Ring-Opening Metathesis Polymerization of 1,2-Dihydroazete Derivatives

Abstract

Fischer carbenes have recently found great utility in the construction of degradable metathesis materials, but investigations have been limited to oxygen-containing enol ether monomers. Here, the ring-opening metathesis polymerization of 1,2-dihydroazetes is reported. The polymerization proceeds regioselectivity, and the resulting molecular weights are targetable by adjusting the Grubbs initiator loading. Under acidic conditions, the resulting polymers degrade into 3-aminopropanal derivatives through hydrolysis of the recurring enamide motifs in the polymer backbone. Additionally, the underlying kinetics and thermodynamics of the polymerization were studied through DFT calculations to elucidate the origins of metathesis regioselectivity. This work further expands the suite of monomers available to generate degradable metathesis materials and provides a flexible platform for target applications.

Graphical Abstract

An exploration of 1,2-dihydroazetes in ring-opening metathesis polymerization (ROMP) is reported. The 4-membered rings readily polymerized using the Hoveyda-Grubbs 2^nd generation initiator and maintained living chain-ends for block polymer synthesis. This study gives new insights into the reactivity and limitations of enamine derivatives in metathesis processes, while also offering a new approach to degradable metathesis materials with tunable properties.

Introduction

Ring-opening metathesis polymerization (ROMP) with heteroatom-substituted cycloalkenes has seen a renaissance in recent years. While these systems were previously considered to be incompatible with metathesis polymerization due to the limited reactivity of the Fischer carbene generated upon ring-opening^[1], Xia’s landmark homopolymerization of dihydrofuran (DHF) demonstrated its viability and revitalized interest in this area^[2]. Ensuing studies demonstrated the ability of DHF to readily copolymerize in an alternating fashion with enyne^[3], ynyne^[4], cyclobutenes^[5], and norbornene^[6] comonomers. In addition to revealing unexpected metathesis competence, these systems introduced labile enol ether motifs into the polymer backbone. Plastic waste that persists in the environment is an urgent challenge to modern society, and this provided a facile strategy to introduce degradability into metathesis-derived materials which historically contain all-carbon backbones.

While DHF has received increasing attention in the literature, very little has been explored to evaluate other heteroatom-substituted cyclic alkenes in ROMP. Extension to enamine derivatives would offer an increased valency to the heteroatom, thereby permitting incorporation of functional sidechains to tune material properties, while still retaining the same capability for degradation^[7]. Grubbs and coworkers reported the viability of metathesis between nitrogen and sulfur-substituted alkenes, but this chemistry was not further translated into a polymerization manifold^[1a]. In this work, the ring-opening metathesis polymerization (ROMP) of strained 1,2-dihydroazete (DHA) monomers that contain an embedded enamine motif is reported that produces functional and degradable materials.

Results and Discussion

To evaluate the potential of enamine derivatives in ROMP, the 1,2-dihydroazete (DHA) scaffold was selected for initial studies (Scheme 1). As conventional wisdom in ROMP dictates the need for ring strain, the four-membered heterocycle was selected based on the richness of metathesis literature on cyclobutene derivatives^[8]. The DHA derivatives were synthesized starting from inexpensive N-Boc-azetidin-3-one in 3–4 steps in 31–70% overall yields (Scheme S1) through modification of literature procedures.^[9] Boc, benzoyl, pivaloyl, or tosyl groups were readily appended to the nitrogen atom to evaluate the steric and electronic impacts on polymerization. The 5-membered dihydropyrrole derivative N^Boc-DHP was also prepared to evaluate the role of ring-strain in the system following analogous procedures (Figure S1–9 and Scheme S2).

Scheme 1.

(A) Homopolymerization of DHF. (B) Alternating copolymerization of DHF with alkyne derivatives, cyclobutenes, and norbornenes. (C) Design and synthesis of enamine-containing polymers via ROMP of 1,2-dihydroazete derivatives (N^R-DHA).

N^Bz-DHA was selected as the model monomer to evaluate competence in ROMP using ruthenium-based initiators. Grubbs 1 (G1), Grubbs 2 (G2), Grubbs 3 (G3), and Hoveyda Grubbs (HG2) were all examined in THF with a monomer/initiator ratio ([M]₀/[I]₀) of 100/1 (Table 1)^[10]. Ethyl vinyl ether (EVE) was selected as the terminating agent to remove the ruthenium chain end and produce a methylene end group. While 25 % conversion of N^Bz-DHA was observed with G1 over 48 hours (Table 1, entry 1), no conversion was observed with G3 (Table 1, entry 3). Conversion of N^Bz-DHA was improved with G2, giving the desired polymer PN^Bz-DHA with a slightly lower than theoretical number average molecular weight (M_n) and moderate dispersity (Table 1, entry 2; M_n^exp. = 11.4kg/mol, M_n^cal. = 15.9 kg/mol, Ð = 1.63). Interestingly, ROMP of N^Bz-DHA initiated by HG2 gave a near theoretical molecular weight value and lower dispersity (Table 1, entry 4; M_n = 13.3 kg/mol, Ð = 1.43). While HG2 is usually ineffective at controlling polymerization due to slow rates of initiation, Choi has shown the efficient ROMP of cyclobutene derivatives with HG2 due to coordination of the ruthenium center to backbone alkenes during propagation (vide infra)^[11].

Table 1.

Ring-opening metathesis polymerization of N^R-DHAs

Entry	Monomer	[M]0/[I]0d	Initiator	Time (h)	Mn,cal.(g/mol)	Mn,exp.(g/mol)e	Ð f	Conversion (%)
1a	NBz-DHA	100/1	G1	48	15900	-	-	25
2a	NBz-DHA	100/1	G2	48	15900	11350	1.63	>95
3a	NBz-DHA	100/1	G3	48	15900	-	-	<5
4a	NBz-DHA	100/1	HG2	42	15900	13290	1.43	>95
5	NBz-DHA	100/1	HG2	42	15900	13170	1.41	>95
6b	NBz-DHA	100/1	HG2	48	15900	7010	1.75	68
7	NBz-DHA	50/1	HG2	18	8000	8161	1.36	>95
8	NBz-DHA	25/1	HG2	6	4000	5770	1.29	>95
9	NBz-DHA	150/1	HG2	67	23900	19480	1.47	>95
10	NBz-DHA	200/1	HG2	93	31800	28660	1.44	>95
11	NBz-DHA	250/1	HG2	93	39800	33550	1.55	>95
12	NBz-DHA	1000/1	HG2	95	159100	48300	1.72	43
13	NBoc-DHA	100/1	HG2	2	15500	18450	1.51	>95
14	NPiv-DHA	100/1	HG2	63	13900	11370	1.63	>95
15c	NTs-DHA	50/1	HG2	65	10500	4370	1.79	62
16	NBoc-DHA/NBz-DHA	100/25/1	HG2	0.5/40	19800	15900	1.32	>95/>95
17	NBoc-DHP	50/1	HG2	32	8450	-	-	<5

^aROMP was performed under a N₂ atmosphere.

^bThe solvent was DCM.

^cThe concentration was set as 0.7M for the lower solubility of N^Ts-DHA.

^dInitial equivalents of N^R-DHAs/Grubbs catalyst.

^eDetermined by SEC analysis in chloroform.

^fM_w/M_n.

Notably, polymerization performed under a nitrogen atmosphere (Table 1, entry 4) and an air atmosphere (Table 1, entry 5) showed similar performance, possibly attributed to the pendant coordination of the olefin moiety, coupled with the reduced reactivity of the Fischer-type carbene. For convenience, all future polymerizations were performed under air atmosphere without degassing protocols. Dichloromethane (DCM) was also examined as a polymerization solvent for N^Bz-DHA (Table 1, entry 6)^[12]. This led to a slower rate of polymerization with 68 % conversion of N^Bz-DHA after 48 h. The higher polymerization rate in THF may be attributed to coordination of the Lewis basic oxygen to the ruthenium center, thereby facilitating dissociation of the pendant alkene in the propagating chain.

The HG2-initiated ROMP of N^Bz-DHA demonstrated some features of controlled polymerization, such as the linear increase in molecular weight with feed ratio and a first order kinetic profile (Figure 1 and S14). Polymerization of N^Bz-DHA at [M]₀/[I]₀ ratios of 25/1 and 50/1 displayed M_n of 5.8 and 8.2 kg/mol and Ð of 1.29 and 1.36, respectively (Table 1, entries 7–8). Changing the [M]₀/[I]₀ ratio to 150/1, 200/1 and 250/1 linearly increased the M_n to 19.5, 28.7 and 33.6 kg/mol, respectively, while maintaining a Ð of ~1.50 (Table 1, entries 9–11). The modest dispersity values of the polymerization suggest a relatively slow initiation with HG2. The polymerization begins to fail at higher molecular weights, with an [M]₀/[I]₀ ratio of 1000/1 resulting in incomplete conversion and a broader molecular weight distribution (Table 1, entry 12). Next, a polymer with a degree of polymerization of 30 was characterized via matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) mass spectrometry after quenching with EVE (Figure 1D). The resulting spectrum predominantly displayed peaks corresponding to the matrix and proton adducts (Figure S15). Notably, the consistent mass interval of 159.1 Da between the major peaks is indicative of the molar mass of the N^Bz-DHA repeat unit. Furthermore, the detected ions exclusively contained the iPrO−PhCH− and CH₂− end groups, thereby confirming the chain end control and the high efficacy of the polymerization.

Figure 1.

HG2-Catalyzed ROMP of N^Bz-DHA (A) Overlay of SEC curves at different [M]₀/[I]₀ ratios. (B) Plots of M_n and Ð as a function of the [M]₀/[I]₀ ratio. (C) Overlay of SEC curves of the precursor polymer P(N^Boc-DHA)₂₅ and the copolymer P(N^Boc-DHA)₂₅-b-P(N^Bz-DHA)₁₀₀. (D) MALDI-TOF mass spectrum of PN^Bz-DHA, quenched by EVE.

Changing the nitrogen substituent of the DHA monomer to Boc (N^Boc-DHA) or pivalate (N^Piv-DHA) led to similar performance under the standard conditions to that of N^Bz-DHA (Table 1, entries 13–14, and Figure S10–11). Examination of tosylated N^Ts-DHA, however, only reached 62% conversion after ~65 hours, suggesting diminished reactivity compared to the acylated DHA derivatives (Table 1, entry 15). To further verify the retention of the ruthenium chain-end after polymerization, a diblock polymer was prepared by polymerizing N^Boc-DHA followed by addition of N^Bz-DHA (Table 1, entry 16). As can be seen by SEC analysis, the monomodal peak of the first block completely shifts to an earlier elution time after chain extension, supporting diblock formation (Figure 1C and Figure S13). Since ring strain presumably plays a critical role in this polymerization, the five-membered dihydropyrrole derivative N^Boc-DHP was investigated (Figure S9)^[13]. As anticipated, only trace conversion of N^Boc-DHP was observed at [M]₀/[I]₀ ratio of 50/1 under the standard reaction conditions (Table 1, entry 17).

The thermal behavior of the PN^R-DHAs were investigated via thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). PN^Boc-DHA showed a decomposition temperature (T_d5%) of ~ 202 °C due to the thermal decomposition of Boc group (Figure S16). The other PN^R-DHAs all displayed good thermal stability with a T_d5% over ~270 °C. The T_g of the polymers were tunable over a range of ~51−105 °C by altering side group structure, which provided a broad window for material processing (Figure S17–21).

The protons resonances observed in the PN^Bz-DHA ¹H NMR spectrum is broad and complex (Figure 2 and Figure S12). Likewise, the protons present in the N^Bz-DHA monomer also exhibit significant broadening (a, b, and c). This suggests the coexistence and rapid interconversion of the four possible rotamers on the NMR timescale (Figure 2A, I-1, I-2, I-3 and I-4). Density functional theory (DFT) calculations on the B3LYP/6–31G* level of theory supported the similar energy of the four possible isomers (free energy differences less than ~0.1 kcal/mol) and relatively low energy barriers for both rotation (17.4 and 12.1 kcal/mol for I-TS2 and I-TS4, respectively) and flipping (1.9 and 2.9 kcal/mol for I-TS1 and I-TS3, respectively) processes (Figure 2A). When a CDCl₃ solution of N^Bz-DHA was cooled to ~-2 °C, the proton peaks resolved, due to the inhibition of amide bond rotation with higher energy barriers (Figure 2C).

Figure 2.

(A) Rapid interconversion of four N^Bz-DHA isomers via rotation and flipping processes. ¹H NMR spectra of N^Bz-DHA at room temperature (B) and at −2 °C (C) and PN^Bz-DHA (D) in CDCl₃.

The abundant enamide motifs decorating the PN^R-DHAs backbone present the potential for backbone cleavage under acidic conditions. To investigate degradation, PN^Boc-DHA was dissolved in anhydrous MeOH containing 10 eq of HCl. According to ¹H NMR, PN^Boc-DHA can be completely degraded (>95%) into small molecules within minutes to give 3,3-dimethoxypropan-1-amine as the major product (Figure S22B, bottom), which supported by a sharp decrease in molecular weight by SEC (Figure S22A). The same product is generated upon methanolysis of the N^Boc-DHA monomer under the identical conditions (Figure S22B, middle). Similarly, PN^Bz-DHA featuring a more acid stable benzoate substituents also undergoes facile degradation into small molecules under acidic aqueous conditions. As illustrated in Figures 3A and 3B, a gradual decrease in molecular weight of PN^Bz-DHA observed upon stirring in a TFA/H₂O/DCM solvent mixture over 48 hours. A more rapid degradation of PN^Bz-DHA can be accomplished within ~5 minutes in a homogeneous HCl/MeOH solution, with N^Bz-DMA (N-(3,3-dimethoxypropyl)benzamide) identified as the predominant degradation product (Figure 3C).

Figure 3.

Acid-Catalyzed degradation of PN^Bz-DHA. (A) Overlay of SEC curves at various time points during the degradation process in TFA/H₂O/DCM. (B) Plots of M_n as a function of degradation time. (C) Overlay of the ¹H NMR spectra in MeOD of PN^Bz-DHA (top), the degraded PN^Bz-DHA (bottom), and N^Bz-DHA after hydrolysis (middle)as a reference.

The degradation experiments also gave insights into the polymer regiochemistry, as a minor product (<10%) was identified as N,N’-(but-2-ene-1,4-diyl)dibenzamide via LC-MS analysis (Figure S23). This degradation product corresponds to the hydrolysis of small quantities of head-to-head (H–H) linkages with a measured regioselectivity of approximately 90%. This result aligns with the high regioselectivity of metathesis for the nitrogen-substituted alkenes N-vinyl carbazole and N-vinyl(pyrrolidinone) previously studied by Grubbs^[1a].

To better understand the nature of polymerization, a mechanistic study of the N^R-DHA ROMP was performed through DFT calculations^[14]. To simplify the calculations, N^MeCO-DHA was used as a model monomer and G2 as initiator. The free energies of key intermediates (INTs) and transition states (TSs) for both the initiation and chain propagation steps are summarized in Figure 4 and Figure S25, respectively. To elucidate the origin of head-to-tail regioselectivity of the unsymmetrical N^R-DHA monomers, two possible orientations of the monomer-ruthenium carbenoid were considered. The orientation which results in a nitrogen-substituted ruthenium carbenoid was designated pathway H (head), and the orientation resulting in a carbon-substituted ruthenium carbenoid was termed the pathway T (tail). The DFT calculations start with the dissociation of tricyclohexylphosphine (PCy₃) from G2 (1 → 2, Figure 4). Next, the coordination and cycloaddition of the 14-electron complex was calculated in the H and T orientations. The resulting energy barriers for the metallacyclobutane formation are highest in both H and T pathways (17.3 and 16.0 kcal/mol, respectively), indicating that cycloaddition is the rate-determining step of initiation. The 1.27 kcal/mol higher energy of H-TS1 compared to T-TS1 implies the pathway T is kinetically favored over pathway H.

Figure 4.

Mechanistic Investigation of the ROMP by DFT Calculation. Free energy profile of ROMP of N^MeCO-DHA initiated by G2.

The ring-opening product could be stabilized by intramolecular olefin or carbonyl coordination to ruthenium center^[15]. Therefore, both coordination modes (5 and 6) were considered for the N^MeCO-DHA monomer in both H and T pathways. Consistent with prior experimental work by Choi^[11], the free energy of olefin-coordinated complexes 5 were found to be lower in energy than ester-coordinated complexes 6 (−25.8 kcal/mol vs −22.5 kcal/mol for pathway H). Furthermore, the ~15.4 kcal/mol higher free energy of T-5 compared to H-5 correlates with the observed regioselectivity from the viewpoint of thermodynamics. This regioselectivity was also validated experimentally by the sole existence of alkylidene signals at the ~12.0 – 15.0 ppm range in ¹H NMR spectrum of the mixture of HG2/N^R-DHAs, corresponding to the Fischer-type H carbene proton signals of the propagating species (Figure S24)^[1a].

Since the observed regioselectivity does not fully account for the kinetically favored T pathway for initiation, the ensuing propagation step was also investigated via DFT starting from intermediate H-5. Similar with the case of initiation, both carbene-monomer orientations were evaluated for coordination/cycloaddition and labeled as pathway H-H and pathway H-T, respectively. As shown in Figure S25, the energy barrier calculated for pathway H-T (14.3 kcal/mol) is 3.3 kcal/mol higher than that for pathway H-H (11.0 kcal/mol). Similarly, pathway H-H demonstrated a 14.7 kcal/mol lower overall free energy difference for ring-opening compared to pathway H-T. This suggests that the initiation event has reduced regioselectivity, which then becomes primarily head-to-head (pathway H) in ensuing propagation events.

To gain further insight into the origins of the cycloaddition regioselectivity, energy decomposition analysis (EDA) was performed on the activation energy difference (ΔΔE^‡) between the H-TS1 and T-TS1. ΔΔE^‡ can be decomposed to the contribution from steric interactions (ΔΔE_steric), orbital interactions (ΔΔE_orb), and electrostatic interactions (ΔΔE_ele), allowing each of the individual factors impacting regioselectivity to be compared (Table S2–S4; see the Computational Details in SI for more information)^[16]. As shown in Figure 5, the EDA results indicated that steric effects (ΔΔE_steric = −68.2 kcal/mol) positively contribute to H regioselectivity. However, orbital and electrostatic interactions (ΔΔE_orb = 38.0 kcal/mol and ΔΔE_ele = 27.7 kcal/mol) are unfavorable factors for H regioselectivity due to the higher orbital matching (Figure S26) and stronger coulombic attraction (Table S5) between the ruthenium complex and DHA fragments in T-TS1. These findings were surprising since it was presumed electronic factors would guide the cycloaddition to pathway H. This could be impacted by the electron-withdrawing groups on the DHA monomers, and further investigation of the relative impacts of ΔΔE_steric, ΔΔE_orb, and ΔΔE_ele in the cycloaddition reactions of other electron-rich olefins is underway.

Figure 5.

Energy decomposition analysis of the energy difference between transition states H-TS1 and T-TS1.

Conclusion

In summary, the ROMP of 1,2-dihydroazetes under ambient conditions to afford degradable materials has been developed. In the presence of HG2 as the initiator, polymerization can rationally target different molecular weights and proceeds with high regioselectivity. The effects of substituents on the 1,2-dihydroazete scaffold were investigated to show broad tolerance of acyl derivatives, while reduced rates of metathesis were observed with a sulfonyl 1,2-dihydroazete. The overall polymerization was studied via DFT calculations to demonstrate the relative roles of initiation and propagation to give rise to an overall regio-controlled polymerization. The resulting materials were readily degraded into small molecule fragments under acidic conditions via cleavage of the enamide linkages, further expanding the suite of monomers to generate degradable metathesis materials.