    The monomers shown in Figure 1 were mixed at 40 mass% with bisphenol A‐glycidyl methacrylate  (bisGMA). The photoinitiator system consisted of DMPA (2,2‐dimethoxy‐2‐phenylacetophenone, λmax=365  nm) and DPI‐PF6  (diphenyliodonium hexafluorophosphate) at 0.2 mass% and 0.4 mass%,  respectively.  Butylated hydroxytoluene (BHT) was added at 0.1 mass% to each formulation as a free‐radical inhibitor.  For the dentin microtensile bond strength test only, experiments were conducted with fully formulated  adhesives containing 40 vol% of ethanol to provide appropriate viscosity for proper dentin penetration  and subsequent volatilization by air drying. All photocuring procedures were accomplished by a mercury  arc lamp (Acticure 4000 UV Cure, Mississauga, Canada) filtered to 320–500 nm at 630 mW/cm2 measured  directly at the sample surface using a thermopile power meter (Molectron PM100, Portland, OR, USA).  The choice of light source was intended to match the initiator system used.    Kinetics of polymerization    The  kinetics  of  polymerization  were  assessed  in  near‐IR  spectroscopy  (Nicolet  6700,  Thermo  Scientific, USA) in real time during the photopolymerization of disc‐shaped samples (10 mm in diameter  and  0.8 mm  in  thickness; measured with  a  digital  caliper  to  0.01 mm)  for  300  seconds  (n  =  3).  Each  spectrum was collected with 2 scans at 4 cm‐1 resolution.  This resolution allowed for baseline correction  without compromising the sampling rate and signal‐to‐noise ratio. The final carbon‐carbon double bond  conversion (final DC) was calculate based on the areas of the peaks (obtained with the processing tool in  the OMNIC software) at 6165 and 6135 cm‐1, which correspond to the vinyl overtone for methacrylates  and  methacrylamides,  respectively.  The  maximum  rate  of  polymerization  (RPMAX),  representing  the  reactivity  of  the monomers, was  determined  as  the  first  derivative  of  the  degree  of  conversion  as  a  function of the time. The degree of conversion at the maximum rate of polymerization (DC at RPMAX) was  used to estimate the time point in conversion at which diffusional limitations lead to deceleration.     Water sorption and solubility     Water sorption (WS) and solubility (SL) were measured according to the ISO 4049:2019. Briefly,  the same samples obtained in the polymerization kinetics test (n=3), after having their initial mass M1  determined, were immersed in 5 mL of triple distilled water for 7 days. At the end of this period, M2 was  measured and the samples were stored in a desiccator containing silica gel and connected to the house  vacuum. Sample weights were measured daily until the final mass did not change to the nearest 0.0001 g  (M3). WS and SL were calculated in µg/mm3 according the following equations, where V is the volume of  the disc in mm3: 
Figure imgf000033_0001
Storage modulus in shear    The storage modulus in shear (G’, n=5) was assessed in an oscillatory rheometer (Discovery HR‐1  Hybrid  Rheometer,  TA  Instruments,  New  Castle,  DE,  USA),  using  an  8‐mm  diameter  aluminum  plate  attached  to  the  upper  fixture  and  an  acrylic  plate mounted  to  the  UV‐Vis  accessory  on  the  bottom.  Approximately  0.02  g  of  each material  (the  exact mass was  recorded  for  each  specimen  and used  to  calculate G’) was placed between the parallel plates, and the light was delivered through the acrylic via  the optical apparatus in the UV‐Vis accessory. Samples were tested in oscillation mode (sine wave) at 10  Hz and 0.1% strain with a gap of 0.3 mm during the photopolymerization for 300 s (n = 3).     Dentin microtensile bond strength    Selected  formulations  with  the  highest  G’  and  lowest  WS  and  SL  were  subjected  to  dentin  microtensile bond strength testing (µTBS). Sound human dentin of extracted caries‐free third molars was  used  as  the  substrate.  The  study  was  approved  by  the  Oregon  Health  &  Science  University  IRB  (IRB00012056). The enamel was removed and the resulting surface was roughened by hand with  light  pressure and one pass across wet #600 silicon carbide paper to simulate smear layer formation. The dentin  surface was etched for 15 s with 37% phosphoric acid (3M ESPE), rinsed and dried with the aid of gentle  air stream for about 10 s. Two layers of the adhesive were applied and, after solvent evaporation, the  second layer was photocured for 60 s at 630 mW/cm2 by the mercury arc lamp. Restorative procedures  consisted  of  a  block  of  Filtek  Supreme  (shade  A2  ‐  3M  ESPE)  built  in  2  increments  of  2  mm  each,  photoactived with  the  light guide directly over  the  surface  for 20  s at 1200 mW/cm2 with an EliparTM  DeepCure‐S LED (3M ESPE). Adper Single Bond (3M ESPE) was tested as a commercial adhesive control, in  two consecutive layers, air‐dried to remove excess solvent, and photoactivated for 20 s using the same  light curing unit settings (n=6).     24 hours after  the  restorative procedures,  teeth were  sectioned under water  in a  slow speed  diamond saw (Accutom‐50, Struers) to obtain sticks of 1 mm2 cross‐sectional area (checked with a digital  caliper to 0.01 mm). The sticks were tested after 24 h or 6 months water storage at 37 °C. Sticks were  glued with cyanoacrylate (Zap‐it, Dental Ventures of America, Corona, CA, USA) onto custom‐made jigs  (Odeme Equipment,  Luzerna,  SC, Brazil)  attached  to a universal  testing machine  (Criterion MTS,  Eden  Prairie, MN, USA) and tested in tension until failure (0.5 mm/min).       Statistical Analysis    Data was statistically analysed by one‐way ANOVA and Tukey’s test (α = 0.05), after assessment  of normality and homoscedasticity. For µTBS, Student’s t‐test was carried out to compare the effect of  the storage time (α = 0.05). In the instances where the normality tests failed, the nonparametric Kruskal‐ Wallis test was carried out (α = 0.05).     Results    Kinetics of polymerization curves (average of three curves) are depicted in Figure 2 and results  shown in Table 1. RPMAX ranged between 0.11 and 0.03 %.s‐1, with TEGDMA and HEMAM Hy showing the  highest and  lowest values,  respectively. The other groups were  statistically  similar  (Table 1). A  similar  trend was found for the DC at RPMAX results, which ranged between 21.0 and 8.7%, with the methacrylates  TEGDMA and HEMA showing  the highest values and HEMAM Hy  the  lowest.  In  terms of  final DC,  the  monofunctional HEMA and HEMAM showed the highest values (89.0 and 83.2%, respectively) and the  hybrid versions HEMAM Hy, 2EM Hy and 2dMM Hy the lowest (63.5, 63.3, and 59.4%, respectively). In  general,  the  alpha‐substituted  methacrylamides  2EM  and  2dMM  showed  lower  values  than  the  monofunctional methacrylate control HEMA (73.6, 76.7 and 89.0%, respectively).      Regarding water sorption and solubility (Figure 7), the WS values ranged between 33.4±3.2 and  183.0±5.7 µg/mm3 with the highest value being for the methacrylamide HEMAM, followed by 2EM, HEMA  and 2dMM  (101.3±1.5,  93.9±4.8,  and 79.1±0.9 µg/mm3,  respectively).  TEGDMA and  the hybrids were  similar  (35.5±1.8,  38.7±1.8,  44.0±0.8,  and  33.4±3.2  µg/mm3,  respectively).  In  terms  of  SL,  the  results  ranged between  ‐12.7±1.6  and 6.4±2.2 µg/mm3  for HEMA and  2EM/2dMM,  respectively.  The hybrids  HEMAM Hy, 2EM Hy and 2dMM Hy were statistically similar to TEGDMA (‐1.6±0.0, 0.0±0.0, ‐0.5±2.4, and  ‐4.2±6.0 µg/mm3, respectively).      The  shear  storage modulus, G’,  values  ranged between 160.7±8.0  and 115.7±7.0 MPa  for  the  hybrids HEMAM Hy and 2dMM Hy, respectively (Figure 4). In general, the groups were statistically similar  and significant difference was only observed between HEMAM Hy versus TEGDMA, 2EM and 2dMM Hy.       Dentin µTBS results are shown in Figure 5. Single Bond showed statistically higher values at both  48 h and 6 months (53.4±9.8 and 43.3±5.3 MPa, respectively), while all other groups were statistically  similar to each other (ranging between 42.3±9.6 and 27.9±6.0 MPa and between 32.7±3.3 and 19.2±4.5  MPa for 48h and 6 months storage time, respectively). The µTBS decreased for all materials between 48  h and 6 months, and this reduction was statistically significant for the HEMA and two 2dMM compounds.  The  formulation  containing  the  monofunctional  methacrylamide  (HEMAM)  showed  the  lowest  bond  strength reduction (about 9%) after 6 months of aging, while the other groups showed a decrease ranging  between 18 and 33%.    Discussion  The  limited  clinical  durability  reported  for  current  esthetic,  direct  dental  resin  composite  materials highlights the need for the development of alternative monomers to replace the widely‐used  methacrylates  which,  despite  the  high  reactivity  and  reasonable  mechanical  properties,  are  highly  susceptible  to hydrolytic  and enzymatic degradation due  to  the presence of  ester bonds  [Finer et  al.,   Journal of Dental Research. 2004;83:22‐6; Finer et al., Biomaterials. 2004;25:1787‐93; and Kermanshahi  et  al.,  Journal  of  dental  research.  2010;89:996‐1001].  Experimental  dental  adhesive  formulations  containing methacrylamides have shown significant long term dentin bonding stability, in spite of their  lower  reactivity,  and  of  the  high  hydrophilicity  that  resulted  in  reduced  values  of  certain mechanical  properties  [Fugolin  et  al.,  Dental  Materials.  2019;35:686‐96;  and  Rodrigues  et  al.,  Dental  Materials.  2018;34:1634‐44]. In an attempt to improve the reactivity of the amides and control their water sorption,  in  this  study hybrid methacrylamide‐methacrylate difunctional monomers were designed,  synthesized  and tested as alternative co‐monomers for HEMA‐free dental adhesive formulations. The results showed  that  except  for  HEMAM Hy,  all  hybrid  versions  showed  reactivity  (RPMAX)  similar  to  the methacrylate  controls (TEGDMA and HEMA). HEMAM was expected to present the highest reactivity due to the absence  of bulky substituents. The absence of substituents,  in theory, would facilitate  the access of  the amine  radicals  to the vinyl groups. Albeit not statistically significant,  the opposite was actually observed:  the  non‐substituted HEMAM showed 45% lower RPMAX than the alpha‐substituted versions. Steric interactions  of substituents near amide bonds have been shown to cause slight rotation about the amide C‐N bond  [Wang et al.,  Journal of the American Chemical Society. 1991;113:5757‐65], reducing the ability of the  nitrogen atom to donate electrons into the conjugated system. This distortion of the amide bond results  in  a  longer  amide  C‐N  bond  with  less  double  bond  character  [Wang  et  al.,  Journal  of  the  American  Chemical Society. 1991;113:5757‐65]. Compared with the non‐substituted HEMAM, the distorted amides  of the 2EM and 2dMM versions are not able to stabilize a radical as effectively, which could increase the  rate of polymerization (Figure 6).    Figure 6 depicts steric interactions of α‐carbon alkyl substituents have been shown to cause 2°  and 3° amides to twist about the C‐N bond. The resulting “distorted” amides have less pi‐orbital overlap  resulting in lengthened C‐N bonds and less electron donation of the lone pair into the conjugated system  of the amide [16]. In the context of this work, the reduced electron donation and resulting reduction in  radical  stabilization  is  being  used  as  a  possible  explanation  for  the  reduced  reactivity  and  rate  of  polymerization  between  non‐substituted  monomers  and  monomers  with  one  or  more  α‐carbon  substituents.  One additional explanation is based on the electron‐donating nature of the alkyl chains, which  may have created a partial negative charge on the alpha‐carbon in 2EM and 2dMM [Bruice PY. Essential  organic chemistry2016]. Combined with the negative partial charge inherent in the amide bond, this might  have led to a spatial separation from the electron‐rich vinyl group and, ultimately, exposed the double  bond to free radical propagation. In short, the attachment of a second vinyl functionality to a sterically‐ hindered chemical structure made the resultant hybrid compound (HEMAM Hy) even less reactive.      In general, all hybrid versions showed numerically or  statistically  (or both)  lower RPMAX, DC at  RPMAX and Final DC  than  their OH‐bearing versions. This was expected,  since  the  reaction  involves co‐ polymerizations  between  difunctional  and  monofunctional  monomers,  each  with  distinct  individual  reactivities. Expectations were that autoacceleration and autodeceleration would be impacted, ultimately  leading  to  structural  heterogeneity,  unequal  functional  group  reactivity  and  a  delay  in  volumetric  shrinkage rate [Anseth et al., Chemical Engineering Science. 1994;49:2207‐17]. The decrease in reactivity  in systems containing high ratios of multifunctional molecules is related to polymer crosslinking, which  impairs macro‐radical diffusion in the reaction environment. Since the mobility of the reactive species is  hindered, both  the  termination and propagation kinetic  constants decrease, which explains  the  lower  rates  of  polymerization.  In  addition,  the  propagation  becomes  diffusion‐controlled  earlier  in  the  conversion in systems with higher ratios of difunctional monomers, as evidenced by the lower DC at RPMAX  results. At RPMAX, diffusional limitations reach a threshold beyond which the reaction starts to decelerate,  until  the network completely vitrifies. DC at RPMAX  results demonstrated  that HEMAM Hy showed the  lowest conversion at that point, which indicates its network vitrified much sooner in conversion.   One additional factor to be considered is the unequal functional‐group reactivity in difunctional  monomers.  It  has  been  demonstrated  that,  on  average,  only  one  unit  of  double  bonds  reacts  per  monomer  independent  of  the  number  of  functionalities  (from  one  to  five  ‐  [Anseth  et  al.,  Chemical  Engineering Science. 1994;49:2207‐17]. As one of the functional groups reacts and forms a covalent bond  with a growing  chain and/or another molecule, a  congestion by  the physical presence of  surrounding  ligands is created, which slows down or even prevents reaction at the second functional group [Anseth et  al., Chemical Engineering Science. 1994;49:2207‐17]. In molecules with short and rigid carbon chains, such  as the hybrids tested in the present study, this congestion is even stronger due to the close proximity of  the functionalities and the hindrance to molecular stretching or rotation. The presence of aliphatic side  chains  in  some of  the molecules  compound  the  steric  hindrance  effects.  Furthermore,  for  the  hybrid  monomers, the process is further complicated by the inherent unequal reactivity between methacrylates  and methacrylamides. The methacrylamides are markedly less reactive than the methacrylates due to the  strong  resonance  stabilization  of  the  vinyl  group  provided  by  the  nitrogen  atom  [Miyake  et  al.,  Macromolecules.  2009;42:1462‐71].  In  other  words,  despite  having  the  same  number  of  mesomeric  structures, the amide functionality is more stabilized than the ester due to the fact that the nitrogen atom  is  less electronegative  than  the oxygen and,  consequently,  is  a better donor of nonbonding electrons  [Kucharski et al., Journal of Applied Polymer Science. 1997;64:1259‐65]. Therefore, it can be postulated  that the more reactive methacrylate reacted first, further decreasing the reactivity of the already stable  methacrylamide functionality.  Even though this falls outside the scope of this study, one future strategy  to balance this uneven reactivity between the methacrylate and methacrylamide could be to vary the  extender chain length, which could be tailored to modulate molecular degree of freedom, and therefore,  make the methacrylamide vinyls more readily available to react [Ogliari et al., Dent Mater. 2008;24:165‐ 71].    Interestingly, in the kinetics curves profiles of HEMA, HEMAM and HEMAM Hy, two distinct slopes  are noticed (Figure 9), which may indicate the presence of two phases with different compositions as the  polymerization reactions take place at different rates [Pfeifer et al., Journal of Polymer Science Part A:  Polymer  Chemistry.  2014;52:1796‐806].  The  decrease  in  viscosity  promoted  by  the  incorporation  of  HEMA, HEMAM and HEMAM Hy into the formulations may increase the mobility of the system, which  may  have  caused  the  polymerization  of  the  more  reactive  bisGMA  to  take  place  more  or  less  independently,  at  a  faster  rate  and  with  earlier  vitrification  compared  with  the  other  co‐monomers  [[Pfeifer et al., Journal of Polymer Science Part A: Polymer Chemistry. 2014;52:1796‐806]. On the other  hand, the polymerization of the diluent‐rich phase is hypothesized to have taken place at a slower rate,  with delayed gelation and vitrification.  It  has been  shown  that during  the  co‐polymerization between  methacrylates and methacrylamides, a radical is easily formed from a methacrylate molecule and it more  likely  reacts  with  a  like  monomer  [Anseth  et  al.,  Chemical  Engineering  Science.  1994;  49:2207‐17].  Conversely, the amide radical has been shown to more likely react with the more reactive methacrylate  rather than with another  lower reactivity methacrylamide molecule, thereby enriching the co‐polymer  with methacrylate  units  in  comparison  with  the  initial  comonomer  ratio  [Kucharski  et  al.,  Journal  of  Applied  Polymer  Science.  1997;64:1259‐65].  In  short,  this  differential  reactivity  may  have  led  to  the  formation of interpenetrating polymer networks (IPNs) [Dean et al., Polymer International. 2004;53:1305‐ 13]. The lowest reactivities of HEMAM and especially HEMAM Hy are consistent with the possibility of IPN  formation. It is interesting to note that the conversion at which the kinetic curve enters the deceleration  phase  shifts  to  earlier  stages  as  the  monomer  reactivity  decreases,  which  indicates  a  reduction  in  diffusivity of  both polymer  and monomer  species  [Anseth et  al.,  Chemical  Engineering  Science.  1994;  49:2207‐17]. Finally, the non‐substituted HEMAM showed statistically higher final degree of conversion  than the alpha‐substituted versions 2dMM and 2EM. The increase in final double bond conversion showed  by HEMAM may be associated with the relative lower viscosity of this compound, which likely played a  role  in  preserving  sufficient mobility  in  the  system  up  to much  higher  levels  in  conversion  [Odian  G.  Principles of polymerization: John Wiley & Sons; 2004].     Methacrylamides  have  hydrogen‐bond  acceptor  (O‐H  dipole)  and  hydrogen‐bond  donor  (N‐H  dipole) capabilities, which favors their interaction with water [DeRuiter et al., Principles of Drug Action.  2005;1:1‐16]. Therefore, one additional reason for the incorporation of the methacrylate functionality on  the  secondary  methacrylamides  was  to  reduce  the  latter’s  hydrophilicity.  The  methacrylate‐ methacrylamide  hybrids  (HEMAM  Hy,  2EM  Hy,  and  2dMM  Hy)  showed  dramatic  reduction  in  water  sorption  in  comparison  to  their methacrylamide versions  (HEMAM, 2EM, and 2dMM)  (Figure 7), with  methacrylate hybrids showing 3 to 6‐fold greater log P values. This means they are a lot more hydrophobic  than the methacrylamide analogs.   Molecular  weight  (MW),  partition  coefficient  (log  P)  and  percentage  of  carbon  double  bonds  from  methacrylamide and methacrylate functional groups (% [C=C]), and final degree of conversion (Final C=C)  of the tested co‐monomers.    
Figure imgf000039_0001
  Several factors contribute to this increased hydrophobic character: increase in molecular weight,  substitution of the hydrophilic hydroxyl group and addition of an aliphatic side radical, which all decrease  the molecule polarity [Bruice PY. Essential organic chemistry2016]. The positive results of SL shown by the  alpha‐substituted  methacrylamides  (2EM  and  2dMM)  indicate  a  higher  degree  of  mass  loss  due  to  leaching out of unreacted monomers – the final degree of conversion was 75% on average.      Regarding  the  mechanical  properties,  it  was  expected  that  the  incorporation  of  difunctional  molecules into the formulations would enhance the crosslinking and, ultimately, the shear modulus and  µTBS. However, no clear trend was identified in the shear storage modulus results among the difunctional  molecules. HEMAM Hy showed the highest values and 2dMM Hy and TEGDMA the lowest ones, which  indicates that the molecular packing and the intermolecular interactions are playing key roles. It is known  for co‐polymerizations between TEGDMA and bisGMA that heterogeneous and poorly‐packed polymer  networks result, due to TEGDMA’s tendency to cyclization, as well as bisGMA’s rigidity [Pfeifer et al., Eur  Polym J. 2011;47:162‐70]. Cyclization is likely in difunctional molecules with flexible backbones, ultimately  leading to the formation of a network with reduced cross‐linking density and glass transition temperature,  despite  the  high  levels  of  final  degree  of  conversion  [Anhseth  et  al.,  Chemical  Engineering  Science.  1994;49:2207‐17;    Elliot  et  al.,  Dental  Materials.  2001;17:221‐9;  and  Boots  et  al.,  Polymer  Bulletin.  1984;11:415‐20].  In  addition,  the  flexibility  of  the  pendant  groups  and  crosslinks make  the  TEGDMA  molecule susceptible to rotational motion and with tendency to occupy more space, which compromises  the packing efficiency and increases the free volume [Pfeifer et al., Eur Polym J. 2011;47:162‐70]. And  finally,  at  the  relatively high  irradiances used  in  this  study,  the polymerization  reaction  takes place at  higher rates (as evidenced by the RPMAX results), leading to the formation of a stiff framework with greater  free volume [Pfeifer et al., Eur Polym J. 2011;47:162‐70]. In the case of 2dMM Hy, the presence of two  bulky methyl substituent groups (each with three terminal hydrogens), jeopardizes the molecular packing  arrangement. The combination with the second functionality on the rigid backbone makes 2dMM Hy a  bulkier and highly sterically hindered molecule, which may have compromised not only the reactivity but  also  the  polymer  network  structure.  Conversely,  the  structure  of  HEMAM  Hy  does  not  contain  any  substituents, and its polymerization reaction took place at slow rates which, in tandem with the potential  phase  separation  indicated  by  the  double‐staged  kinetic  profile,  may  have  led  to  toughening  of  the  material, as previously demonstrated [Naficy et al., Journal of Applied Polymer Science. 2013;130:2504‐ 13]. On a related note, bars were prepared for dynamic mechanical analysis test, but the experiment was  not conducted because, after the post‐curing heat processing necessary prior to the DMA test (16 hours  at 180°C), the bars of HEMAM Hy, 2EM and 2dMM groups became too brittle and showed evidence of  significant  internal  cracking  (Figure 8).  Though  it  is not  completely  clear why  this happened  for  these  specific groups, it can be speculated that the aforementioned molecular packing characteristics may have  drastically reduced the toughness of the materials, which caused them to break upon thermal contraction.    And finally, in respect to the µTBS results, SB showed statistically higher values at both 48 h and  6 months,  while  all  other  groups were  statistically  similar  to  each  other.  The  μTBS  decreased  for  all  materials between 48 h and 6 months, and this reduction was significant for the HEMA and two 2dMM  compositions.  The  formulation  containing  the monofunctional methacrylamide  (HEMAM)  showed  the  lowest bond strength reduction (about 9%) after 6 months of aging, while the other groups showed a  decrease  ranging  between  18  and  33%.  The  bonding  stability  of  some  of  these  methacrylamides  is  surprising given their high WS, reduced conversion and mechanical properties compared with the HEMA  control. These results follow the same trend reported previously, and it points to the complexity of dentin  bonding,  which  is  not  directly  related  to  the monomer’s  properties  [Fugolin  et  al.,  Dental Materials.  2019;35:686‐96].  Interestingly, the interaction between the methacrylamides and the dentin substrate  was chemical‐structure dependent, which makes  it difficult  to draw general  conclusions.  Studies have  shown that the amides are able to establish hydrogen bonds with specific sites of the collagen, which may  have contributed to some form of substrate reinforcement [Tatiana et al., Colloid and Polymer Science.  2018;296:1555‐71].       The  hybrid  strategy  resulted  in molecules with markedly  lower  water  sorption.  The  potential  increase in reactivity was overshadowed by electronic and steric factors on the tested monomers. Even  though the microtensile bond strength was not improved in relation to the control, the stability of the  bond observed with selected groups is an encouraging result.              This description of embodiments is non‐limiting and provided as examples of combinations of  elements that are supported herein.  Additional combinations of elements are also understood to be  within the scope of this disclosure.    Additional non‐limiting exemplary embodiments for the subject matter disclosed herein are  provided below.     Embodiment 1 provides a dental adhesive composition comprising one or more monomer  compounds selected from the group of: 
Figure imgf000041_0001
 
Figure imgf000042_0001
.    Embodiment 2 provides a dental adhesive composition comprising one or more monomer  compounds selected from the group of: 
Figure imgf000042_0002
    Embodiment 3 provides a dental adhesive composition comprising one or more monomer  compounds selected from the group of: 
Figure imgf000042_0003
    Embodiment 4 provides a dental adhesive composition comprising one or more monomer  compounds selected from the group of: 
Figure imgf000043_0001
    Embodiment 5 provides a dental adhesive composition comprising one or more monomer  compounds selected from the group of: 
Figure imgf000043_0002
.    Each of separate Embodiments 6 through 20 provides a dental adhesive composition comprising  the monomer compound as identified for the individual embodiments by number below:   
Figure imgf000043_0003
  (
Figure imgf000044_0001
       Embodiment 21 comprises the dental adhesive composition of any of Embodiments 1 through  20, further comprising a co‐monomer compound selected from the group of bisphenol A diglycidyl ether  dimethacrylate (BisGMA), triethylene glycol dimethacrylate (TEGDMA), urethane dimethacrylate  (UDMA), ethylene glycol dimethylacrylate (EGDMA), ethane‐1,2‐diyl bis(2‐methylacrylate) (PEGDMA),  ethoxylated bisphenol A dimethacrylate (EBPADMA), ethylene glycoldi(meth)acrylate, hexanediol  di(meth)acrylate, tripropylene glycol di(meth)acrylate, butanediol di(meth)acrylate, neopentyl glycol  di(meth)acrylate, diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, dipropylene  glycol di(meth)acrylate, allyl (meth)acrylate, 1,6‐hexanediol dimethacrylate (HEDMA), 1,6‐ hexamethylene glycol dimethacrylate (HGDMA), and divinyl benzene, or derivatives thereof.  Embodiment 22 comprises the dental adhesive composition of Embodiment 21, wherein the co‐ monomer compound is BisGMA.  Embodiment 23 comprises the dental adhesive composition of Embodiment 21, wherein the co‐ monomer compound is TEGDMA.  Embodiment 24 comprises the dental adhesive composition of Embodiment 21, wherein the co‐ monomer compound is UDMA.  Embodiment 25 comprises the dental adhesive composition of Embodiment 21, wherein the co‐ monomer compound is EGDMA.  Embodiment 26 comprises the dental adhesive composition of Embodiment 21, wherein the co‐ monomer compound is PEGDMA.  Embodiment 27 comprises the dental adhesive composition of any of Embodiments 21 through  26, wherein:    a)  the relevant one or more monomers indicated in Embodiments 1 through 20 comprise  from about 35% to about 45%, by weight, of the dental adhesive composition; and  b)  the relevant co‐monomer compound indicated in Embodiments  21 through 26  comprises from about 55% to about 65%, by weight, of the composition.  Embodiment 28 comprises the dental adhesive composition of any of Embodiments 21 through  26, wherein:    a)  the relevant one or more monomers indicated in Embodiments 1 through 20 comprise  from about 37% to about 43%, by weight, of the dental adhesive composition; and  b)  the relevant co‐monomer compound indicated in Embodiments  21 through 26  comprises from about 57% to about 63%, by weight, of the composition.    Embodiment 29 comprises the dental adhesive composition of any of Embodiments 1 through  28, wherein the dental adhesive composition further comprises a photoinitiator.  Embodiment 30 comprises the dental adhesive composition of Embodiments 29, wherein the  photoinitiator or polymerization initiator is selected from the group of camphorquinone (CQ);  trimethylbenzoyl‐diphenyl‐phosphine oxide (TPO); Ethyl‐4‐dimethylamino benzoate (EDMAB); 2,2‐ Dimethoxy‐2‐phenylacetophenone (DMPA); Bisacylphosphine oxide (BAPO); 1‐Phenyl‐1,2‐propanedione  (PPD); phosphine oxide compounds, including naphthacene (APO), 9‐anthracene (APO), and;  1‐phenyl‐ 1,2‐propanedione (PPD); thioxanthone (TX) and its derivatives; dibenzoyl germanium derivatives, such  as benzoyltrimethylgermane (BTG) and dibenzoyldiethylgermane; hexaarylbiimidazole derivatives; silane  based derivatives; (diethylgermanediyl)bis((4‐methoxyphenyl)methanone) (Ivocerin); benzenesulfinic  acid sodium salt (BS); diaryliodonium salts (such as diphenyliodonium chloride or iodonium salt  [diphenyliodonium hexafluorophosphate (DPIHP or DPI‐PF6 ))], or a bromide, iodide, or  hexafluorophosphate thereof; lithium phenyl‐2,4,6‐trimethylbenzoylphosphinate; 2‐hydroxy‐1‐[4‐(2‐ hydroxyethyl)phenyl]‐2‐methyl‐1‐propanone (Irgacure 2959); and benzoyl peroxide (BPO).  Embodiment 31 comprises the dental adhesive composition of any of Embodiments 29 and 30,  wherein the photoinitiator or polymerization initiator is selected from the group of 2,2‐Dimethoxy‐2‐ phenylacetophenone (DMPA), diphenyliodonium hexafluorophosphate, and (diethylgermanediyl)bis((4‐ methoxyphenyl)methanone) (Ivocerin), or a combination thereof.  Embodiment 32 comprises the dental adhesive composition of any of Embodiments 29, 30, and  31, wherein the photoinitiator or polymerization initiator is selected from the group of 2,2‐Dimethoxy‐2‐ phenylacetophenone (DMPA) and diphenyliodonium hexafluorophosphate, or a combination thereof.  Embodiment 33 comprises the dental adhesive composition of any of Embodiments 29, 30, 31,  and 32, wherein the composition further comprises a chemical inhibitor/stabilizer/free radical scavenger  selected from the group of butylated hydroxytoluene (BHT), hydroquinone, 2,5‐di‐tert‐butyl  hydroquinone, monomethyl ether hydroquinone (MEHQ), and 2,5‐di‐tertiary butyl‐4‐methylphenol, 3,5‐ di‐tert‐butyl‐4‐hydroxyanisole (2,6‐di‐tert‐butyl‐4‐ethoxyphenol), 2,6‐di‐tert‐butyl‐4‐ (dimethylamino)methylphenol or 2‐(2′‐hydroxy‐5′‐methylphenyl)‐2H‐benzotriazole, 2‐(2′‐hydroxy‐5′‐t‐ octylphenyl)‐2H‐benzotriazole, 2‐(2′‐hydroxy‐4′,6′‐di‐tert‐pentylphenyl)‐2H‐benzotriazole, 2‐hydroxy‐4‐ n‐octoxybenzophenone, 2‐(2′‐hydroxy‐5′‐methacryloxy‐ethylphenyl)‐2H‐benzotriazole, phenothiazine,  and HALS (hindered amine light stabilizers).     Embodiment 34 comprises the dental adhesive composition of Embodiment 33, wherein the  composition comprises a chemical inhibitor/stabilizer/free radical scavenger at a concentration of from  about 0.01% to about 0.5%, by weight.    Embodiment 35 comprises the dental adhesive composition of any of Embodiments 33 and 34,  wherein the composition comprises a chemical inhibitor/stabilizer/free radical scavenger at a  concentration of from about 0.05% to about 0.3%, by weight.    Embodiment 36 comprises the dental adhesive composition of any of Embodiments 33, 34, and  35, wherein the composition comprises a chemical inhibitor/stabilizer/free radical scavenger at a  concentration of from about 0.05% to about 0.2%, by weight.    Embodiment 37 comprises the dental adhesive composition of any of Embodiments 33, 34, 35,  and 36, wherein the composition comprises a chemical inhibitor/stabilizer/free radical scavenger is  butylated hydroxytoluene (BHT).  Embodiment 38 comprises the dental adhesive composition of any of Embodiments 1 through  37, wherein the dental adhesive composition further comprises a self‐etching agent.  Embodiment 39 comprises the dental adhesive composition of Embodiment 38, wherein the  self‐etching agent comprises a carboxylic acid, phosphonic acid, or phosphate groups  Embodiment 40 comprises the dental adhesive agent of any of Embodiments 38 and 39,  wherein the self‐etching agent is selected from the group of 10‐methacryloyloxydecyl dihydrogen  phosphate (10‐MDP or MDP, CAS Reg. No. 85590‐007), methacryloxyethyl hydrogen phenyl phosphate (Phenyl-P), methacryloyloxydodecylpyridinium bromide (MDPB), 4‐methacryloyloxyethyl  trimellitate anhydride (4‐META), 4‐methacryloyloxyethyl trimellitic acid (4‐MET), 11‐methacryloyloxy‐ 1,1‐undecanedicarboxylic acid (MAC10), 4‐acryloyloxyethyl trimellitate anhydride (4‐AETA), 2‐ methacryloyloxyethyl dihydrogen phosphate (MEP), dipentaerithritol pentaacrylate phosphate (PENTA‐ P), hydroxyethylmethacrylate phosphate (HEMA‐P), hydroxyethylacrylate phosphate (HEA‐P),  bis(HEMA)‐P {bis(hydroxyethylmethacrylate) phosphate), bis(HEA)‐P {bis(hydroxyethylacrylate)  phosphate), bis(meth)acryloxypropyl)phosphatephosphate methacrylates, acrylic ether phosphonic acid  and other phosphoric acid esters.   Embodiment 40 provides a kit, the kit comprising a useful amount of a dental adhesive  composition selected from any of Embodiments 1 through 39, and directions for the use of the adhesive  dental composition.  

Claims

What is claimed:
1. A dental adhesive composition comprising one or more compounds selected from the group of:
Figure imgf000048_0001
2. The dental adhesive composition of Claim 1, further comprising a co-monomer compound selected from the group of bisphenol A diglycidyl ether dimethacrylate (BisGMA), triethylene glycol dimethacrylate (TEGDMA), urethane dimethacrylate (UDMA), ethylene glycol dimethylacrylate (EGDMA), ethane-1, 2-diyl bis(2-methylacrylate) (PEGDMA), ethoxylated bisphenol A dimethacrylate (EBPADMA), ethylene glycoldi(meth)acrylate, hexanediol di(meth)acrylate, tripropylene glycol di(meth)acrylate, butanediol di(meth)acrylate, neopentyl glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, dipropylene glycol di(meth)acrylate, allyl
(meth)acrylate, 1,6-hexanediol dimethacrylate (HEDMA), 1,6-hexamethylene glycol dimethacrylate
(HGDMA), and divinyl benzene.
3. The dental adhesive composition of Claim 2, wherein the co-monomer compound is selected from the group of BisGMA, TEGDMA, UDMA, EGDMA, and PEGDMA.
4. The dental adhesive composition of claim 3, wherein: a) the one or more compounds selected from the group of Claim 1 comprise from about
35% to about 45%, by weight, of the dental adhesive composition; and b) the co-monomer compound selected from the group of BisGMA, TEGDMA, UDMA,
EGDMA, and PEGDMA comprises from about 55% to about 65%, by weight, of the composition.
5. The composition of Claim 4 further comprising a photoinitiator.
6. The composition of Claim 5 comprising from about 0.1 to about 0.3% by weight DMPA.
7. The composition of Claim 5 comprising from about 0.2% to about 0.6% DPI-PF6.
8. The composition of Claim 5 comprising from about 0.1 to about 0.3% by weight DMPA and from about 0.2% to about 0.6% DPI-PF6.
9. The dental adhesive composition of Claim 4 comprising: a) from about 35% to about 45% by weight a compound selected from the group of: and
Figure imgf000049_0001
b) from about 55% to about 65%, by weight, a co-monomer compound selected from the group of BisGMA, TEGDMA, UDMA, EGDMA, and PEGDMA.
10. The composition of Claim 9 further comprising a photoinitiator.
11. The dental adhesive composition of Claim 4 comprising:
Figure imgf000050_0002
; and b) from about 55% to about 65%, by weight, a co-monomer compound selected from the group of BisGMA, TEGDMA, UDMA, EGDMA, and PEGDMA.
12. The composition of Claim 11 further comprising a photoinitiator.
13. The dental adhesive composition of Claim 4 comprising:
Figure imgf000050_0001
; and b) from about 55% to about 65%, by weight, a co-monomer compound selected from the group of BisGMA, TEGDMA, UDMA, EGDMA, and PEGDMA.
14. The composition of Claim 13 further comprising a photoinitiator.
15. The dental adhesive composition of Claim 4 comprising: a) from about 35% to about 45% by weight a compound selected from the group of:
Figure imgf000051_0001
b) from about 55% to about 65%, by weight, a co-monomer compound selected from the group of BisGMA, TEGDMA, UDMA, EGDMA, and PEGDMA.
16. The dental adhesive composition of Claim 15 further comprising a photoinitiator.
17. The dental adhesive composition of Claim 16, wherein the photoinitiator is one or more agents selected from the group of DMPA and DPI-PF6.
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Citations (3)

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