Synthesis of functional polyacrylamide (co)polymers by organocatalyzed post-polymerization modification of non-activated esters

The broad application of polyacrylamides (PAMs) has greatly promoted the development of new synthetic methods to prepare PAM-based functional (co)polymers regarding their traditional preparation via the direct polymerization of various acrylamide monomers. Herein, we have explored the post-polymerization modification of the poly(2,2,2-trifluoroethyl acrylate) (PTFEA) homopolymer, a typical non-activated ester, and various amines using the organo-catalytic system involving 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,2,4-triazole (TA). The reaction kinetics (e.g., the optimized reaction solvent, temperature, time, initial molar ratio of amines to esters and the molar ratio of DBU to TA) were carefully studied with the modulus substrate of iso-propylamine as the formed poly(iso-propyl acrylamide) (PNIPAM) representing the most investigated PAM. The full and partial amidation of the esters in PTFEA could be precisely regulated just by controlling the kinetic conditions to give (co)polymers with designable compositions and structures. We have demonstrated that the poly(N-acryloyl pyrrolidine) obtained by the post-polymerization modification of non-activated ester and pyrrolidine exhibited a noticeable phase transition, which confirmed the robustness and versatility of the post-polymerization modification. The described method paves the way for the synthesis of various (co)polymers with amide side chains from readily available polymer precursors.

Theato et al. reported the rst example of the activation of non-activated esters including poly(2,2,2-triuoroethyl methacrylate) (PTFEMA) and poly(methyl methacrylate) (PMMA) in the presence of the 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,2,4-triazole (TA) co-catalytic system. 33Herein, the nonactivated ester poly(2,2,2-triuoroethyl acrylate) (PTFEA) was chosen as the model ester with DBU and TA being the promoters to systematically explore the details (e.g., the reaction kinetics, the inuence of solvent, and reaction time, the initial molar ratio of amines to esters, the scope of amine) in the transformation of stable ester with a variety of functional primary or secondary amines (Scheme 1).Based on the exploration, the (co)polymers of PAMs were prepared and one thermosensitive homopolymer of poly(N-acryloyl pyrrolidine) was also prepared.We envision that this research could facilitate the preparation of PAM-based materials and advance the understanding of the transformation reaction between non-activated esters and amines.

Studying the reaction kinetics of the postpolymerization between PTFEA and amines
The PTFEA macromolecular precursor was rstly synthesized by traditional FRP, given its non-activated ester features (the pK a value is ∼23.5 in DMSO for CF 3 CH 2 OH 44 ) as well as structure similarity aer post-polymerization reactions with amines to PAMs.Although the uncontrollable polymerization process for traditional FRP generally suffers from high values of Đ in comparison with controllable FRP (e.g., ATRP and RAFT), the disadvantage was preferably utilized herein to further demonstrate the robustness and versatility of the protocol.Isopropylamine was selected as the substrate to evaluate the reaction kinetics of the post-polymerization reactions in the presence of the TA and DBU co-catalytic system due to the feasible detection of isopropyl groups in 1 H NMR spectra as well as the distinguishable signal position from that of the precursor.Samples were taken at regular time intervals during the kinetic experiments and analyzed by 1 H NMR to calculate the conversion of the esters (Fig. 1A).Remarkably, the peak intensity attributed to the methylene protons of -CF 3 CH 2 showed a gradual decrease alongside the reaction times (almost negligible aer 40 h) while the intensity of newly formed signals resulting from the methine and methyl protons of -NHCH(CH 3 ) 2 increased with the increasing reaction times.Additionally, the appearance of a signal assigned to the proton from -NHCH(CH 3 ) 2 indicated the formation of amide bonds in the post-polymerization reaction.
We then focused on the screening of the reaction conditions, such as solvent, temperature, time, catalyst loading, etc., to achieve high efficiency of ester conversion.Fig. 1B shows the inuence of solvent on the conversion of esters, and three kinds of solvents (1,4-dioxane, ACN and DMF) with different polarities were explored.The conversion of esters using DMF as the solvent was the highest, while that using 1,4-dioxane was the lowest for the same times, which is due to the better solubility of the formed PNIPAM in highly polar solvents.However, considering the higher boiling point of DMF that makes the removal process difficult, ACN was used as the solvent (the conversion of ester is a little lower than that in DMF).From Fig. 1B we also could conclude that the esters were almost transformed into amides within 40 h with iso-propylamine.
According to Theato's publication, 33 the initial molar ratio of DBU to TA plays a crucial role in determining the nal conversion of esters to amides.Fig. 1C displays the inuence of the initial molar ratio of amine to esters on the conversion of esters.It is noticeable that the conversion of esters in the presence of only DBU or TA seems particularly low (∼36% for DBU and ∼20% for TA).When DBU and TA were both added, the conversion increased sharply even with a ratio of DBU/TA = 1/1.Attractively, the conversions of esters showed an increment with increasing the ratio of DBU to TA, whereas the conversion of esters for 4 : 1 and 3 : 1 seemed the same, indicating the optimal ratio of 3 : 1 for DBU/TA.Aer that, the inuence of the initial ratio of DBU to TA was also estimated (Fig. 1D).Similar to the phenomenon in the screening of the DBU to TA ratio, the conversion of esters showed an increment with increasing the amine until a 6 : 1 ratio of amine to esters was reached.Although the conversion of esters increased with increasing the temperature (the data is not shown), room temperature was chosen as the reaction temperature due to the lower boiling point and instability of some amines at elevated temperatures.Based on the above results, the optimized reaction conditions for the post-polymerization of PTFEA with iso-propylamine are  as follows: the initial ratio of esters was DBU : TA : amine = 1 : 3 : 1 : 6 with ACN solvent and the initial concentration of ester was 1.0 mol mL −1 , which are selected reaction conditions for subsequent experiments.

Evaluating the scope of amines and preparing the (co) polymers of PAMs
Based on the reaction conditions established above, we then continued to explore the diversity of the DBU/TA catalytic postpolymerization modication of non-activated esters, aiming to prepare various PAAs.Table 1 summarizes the results of the obtained samples aer the transformation reaction of amines and PTFEA.Besides iso-propylamine, six commercially available amines were also tested, including primary (propylamine, cyclohexylamine, benzylamine and 1-cyclohexen-1ylethylamine), secondary (diethyl amine and pyrrolidine), aromatic (benzylamine) and cyclic amines (pyrrolidine), where the difference exists in the basicity, nucleophilicity and steric hindrance.Remarkably, the conversion of esters for the amines was higher than 97%, except for the benzylamine (∼89%) under our optimized conditions, suggesting the substrate diversity of the DBU/TA co-catalytic system for non-activated esters with quantied transformation.Moreover, there seemed to be no other side reactions, such as cross-linking, as the values of dispersity (Đ) of the isolated polymers showed little changes.(Fig. 2A), the methylene protons of the ethyl group (-N(CH 2 CH 3 ) 2 ) from poly(N,N-diethyl acrylamide) (Fig. 2B), the methylene protons adjacent to the nitrogen atom from poly(Nacryloyl pyrrolidine) (Fig. 2C), the methine proton of the cyclohexyl group from poly(N-cyclohexyl acrylamide) (Fig. 2D), the methylene protons of the benzyl group (-NHCH 2 Ph) from poly(N-benzyl acrylamide) (Fig. 2E) and the double bond proton of cyclohexene from poly(N-[(1-cyclohexen-1-yl)ethyl]-2acrylamide) (Fig. 2F).Although it is generally considered that the amidation between non-activated esters and amines by post-polymerization modication may be incomplete due to the macromolecular structure, the selected amines herein all performed with high efficiency to transform the esters in PTFEA, where the formed triuoroethanol and the DBU/TA co-catalysts promoted the transformation.
It is well known that the physical and chemical properties of PAMs are heavily dependent on the composition and structure of the macromolecules.Particularly, the lower critical solution temperature (LCST) or upper critical solution temperature (UCST) could be nely mediated by introducing hydrophilic or hydrophobic segments to PAMs, for example, the most studied one, PNIPAM. 45We then tried to prepare (co)polymers based on PNIPAM to further demonstrate the robustness of the DBU/TA co-catalytic post-polymerization modication of the nonactivated ester.Firstly, equimolar amounts of isopropylamine, propylamine, benzylamine and 1-cyclohexen-1ylethylamine were added (the total amount of amines to ester was also 6 : 1) to conduct the post-polymerization reaction, considering the different nucleophilicities of the selected amines.As shown in Fig. 3, the fraction of ester groups decreased with the reaction time, while iso-propylamine showed a faster rate of incorporation than the less nucleophilic propylamine, benzylamine and 1-cyclohexen-1-ylethylamine, 34,46 indicating the plausible preparation of PNIPAMbased (co)polymers using DBU/TA catalytic non-activated transformation of esters to acrylamides.
Regarding the high-efficiency transformation of esters to amides with iso-propylamine, it is possible to precisely regulate the composition of PNIPAM-based PAMs through postpolymerization modication.As shown in Scheme 2, the amidation was rstly carried out between PTFEA and iso-propylamine and then 1-cyclohexen-1-ylethylamine was used to transform the residual esters, where the double bonds could be further utilized.Based on the amidation kinetics of isopropylamine to esters, the transformation of esters to isopropyl acrylamides could be nely designed, depending on the reaction time.
Tables 2 and 3 summarize the results of the obtained PTFEAco-PNIPAM and poly(N-[(1-cyclohexen-1-yl)ethyl]-2-acrylamide)co-PNIPAM (co)polymers, respectively.As shown in Fig. 4A-C, the conversion of esters can reach ∼41%, 55% and 71% with reaction times of 4 h, 6 h and 14 h, respectively.However, the Đ values of the PAMs increased from 1.21 for PTFEA to around 1.40 for PTFEA-co-PNIPAM, which is due to the interaction between the column and PNIPAM.Aer the introduction of 1cyclohexen-1-ylethylamine, the signal due to the methylene protons of the triuoro ethyl groups around 4.47 ppm completely disappeared according to Fig. 4D-F, while the typical signal of double bonds from poly(N-[(1-cyclohexen-1-yl) ethyl]-2-acrylamide) appeared at 5.31 ppm.Thus, we could prepare PNIPAM-based PAMs from the non-activated esters by partial or full amidation and the composition and structure could be nely regulated.In addition, considering the wide scope of the utilized amines with DBU/TA co-catalysts, we envision that a variety of functional PAMs could be facilely synthesized.

Evaluating the scope of amines and preparing the (co) polymers of PAMs
We nally focused on the application of the post-polymerization modication of the DBU/TA-catalyzed amidation of nonactivated esters and amines.Poly(N-acryloyl pyrrolidine), a temperature-sensitive PAM with the LCST of around 50 °C, 47   prepared through the FRP of N-acryloyl pyrrolidine that is generally synthesized with pyrrolidine and acryloyl chloride (highly corrosive chemical), 48 was therefore prepared by the amidation of pyrrolidine and PTFEA herein to overcome the disadvantages of the traditional synthesis method.It is well known that phase separation is derived from the disparity between the dissolved polymers and solvents or the hydrophobic interaction. 49As shown in Fig. 5A, the aqueous solution of poly(N-acryloyl pyrrolidine) was transparent at room temperature and became an opaque solution by gradually elevating the solution temperature, which conrmed the occurrence of phase separation for the tested polymer.Attractively, the solution turned transparent again by gradually decreasing the temperature, indicating the reversible thermosresponsive phase transition.1][52] An endothermic peak was observed on the DSC curve (Fig. 5B) of the polymer obtained from the postpolymerization reaction, which indicated that the phase separation process undoubtedly occurs at this stage.
To further investigate the temperature sensitivity behavior of the obtained poly(N-acryloyl pyrrolidine), a temperature variation 1 H-NMR study was carried out.The proton signals of a molecularly dissolved polymer in the solvent can be detected and show a noticeable attenuation upon desolvation and can even collapse (aer phase transition) when the solution temperature is increased. 53As shown in Fig. 6, the solvation/ desolvation processes were well monitored by the temperature-variation 1   elevating the solution temperature, the signals of the polymer showed a discernible down-eld shi and the attenuation phenomenon could also be observed, undoubtedly testifying to the desolvation process (the phase transition) of the polymer by elevating the temperature.In addition, the 1 H NMR signal intensity gradually increased with the slow cooling of the same solution (data not shown).The results from DSC and temperature-variation 1 H NMR investigations indisputably corroborate the versatile and robust preparation of PAMs by the DBU/TA co-catalytic amidation of non-activated esters.Further studies on the detailed investigation of the phase transition behaviors of various functional PAMs and their applications are in progress in our lab.

Conclusion
In summary, we have surveyed the reaction kinetics for the DBU/TA co-catalytic post-polymerization modication of the non-activated ester of PTFEA and iso-propylamine and demonstrated that the esters could be fully or partially transformed into iso-propyl acrylamide in a controllable way based on the reaction kinetics.PNIPAM-based functional PAMs with pendant double bonds were also successfully synthesized by the straightforward post-polymerization modication reaction.The poly(N-acryloyl pyrrolidine) prepared by the amidation of PTFEA and pyrrolidine showed distinguishable phase transition behavior according to the DSC and temperature-variation 1 H NMR characterizations.Therefore, the DBU/TA co-catalyzed transformation of non-activated esters to acrylamide seems to be a plausible protocol to directly prepare diverse PAMs (co) polymers.

Characterizations
A Bruker AV400 NMR spectrometer was used to analyze the proton nuclear magnetic resonance ( 1 H NMR) of the samples while deuterated chloroform (CDCl 3 ) or dimethyl sulfoxide (DMSO-d 6 ) was used as the solvent with tetramethylsilane (TMS) as the internal standard.The apparent number-average molecular weight (M n,SEC ) and Đ of the puried sample precursors were recorded on a size exclusion chromatograph (SEC, Waters) equipped with a 1515 pump and a 2414 differential refractive index detector with THF or dimethylformamide (DMF) (Aladdin, HPLC) eluent at a ow rate of 1.0 mL min −1 (35 °C).All the samples were dissolved in the eluent at a concentration of 5.0 mg mL −1 and then a 0.40 mm hydrophobic membrane was used to lter the solution.The experimental molecular weights were calculated according to a standard  curve using a series of monodisperse polystyrenes as the standard samples.Fourier-transform infrared (FT-IR) spectra were recorded on an FT-IR-Digilab FTS3100 spectrometer with potassium bromide (KBr) pellets.Differential scanning calorimetry (DSC) was conducted on a Mettler Toledo DCS 3 machine under a nitrogen ow of 50 mL min −1 .The experimental temperature was lowered to 5 °C and maintained for another 5 min.Subsequently, it was reheated to 80 °C at a rate of 2 °C min −1 and the phase change temperature was dened as the transition center of the DSC curve.The typical procedure for the traditional free-radical polymerization of TFEA using AIBN as the initiator is as follows.AIBN (53.3 mg, 0.325 mmol, 1 equiv.)and TFEA (5.0 g, 32.5 mmol, 100 equiv.)were added to a Schlenk reactor lled with 10 mL of puried THF.The solution was then degassed in three freeze-pump-thaw cycles before being placed into an oil bath at 70 °C.Aer polymerization for 10 h, the mixture was added to n-hexane dropwise and then the ltrate was collected (two times).Finally, the solid was dried in a vacuum oven at 40 °C for 24 h to give viscous PTFEA (M n,SEC = 8800 g mol −1 , Đ = 1.32). 1  The typical procedure for the post-polymerization reaction of PTFEA with an amine is carefully described as follows: PTFEA (135 mg, 1 mmol, 1 equiv.),TA (69 mg, 1 mmol, 1 equiv.),DBU (456 mg, 3 mmol, 3 equiv.)and iso-propylamine (354 mg, 6 mmol, 6 equiv.)were added sequentially to a ask lled with 5 mL of acetonitrile (ACN).A portion of the mixture was withdrawn for the characterization to survey the reaction kinetics at different times, e.g., 1 H NMR and SEC.Aer the designated time, 10 mL dichloromethane (DCM) was added and the solution was extracted with 1 M HCl (aq.) 3 times.The organic phase was collected, dried with MgSO 4 and then concentrated.The remaining mixture was poured into a large excess of n-hexane, decanted and dried in a vacuum oven at 40 °C for 24 h to give white solid poly(N-isopropylacrylamide) (PNIPAM).Other postpolymerization reactions with single amine were prepared in a similar procedure and the results are summarized in Table 1 and Fig. 2 (PNIPAM, M n,SEC = 9400 g mol −1 , Đ = 1.45). 1  4.3.3.Post-polymerization modication of PTFEA with different amines.The typical process for the postpolymerization reaction of PTFEA with iso-propylamine and 1cyclohexen-1-yl-ethylamine is carefully described herein: PTFEA (270 mg, 2 mmol, 1 equiv.),TA (138 mg, 2 mmol, 1 equiv.),DBU (912 mg, 6 mmol, 3 equiv.)and iso-propylamine (708 mg, 12 mmol, 6 equiv.)were added to a ask lled with 10 mL of ACN.Aer the designated time, the unreacted amine was expelled under reduced pressure.Subsequently, 1-cyclohexen-1ylethylamine (756 mg, 6 mmol, 6 equiv.to PTFEA) was added to the ask at room temperature for 24 h.The reaction mixture was treated similarly to the method described above to give random copolymer poly(N-[(1-cyclohexen-1-yl)ethyl] acrylamide) x -co-PNIPAMy, Fig. 6), where x and y are the molar fractions of the amines in the attained polymers. 1

Scheme 1
Scheme 1 Schematic illustration of the transformation reaction of esters and amines.

Fig. 1
Fig. 1 Kinetics studies of the post-polymerization modification of PTFAE and iso-propylamine: (A) the evolution of the 1 H NMR spectra with time, (B) screening of solvents, the influence of the initial molar ratio of (C) amine to esters and (D) DBU to TA on the reaction.

Fig. 2
shows the 1 H NMR spectra of the puried polymers aer post-polymerization with various amines.The proton signals located at 3.20, 3.35, 3.40, 3.72, 4.24 and 5.31 ppm were assigned to the typical peaks of the methylene protons adjacent to the amide (-NHCH 2 CH 2 CH 3 ) from poly(N-propyl acrylamide)

4. 1 . Materials 2 , 2 , 2 -
Triuoroethyl acrylate (TFEA) from Aldrich was passed through a column lled with basic aluminum oxide before use.Azodiisobutyronitrile (AIBN) from Aladdin was recrystallized with ethanol three times and stored at −10 °C.Tetrahydrofuran (THF) (Tianjin Chemical Reagent Co., Ltd China) was freshly distilled from sodium/benzophenone mixture under a protective nitrogen atmosphere.Other reagents from Aladdin or TCI were used as received.

Fig. 5 (
Fig. 5 (A) Illustration of the phase transition upon heating and cooling the aqueous solutions of poly(N-acryloyl pyrrolidine) obtained from the post-polymerization reaction (25 to 40 °C), and (B) the DSC thermogram.

Table 1
Results of the post-polymerization modification with various amines a Reaction conditions: 6 equiv. of amine to esters, DBU : TA = 3 : 1 (molar ratio) in ACN at room temperature for 48 h.b Determined by SEC.c Determined by 1 H NMR.