Synthesis and Structural Characterization of Novel Urethane-Dimethacrylate Monomers with Two Quaternary Ammonium Groups Based on Cycloaliphatic Diisocyanates ^†

Abstract

Diseases such are caries affect approximately 25% of the worldwide population. Such a state requires novel, antibacterial materials. This research aimed to synthesize and characterize the structures of two urethane-dimethacrylate monomers showing possible antibacterial activity for dental composite restorative materials (DCRMs). The monomers were based on isophorone diisocyanate (IPDI) and dicyclohexylmethane 4,4′-diisocyanate (CHMDI). The structures of the monomers and their key elements were confirmed with the application of spectroscopy methods. Nuclear Magnetic Resonance Spectroscopy (¹H and ¹³C NMR) and Fourier Transform Infrared Spectroscopy (FTIR) were applied. The monomers were synthesized and their structures were confirmed with the abovementioned techniques.

1. Introduction

The urethane-dimethacrylate (UDMA) monomer, which is synthesized from trimethylhexamethylene diisocyanate and 2-hydroxyethyl methacrylate (HEMA), is commonly used in dental composite restorative materials (DCRMs) due to its excellent physicochemical and mechanical properties [1,2,3]. However, in recent years, there has been growing interest in DCRMs that possess antibacterial properties in response to the increasing demand for preventing secondary caries [4,5,6,7,8,9]. An effective strategy for achieving long-lasting antibacterial properties is covalent anchoring of a monomeric biocide within the polymeric matrix of a DCRM [10]. Dimethacrylate monomers with quaternary ammonium groups (QADMAs) were demonstrated to be especially effective [11,12,13,14,15]. Despite extensive research on QADMA-based DCRM matrices, the design and synthesis of novel monomers with tailored structures remain an important area of study.

Since 2019, our research group has been working on developing new urethane-dimethacrylates featuring two quaternary ammonium groups (QAUDMAs). These monomers were synthesized from 2-(methacryloyloxy)ethyl-2-alkylhydroxyethylmethylammonium bromide (QAHAMA-n, where n represents the carbon chain length of 8, 10, 12, 14, or 16) and aliphatic diisocyanates, including 2,4,4-trimethylhexamethylene diisocyanate (TMDI) [16,17] and 1,3-bis(1-isocyanato-1-methylethyl)benzene (TMXDI) [18]. We found that both the selection of the diisocyanate precursor and the length of the N-alkyl substituent significantly affected the final properties of the QAUDMAs and their copolymers with common dimethacrylates, specifically bisphenol A diglycidyl methacrylate (Bis-GMA) and triethyleneglycol dimethacrylate (TEGDMA).

In this study, we report the synthesis and structural characterization of new QAUDMA monomers that contain two quaternary ammonium groups. These monomers were obtained from 2-(methacryloyloxy)ethyl-2-dodecylhydroxyethylmethylammonium bromide (QAHAMA-12) and cycloaliphatic diisocyanates, including isophorone diisocyanate (IPDI) and dicyclohexylmethane 4,4′-diisocyanate (CHMDI).

2. Materials and Methods

2.1. Materials

Synthesis substrates, such as methyl methacrylate (MMA), N-methyldiethanolamine (MDEA), and dodecyl bromide (DDB), were purchased from Acros Organics (Geel, Belgium). Diisocyanates, isophorone diisocyanate (IPDI), and dicyclohexylmethane 4,4′-diisocyanate (CHMDI), as well as phenothiazine (PTZ), camphorquinone (CQ), N,N-dimethylaminoethyl methacrylate (DMAEMA), and tetramethylsilane (TMS), were purchased from Sigma-Aldrich (St. Louis, MO, USA). Dibutyltin dilaurate (DBTDL) was purchased from Fluka (Charlotte, NC, USA). Deuterated solvents, namely trichloromethane (CDCl₃) and dichloromethane (CD₂Cl₂), were purchased from Deutero GMBH (Kastellaun, Germany). Potassium carbonate (K₂CO₃) and magnesium sulfate (MgSO₄) were purchased from Chempur (Piekary Śląskie, Poland). Solvents such as toluene, trichloromethane (CHCl₃), and dichloromethane (CH₂Cl₂) were purchased from Stan-lab (Lublin, Poland).

2.2. Synthesis of Monomers Possessing Quaternary Ammonium Groups

2.2.1. Synthesis of N,N-(2-hydroxyethyl)methylaminoethyl Methacrylate (HAMA)

Novel monomers possessing quaternary ammonium groups were obtained using a three-step process. The synthesis procedure has been described in the literature [16].

In the first step, MMA, MDEA, K₂CO₃, PTZ, and toluene were introduced to a 1000 mL round-bottom flask (Figure 1). The round-bottom flask was equipped with a standard distillation kit. The reaction was carried out for 2.5 h in the temperature range of 65–100 °C. The amounts of substrates and other substances used in the reaction are listed in

Table 1. The amounts of chemical substances used in the first step of synthesis.

Substance	Mass (g)	Moles (mol)
Substrates
MMA	100.12	1.00
MDEA	79.85	0.67
Transesterification catalyst
K2CO3	14.40	1
Polymerization inhibitor
PTZ	0.05	1
Solvent
Toluene	346	1

¹ The number of moles was insignificant.

.

After 2.5 h, the reaction mixture was cooled down and filtered. Then, the mixture was mixed with distilled water in a 2:1 ratio. Next, the aqueous phase was mixed with trichloromethane in a 3:1 ratio. The residual water was removed from the trichloromethane solution with MgSO₄ overnight. The solvent was evaporated with a rotary evaporator under reduced pressure (30 mbar). The crude HAMA was purified by vacuum distillation (3 mbar), with fraction boiling at 110–130 °C. The yield of the reaction was 14%.

2.2.2. Synthesis of 2-(Methacryloyloxy)ethyl-2-dodecylhydroxyethylmethylammonium Bromide (QAHAMA-12)

The second step of the synthesis was the N-alkylation of HAMA with alkyl bromide. HAMA, DDB, and PTZ were introduced to a 250 mL three-neck round-bottom flask (Figure 2). The exact amounts of chemical substances used in this step are presented in

Table 2. The amounts of chemical substances used in the reaction for obtaining QAHAMA-12.

Substance	Mass (g)	Moles (mol)
Substrates
HAMA	20.00	0.107
DDB	26.67	0.107
Polymerization inhibitor
PTZ	0.01	1

¹ The number of moles was insignificant.

.

The reaction was carried out for 5 days at 82 °C with the application of an oil bath and mechanical stirrer.

2.2.3. Synthesis of Quaternary Ammonium Urethane-Dimethacrylate Monomers (QA12 + IPDI and QA12 + CHMDI)

The final step of the synthesis was the addition of QAHAMA-12 to diisocyanate (Figure 3). A 50% solution of QAHAMA-12 and DBTDL in CH₂Cl₂ was introduced to a 250 mL three-neck round-bottom flask. The flask was equipped with a dropping funnel, reflux condenser, and thermometer. The mixture was brought to the boiling point of CH₂Cl₂ (approx. 42 °C), and then a 50% solution of diisocyanate was dropped into the boiling mixture for 1.5 h. The exact amounts of substrates and other chemical substances used in the final step are presented in

Table 3. The names of QAUDMA monomers and quantities of chemical substances used in the reaction of their synthesis.

QAUDMA	Substance	Mass (g)	Moles (mol)
QA12 + IPDI	QAHAMA-12	20.34	0.047
	IPDI	5.18	0.023
	DBTDL	0.008	1
QA12 + CHMDI	QAHAMA-12	22.82	0.052
	CHMDI	6.86	0.026
	DBTDL	0.009	1

¹ The number of moles was insignificant.

.

After 1.5 h, the reaction was carried out for another 5 h, maintaining the boiling temperature of the solvent. Next, the mixture was cooled down and the solvent was evaporated with a rotary evaporator under reduced pressure (first 30 mbar, then 3 mbar). The obtained resins were placed in a laboratory dryer (SLW 53 STD, Wodzisław Śląski, Poland) at 42 °C for 24 h.

2.3. Nuclear Magnetic Resonance Spectroscopy (NMR)

¹H and ¹³C spectra were obtained with the application of a 300 MHz NMR spectrometer (UNITY/INOVA, Varian, Palo Alto, CA, USA). The ¹H spectra were obtained with 512 scans and the ¹³C spectra with 40,000 scans. The deuterated solvents were CD₂Cl₂ and CDCl₃, with TMS as the internal standard.

2.4. Fourier Transform Infrared Spectroscopy (FTIR)

FTIR spectra were obtained using the Spectrum Two spectrometer (Perkin-Elmer, Waltham, MA, USA) with 128 scans at a resolution of 1 cm⁻¹.

3. Results

3.1. ¹H NMR

Figure 4a presents the ¹H NMR spectra of QA12 + IPDI. Table S1 in the Supplementary Materials lists all peaks visible in the NMR spectra for QA12 + IPDI. Figure 4b shows the ¹H NMR spectra of QA12 + CHMDI; all peaks are also presented in Table S2 (in the Supplementary Materials).

3.2. ¹³C NMR

Figure 5a,b present the 13C NMR spectra of QA12 + IPDI and QA12 + CHMDI. Tables S3 and S4 in the Supplementary Materials list all peaks visible in the ¹³C NMR spectra, respectively, for QA12 + IPDI and QA12 + CHMDI.

3.3. FTIR Spectra

Figure 6a shows the FTIR spectra of QA12 + IPDI, and Figure 6b presents the FTIR spectra of QA12 + CHMDI. Table S5 (in the Supplementary Materials) lists all peaks visible in the FTIR spectra of QA12 + IPDI, and Table S6 (in the Supplementary Materials) collects all peaks of QA12 = CHMDI present in the FTIR spectra.

4. Discussion

Two novel monomers were synthesized. The procedure known from the literature was adapted. This procedure was developed to obtain monomers based on 1,6-diisocyanato-2,2,4-trimethylhexane (TMDI) possessing various lengths of the N-alkyl substituent [16]. In this research, instead of TMDI, isophorone diisocyanate (IPDI) and dicyclohexylmethane 4,4′-diisocyanate (CHMDI) were used, as well as brododecane instead of alkyl bromides of various lengths. The synthesis procedure required modification. The time of the addition reaction of QAHAMA-12 to diisocyante was extended from 3 h to 5 h (Figure 3). A new step was also added to the procedure, namely thermal treatment for 24 h at 40 °C, due to the presence of an isocyanate group peak in FTIR after the evaporation of dichloromethane. The result was QA12 + IPDI and QA12 + CHMDI (Figure 7)—two yellowish, viscous liquids.

The spectroscopic analysis of the novel monomer structures, with the application of NMR and IR techniques, confirmed the structures of QA12 + IPDI and QA12 + CHMDI. Key elements of these monomer structures are methacrylate groups, N-alkyl substituents, quaternary ammonium groups, urethane bonds, and a diisocyanate core. In the ¹H NMR spectra, the signals of the methacrylate groups are visible at 1.94 ppm (-CH₃) as well as 5.67 ppm and 6.12 ppm (=CH₂) for both monomers (Figure 4a; Figure 4b; Table S1; Table S2). In the ¹³C NMR spectra, the signals of the methacrylate groups are visible at 19 ppm (-CH₃) and 127 ppm and 128 ppm (=CH₂) for QA12 + IPDI and QA12 + CHMDI, respectively; 135 ppm and 136 ppm (=CH₂-C<) for QA12 + IPDI and QA12 + CHMDI, respectively; and 166 ppm (-COO-) for both monomers (Figure 5a; Figure 5b; Table S3; Table S4). Signals coming from the N-alkyl substituents visible in the ¹H NMR spectra are at 3.30–3.70 ppm (N⁺-CH₂-CH₂-(CH₂)₉-CH₃) for QA12 + IPDI and QA12 + CHMDI, 1.55–1.71 ppm (N⁺-CH₂-CH₂-(CH₂)₉-CH₃) for both monomers, 1.25–1.32 ppm (N⁺-CH₂-CH₂-(CH₂)₉-CH₃) for both monomers, and 0.86 ppm and 0.85 ppm (N⁺-CH₂-CH₂-(CH₂)₉-CH₃) for QA12 + IPDI and QA12 + CHMDI, respectively (Figure 4a; Figure 4b; Table S1; Table S2). In the case of the ¹³C NMR spectra, the signals of the N-alkyl substituents are visible at 58–66 ppm for QA12 + IPDI and 55–66 ppm for QA12 + CHMDI (-N⁺-CH₂-(CH₂)₁₀-CH₃), 23–46 ppm and 23–35 ppm (-N⁺-CH₂-(CH₂)₁₀-CH₃) for QA12 + IPDI and QA12 + CHMDI, respectively, and 14 ppm (-N⁺-CH₂-(CH₂)₁₀-CH₃) for both monomers (Figure 5a; Figure 5b; Table S3; Table S4). The hydrogen of the urethane bond is visible at 6.20 ppm and 6.93 ppm for QA12 + IPDI and at 6.27 ppm and 6.44 ppm for QA12 + CHMDI (Figure 4a; Figure 4b; Table S1; Table S2); in the ¹³C NMR spectra, the carbon of the urethane bond is present at 155 ppm for both monomers (Figure 5a; Figure 5b; Table S3; Table S4). The IPDI core signals in the ¹H NMR spectra are visible at 0.86–1.90 ppm (CH₃-, -CH₂-), 2.89 ppm (-CH₂-NH-), and 3.30–3.70 ppm (>CH-NH-) (Figure 4a; Table S1), and in the ¹³C NMR spectra, the signals are visible at 23–46 ppm (CH₃-, -CH₂-, >C<) and 58–66 ppm (-CH₂-, >CH-) (Figure 5a; Table S3). In the ¹H NMR spectra, the signals of the CHMDI core are visible at 0.85–1.94 ppm (-CH₂-; >CH-) and 3.30–3.70 ppm (>CH-) (Figure 4b; Table S2); in the ¹³C NMR spectra, the signals are present at 23–55 ppm (-CH₂-, >CH-), 49 ppm (-CH₂-), and 51 ppm (>CH-) (Figure 5b; Table S4). In the FTIR spectra, the 1urethane bond is visible at 3215 cm⁻¹, as well as at 1534 cm⁻¹ (QA12 + IPDI) and 1536 cm⁻¹ (QA12 + CHMDI), while quaternary ammonium groups are present at 941 cm⁻¹ for both monomers (Figure 6a; Figure 6b; Table S5; Table S6).

5. Conclusions

In the scope of this research, two novel monomers based on isophorone diisocyanate (IPDI) and dicyclohexylmethane 4,4′-diisocyanate (CHMDI) were synthesized. The monomers possessed key elements in their structures: two methacrylate groups, two N-alkyl substituents possessing 12 carbon atoms, two quaternary ammonium groups, two urethane bonds, and a core based on the abovementioned diisocyanates. The structures of these monomers were confirmed with Proton and Carbon Nuclear Magnetic Resonance Spectroscopy (¹H and ¹³C NMR) and Fourier Transform Infrared Spectroscopy (FTIR). All of the key elements of the structures were present in the obtained spectra.

Future research should focus on the characterization of novel monomers and copolymerization with dental monomers used in DCRM matrices. Further research should determine the physicochemical and mechanical properties, as well as the antibacterial activity, of the copolymers.