Transesterification or polymerization? Reaction mechanism and kinetics of 2-(diethylamino)ethyl methacrylate with methanol and the competitive effect on free-radical polymerization

Abstract

Transesterification of 2-(diethylamino)ethyl methacrylate (DEAEMA) with methanol leads to the formation of methyl methacrylate (MMA) and 2-(diethylamino)ethanol; this alcoholysis reaction is studied by Density Functional Theory (DFT) calculations and in situ¹H-NMR measurements. The transesterification mechanism involves the cooperative effect of methanol. Second-order transesterification kinetics and Arrhenius parameters (A and E_a) are reported. Furthermore, the competition between transesterification and (co)polymerization between DEAEMA and the MMA transesterification product, using 2,2-azobis (2-methylpropionitrile) (AIBN) as an initiator at 70 °C, has been analysed. In experiments with a DEAEMA : methanol molar ratio of 1 : 46 the copolymerization results in a large proportion of the MMA copolymer composition (F_MMA) of 60 mol%; with an equimolar ratio the transesterification is avoided and the F_MMA is only 2 mol%. F_MMA can also be tuned by modification of the DEAEMA : AIBN molar ratio. Therefore, this work provides guidelines for the synthesis of well-defined poly(DEAEMA) and poly(DEAEMA-co-MMA) in primary alcohols.

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Introduction

For decades, the family of ternary amino-containing methacrylates (TAMAs) has been very used in the synthesis of multi-stimuli-responsive (co)polymers,^1–3 with 2-(diethylamino)ethyl methacrylate (DEAEMA) and 2-(dimethylamino)ethyl methacrylate (DMAEMA) monomers being the most commonly used due to their commercial availability. The protonation–deprotonation of N in the amino functionality has been demonstrated to occur directly as a result of an applied gradient of pH in the environment for TAMA-based (co)polymers. As a result, electrostatic repulsions occur between amino groups and the solvent, leading to phase transition or conformational changes.^2,4 Furthermore, the (dialkylamino) ethyl groups produce temperature sensitivity that generates a low critical solution temperature (LCST) at around 40–50 °C.^4,5 Since properties such as LCST,⁶ particle size⁷ and ζ-potential,² as well as biocompatibility⁸ are influenced by the copolymer composition, it is essential to accurately quantify the DEAEMA content in the polymer chains.

Although poly(DEAEMA) and its copolymers have significant relevance in several fields of application and a great number of studies have been reported in the last decades,^9–11 the kinetic basis of TAMA polymerization reported hitherto is scarce. Generally, TAMA-based (co)polymers have been synthesized by free radical polymerization in bulk and homogeneous phases using aqueous, organic, and inorganic solvents or a mixture of them. However, since DEAEMA and DMAEMA are weak bases with pK_a of 8.8 (ref. 12) and 8.4 (ref. 13) at 25 °C, respectively, and some solvents can act as nucleophiles, e.g. protic solvents (alcohols and water), a solvolysis reaction can be carried out.

The most studied solvolysis of TAMAs has been the hydrolysis in H₂O. Firstly, van de Wetering et al.¹³ analysed the impact of hydrolysis on three TAMAs and the results showed that half of the initial DMAEMA lost the amino functionality at 17 h with pH 7.4 and 37 °C. This was ascribed to an interaction between the protonated dimethylamino group and the ester carbonyl, which makes the ester more susceptible to nucleophilic attack of a hydroxyl ion and leads to an efficient hydrolysis. At alkaline pH (>pK_a), no differences in stability between the compounds were found. The results of Zheng et al.¹⁴ indicated the dependency of DMAEMA hydrolysis on pH and temperature, where its rate increases with more basic media, high temperatures, and also with bulky alkyl substituents attached to the N atom. The estimated Arrhenius parameters for a pseudo first-order kinetic constant were the frequency factor of ln(A) = 18.25 s⁻¹ and activation energy of E_a = 72.2 ± 3 kJ mol⁻¹ for a temperature interval of 25 to 60 °C in inherent pH.¹⁵ More recently, Ajogbege et al.¹⁶ investigated the influence of pH and temperature on the Arrhenius parameters for the hydrolysis of DEAEMA in D₂O using in situ¹H-NMR spectroscopy measurements, where the protonated state of DMAEMA provided more stability. These findings resulted in values of pseudo first-order parameters for ln(A) of 10 and 17.4 s⁻¹ and E_a, of 55.4 and 69.6 kJ mol⁻¹ as the pH increased from 8 to 10.1, respectively. During the DMAEMA homopolymerization conducted with the 2,2′-azobis(2-methyl-propionamidine) dihydrochloride initiator in D₂O at 50 and 60 °C, the formation of deuterated methacrylic acid (MAA-d₁) and a hydroxyalkylamine produced by hydrolysis significantly affected the kinetic behaviour, molecular weight and composition of the obtained poly(DMAEMA-co-MAA-d₁). A copolymer composition of MAA-d₁ (F_MMA-d1) greater than 30 mol% was formed using a solution pH of 10.1. However, hydrolysis was completely avoided by adjusting the pH of the solution to 1.0 and 4.0, due to the fully ionized DMAEMA. Indeed, TAMAs are very susceptible to hydrolysis under specific pH conditions, but the resulting TAMA polymers are stable to solvolysis and modification of their compositions is less significant.^13,17 In contrast, polymers based on tertiary amino-containing acrylates are very susceptible to solvolysis.¹⁸

Although the hydrolysis of TAMAs, especially DMAEMA, and its influence on polymerization have recently been addressed, the transesterification of TAMAs (alcoholysis) has not been deeply analysed to the best of our knowledge. Generally, primary alcohols, such as methanol (CH₃OH), act as nucleophiles and attack esters, resulting in a new alcohol and a new ester compound. Due to the fact that ester transesterification with alcohol is carried out in a very slow transformation, since alcohols are poor nucleophiles and ester contains basic leaving groups, it is common practice to increase its rate by adding an acid catalyst,¹⁹ a conjugate base of the reacting alcohol, or a metal catalyst.^20–24 However, according to Bories-Azeau and Armes,²⁵ DMAEMA is susceptible to transesterification with primary alcohols without the presence of a catalyst, leading to the formation of methyl methacrylate (MMA) and 2-(dimethylamino)alcohol, Scheme 1. Although this finding has been reported for more than 20 years, no studies have been conducted to explain it and propose a mechanism for the transesterification of the TAMA family. The relative propensity of TAMAs toward alcoholysis has been reported as DEAEMA > DMAEMA > 2-(diisopropylamino)ethyl methacrylate, suggesting a base-catalyzed transesterification.^25,26 DMAEMA polymerization using CH₃OH at ambient temperature carried out by Bories-Azeau and Armes resulted in an F_MMA of 26 mol%, therefore, the MMA formed in situ was able to integrate with the DMAEMA monomer and generate poly(DMAEMA-co-MMA). In the same study, a mixture of water/CH₃OH was used as a solvent to increase the polymerization rate and avoid the formation of poly(DMAEMA-co-MMA), but no details on the pH of the experiments were provided. Additionally, a high selectivity of TAMA-based polymers (conditions for no TAMA transesterification) was observed when a secondary alcohol (such as 2-propanol) was used as a solvent. In fact, this finding was explored in RAFT polymerization using tert-butanol to avoid transesterification, first by Arredondo et al.²⁷ conducting DMAEMA experiments and later by Quiñonez Angulo²⁸ for copolymerization of poly(ethylene glycol)methyl ether methacrylate (PEGMA) and either DEAEMA or DMAEMA.

Scheme 1 Transesterification of DEAEMA with primary alcohol.

Although the products of the TAMA transesterification have been observed using only primary alcohols at low or medium temperatures,^25–28 the same reaction has not produced another methacrylate monomer in large amounts during processes involving an alkyl methacrylate with primary alcohols, indicating that N in the amino group must play a key role in the process.

On the other hand, poly(TAMA-co-MMA) presents exceptional characteristics and has been widely used in several fields, e.g. against the adsorption of bovine serum albumin,²⁹ free-standing hydrogels,³⁰ antimicrobial agents,³¹ drug delivery nanodevices,³²etc. The use of alcohols for the synthesis of methacrylate copolymers is also common, due to the enhanced propagation rate with regard to bulk or organic solvents.³³

Moreover, tandem transesterification and copolymerization should have a complex kinetic mechanism with a penultimate effect and solvent-dependent reactivity ratios.³⁴

Even though knowledge of the reaction conditions to achieve the homopolymerization of DEAEMA, namely the avoidance of the transesterification during the reaction, is very important for the development of some smart materials, this route of synthesis can provide an easy way for the copolymerization of poly(DEAEMA-co-MMA), where a specific copolymer composition is desirable. This focus has been examined in the present work; we first propose a mechanism of DEAEMA transesterification based on Density Functional Theory (DFT) calculations. With this part of the information, we subsequently investigated the transesterification rate of DEAEMA using methanol-d₄ (CD₃OD) as a unique solvent at three levels of initial weight DEAEMA ratio (ω_M0) and four temperatures. The rate coefficients were then estimated to satisfy the complete kinetic picture. Finally, we analysed the competition between the transesterification and the (co)polymerization processes, and they were characterized in terms of their monomer conversions, degree of alcoholysis, remaining monomer composition, and copolymer composition. In both experimental parts, in situ¹H-NMR measurements were used as the principal experimental tool to avoid unnecessary sample manipulations.

Experimental

Materials

2-(Diethylamino)ethyl methacrylate (DEAEMA, 99%) and methanol-d₄ (CD₃OD, 99% atoms D) were used in the transesterification reactions, in which DEAEMA was purified by stirring in the presence of inhibitor remover beads (for hydroquinone and monomethyl ether hydroquinone). In polymerization reactions, in addition to the aforementioned reagents, chloroform-d (CDCl₃, 99.8% of the D atom), chloroform (CHCl₃ ACS reagent, 99.8%), methanol (CH₃OH, ACS reagent, 99.8%), 2,2-azobis (2-methylpropionitrile) (AIBN, 99%) and 1,3,5-trioxane (99%) were added to recipes, in which AIBN was recrystallized twice from ethanol before use. All other reagents were used as received and purchased from Sigma-Aldrich.

Transesterification

Transesterification reactions were performed in quick pressure valve NMR tubes of 5 mm diameter, by heating and acquiring ¹H-NMR spectra along time on a Bruker Avance III HD 400N 400 MHz spectrometer with a 5 mm multinuclear BBI-decoupling probe with a Z grad. The spectrometer is equipped with a SampleXpress 5 mm tube autosampler and a BCU II flow unit to control the temperature of the probe. The ¹H-NMR spectrum acquisition was conducted with ¹H 30° pulse direct excitation, a total of 8 scans, 65 K complex data points, a spectral width of 3874 Hz, a recovery delay of 1 s and an acquisition time of 8.4 s. No apodization function was used prior to the Fourier transformation. The chemical shifts (ppm) were relative to the remaining non-deuterated CH₃OH signals (from CD₃OD) which were used as the internal reference.

Homogeneous solutions of DEAEMA and CD₃OD were prepared in glass vials, and initial weight DEAEMA ratios of ω_M0 = 10, 30 and 60 wt%. Aliquots of the prepared solutions were transferred to NMR tubes resulting in a sample solution height of approximately 5.5 cm (∼0.50 g). The prepared solutions were degassed by three freeze–pump–thaw cycles prior to heating. Subsequently, each NMR tube was sealed and inserted into the NMR instrument, which was programmed to heat up and perform automatic collection of ¹H-NMR spectra, every so often from 17 to 24 hours. The reaction temperatures were 26.8, 43.5, 60 and 70 °C.

As an example, for the ω_M0 = 10 wt% (1 : 46 (DEAEMA : D₃OD) molar ratio) experiment at 70 °C: in a glass vial 0.049 g (0.26 mmol) of DEAEMA were weighed, followed by 0.44 g (12.27 mmol) of CD₃OD, and the capped vial was vortexed for 5 minutes. A fraction of the resulting homogeneous solution was transferred to the NMR tube and then degassed. The sealed NMR tube was placed on the instrument and thermally equilibrated at 26.8 °C, then a first ¹H-NMR spectrum was acquired and with this, after the corresponding signals were integrated, the real DEAEMA : CD₃OD molar ratio was checked. After that, the probe was heated to 26.8 °C (to avoid loss of quality of the shimming sample, the auto-shimming mode was activated in the Topspin 3.6.2 software), and as soon as the target temperature was reached the first spectrum was acquired. Then, the spooler mode in the Topspin software was used to program the acquisition of the remaining spectra as a function of time, for 24 hours. Finally, the signals corresponding to the transesterification products in the ¹H-NMR spectra were integrated using the Bruker Topspin software.

¹³C (100.5 MHz) and two-dimensional (COSY, HSQC) NMR spectra were obtained at room temperature with a 400 MHz Bruker Avance III HD 400 N spectrometer (with a 5 mm multinuclear BBI-decoupling probe with a Z grad).

Free radical (co)polymerization

Similar to the procedure described above, homogeneous solutions of DEAEMA as a monomer, CH₃OH as an alcohol source, AIBN as an initiator, 1,3,5-trioxane as an internal reference (for species quantification), and CDCl₃ as a deuterated solvent were prepared in glass vials. Aliquots of the prepared solutions were transferred to the NMR tubes resulting in a sample solution height of approximately 5.50 cm (∼0.50 mL). The prepared solutions were degassed by three freeze–pump–thaw cycles before heating. Subsequently, each NMR tube was sealed and inserted into the NMR instrument, which was programmed to heat up and perform automatic collection of ¹H-NMR spectra. Different monomer : alcohol source molar ratios were evaluated at 70 °C, for 24 hours of reaction.

As an example, for an experiment with the 1 : 8 (DEAEMA : CH₃OH) molar ratio: in a glass vial 7.78 × 10⁻³ g (4.74 × 10⁻² mmol) of AIBN were weighed, followed by 0.034 g (0.38 mmol) of 1,3,5-trioxane, 0.81 g (4.39 mmol) of DEAEMA, 1.17 g (36.40 mmol) of CH₃OH and 1.49 g (12.39 mmol) of CDCl₃. The capped vial was vortexed for 5 minutes, then a fraction of the resulting homogeneous solution was transferred to the NMR tube and then degassed. The sealed NMR tube was placed in the NMR equipment to carry out the copolymerization reaction, following the same procedure described for the case of transesterifications.

Theoretical calculations

To rationalize the mechanism of the DEAEMA transesterification reaction with CH₃OH, electronic structure calculations using DFT were performed to obtain the relevant intermediaries and transition states involved in the process. Calculations were carried out using the B3LYP functional (unrestricted Kohn–Sham approach) and the set of def2TZVP bases, including dispersion corrections (D3BJ) and implicitly considering the effect of the solvent CH₃OH by using the polarizable continuum model.^35–39 Since several parts of the potential energy surface of the DEAEMA–CH₃OH adduct are relatively flat, the accuracy for the evaluation of the two-electron integrals was increased (Acc2E = 14) and, a finer grid (SuperFineGrid) was used for the evaluation of the exchange-correlation numerical integrations in the DFT part. In addition, a stricter criterion (opt = tight) was considered for the force limits and the step size to determine the convergence in the geometry optimization. The nature of the stationary points was verified by evaluating the vibrational frequencies. To check the connectivity between the stationary points, intrinsic coordinate reaction calculations were performed. All of the above was performed using the Gaussian 16 program.⁴⁰

Results and discussion

Transesterification

Transesterification mechanism between DEAEMA and methanol. Typically, a transesterification process is the conversion of a carboxylic acid ester to a different carboxylic acid ester using an alcohol as the reactive and solvent in the presence of an acid catalyst. Here, DEAEMA transesterification occurs in the absence of an acid catalyst, and it is believed that the tertiary amine catalysed the reaction forming an adduct with a molecule of the solvent; CH₃OH interacts simultaneously with the amine and ester groups stablishing N⋯H and O⋯C bonds, since a tertiary amine is not strong enough to deprotonate the hydroxyl group. Apparently, the formation of this adduct avoids the competitive Michael addition reaction of CH₃OH to the conjugated double bond. Fig. 1 shows the reaction scheme for the transesterification reaction of DEAEMA with CH₃OH, where the electronic energies of the stationary points of the molecular system are plotted in relevant parts of the potential energy surface. In terms of the energetic and structural information provided by this diagram, the mechanism can be summarized in three stages.

Fig. 1 Reaction scheme for the transesterification process of DEAEMA with a CH₃OH molecule, obtained from electronic structure calculations at the UB3LYP-PCM(methanol)/def2TZVP level of theory: a) methanol attack to carbonyl, b) adduct conformational changes, c) ester C–O bond cleavage. Bold numbers denote minima (reactants, intermediaries and products) on the potential energy surface, while TSi denotes the i-th transition state. Energies are referenced to 1 (see Fig. S1 and S2 in the ESI† for a detailed version of the diagram).

In stage I (Fig. 1a), the limiting step involves the formation of the DEAEMA–methanol adduct, where, to access the corresponding transition state (TS₁) from an initial DEAEMA–CH₃OH intermolecular complex, it is necessary to overcome an energy barrier of 24.05 kcal mol⁻¹ (100.62 kJ mol⁻¹). Regarding changes in molecular geometries, by going from 1 to 2 the methanol molecule transfers the OH proton to the amine, while the CH₃O moiety forms an O–C bond with the carbonyl of the ester. Then, passing through TS₂, the amine proton migrates to the oxygen of the carbonyl group, and subsequently, a rotation of this hydrogen around the C–O bond takes place in the opposite direction of the amine (E₃ − E_TS3 = 12.07 kcal mol⁻¹), allowing the recovery of the conformational flexibility around the central part of the molecule. This paves the way for the structural changes to be performed in the following stage, because it is known that the tetrahedral addition intermediate is unstable and N,N-diethylethanol is released in order to recover the carbonyl group and form the methyl methacrylate.

In stage II (Fig. 1b), a series of conformational changes occur, involving small energy barriers of less than 2 kcal mol⁻¹, where the system adopts the reactive conformation necessary to facilitate the breaking of the OC bond. Finally, in stage III (Fig. 1c), the system must be supplied with 29.15 kcal mol⁻¹ (121.96 kJ mol⁻¹) to pass through TS₇, in order to carry out the cleavage of the C–O bond, as well as the migration of hydrogen, to give rise to the observed products of the reaction. A recreation of the reaction mechanism relating the reagents, transition states, intermediates and products is seen in the file Transesterification_reaction_movie.

Other reaction routes exist, but the energy changes involved are larger, so they do not represent major kinetic competition to the proposed mechanism. As an example, the direct deprotonation of CH₃OH by the amine involves an initial unfavourable energy change of 47.43 kcal mol⁻¹. Besides the presence of the Michael addition product was not identified in the NMR experiments, so this other possibility was ruled out.

However, the energy barriers obtained in the proposed mechanism differ by a factor of 2, from the estimated value of the activation energy of the kinetic analysis using the experimental data (vide infra). This difference remains relatively unchanged if, instead of using electronic energies, suitable Gibbs free energies obtained from gas-phase thermochemical calculations are used. We attribute the difference to the inadequate description of the solvent by explicitly considering only one molecule of CH₃OH. It is well known that the calculated energy barriers for proton migration reactions, in hydrogen-bonded solvents, decrease when more than one solvent molecule is explicitly considered, due to a cooperative effect.^41–44 Thus, as an additional possibility, transition states analogous to TS₁ and TS₇ were obtained, but considering two methanol molecules in the calculations.

Fig. S3 in the ESI† shows the structures obtained for these transition states. In the analogous case of TS₇, when considering the two solvent molecules, the barrier decreases by 6.23 kcal mol⁻¹ with respect to that observed in Fig. 1. Moreover, in this situation, the conformational changes of stage II are not necessary, since because of the increased flexibility induced by the additional solvent molecule, the reaction can take place right after the amine transfers the proton to the carbonyl. On the other hand, taking into consideration a CH₃OH molecule bonded to the carbonyl in the TS₁ analogue, the barrier decreases by 5.13 kcal mol⁻¹. In this case, the electrophilic character of the carbonyl increases by the interaction with the molecule of solvent and the other methanol molecule may react with the carbonyl initiating the transesterification process. These examples show that the consideration of an additional solvent molecule moves the observed energy barriers in the right direction, with reference to the experimental values. Importantly, the values of these barriers are very similar to those reported for transesterification reactions in analogous systems using an acid catalyst.⁴⁵ A more general mechanism considering TS₁ and TS₇ transition states from the theoretical analysis is provided in Scheme 2.

Scheme 2 Plausible mechanism for transesterification of DEAEMA with CH₃OH.

On the other hand, Fig. 2 shows the signal assignations of the ¹H-NMR spectra at 70 °C during 17 h of reaction with the DEAEMA monomer presenting the following peaks (DOCD₃, 400 MHz): (1a) 6.10 ppm (1H, CH=C), (1b) 5.61 ppm (1H, CH=C), (5) 4.26 ppm (2H, CH₂–O), (6) 2.79 ppm (2H, CH₂–N), (7) 2.62 ppm (4H, (CH₂)₂–N), (3) 1.95 ppm (3H, CH₃–C), and (8) 1.07 ppm (6H, 2(CH₃–C)). Transesterification products have peaks and multiplicities at different chemical shifts (δ) than those of DEAEMA, MMA-d₃: (1a*) 6.07 ppm (1H, CH=C), (1b*) 5.59 ppm (1H, CH=C), (9*), 3.64 ppm (3H, CH₃–C) (for MMA no deuterated, CH₃OH), (3*) 1.95 ppm (CH3, CH₃–C); and hydroxyalkylamine: (OH): 4.33 ppm (1H, HO–C), (5*) 3.62 ppm (2H, CH₂–O), (6* and 7*) 2.61 ppm (2H + 4H; CH₂–N, (CH₂)₂–N), and (8*) 1.07 ppm (6H, 2(CH₃–C)). Additionally, the peak at 4.35 ppm corresponds to water contained in the methanol.⁴⁶ The ¹H-NMR spectra of DEAEMA and MMA monomers in CD₃Cl are shown in Fig. S4 and S5 in the ESI.† HSQC NMR spectroscopy was used to confirm the assignment of the signals, as shown in Fig. S6 in the ESI.†

Fig. 2 Scheme of transesterification between DEAEMA and CD₃OD, and stacked ¹H-NMR spectra at t = 0, 1, 2, 4, and 17 h for transesterification between DEAEMA and CD₃OD with an initial ratio ω_M0 = 10 wt% at 70 °C.

Degree of alcoholysis. The degree of alcoholysis or transesterification (D_a) is the amount of DEAEMA transformed to deuterated methacrylate methyl (MMA-d₃) and 2-(diethylamino)ethanol (d₁), presenting a 1 : 1 molar ratio between the products on the right of the scheme shown in Fig. 2. D_a (mol%) is estimated with the following eqn (1):The results of three experimental sets with different percentages of initial DEAEMA monomer (ω_M0 = W_M0/((W_M0 + W_sol)), wt%) in the solution (CD₃OD) and temperatures are shown in Fig. 3. Surprisingly, the experiment with ω_M0 = 10 wt% and T = 26.8 °C (approx. room temperature) shown in Fig. 3a results in a very high value of D_a = 80% after 24 h of reaction; therefore, the solution presents a monomer mixture of 20% of DEAEMA and 80% of deuterated methyl methacrylate (O–CD₃, MMA-d₃). If the temperature increases to 43.5 °C, the transesterification rate also increases to reach a value of D_a = 90% in 17 h. A total conversion of DEAEMA to MMA-d₃ (D_a = 100%) is obtained at 10 h and 7 h at T = 60 °C and 70 °C, respectively. A higher DEAEMA content in the solution decreases the transesterification rate; for example, in the experiment with ω_M0 = 30 wt% and T = 26.8 °C results in a value of D_a = 65% within 24 h (Fig. 3b), but if ω_M0 increases to 60 wt%, the value of D_a decreases to 24% in 24 h. The formation of a second monomer (MMA-d₃) in the DEAEMA/CD₃OD solution at 26.8 °C and ω_M0 = 60% (0.47 M) is faster than the hydrolysis of DMAEMA/D₂O at 0.5 M, 25 °C and pH = 7.9, where the formation of deuterated methacrylic acid (MA-d₁) was 18% in 50 h.¹¹ However, an increase in the pH of the DMAEMA/D₂O solution leads to a faster hydrolysis process.^13,16 Although it is clear that transesterification and hydrolysis are important competitive pathways that should be taken into account in processes involving TAMAs in alcoholic and aqueous solvents, such as free radical polymerizations, this has been overlooked until now.

Fig. 3 Evolution of the degree of alcoholysis (D_a, mol%) in time and variation of the reaction temperature (labels). The value of ω_M0 was varying at: a) 10, b) 30, and c) 60 wt%. Symbols are the experimental data obtained via¹H-NRM in situ measurements and lines represent a model prediction with a second-order kinetic equation and using eqn (2)–(6).

Kinetic rate coefficients. The integral method was used to determine a second-order reaction of DEAEMA transesterification with CD₃OD, which was considered to estimate the kinetic rate coefficients k_tran (L mol⁻¹ s⁻¹) through a linear regression of eqn (2):^43,47where . Furthermore, when t = t_1/2 the value of . and the half-life for the second-order reactions is calculated using the following eqn (3).The estimated values of k_tran are shown in Table 1 and the second-order plots for each experiment are illustrated in Fig. 4. Additionally, a pseudo-first order reaction was used to estimate the values of k_tran (L mol⁻¹ s⁻¹) and the results are shown in section S.5 in the ESI.† Both estimation methodologies using pseudo-first- and second-order reactions exhibit a perfect fit for all experiments in the linear regression plots. As expected, the estimated values of t_1/2 between pseudo first and second-order are similar for high values of M (ω_M0 = 10 and 30 wt%), but significant differences of k_tran and t_1/2 are observed for experiments in which M tends to one (e.g. ω_M0 = 60 wt%, M = 3.4). For example, the discrepancy between t_1/2 for the first and second-order is approximately 13 h for the experiment at T = 26. This is due to the fact that there is no excess of CD₃OD in the experiments and its concentration changes as a function of time, therefore, the pseudo first-order expression is not valid for this set of experiments.

Table 1 Transesterification rate coefficients (k_tran) and the corresponding half-lives (t_1/2) of DEAEMA in CD₃OD for a temperature range from 26.8 to 70 °C, estimated by a second-order reaction, eqn (2) and (3), respectively

ω M0 (wt%)	T (°C)	k tran (L mol^−1 s^−1)	R ^2	t 1/2 (h)
10	26.8	8.66 × 10^−7	1	10.04
	43.5	2.29 × 10^−6	0.99	3.82
	60.0	5.12 × 10^−6	0.99	1.70
	70.0	8.93 × 10^−6	0.99	0.97
30	26.8	7.08 × 10^−7	0.99	15.83
	43.5	1.97 × 10^−6	0.99	5.68
	60.0	3.75 × 10^−6	0.99	2.97
	70.0	6.23 × 10^−6	0.99	1.79
60	26.8	2.97 × 10^−7	0.99	70.11
	43.5	6.19 × 10^−7	0.99	34.87
	70.0	1.63 × 10^−6	0.99	13.17

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Fig. 4 Second-order kinetic plots for transesterification analysed with eqn (3), varying the temperature (labels) and ω_M0: a) 10 wt%, b) 30 wt% and c) 60 wt%. Symbols are the experimental data and lines are regressions with the estimated values shown in Table 1.

The dependency of temperature on the DEAEMA kinetic parameters was investigated at four levels, from a low temperature (26.8 °C) to a typical temperature (70 °C) for free radical polymerization. The higher temperature was limited for the boiling point of CD₃OD (65.4 °C),⁴⁸ but in a closed system with a vacuum, its temperature can be increased to 70 °C without any change in the solvent phase. The lower limit was approximated to the standard ambient temperature (25 °C). As the temperature increases, the transesterification is significantly faster, as shown in Fig. 3 for all the values of ω_M0, and ln(k_tran) is also linearly increased as a function of T⁻¹, Fig. 5. Surprisingly, the plot shows an important shift in both the slopes of the linear regressions, which is proportional to the activation energy (E_a), also in the intercept that is related to the frequency factor (A) in the Arrhenius expression, eqn (4):

The estimated values of E_a and A are shown in Table 2 for each condition of ω_M0, showing excellent fits for the three sets of data (R² > 0.997). A higher DEAEMA concentration leads to a decrease in collision frequency, from 77.45 to 0.23 L mol⁻¹ s⁻¹ for ω_M0 = 10 and 60 wt%, respectively. Also, an increase in monomer amount results in significantly lower values of E_a. A similar influence was observed by Ajogbeje et al.¹⁶ for the DMAEMA hydrolysis with D₂O during the variation of the pH of the aqueous medium, where the values of A and E_a were higher as the medium became more basic. For the case of transesterification, the observed increase to a higher dissolution in both kinetic parameters would be related to the intramolecular interaction between the N atom, DO- of CD₃OD, and the carbonyl-CO, giving rise to cyclic transition states, such as TS₁ and TS₇, see Scheme 2 or Fig. S3 in the ESI,† and the cooperative effect. On the one hand, several studies support the formation of cyclic transition states.^13,18,49,50 On the other hand, a higher concentration of DEAEMA leads to a higher number of intermolecular interactions and a self-catalytic effect is observed with a decrease in the activation energy.

Fig. 5 Kinetic analysis of the transesterification rate coefficient in the temperature interval from 26.8 to 70 °C and ω_M0 from 10 to 60 wt%. a) Arrhenius plots and b) 3D plot of the evolution of k_tran as a function of [DEAEMA]₀ and temperature. Symbols denote the experimental data and lines the regressions. The 3D surface has been calculated according to eqn (4)–(6).

Table 2 Arrhenius parameters, 95% confidence intervals and values of R² estimated with linear regressions from k_tran summarized in Table 1 between 26.8 and 70 °C

ω M0 (wt%)	M (−)	ln(A) (L mol^−1 s^−1)	E A (kJ mol^−1)	R ^2
10	49.93	4.35 (±0.37)	45.65 (±0.99)	0.998
30	13.42	2.76 (±0.79)	42.09 (±2.14)	0.992
60	3.46	−1.48 (±0.17)	33.77 (±0.43)	0.999

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Empirical expressions have been derived to capture the influence of ω_M0 on the frequency factor, eqn (5), and the activation energy, eqn (6), using polynomial regressions for both kinetic parameters, as shown in Fig. S10 in the ESI.†

ln(A) (L mol⁻¹ s⁻¹) = 4.77 − 0.03ω_M0 − 1.24 × 10⁻³ω_M0² (5)

E_A (kJ mol⁻¹) = 46.84 − 0.10ω_M0 − 1.99 × 10⁻³ω_M0² (6)

The values of k_tran are estimated by substituting the previous expressions in eqn (4), and are plotted in Fig. 5b as a surface; the differences between the predicted and experimental constants (spheres) are less than 8.5%, showing an excellent fit, with a sum of square differences SSD = 2.13 × 10⁻¹³ and a coefficient of determination R² = 0.997. The transesterification rate coefficient is clearly dependent on the [DEAEMA]₀ and temperature, being more favourable as [DEAEMA]₀ is reduced and temperature is increased. The evolution of D_a for each experiment was simulated using second-order kinetic coefficients, and the curves are compared with the experimental data in Fig. 3. The prediction curves using ω_M0 = 10, 30, and 60% overlap with the experimental data in most of the profiles, indicating good estimated kinetic parameters. The previous results are qualitatively in agreement with those calculated by a DFT approach. The kinetic information generated by transesterification is very important in the determination of amino functionality lost during polymerization in alcoholic solvents, which in most of the studies has been negligible.

Copolymerization of DEAEMA and MMA

To understand the effect of the transesterification reaction on the free radical polymerization, a set of experiments was conducted in NMR tubes containing CD₃OD, DEAEMA, and AIBN as reagents at 70 °C. It is proposed that due to transesterification during the reaction, MMA-d₃ formed in situ can react with the remaining DEAEMA monomer and produce poly(DEAEMA-co-MMA-d₃), resulting in a concurrent tandem polymerization and transesterification, Scheme 3. The copolymer composition depends on the concentrations of DEAEMA and CD₃OD, as well as the temperature, as demonstrated below.

Scheme 3 Copolymerization of DEAMA and MMA-d₃.

Poly(DEAEMA-co-MMA) formation. When performing the analysis by ¹³C-NMR in the zone of carbonyl signals of the copolymers obtained at the end of the respective kinetic study, the formation of copolymers poly(DEAEMA-co-MMA) is evidenced by the shape and number of signals of the carbonyls, as a consequence of the change in the microstructure of the copolymers, due to a change in the molar composition by a different incorporation of MMA. Changes in microstructure in synthetic vinyl polymers and copolymers can be analysed by ¹³C-NMR, in particular by the analysis of carbonyl signals sensitive to changes in tacticity and molar compositions.^47,51 In Fig. 6, it can be seen how the shape of the carbonyl signal in both comonomers changes depending on the value of ω_M0 in the monomer composition. For comparison, the chemical shift of the carbonyl signal of atactic poly(MMA) is reported at 176 to 179 ppm,⁵² very similar to that of pure poly(DEAEMA) shown in Fig. 6a. The spectrum of poly(DEAEMA-co-MMA-d₃) is illustrated in Fig. 6e, due to the high degree of transesterification involved in formation a high content of poly(MMA-d₃) is observed; however, the carbonyl signal partner of Fig. 6e differs from that of pure atactic poly(MMA), Fig. 6a, as well as from the spectrum presented in Fig. 6b–d. It is mainly attributable to the spin interaction of the carbon with deuterium.

Fig. 6 Partial ¹³C-NMR (100 MHz, r.t., δ in ppm) spectra of copolymers for the molar ratios of DEAEMA : CD₃OD (or CH₃OH) of: a) 1 : 0, pure poly(DEAEMA), b) 1 : 4, c) 1 : 8, d) 1 : 1 and e) 1 : 46.

Effect of the stoichiometric ratio of DEAEMA : methanol on the kinetics, the remaining monomer, and copolymer composition. First, a highly diluted experiment analogous to the previous one with a DEAEMA : CD₃OD = 1 : 46 molar ratio (ω_M0 = 10 wt%), but with the addition of the AIBN initiator (DEAEMA : AIBN = 92 : 1 molar ratio), is performed. Fig. 7 shows the ¹H-NMR spectra of the mixture of DEAEMA, CD₃OD, and AIBN at t = 0, and the generation of sub-products and polymers at t = 0, 1, 3, 6 and 24 h of reaction. Although a rigorous methodology was performed to avoid transesterification before acquisition of the first spectrum (t = 0), the signal at 3.65 ppm (5*) indicates the formation of 2-(diethylamino)ethanol and the signals at 5.60 and 6.07 ppm confirm the generation of MMA-d₃. As shown in the stacked spectra, the amount of remaining MMA-d₃ is almost equal to DEAEMA in the mixture at 1 h, and after 6 h the signal 5 corresponding to the DEAEMA monomer has vanished. Additionally, a wide signal at 4.1 ppm (e) is observed after 15 min, corresponding to the –OCH₂– of the DEAEMA units incorporated in the copolymer.

Fig. 7 Stacked ¹H-NMR spectra (400 MHz, r.t., δ in ppm) at t = 0, 1, 3, 6, and 24 h for copolymerization of DEAEMA and MMA-d₃ with an initial ratio ω_M0 = 10 wt% and DEAEMA : AIBN = 92 : 1 molar ratio in CD₃OD at 70 °C. The signal assignments correspond to Scheme 3.

The fraction of MMA formed during the process (D_a) is estimated with the equimolar formation of 2-(diethylamino)ethanol. DEAEMA conversion (X_DEAEMA) is the ratio between the moles of DEAEMA in the copolymer and the initial moles of DEAEMA. The remaining monomer composition (f_DEAEMA and f_MMA-d3) and the copolymer composition (F_DEAEMA and F_MMA-d3) are also estimated. All ratios are described in section S.8 in the ESI.†

In Fig. 8a, the profiles of X_DEAEMA, D_a, and the percentage of remaining DEAEMA (DEAEMA) are illustrated as a function of time. Analysing the data, only a low proportion (26.7 mol%) of [DEAEMA]₀ is polymerized and stopped prematurely at 5 h. Since the transesterification rate is relatively higher than the polymerization rate, a large amount of DEAEMA is transformed into MMA-d₃ as indicated by the D_a value of 73.3 mol%. While MMA-d₃ is only generated before 5 h of reaction (X_tot = 60 mol%), it is consumed continuously throughout the process. Under these conditions, it is clear that the final mixture is composed of poly(DEAEMA-co-MMA-d₃) and poly(MMA-d₃), the former is generated in the first stage when DEAEMA and MMA-d₃ monomers are present in the medium and the latter is generated when the DEAEMA monomer has been totally exhausted and then the MMA-d₃ monomer only remains in the reaction mixture, Fig. 8a and b. The copolymer is enriched with DEAEMA for X_tot lower than 60 mol%, but this is constantly decreasing as MMA-d₃ is generated and DEAEMA is exhausted, at 60% an equimolar composition of DEAEMA : MMA (50 : 50 mol%) is reached, and above that conversion, the MMA-d₃ copolymer composition presents a high value of F_MMA = 63 mol%. In fact, a white solution was observed after a day of experiment; the precipitated mass was separated and characterized by ¹³C-NMR and ¹H-NMR, resulting in the proportion of poly(MMA-d₃) of 95 mol%, Fig. S11–S13 in the ESI.† Therefore, the final material only contains a low proportion of amino functionality, which will dramatically affect its thermo- and pH-sensitivity properties.

Fig. 8 Copolymerization/transesterification of DEAEMA in a mixture of methanol/CDCl₃ at 60 °C to form poly(DEAEMA-co-MAA) with DEAEMA : AIBN molar ratio of 92 : 1 and DEAEMA : methanol of: a)–c) 1 : 46, d)–f) 1 : 8, g)–i) 1 : 4, and j)–l) equimolar, 1 : 1. a), d), g) and j) consumption profiles of: DEAEMA (DEAEMA), DEAEMA incorporated into (co)polymer (XDEAEMA), and degree of transesterification (D_a), b), e), h) and k) remaining monomer composition (mol%), c), f), i) and l) copolymer composition (mol%). CD₃OD was only used for the experiment with a 1 : 50 (DEAEMA : alcohol) molar ratio and for the other experiments CH₃OH was used.

On the other hand, different studies have used solvent mixtures to increase the miscibility of some components of the TAMA-containing polymer system, such as protic solvents (alcohols, water, etc.) and non-protic organic solvents.^53–55 Additionally, the combination of solvents is used in the actual study to increase the DEAEMA concentration regarding the alcohol, avoiding high viscosity of the medium and the problems with the acquisition of the spectra.

Here, a solvent mixture of CH₃OH/CD₃Cl was used and the kinetic behaviour of transesterification and copolymerization was followed by using ¹H-NMR in situ measurements. Chloroform acts as an inert solvent in the reaction since it does not present any inter- and/or intramolecular interaction. However, the amount of CH₃OH gives rise to the transesterification of DEAEMA and the MMA subproduct (no deuterated). According to the previous results of this work, the transesterification rate should suffer a decrease when the DEAEMA content increases, Fig. 3; hence, 1 : 8 (ω_M0 = 41 wt%), 1 : 4 (ω_M0 = 58 wt%), and 1 : 1 (ω_M0 = 84.6 wt%) DEAEMA : CH₃OH molar ratios were analysed.

In the next two experiments, the amount of DEAEMA is increased in the molar ratios of DEAEMA : CH₃OH at 1 : 8 and 1 : 4 to explore the kinetic behaviour under moderate dissolution conditions using concurrent tandem transesterification and polymerization, and these reaction conditions are commonly used in TAMA (co)polymerization.

An excess of alcohol in 1 : 8 (DEAEMA : CH₃OH) molar ratio was first studied. In this case, DEAEMA is consumed after 10 h (see DEAEMA) by a copolymerization pathway (X_DEAEMA) faster than transesterification (D_a), Fig. 8d. Therefore, an increase in the DEAEMA content results in a significant impact on the transesterification, reducing its rate and promoting the copolymerization between DEAEMA and the MMA formed in situ. The estimated values of X_MMA are higher than those of the previous experiment with only CD₃OD as a solvent; after 17 h the DEAEMA and MMA monomers were consumed totally consumed (X_tot > 97%). As shown in Fig. 8e, both monomers are present throughout the reaction, giving rise to a copolymer in solution without the possible existence of homopolymer chains; below X_tot = 75% the remaining monomer mixture is reached by DEAEMA and above it a higher level of MMA is observed. A system of competitive reactions is obtained under these conditions, because both kinetic steps contribute to the growth of the chains throughout the process, resulting in a random copolymer with a final composition of 67 and 33 mol% DAEAMA and MMA, respectively, Fig. 8f. A value of F_DEAEMA = 62 mol% was estimated in the sample after purification of the monomers. Additionally, experiments in Schleck tubes were carried out at different reaction times of 0.5, 4 and 7 h. After purification, the samples were analysed by Differential Scanning Calorimetry (DSC). The glass transition temperatures (T_g) were −18.5, −11, and −6.6 at 0.5, 4, and 7 h, respectively, Fig. S14 in the ESI.† As a result, the copolymer composition is enriched with MMA during the tandem process, which is consistent with the in situ¹H-NMR analysis.

In the next experiment, the concentration of the CH₃OH was decreased and the profiles of X_DEAEMA, X_MMA, D_a, and DEAEMA as a function of time for a 1 : 4 (DEAEMA : CH₃OH) molar ratio are plotted in Fig. 8g, the remaining monomer composition f_DEAEMA and f_MMA in Fig. 8h, and the copolymer composition F_DEAEMA and F_MMA in Fig. 8i. Fast consumption of the DEAEMA monomer is observed, depleting in 10 h. Only 10% of the initial concentration of DEAEMA is consumed by transesterification to produce MMA and 90% by polymerization, thus the process is governed by a high copolymerization rate. It is assumed that the copolymerization runs under starved MMA conditions, in which the MMA is consumed as soon as it is generated. Therefore, the remaining monomer mixture is predominantly composed of DEAEMA during the reaction, Fig. 8h. The resulting copolymer is enriched with 91% DEAEMA and only 9% MMA as shown in Fig. 8i, which is very different in terms of the composition of 67% DEAEMA and 33% MMA obtained in the experiment conducted with a 1 : 4 (DEAEMA : CH₃OH) molar ratio.

Finally, an equimolar ratio of DEAEMA : CH₃OH was employed with the objective of completely avoiding transesterification with DEAEMA. In fact, this goal was achieved because it is supported by the very low resulting values of D_a during the 17 h of reaction, Fig. 8j. From the total initial DEAEMA, an amount of X_DEAEMA = 98 mol% is polymerized and 2 mol% is lost through transesterification, leading to a homopolymerization of DEAEMA. Additionally, the consumption of DEAEMA is slow under these conditions, since it is exhausted over the course of 10 h compared to the time of 5 h for that experiment with a molar ratio of 1 : 8 (DEAEMA : CH₃OH), Fig. 8aversusFig. 8j. Both the remaining monomer mixture (Fig. 8k) and the copolymer compositions (Fig. 8l) are enriched with poly(DEAEMA) in the course of the 17 h reaction, producing DEAEMA chains with a high F_DEAEMA of 98 mol%, which was confirmed after sample purification (F_DEAEMA = 99%), see Fig. S15–S17 in the ESI.†

Effect of the initiator concentration. The polymerization rate can easily be modified with a change of initial concentration of the initiator in the experiment, resulting in a direct impact on the transesterification rate, due to the dependence of the DEAEMA concentration in both processes. To study this phenomenon, we analyse the molar ratio of DEAEMA : AIBN decreased from 92 : 1 to 200 : 1 in the experiment with ω_M0 = 10 wt% at 70 °C (only CD₃OD as solvent), maintaining constant the ratio M; the comparison between both experiments is illustrated in Fig. 9. A slower copolymerization rate is reflected in the lower conversion values of X_tot, X_DEAEMA and X_MMA-d3 shown in Fig. 9a and b for a molar ratio 200 : 1; e.g., the final value of X_tot of 83% for the 92 : 1 molar ratio is twice that for the 200 : 1 ratio (39%). The profile of X_tot for the experiment with the lower amount of initiator reflects a strong change of slope at 4 h due to the exhaustion of DEAEMA. The lower consumption of the DEAEMA monomer by polymerization leads to a higher availability of the monomer for its transesterification with CD₃OD and increases the degree of alcoholysis D_a to 90 mol%, Fig. 9a. The analogous profile of D_a estimated for the transesterification experiments illustrated in Fig. 3a is compared with that estimated in the copolymerization for the molar ratio DEAEMA : AIBN = 200 : 1, resulting in an overlap of both curves. Therefore, the process has high selectivity to transesterification and MMA-d₃ formation under these reaction conditions.

Fig. 9 Copolymerization/transesterification of DEAEMA in CD₃OD at 60 °C to form poly(DEAEMA-co-MAA-d₃) with 92 : 1 (DEAEMA : AIBN) molar ratio (open symbols) or 200 : 1 (closed symbols) both with 1 : 50 (DEAEMA : CD₃OD) molar ratio, a) degree of transesterification (D_a) and total conversion (X_tot). b) Consumption profiles of DEAEMA incorporated into (co)polymer (X_DEAEMA) and MMA incorporated into (co)polymer (XMMA). c) Remaining monomer composition, f_i (mol%). d) Cumulative copolymer composition, F_i (mol%).

Decreasing the concentration level of the initiator results in a change in the remaining monomer mixture from a DEAEMA-enriched solution to an MMA-enriched solution in a short period, but only 40% of X_tot can be achieved in 24 h, Fig. 9a and c. In the first stage of the reaction, the copolymer chains are formed with a high DEAEMA content, but since MMA is generated by a fast transesterification, the chains are enriched with MMA until they reach 80% of the accumulated composition at 22 h, Fig. 9d. It is estimated that 37 mol% of the total mass of macromolecules are formed by homopolymer chains of MMA-d₃, which are generated above X_tot = 20 mol%. In fact, a white precipitate was observed after 24 h of reaction, Fig. S18 in the ESI.†

These results indicate that batch DEAEMA polymerizations in CH₃OH (and possibly other primary alcohols) under mild temperature and low levels of initial concentration of the initiator undergo a high selectivity for transesterification and in situ formation of the MMA monomer, leading to a copolymer with strong composition drift (even homopolymer chains) and loss of amino functionality in the final material. Such conditions could be easily achieved in reversible-deactivation radical polymerizations (RDRP),^56–58 specifically during processes with significantly long preequilibrium periods. However, gradient and alternated copolymers could be prepared via concurrent tandem RDRP and transesterification such as in previous studies,⁵⁹ but without the use of metal catalysts.

Conclusions

The mechanism of transesterification of DEAEMA with methanol to produce MMA and aminoethanol has been elucidated via a DFT approach; the postulated mechanism for an equimolar ratio of reagents comprises three principal stages: i) a limiting step of the amine protonation while the CH₃O moiety forms an O–C bond with the carbonyl of the ester; then the adduct suffers structural chances to recover the conformational flexibility around the central part of the molecule; ii) this step is principally governed for conformational changes of the adduct, and iii) a cleavage of the C–O bond in the adduct, as well as the migration of hydrogen, giving rise to the observed products of the reaction. It is important to note that a cooperative effect of the solvent molecules that participate in the hydrogen bonding between DEAEMA and methanol is plausible, which leads to a reduction in the energetic barriers of the transition states and regeneration of the methanol molecules in the products.

In situ NMR spectroscopy and a second-order reaction were used in the kinetic studies of the transesterification of DEAEMA with a primary alcohol. Surprisingly, the experiment with ω_M0 = 10 wt% and T = 26.8 °C resulted in an almost complete transesterification process (D_a = 80%) after only one day. However, increasing the content of DEAEMA (higher ω_M0), the transesterification degree is lowered, which is consistent with the hypothesis of the cooperative effect of solvent molecules, because E_a decreases as the value of ω_M0 increases. A second order expression is presented to describe the transesterification rate coefficient with Arrhenius parameters depending on ω_M0, showing a good fit with the experimental data over a wide temperature interval.

Additionally, the operating conditions of the transesterification of DEAEMA that give rise to MMA generation, both monomers in the presence of a thermal initiator and competitive (co)polymerization, were also studied. The kinetic complexity of this system increases as a result of the in situ formation of MMA during the reaction, the initiator decomposition rate, homopolymerization, and copolymerization processes. The incorporation of MMA into the propagating chains was validated via NMR analysis. For highly diluted DEAEMA experiments (46 : 1 (DEAEMA : CH₃OH) molar ratio), a fast transesterification rate was observed, leading to a mixture with MMA composition as high as 67 mol%, with most of them forming homopolymer chains due to fast DEAEMA exhaustion in the first stage of reaction. However, if an equimolar ratio of DEAEMA : CH₃OH is analysed, the transesterification is practically avoided, giving rise to a DEAEMA copolymer composition of 98 mol%; therefore, the process is mainly governed by DEAEMA homopropagation, preserving the amino functionality. Furthermore, the amount of MMA transesterification product, as well as the copolymer composition, can also be regulated by modifying the concentration of initiator. These results provide guidelines for the synthesis of well-defined DEAEMA copolymers in primary alcoholic media used in stimuli-responsive materials in which avoiding transesterification is desirable. However, transesterification offers a new route of synthesis for the solution free radical copolymerization of TAMAs and alkyl or functionalized methacrylates, and efforts are being made to model the kinetics and implement RDRP techniques.

Data availability

The data supporting this article have been included as part of the ESI.†

Author contributions

Conceptualization, I. Z. G.; methodology: J. C. R., J. F. E. M., and R. T. L.; validation, J. C. R., R. T. L.; investigation: all the authors; NMR and laboratory resources, J. F. E. M. and R. T. L.; DFT calculations and discussions, J. J. C. and A. O. T.; writing—original draft preparation, I. Z. G., writing—review and editing, I. Z. G., A. O. T. and R. T. L.; visualization, I. Z. G.; project administration: I. Z. G.; funding acquisition: I. Z. G. All authors have given approval to the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Ivan Zapata-González thanks the CIQA for financial support through the program of Internal projects, number 6754.

Notes and references

1. J. Ramos, J. Forcada and R. Hidalgo-Alvarez, Chem. Rev., 2014, 114(1), 367–428,  DOI:10.1021/cr3002643.
2. A. González-Urías, I. Zapata-González, A. Licea-Claverie, A. F. Licea-Navarro, J. Bernaldez-Sarabia and K. Cervantes-Luevano, Colloids Surf., B, 2019, 182, 110365,  DOI:10.1016/j.colsurfb.2019.110365.
3. Q. R. Huang, W. Volksen, E. Huang, M. Toney, C. W. Frank and R. D. Miller, Chem. Mater., 2002, 14(9), 3676–3685,  DOI:10.1021/cm020014z.
4. S. H. Cho, M. S. Jhon, S. H. Yuk and H. B. Lee, J. Polym. Sci., Part B: Polym. Phys., 1997, 35, 595–598,  DOI:10.1002/(SICI)1099-0488(199703)35:4<595::AID-POLB7>3.0.CO;2-P.
5. M. Okubo, H. Ahmad and T. Suzuki, Colloid Polym. Sci., 1998, 276, 470–475,  DOI:10.1007/s003960050268.
6. M. P. J. Miclotte, S. B. Lawrenson, S. Varlas, B. Rashid, E. Chapman and R. K. O'Reilly, ACS Polym. Au, 2021, 1(1), 47–58,  DOI:10.1021/acsami.2c15024.
7. A. Pikabea, J. Ramos and J. Forcada, Part. Part. Syst. Charact., 2013, 31, 101–109,  DOI:10.1002/ppsc.201300265.
8. D. S. Spencer, A. B. Shodeinde, D. W. Beckman, B. C. Luu, H. R. Hodges and N. A. Peppas, J. Controlled Release, 2021, 332, 608–619,  DOI:10.1016/j.jconrel.2021.03.004.
9. V. D. Lechuga-Islas, M. Trejo-Maldonado, I. Anufriev, I. Nischang, İ. Terzioğlu, J. Ulbrich, R. Guerrero-Santos, L. E. Elizalde-Herrera, U. S. Schubert and C. Guerrero-Sánchez, Macromol. Biosci., 2023, 23, 2200262,  DOI:10.1002/mabi.202200262.
10. V. D. Lechuga-Islas, G. Festag, M. Rosales-Guzman, O. E. Vega-Becerra, R. Guerrero-Santos, U. S. Schubert and C. Guerrero-Sanchez, Eur. Polym. J., 2020, 124, 109457,  DOI:10.1016/j.eurpolymj.2019.10.
11. R. Yañez-Macias, I. Alvarez-Moises, I. Perevyazko, A. Lezov, R. Guerrero-Santos, U. S. Schubert and C. Guerrero-Sanchez, Macromol. Chem. Phys., 2017, 218(10), 1700065,  DOI:10.1002/macp.201700065.
12. A. Darabi, P. G. Jessop and M. F. Cunningham, Chem. Soc. Rev., 2016, 45, 4391,  10.1039/C5CS00873E.
13. P. van de Wetering, N. J. Zuidam, M. J. Van Steenbergen, O. A. G. J. van der Houwen, W. J. M. Underberg and W. E. Hennink, Macromolecules, 1998, 31(23), 8063–8068,  DOI:10.1021/ma980689g.
14. P. Zheng, X. Su, C. Fei, X. Shi, H. Yin and Y. Feng, J. Polym. Sci., Part B: Polym. Phys., 2018, 56(12), 914–923,  DOI:10.1002/polb.24606.
15. The estimated values using linear regression and the temperature and ln(k) values obtained from Table 1 of ref. 11 are A = 3.10 × 10⁷ s⁻¹ and 69.51 ± 3 kJ mol⁻¹.
16. O. Ajogbeje, I. Lacík and R. A. Hutchinson, Polym. Chem., 2023, 14(21), 2624–2639,  10.1039/D3PY00350G.
17. N. P. Truong, Z. M. J. Burges, N. A. McMillan and M. J. Monteiro, Biomacromolecules, 2011, 12(5), 1876–1882,  DOI:10.1021/bm200219e.
18. P. Cotanda, D. B. Wright, M. Tyler and R. K. A. O'Reilly, J. Polym. Sci., Part A: Polym. Chem., 2013, 51(16), 3333–3338,  DOI:10.1002/pola.26730.
19. P. Y. Bruice, Organic Chemistry, Person Education Inc, Prentice Hall, 5th edn, 2007, p. 744.
20. J. Otera, Transesterification, Chem. Rev., 1993, 93, 1449–1470,  DOI:10.1021/cr00020a004.
21. J. Otera and J. Nishikido, Esterification: Methods, Reactions, and Applications, Wiley-VCH Verlag GmbH & Co. KGaA, 1st edn, 2009,  DOI:10.1002/9783527627622.
22. G. A. Grasa, R. Singh and S. P. Nolan, Synthesis, 2004, 7, 971–985,  DOI:10.1055/s-2004-822323.
23. H. E. Hoydonckx, D. E. De Vos, S. A. Chavan and P. A. Jacobs, Top. Catal., 2004, 27, 83–96,  DOI:10.1023/B:TOCA.0000013543.96438.1a.
24. J. Q. Ng, H. Arima, T. Mochizuki, K. Toh, K. Matsui, M. Ratanasak, J. Y. Hasegawa, M. Hatano and K. Ishihara, ACS Catal., 2021, 11(1), 199–207,  DOI:10.1021/acscatal.0c04217.
25. X. Bories-Azeau and S. P. Armes, Macromolecules, 2002, 35(27), 10241–10243,  DOI:10.1021/ma021388g.
26. P. Quiñonez-Angulo, R. A. Hutchinson, Á. Licea-Claveríe, E. Saldívar-Guerra and I. Zapata-González, Polym. Chem., 2021, 12(37), 5289–5302,  10.1039/d1py00750e.
27. J. Arredondo, P. Champagne and M. F. Cunningham, Polym. Chem., 2019, 10(15), 1938–1946,  10.1039/C8PY01803K.
28. P. Quiñonez Angulo, Synthesis, Kinetic Study and Applications of Smart Copolymers with Amino-Containing Groups and PEGMAs, Ph.D. Thesis, Tecnológico de Tijuana/TecNM, B.C., México, 2022.
29. S. Mushtaq, M. A. Abbas, H. Nasir, A. Mahmood, M. Iqbal, H. A. Janjua and N. M. Ahmad, Sci. Rep., 2023, 13, 4572,  DOI:10.1038/s41598-023-27515-5.
30. J. Y. Zheng, M. J. Tan, P. Thoniyot and X. J. Loh, RSC Adv., 2015, 5(76), 62314–62318,  10.1039/C5RA12816A.
31. L. M. Thoma, B. R. Boles and K. Kuroda, Biomacromolecules, 2014, 15(8), 2933–2943,  DOI:10.1021/bm500557d.
32. Q. Chen, W. Lin, H. Wang, J. Wang and L. Zhang, RSC Adv., 2016, 6(72), 68018–68027,  10.1039/c6ra10757e.
33. S. Beuermann, Macromolecules, 2004, 37(3), 1037–1041,  DOI:10.1021/ma0354647.
34. S. K. Fierens, P. H. M. Van Steenberge, M. F. Reyniers, D. R. D'hooge and G. B. Marin, React. Chem. Eng., 2018, 3(2), 128–145.
35. A. D. Becke, J. Chem. Phys., 1993, 98(7), 5648–5652,  DOI:10.1063/1.464913.
36. P. J. Stephens, F. J. Devlin, C. F. Chabalowski and M. J. Frisch, J. Phys. Chem., 1994, 98(45), 11623–11627,  DOI:10.1021/j100096a001.
37. F. Weigend and R. Ahlrichs, Phys. Chem. Chem. Phys., 2005, 7, 3297–3305,  10.1039/B508541A.
38. S. Grimme, S. Ehrlich and L. Goerigk, J. Comput. Chem., 2011, 32, 1456–1465,  DOI:10.1002/jcc.21759.
39. J. Tomasi, B. Mennucci and R. Cammi, Chem. Rev., 2005, 105, 2999–3094,  DOI:10.1021/cr9904009.
40. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery Jr, J. E. Peralta, F. Ogliaro, M. J. Bearpark, J. J. Heyd, E. N. Brothers, K. N. Kudin, V. N. Staroverov, T. A. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman and D. J. Fox, Gaussian 16 Rev. C.01, 2016.
41. S. Y. Park and D. J. Jang, J. Am. Chem. Soc., 2010, 132(1), 297–302,  DOI:10.1021/ja907491u.
42. S. Morpurgo, M. Bossa and G. Morpurgo, Adv. Quantum Chem., 2000, 36, 169–183,  DOI:10.1016/S0065-3276(08)60483-9.
43. Y. Zhao and T. Gennett, Phys. Rev. Lett., 2014, 112, 076101,  DOI:10.1103/PhysRevLett.112.076101.
44. S. Banerjee, A. Pabbathi, M. C. Sekhar and A. Samanta, J. Phys. Chem. A, 2011, 115(33), 9217–9225,  DOI:10.1021/jp206232b.
45. P. L. Silva, C. M. Silva, L. Guimarães and J. R. Pliego, Theor. Chem. Acc., 2015, 134, 1591,  DOI:10.1007/s00214-014-1591-5.
46. G. R. Fulmer, A. J. M. Miller, N. H. Sherden, H. E. Gottlieb, A. Nudelman, B. M. Stoltz, J. E. Bercaw and K. I. Goldberg, Organometallics, 2010, 29(9), 2176–2179,  DOI:10.1021/om100106e.
47. O. Levespiel, The chemical Reactor Omnibook, OSU Book Stores, Inc., Corvallis, Oregon, 1989, p. 2.3.
48. Sigma Aldrich, https://www.sigmaaldrich.com/MX/en/product/aldrich/343803, acceded on July 4th, 2024.
49. G. Aksnes and P. Froyen, Acta Chem. Scand., 1966, 20(6), 1451–1455,  DOI:10.3891/acta.chem.scand.20-1451.
50. M. Přádný and S. Ševčík, Makromol. Chem., 1985, 186(1), 111–121,  DOI:10.1002/macp.1985.021860111.
51. P. A. Mirau, Practical guide to understanding the NMR of polymers, John Wiley & Sons, 2005.
52. G. Nguyen, M. Matlengiewicz and D. Nicole, Analusis, 1999, 27(10), 847–853,  DOI:10.1051/analusis:1999152.
53. M. Baowei, L. H. Gan, Y. Y. Gan, X. Li, P. Ravi and K. C. Tam, J. Polym. Sci., Part A: Polym. Chem., 2004, 42, 5161–5169,  DOI:10.1002/pola.20228.
54. B. Mao, L. H. Gan, Y. Y. Gan, X. Li, P. Ravi and K. C. Tam, J. Polym. Sci., Part A: Polym. Chem., 2004, 42(20), 5161–5169,  DOI:10.1002/pola.20228.
55. E. Tang, K. Du, X. Feng, M. Yuan, S. Liu and D. Zhao, Eur. Polym. J., 2015, 66, 228–235,  DOI:10.1016/j.eurpolymj.2015.01.041.
56. M. Manguian, M. Save and B. Charleux, Macromol. Rapid Commun., 2006, 27(6), 399–404,  DOI:10.1002/marc.200500807.
57. L. Zhu, S. Powell and S. G. Boyes, J. Polym. Sci., Part A: Polym. Chem., 2015, 53(8), 1010–1022,  DOI:10.1002/pola.27529.
58. E. Tang, K. Du, X. Feng, M. Yuan, S. Liu and D. Zhao, Eur. Polym. J., 2015, 66, 228–235,  DOI:10.1016/j.eurpolymj.2015.01.041.
59. K. Nakatani, T. Terashima and M. Sawamoto, J. Am. Chem. Soc., 2009, 131, 13600–13601,  DOI:10.1021/ja9058348.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4re00406j

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