Mechanistic study of transesterification in TBD-catalyzed ring-opening polymerization of methyl ethylene phosphate

European Polymer Journal 118 (2019) 393–403

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Mechanistic study of transesterification in TBD-catalyzed ring-opening polymerization of methyl ethylene phosphate

T

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Ilya E. Nifant'eva,b, , Andrey V. Shlyakhtina, Alexander N. Tavtorkina,b, Maxim A. Kosareva, Dmitry E. Gavrilova, Pavel D. Komarovb, Sergey O. Ilyinb, Stanislav G. Karchevskyc, Pavel V. Ivchenkoa,b a

M.V. Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory 1–3, Moscow 119991, Russian Federation A.V. Topchiev Institute of Petrochemical Synthesis RAS, Leninsky Avenue 29, Moscow 119991, Russian Federation c Joint-stock Company “Institute of Petroleum Refining and Petrochemistry”, Iniciativnaya Str. 12, Ufa 450065, Republic of Bashkortostan, Russian Federation b

A R T I C LE I N FO

A B S T R A C T

Keywords: Ring-opening polymerization Polyphosphates TBD DFT Transesterification Branched polymers

It is well known that ring-opening polymerization (ROP) of sterically unhindered cyclic ethylene phosphates, initiated by both organocatalysts and coordination catalysts, is accompanied by transesterification (TE) even at subzero temperatures. To clarify this phenomenon from the mechanistic point of view, we calculated (DFT, B3PW91/DGTZVP) the reaction profiles of the ROP for 2-methoxy-1,3,2-dioxaphospholane-2-oxide (methyl ethylene phosphate, MeOEP) and of the transesterification processes for poly(MeOEP) and trimethyl phosphate (TMP) in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) organocatalyst. We found that the free activation energy of TE is substantially higher (10–13 kcal/mol) than the ROP activation barrier. To verify the calculation results, we investigated the chemical behavior of low molecular weight trimethyl phosphate (TMP) in the TBD-catalyzed polymerization of MeOEP. We demonstrated that TMP was not affected by transesterification, which correlates with the calculation results. However, we found that the polymerization of MeOEP in the presence of TMP leads to the formation of linear poly(MeOEP) with given Pn and narrow MWD even at > 99% monomer conversion degree. A similar pattern was revealed for the synthesis of poly(MeOEP) with the coordination catalyst of aryloxy-alkoxy magnesium complex [(BHT)Mg(μ-OBn)(THF)]2 (BHT = 2,6-di-tert-butyl-4-methylphenoxy). To explain the difference in the chemical behavior of TMP and polyphosphate, we assumed that poly(MeOEP) in the solution represents a dense globule, which leads to a decrease in the entropy of transesterification. To confirm this assumption, we studied the solution behavior of poly(MeOEP) in CHCl3 and in TMP. Both CHCl3 and TMP were found to be poor solvents for poly(MeOEP) in terms of KMH solution theory (α = 0.53 and 0.33, respectively). We assume that it is the conformation of the polymer in the solution that determines the tendency of the polyphosphate towards transesterification.

1. Introduction Poly(ethylene phosphates) (PEPs, Scheme 1a) are attractive for biorelated fields due to their biodegradability, biocompatibility, and structural similarity to nucleic and teichoic acids [1–10]. PEPs are usually obtained by ring-opening polymerization (ROP) of cyclic ethylene phosphate monomers (CEPMs, Scheme 1A). It was demonstrated that 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) [8,11–25], imidazoline carbenes (IC) [13], 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) [11–13,15,26–30] and alkoxy complexes of main group metals [27,31–43] effectively catalyze the polymerization of CEPMs

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(Scheme 1B, C). For sterically unhindered alkyl ethylene phosphates, e.g., methyl ethylene phosphate (MeOEP), the broadening of MWD [13,12] and the formation of branched [12,27] and macrocyclic [13,32] products complicate the polymerization. Even at subzero temperatures, transesterification increased after the complete monomer conversion regardless of the type of the catalyst used [12,13,27,32,42]. At first, this phenomenon can be explained by the “living” nature of the polymer and proximity of activation barriers for transesterification and ROP, just as the formation of macrocyclic products in the polymerization of lactones and lactides was interpreted [44,45]. To clarify the reasons for transesterification, we studied the

Corresponding author at: Leninskie Gory 1–3, Moscow 119991, Russian Federation. E-mail address: [email protected] (I.E. Nifant'ev).

https://doi.org/10.1016/j.eurpolymj.2019.06.015 Received 16 February 2019; Received in revised form 22 May 2019; Accepted 12 June 2019 Available online 13 June 2019 0014-3057/ © 2019 Elsevier Ltd. All rights reserved.

European Polymer Journal 118 (2019) 393–403

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Toluene was refluxed with Na/benzophenone/dibenzo-18-crown-6, distilled and stored under an argon atmosphere. Diethyl ether (Et2O), tetrahydrofuran (THF), and triethylamine (Et3N) were refluxed with Na/benzophenone and distilled prior to use. Heptane and pentane were refluxed for 10 h over sodium and then distilled and stored under an argon atmosphere over sodium. Methanol was refluxed and distilled over magnesium methoxide. CH2Cl2 was refluxed with CaH2, distilled and stored over 4 Å molecular sieves. Benzyl alcohol (BnOH, Acros, 99%) was distilled over BaO and stored under argon. N,N-dimethylformamide (DMF, Sigma-Aldrich, LC grade) and ε-caprolactone (εCL, Sigma-Aldrich, 99.5%) were distilled under reduced pressure and stored under an argon atmosphere. Mono-methoxy substituted poly (ethylene glycol) (MPEG-2000, Sigma-Aldrich) was stirred at 80 °C for 24 h in vacuo (0.01 Torr). Acetic acid, guanidine hydrochloride, bis(3aminopropyl)amine and di-n-butylmagnesium (1.0 M solution in heptane) were used as purchased (Sigma-Aldrich). 2-Chloro-2-oxo-1,3,2dioxaphospholane [27,62], polymerization grade MeOEP [27,63], TBD [52,64] and the single-component coordination catalyst Mg1 with the formula [(BHT)Mg(μ-OBn)(THF)]2 [65] were prepared according to previously described methods (for details, see Appendix A2 in the Supplementary data). 2.3. Polymerization experiments Scheme 1. (A) Synthesis of PEPs; (B) organocatalysts and (C) coordination catalysts used for CEPM polymerization.

2.3.1. Homopolymerization of MeOEP with TBD as a catalyst MeOEP (2.265 g, 16.41 mmol), BnOH (17.7 mg, 0.164 mmol) and TMP (2.321 g, 16.56 mmol) were placed into a flame-dried vial equipped with a magnetic stirrer and septum, and dry CH2Cl2 (2.4 mL) was added. The polymerization was initiated by rapid addition of TBD solution in dry CH2Cl2 (22.7 mg, 0.164 mmol in 0.9 mL) at −20 °C to produce a 2 M MeOEP concentration. The polymerization was terminated after the given time interval by the addition of an excess of acetic acid in CH2Cl2. The monomer conversion was determined using 31P NMR spectroscopy by integration of the monomer (δ = 18.6 ppm) and polymer (δ = –0.19 ppm) resonance signals. The polymer was precipitated twice using a 5-fold excess of dry diethyl ether. The precipitated polymer was redissolved in dry CH2Cl2, and the solvents were removed in vacuo. The yield was 2.12 g (93%). The experiments in the absence of TMP were performed by the same methods with the addition of equimolar amounts of trimethyl phosphate before the injection of TBD. Note that the separation of the poly(MeOEP) prepared in the presence of TMP required repeated precipitation from Et2O to remove the traces of trimethyl phosphate. The protocols of experiments at 50:1 and 200:1 monomer/TBD ratios and the preparation of poly(MeOEP) samples for viscometry experiments are provided in Appendix A4 in the Supplementary data.

polymerization of 2-methoxy-1,3,2-dioxaphospholane 2-oxide (methyl ethylene phosphate MeOEP, Scheme 1a, R = Me) and the transesterification of poly(MeOEP) and trimethyl phosphate (TMP) in the presence of TBD. The choice of TBD was due to the high activity and versatility of this catalyst, as well as the proof and detailed study of TBD-catalyzed polymerization mechanisms for traditional monomers such as lactones, lactides, and cyclic carbonates [46–52]. The results of our work, including the DFT modeling of the TBD-catalyzed ROP of MeOEP and transesterification of polyphosphate, the experiments on MeOEP polymerization in the presence and in the absence of TMP, as well as the study of the rheology of poly(MeOEP) solutions in organic solvents, have led us to the conclusion that the high rate of poly (MeOEP) transesterification is caused by the dense character of the polyphosphate globule in the reaction media. 2. Experimental section 2.1. DFT calculations The molecular structures of stationary points and transition states were optimized using density functional theory (DFT). The Gaussian 09 program was used in all single-point calculations [53]. B3PW91 hybrid functional and DGTZVP basis set [54,55] were used in the optimization. The B3PW91 functional was successfully used earlier in the modeling of ROP of cyclic esters [56–61] and MeOEP catalyzed by magnesium complexes [43]. The optimization of stationary points geometry, frequency analysis, and calculations of entropy corrections were made for the gas phase at 298.15 K. Transition states were found directly by Berny optimization and confirmed by relaxation to different stationary structures after changing key geometric parameters with a step size of ± 0.01 Å. Details of DFT modeling are presented in Appendix A1 in the Supplementary data.

2.3.2. Homopolymerization of MeOEP with Mg1 complex as a catalyst MeOEP (1.381 g, 10.0 mmol) and TMP (1.401 g, 10.0 mmol) were placed into a flame-dried vial equipped with a magnetic stirrer and septum, and dry CH2Cl2 (2.0 mL) was added. The polymerization was initiated by rapid addition of Mg1 solution in dry CH2Cl2 (84.6 mg, 0.1 mmol, 0.2 mmol Mg) at −20 °C to produce a 2 M MeOEP concentration. Termination of the polymerization and separation of the product were performed as described above. The examples of NMR spectra of poly(MeOEP) are presented in Appendix A4 in the Supplementary data. 2.4. Polymer analysis CDCl3 (Cambridge Isotope Laboratories, Inc., D 99.8 atom%) was used as purchased. The 1H and 31P NMR spectra were recorded on a Bruker AVANCE 400 spectrometer (400 MHz) at 20 °C. Mn (NMR) values of polyphosphates were calculated using integral intensities of PhCH2O (δ = 5.07 ppm, 2H) [PhCH2O] and eOCH2CH2Oe (δ = 4.24 ppm, 4H) [OCH2CH2O] by formula (1).

2.2. Solvents, reagents and catalysts All of the synthetic and polymerization experiments were conducted under an argon atmosphere. Commercially available solvents and reagents were purchased from Sigma-Aldrich (Merck KGaA group). 394

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Mn (NMR) =

I [OCH2 CH2 O] × MMon + 108.13 2I [phCH2 O]

cyclic esters. Both mechanisms are feasible for ethylene phosphate ROP (Scheme 2, ways A and B, respectively), but the “amide” mechanism for the ROP of ethylene phosphates was proposed earlier [1,12,67]. We performed DFT modeling of TBD-catalyzed reaction of MeOEP with EtOH for both alternative mechanisms. The comparison of the reaction profiles of “amide” (Fig. 1, left) and “donor-acceptor” (Fig. 1, right) pathways demonstrates that the “donor-acceptor” mechanism is highly favorable and that the difference in activation barriers is ∼26 kcal/mol. More detailed discussion of the modeling of mechanisms A and B is provided in Appendix A1 in the Supplementary data. Note that “amide” mechanism involves the coordination of the oxygen atom of 1,3,2-dioxaphospholane. But, DFT calculations predict the formation of MeOEP–TBD complex with P = O⋯HeN bonding. We detected the formation of TBD–TMP complex when TMP was added to TBD solution in C6D6. After several hours, this complex formed N-methyl-TBD and dimethyl phosphate. The results if these experiments are presented in Appendix A3 in the Supplementary data.

(1)

where 108.13 is the MW of PhCH2OH. Mn (theor) was calculated by formula (2).

Mn (theor ) =

[Mon] × MMon × Conv + 108.13 [Cat ]

(2)

where [Mon] is an initial MeOEP concentration, [Cat] is an initial concentration of the catalyst, TBD/BnOH or 0.5 × [Mg1] due to monomeric nature of catalytic species in BHT-Mg catalyzed ROP of MeOEP [43], Conv is a monomer conversion determined by the integration of the signals of monomer and polymer in the 31P NMR spectra. The amount of branches in poly(MeOEP) was determined using 31 P NMR spectroscopy by integration of the resonance signals of branched (δ 1.2 ppm) and unbranched (δ −1.4 ppm) phosphorus atoms. Size-exclusion chromatography (SEC) of the polymers was performed in dimethylformamide (DMF) containing 0.1 g/L lithium bromide at a flow rate of 1 mL/minute at 50 °C using an Agilent PL-GPC 220 instrument with refractive index detector (Agilent Technologies, CA, USA) equipped with Styragel HR 5E 7.8 × 300 mm column (Waters, MS, USA). PEG standards were used for calibration.

3.2. TBD-catalyzed transesterification Two fundamentally different transesterification mechanisms of poly (MeOEP) are possible (Scheme 3) [12,27]. “Scission” (Scheme 3, route A) results in the formation of a new linear polymer and macroinitiator. “Branching” (Scheme 3, route B) results in the formation of a branched polymer and methoxy initiator. The methoxy initiator can react with polyphosphate, yielding a low MW polymer with –OP(O)(OMe)2 endgroup and macroinitiator (Scheme 3, route C). If the “scission” pathway is preferred, we do not observe any visible changes in the NMR spectra of the polymer, but we do detect the change in its molecular weight and the increase of the polymer dispersity ÐM. If transesterification proceeds along the “branching” pathway, the product contains equal amounts of e(OCH2CH2O)3P(O)e internal fragments and eOCH2CH2OP(O)(OMe)2 end-fragments which can be easily detected by 31P NMR spectroscopy [27]. In view of Scheme 3, DFT modeling of the entire set of the processes occurring in the TBD–initiator–MeOEP reaction mixture can be performed by considering two types of initiators (the macroinitiator and the methoxy initiator) and two types of substrates (the MeOEP monomer and the polyphosphate chain fragment). In our calculations, we used HOCH2CH2OP(O)(OMe)2 as a model of the macroinitiator and MeOP(O)[OCH2CH2OP(O)(OMe)2]2 as an “opened polymer chain”

2.5. Viscometry Viscosity measurements were performed using three techniques. The standard Ubbelohde viscometer (capillary method), DHR-2 rheometer (TA Instruments, DE, USA, rotational viscometry method), and LOVIS 2000 ME viscometer integrated with a DMA 4100 M densimeter (Anton Paar, Graz, Austria, rolling-ball method with 50° capillary tilting angle) were used. The measurements were performed at 20 °C for polymer concentrations in the range 5–50 mg/mL. Viscosity parameters were calculated in the framework of Kuhn-Mark-Houwink theory of polymer solutions [66], see Section 3.4. 3. Results and discussion 3.1. DFT modeling of TBD-catalyzed ROP of MeOEP Two reaction mechanisms, “amide” [46–48] and “donor-acceptor” [49–52], were proposed earlier for the TBD-catalyzed polymerization of

Scheme 2. “Amide” (A) and “Donor-acceptor” (B) mechanisms for the TBD-catalyzed ROP of MeOEP. 395

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Fig. 1. Energy profile obtained by DFT calculations of TBD-catalyzed ring-opening ethanolysis of methyl ethylene phosphate MeOEP for mechanisms A (- - - - - dark gray, left) and B (— black, right) and molecular structures of the key transition states (bond lengths and interatomic contacts are provided in Å).

relative inertness of poly(MeOEP) and TMP in transesterification (ΔG≠ > 30 kcal/mol). The results of calculations contradict the experimental observations: we have shown previously that TBD-catalyzed ROP of MeOEP is accompanied by a transesterification with the formation of branched poly(MeOEP) even at −20 °C [27]. A possible reason for the divergence between the results of DFT calculations and experimental observations may be the technical imperfection of the modeling when comparing the mechanisms of ROP and transesterification. To confirm or discard this reason, we studied the polymerization of MeOEP in the presence of TMP, taking into account the proximity of the calculated ΔG≠ values for transesterification of polyphosphate and trimethyl phosphate. In the event that our estimation of ΔG≠ is incorrect, TMP must undergo the transesterification to form the products of polymer scission containing CH2OP(O)(OMe)2 fragments that can be easily detected by 31P NMR spectroscopy. We performed two comparative polymerization experiments at −20 °C with the MeOEP/catalyst ratio 100:1 in the presence and in the absence of TMP. We found that even after 1 h, the transesterification with TMP does not occur at all. Moreover, the poly(MeOEP) obtained exhibited a narrow MWD (ÐM = 1.12), and the Mn value determined by

model of the polyphosphate fragment. In addition, we calculated the reaction profile for the reaction of the macroinitiator with trimethyl phosphate TMP. The OCH2CH2OP(O)(OMe)2 fragment is able to undergo additional bonding between the phosphate oxygen atom and TBD through a formation of chelate (stationary point I-4B, Scheme 2). We considered such a complex as a common ground state for all reactions studied (Scheme 4). Stationary points and transition states for the ROP of MeOEP and transesterification of the polyphosphate chain fragment and TMP are similar to those presented in Scheme 2B. We found that the reaction profiles for the transesterification of MeOP(O)[OCH2CH2OP(O) (OMe)2]2 by “branching” and “scission” (Fig. 2, right), as well as for transesterification of TMP (Fig. 2, left), appear to be the same. All TE profiles are markedly different from the profile of the ROP of MeOEP (Fig. 2, left), and the free activation energy of the ROP is 10–13 kcal/ mol lower than the free activation energies of the transesterification reactions. The calculated value of the activation barrier of MeOEP polymerization (ΔG≠ ∼20 kcal/mol) corresponds to the rapid process that was observed in practice [27]. However, the calculations predict

Scheme 3. “Scission” (A, C) and “branching” (B) transesterification pathways for poly(MeOEP). 396

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Scheme 4. Common ground state and starting stationary points for the TBD-catalyzed ROP of MeOEP (A), reaction with TMP (B) and transesterification (C, D).

phenomenon, we performed comparative experiments on the polymerization of MeOEP at a lower monomer/catalyst ratio (50:1), in which the complete conversion of the monomer was achieved in a short time (Table 1, runs 3–6); in other words, the probability of transesterification was higher at lower monomer/catalyst ratios. We even found that the polymerization of MeOEP in the presence of TMP was not accompanied by any transesterification whatsoever. Even 45 min after the full conversion of MeOEP (Table 1, run 6), the polymer retained a linear structure characterized by a narrow MWD (ÐM = 1.14), and the 31P NMR spectrum of this polymer did not contain the signals of eOP(O)

SEC (Table 1, run 1) was close to the calculated molecular weight. The poly(MeOEP) obtained in the control experiment under the same conditions without the addition of TMP (Table 1, run 2) was highly branched and characterized by broadened MWD (ÐM = 1.33). Thus, we experimentally demonstrated the chemical inertness of TMP under the mild reaction conditions, and these results correlated with the results of DFT modeling. The formation of completely linear, branching-free polymers with narrow MWD at full monomer conversion in the presence of TMP is a remarkable experimental fact. For a more detailed study of this

Fig. 2. Calculated energy profiles of the TBD-catalyzed ROP of MeOEP and the transesterification of TMP and poly(MeOEP) in G scale (- - - -) and in H scale (——). 397

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Table 1 TBD-catalyzed homopolymerization of MeOEP (−20 °C, [MeOEP] = 2 M in CH2Cl2). Run

Cat.a)

Mon/Cat/TMP ratio

React. time, min

Conv., %b)

Mntheo × 103,c)

Mn × 103 (NMR)d)

Mn × 103 (SEC)e)

ÐMe)

Linear/branched phosphate ratiof)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

TBD TBD TBD TBD TBD TBD TBD TBD TBD TBD TBD TBD TBD Mg1 Mg1 Mg1 Mg1 Mg1

100:1:100 100:1:0 50:1:50 50:1:50 50:1:50 50:1:50 50:1:0 50:1:0 50:1:0 50:1:0 50:1:5 200:1:200 200:1:0 50:1:50 g) 50:1:50 50:1:50 50:1:50 50:1:0

60 60 1 5 15 60 1 5 15 60 15 60 60 1 5 15 60 60

> 99 > 99 73 89 99 > 99 97 99 > 99 > 99 99 99 > 99 99 > 99 > 99 > 99 > 99

13.91 13.91 5.14 6.52 6.93 7.00 7.01 6.97 6.63 7.13 6.93 27.44 29.61 6.87 7.01 7.01 7.01 7.01

14.7 14.3 4.6 6.4 6.9 7.7 6.9 6.9 7.1 6.8 6.9 28.0 27.3 6.4 6.8 6.4 6.9 6.5

12.3 12.6 4.8 6.0 6.8 6.9 7.5 8.1 8.4 8.5 8.8 21.5 27.3 6.4 7.1 6.9 7.4 7.7

1.14 1.33 1.12 1.13 1.13 1.14 1.21 1.26 1.31 1.44 1.28 1.15 1.28 1.19 1.21 1.20 1.23 1.45

> 200 17 > 200 > 200 > 200 ∼200 > 200 95 52 17 > 200 > 200 26 > 200 > 200 > 200 200 18

a) b) c) d) e) f) g)

TBD was used with BnOH initiator in 1:1 ratio, Mg1 is a single-component catalyst. Determined by the integration of monomer and polymer signals in 31P NMR spectra of the reaction mixtures. Calculated by the formula (2), see Section 2.4. Calculated by the formula (1), see Section 2.4. Size exclusion chromatography data (DMF). Determined by comparative integration of the signals of branched (δ −1.5 ppm) and unbranched (δ −0.2 ppm) phosphorus atoms in Molar ratios based on 1 mol of Mg. For experimental details, see Section 2.2 and Appendix A4 in the Supplementary data.

31

P NMR spectra.

according to which the difference in ΔG≠ for the ROP of MeOEP and TE of TMP has a value of ∼13 kcal/mol. However, the calculated difference of ΔG≠ for the ROP of MeOEP and transesterification of poly (MeOEP) is 10–12 kcal/mol, and the reasons for rapid transesterification at the final stages of polymerization still remain unclear.

(OMe)2 end-fragments. However, in the absence of TMP at −20 °C after 1 min of the reaction (Table 1, run 7), a weakly branched polyphosphate with broadened MWD (ÐM = 1.21) was formed. A significant number of branches was recorded in the 31P NMR spectra after 5 min, when the full conversion of the monomer was reached. After that, the number of branches increased, reaching the level of ∼ 6% after 1 h, and the broadening of MWD accompanied the growth of branching (Table 1, runs 8–10). Note that multiple accelerations of transesterification at high levels of cyclic phosphate conversion were noted earlier in many publications [14,26,27]. From a practical point of view, the use of 1:1 TMP/MeOEP ratios makes it difficult to isolate the polymer. We performed the experiment at 1:10 TMP/MeOEP ratio and obtained highly linear polymer (Table 1, run 11). The NMR spectra of polymer samples corresponding to runs 5, 9 and 11 (Table 1) are presented in Fig. 3. The figure shows that the 31P NMR spectrum of the poly(MeOEP) sample that was prepared in the absence of TMP contains additional signals at δ = 1.17 and −1.39 ppm (Fig. 3A), which are related to CH2OP(O)(OMe)2 and (CH2O)3P(O) fragments, respectively [27]. The presence of CH2OP(O)(OMe)2 endfragments was also detected in the 1H NMR spectrum of this sample. These additional signals are negligible in the spectra of linear poly (MeOEP) samples obtained in the presence of TMP (Fig. 3B and C). These samples differ significantly in dispersity: poly(MeOEP) obtained at 1:10 TMP/MeOEP ratio had broadened MWD and substantially higher Mn presumably because of the transesterification via the scission pathway. Note that such signals are also absent in the NMR spectra of polyphosphate obtained at the initial stages of ROP in the absence of TMP (run 7). The impact of TMP can be clearly illustrated by the SEC traces of poly(MeOEP) samples 3–10 (Fig. 4A and B). Similar results were obtained at higher MeOEP/TBD ratios (200:1, Table 1, runs 12 and 13). A linear polymer of the composition BnO (MeOEP)200OH was obtained in the presence of TMP at full monomer conversion, and the ÐM value was 1.15. The polymer BnO (MeOEP)200OH, which was synthesized in the absence of TMP, contained a considerable number of branches and had a highly broadened MWD. Thus, we have demonstrated the inertness of TMP in the reaction mixture containing TBD and ROH initiator. This experimental fact correlates with the results of the comparative DFT simulations,

3.3. Preparation and transesterification of poly(MeOEP) in the presence of coordination catalyst We also investigated the polymerization of MeOEP in the presence of TMP at −20 °C in the presence of the coordination catalyst, aryloxyalkoxy magnesium complex [(BHT)Mg(OBn)(THF)]2 (Mg1, Scheme 1C). This highly active single-component initiator was successfully used earlier in the synthesis of ethylene phosphates, phosphonates and phosphoramidates [27,42,43,68]. The results of these experiments are also presented in Table 1. In the presence of TMP (Table 1, runs 14–17) the polymer samples with narrow MWD were obtained. These polymers did not contain branches or eOP(O)(OMe)2 end-groups. A minor broadening of MWD in comparison with experiments with TBD catalyst (Fig. 4C) is due to the specific mechanism of the ROP of MeOEP initiated by Mg1 [43]. In contrast, in the absence of TMP after 1 h (Table 1, run 18) the polymer with broadened MWD (ÐM = 1.45) was obtained. This polymer contained ∼5% branched fragments. Thus, the coordination catalyst Mg1 and organocatalyst TBD demonstrated similar chemical behavior in polymerization experiments. Given that ROP and TE catalyzed by TBD (this work) and Mg1 [43, Data in Brief] have different reaction mechanisms, it can be proposed that the ease of transesterification of polyphosphate is due to a common factor that does not depend on the type of catalyst. We assume that the solution conformation of poly (MeOEP) may represent such a factor. 3.4. Viscometry of poly(MeOEP) solutions To study the behavior of poly(MeOEP) in solution, we synthesized six samples of linear polymers (Table 2, for details see Section 2.4 and Appendix A4 in the Supplementary data). Polymerization was performed in CH2Cl2 at −20 °C, and the required degree of polymerization of MeOEP was specified by the monomer/catalyst ratio. To simplify the 398

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Fig. 3. Fragments of 1H (left) and 31P (right) NMR spectra of reaction probes of the TBD-catalyzed polymerization of MeOEP at −20 °C after 15 min in the absence (A, run 5) and in the presence of TMP at 1:10 (B, run 11) and 1:1 (C, run 9) TMP/MeOEP initial molar ratios.

TMP is a “good” solvent (similia similibus solvuntur), and the introduction of TMP into the reaction mixture causes the swelling of the dense globule with a formation of polymer solutions containing poly(MeOEP) macromolecules in random-coil conformations. To test this assumption, we studied the solution behavior of the same samples of poly(MeOEP) in trimethyl phosphate (Table 2). Quite unexpectedly, the TMP in relation to the poly(MeOEP) is an even more “poor” solvent than CHCl3 (α = 0.33, Fig. 5, right). Thus, during the study of the viscosity of poly (MeOEP) solutions, we found that this polymer forms polymer globules in both CHCl3 and TMP. According to the calculated reaction profiles (Fig. 2), MeOEP, TMP and the fragment of the poly(MeOEP) chain exhibit the same ability to coordinate TBD molecules. The values of the free activation energy of transesterification for TMP and MeOP(O)[OCH2CH2OP(O)(OMe)2]2 are also close. However, the open polymer chain model used in the evaluation of the activation barrier of polyphosphate transesterification does not take into account the possibility of attractive interaction between the fragments of macromolecules with a formation of polymer globules. The contribution of such interactions is able to reduce the entropy component of the free activation energy. If ΔS≠ is approaching zero, the ΔH≠ is approaching ΔG≠ in its value, and the reaction profile of the ROP in the G scale is moving closer to the profiles of the transesterification of the polyphosphate in the H scale. This effect is illustrated in Fig. 2 for calculated reaction profiles of MeOEP polymerization (left, in black) and poly(MeOEP) transesterifications (right). At the same time, the entropy contribution is maintained for the transesterification of TMP, and the activation barrier remains substantially higher than the ROP activation barrier (the difference in free energies is 12.6 kcal/mol, Fig. 2, left, in blue). Such a noticeable gap leads to the chemical inertness of trimethyl phosphate. Thus, the most likely reason why TMP prevents transesterification is the ability of low

procedure of polymer separation, the reactions were stopped before reaching full MeOEP conversion, which allowed us to obtain poly (MeOEP) samples with narrow MWD without the addition of TMP. CHCl3 was chosen as a solvent that simulates reaction conditions due to its lower volatility in comparison with CH2Cl2, which was acceptable for measurements by the methods used for viscometry (see Section 2.5). We determined the relative viscosities of the solutions of poly(MeOEP) with a molecular weights from 2.6 to 20.5 kDa in the concentration range from 0 to 0.05 M at 20 °C. The data obtained were interpreted in the framework of Kuhn-Mark-Houwink theory using the Eqs. (3) and (4). α [η] = K × Mvis

or

ln[η] = ln K + α × ln Mn

ηr − 1 = [η] + kH [η]2 c + … c

(3) (4)

where [η] – intrinsic viscosity, Mvis – viscometric molecular weight (for ÐM ∼ 1, Mvis = Mn), K and α – empirical parameters describing the polymer–solvent system at a given temperature, c – polymer concentration, ηr – relative viscosity, and kH is Huggins viscometric parameter (4). The results of measurements and calculations are also given in Table 2. The dependence of the characteristic viscosity of poly(MeOEP) solutions on the molecular weight of polymers is presented in Fig. 5 (left). The set of Kuhn-Mark-Houwink scaling relations exhibits linear trends over the entire range of the molar masses. The determined scaling index α was 0.53. The values of the Huggins parameter (Table 2) for poly (MeOEP) samples characterized by Mn ∼ 104 (Table 2, runs 3–6) indicate the aggregation tendency of this polymer. These results allowed us to conclude that CHCl3 is a “poor” solvent for poly(MeOEP) which forms a dense polymeric globule in this media. Initially, we assumed that TMP prevents transesterification because 399

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Fig. 4. SEC traces of poly(MeOEP) samples prepared in the absence (A) and in the presence (B) of TMP (TBD as a catalyst), and in the presence of TMP (C, Mg1 as a catalyst).

4. Conclusions

molecular weight phosphate to experience reversible coordination with the TBD molecule. During polymerization, TMP acts as a competitive inhibitor of polymerization (a noticeable decrease in the rate of the ROP in the presence of TMP confirms this conclusion, see Table 1 and Fig. 4), and at the same time prevents the coordination of polyphosphate fragments, thus protecting the polymer chain from transesterification even at relatively low concentrations.

In our studies, we have set ourselves the task of establishing the ease of transesterification of sterically unhindered poly(alkyl ethylene phosphates) at the final stage of the polymerization of ethylene phosphates. As a result of DFT calculations of the reaction profiles of TBD-catalyzed polymerization of methyl ethylene phosphate and

Table 2 Preparation (−20 °C, 2 M in CH2Cl2), MW characteristics and viscosity parameters of poly(MeOEP) samples. Run

MeOEP/TBD/BnOH ratio

React. time, sec

Conv., %a

Pn (NMR)b

Mntheo × 103,c

Mn × 103 (NMR)b

Mn × 103 (SEC)d

ÐMd

in CHCl3 3

1 2 3 4 5 6

20:1:1 50:1:1 75:1:1 100:1:1 125:1:1 175:1:1

30 45 45 60 90 90

89 81 78 92 88 86

18.3 40.7 55.1 88.0 107.8 148.0

2.57 6.39 8.18 12.81 15.47 20.89

2.63 5.73 7.72 12.26 14.99 20.54

2.1 3.6 4.2 9.7 12.9 14.6

For experimental details, see Section 2.2 and Appendix A4 in the Supplementary data. a Determined by the integration of monomer and polymer signals in 31P NMR spectra of the reaction mixtures. b Calculated using the formula (1), see Section 2.4. c Calculated using the formula (2), see Section 2.4. d Size exclusion chromatography data (DMF). 400

1.16 1.17 1.16 1.19 1.17 1.15

in TMP

[η], cm /g

kH

[η], cm3/g

kH

0.0374 0.0569 0.0649 0.0868 0.0951 0.1101

2.27 1.46 0.77 0.76 0.72 0.75

0.0582 0.0699 0.0773 0.0863 0.0898 0.1065

0.56 0.55 0.51 0.48 0.47 0.45

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Fig. 5. Dependence of characteristic viscosity on molecular weight for poly(MeOEP) in CHCl3 (top) and in TMP (bottom).

and at the same time effectively prevented the scission and branching of polyphosphates. This effect does not depend on the nature of the catalyst. Using TMP as a reaction mixture component, we have successfully synthesized a series of linear poly(MeOEP) samples with narrow MWD even at full monomer conversion. The ability of TMP to block the transesterification can be used in the synthesis of linear polyphosphates with a given Pn in order to design biodegradable and biocompatible materials with required characteristics.

transesterification of poly(MeOEP) and TMP, we found that the free energy of activation of the ROP of MeOEP is 10–13 kcal/mol lower than the activation energies of transesterification processes. To verify the calculation results, we studied the chemical behavior of TMP under the ROP conditions at −20 °C. We found that trimethyl phosphate does not react, which correlates with the calculation results (ΔG≠ ∼30 kcal/ mol). At the same time, the experimental fact of poly(MeOEP) transesterification even at −20 °C required a refinement of the model used in the calculations with an assumption regarding the formation of polymer globules by polyphosphate macromolecules in solution. The results of the viscometry study of poly(MeOEP) solutions in CHCl3 and in TMP confirmed our assumption, and the calculated values of KuhnMark-Houwink parameter α were 0.53 and 0.33, respectively. We propose that the aggregation of polyphosphate reduces the entropic contribution to the free activation energy, which makes it possible to estimate the activation barrier of transesterification with the value of 20 kcal/mol and to clarify the cause of high rates of poly(MeOEP) transesterification even at subzero temperatures. Thus, it is the conformation of the macromolecule in the solution that determines the ease of poly(MeOEP) transesterification. The nature of the catalyst is not of fundamental importance; transesterification was also observed when using a coordination catalyst [(BHT)Mg(OBn)(THF)]2. In the study of the chemical behavior of TMP, we found that this low molecular weight phosphate was not subjected to transesterification

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