Synthesis of poly(disulfide)s with narrow molecular weight distributions via lactone ring-opening polymerization†

We report the first example of controlled polymerization of poly(disulfide)s with narrow molecular weight distributions. 1,4,5-oxadithiepan-2-one (OTP), a disulfide-containing 7-membered ring lactone, was polymerized by using the diphenylphosphate (DPP) catalyzed lactone ring-opening polymerization method. The polymerization proceeded in a living manner, and the resulting polymers displayed very narrow polydispersity index (PDI) values below 1.1 and excellent backbone degradability responding to reducing conditions and UV irradiation.


Introduction
The disulde bond is oen regarded as a dynamic covalent bond with conditional reactivity or meta-stability. 1It can sufficiently maintain molecular integrity, being a reasonably strong bond with typical bond dissociation energies of 60 kcal mol À1 .On the other hand, it can be easily cleaved and exchanged with other bonds in the presence of physical (i.e.light, 2 heat, 3 mechanical force, 4 etc.) or chemical (i.e.radicals, 5 nucleophiles, 6 etc.) stimuli overcoming the dissociation energy barrier.In particular, the reversibility of oxidative coupling and reductive degradation between a disulde and two thiols is a key factor in the structural integrity and controlled reactivity of proteins. 7,8he intriguing properties of disuldes have been popularly studied for application in the elds of polymer and materials science.Disulde acts as a cross-linker between polymeric chains to improve the stiffness of polymeric networks, as shown in vulcanized rubber 9 or disulde-based hydrogels. 10Various pharmaceuticals can be conjugated to polymers or proteins via disulde bonds for drug delivery. 11,12When appropriate signals are applied to the disulde-based materials in a spatiotemporal manner, the disulde bonds degrade either to disintegrate the polymer network structure or to release the active pharmaceuticals from the delivery carrier.UV-responsive self-healing gels, 13 nanogels, 14 and antibody-drug conjugates 12 responding to high glutathione concentrations around cancerous tissues or in the cytosol are all on the frontier of materials and pharmaceutical sciences.
Notwithstanding the recent rapid progress in polymer science, the synthesis of ne polymers containing disulde backbones is very limited, probably due to the vulnerability of disulde bonds under most polymerization conditions.Oxidative coupling of disulydryl monomers, 15 condensation polymerization of disulde-pre-containing monomers 16 and copolymerization of dihalide-containing monomers with sodium disulde 17 are representative strategies for the synthesis of poly(disulde)s.However, the aforementioned step-growth polymerization methods inevitably lead to polymers only with a broad distribution of molecular weights (polydispersity index (PDI) > 2).Chain-growth polymerization has been attempted to obtain poly(disulde)s with more narrow molecular weight distributions (MWDs), but only with limited improvement.9][20][21][22] The formation of these complex product mixtures may be attributed to the limited selectivity of the thiol-disulde exchange between disuldes in the monomer and the polymer backbone.Various reaction conditions were examined to overcome this problem and obtain linear polymers as a major product, but undesired cyclic oligomers were still present with PDI > 1.4. 22Ring-opening metathesis polymerization (ROMP), which is orthogonal with the thiol-disulde exchange reaction, was also applied for the synthesis of poly(disulde)s.However, undesirable interactions between the ruthenium catalyst and disuldes caused not only a large PDI > 1.5 but also a failure in homopolymerization of the disulde monomer. 23From the previous results, we inferred that it is critical to choose polymerization conditions where unwanted thiol-disulde exchange and catalyst-disulde interactions are inhibited for obtaining ne poly(disulde)s with narrow MWDs.

Results and discussion
In this research work, we selected lactone polymerization for the synthesis of poly(disulde)s since numerous catalysts for the controlled polymerization of poly(lactone)s have already been established. 24,25As for the monomer, we designed 1,4,5oxadithiepan-2-one (OTP), an analogue of 3-caprolactone (3CL), where two of the ve methylene groups are replaced with a disulde.We reasoned that the 7-membered ring structure may provide sufficient ring strain for polymerization (Scheme 1).OTP was prepared from the catalytic intramolecular oxidation 26 of an a,u-disulydryl ester formed from 2-mercaptoethanol and 2-thioglycolic acid (see the ESI †).We have screened various catalysts ranging from bases to Lewis and Brønsted acids for the OTP polymerization, but the disulde bonds were vulnerable under most of the reaction conditions, as the catalysts induced undesirable nucleophilic attack on disuldes by enhancing the electrophilicity of disuldes or nucleophilicity of nucleophiles.Among them, diphenylphosphate (DPP), a Brønsted acid with a pK a of 3.88 in DMSO, 27 showed remarkable tolerance to disuldes but strong catalytic activity for the polymerization of OTP.Therefore, we used DPP as the catalyst in all the polymerization reactions below.
The polymerization of OTP was carried out with catalytic DPP and benzyl alcohol (BnOH) as the initiator (I) at various [OTP]/[I] ratios (from [OTP]/[I] ¼ 20 to 180).The general procedure for the polymerization is described in detail in the ESI.† We chose chloroform as the reaction solvent due to the solubility issue of the OTP polymer with a high sulfur content of approximately 43% (w/w).The MWDs were examined by size exclusion chromatography (SEC) (Table 1 and S1, ESI †).Surprisingly, the polymers (P1-P5) were found to have very narrow MWDs (PDI < 1.1) throughout the wide range of the monomer (M) to initiator ratio.The PDI values of poly(OTP)s are even smaller than those of poly(3CL) or poly(d-valerolactone) in previous reports where the same catalyst was utilized. 25M n values from the SEC analysis were in reasonable agreement with the target M n .Additionally, we could conrm the preservation of a well-oriented head-to-tail backbone without disulde exchange and delity of the terminal benzyl group in poly(OTP)s by MALDI-MS and 1 H NMR study (Fig. S7 and S13-S17, ESI †).
To widen the applicability of our method, we investigated various alcohols for initiation.Propargyl alcohol also produced poly(OTP) (P6) with desired molecular weights and a narrow PDI (Fig. S2, ESI †), which gives access to future end group functionalization via the alkyne-azide click reaction. 28Next, when we utilized 2-propanol as the initiator, we could still obtain a narrow MWD (P7, PDI ¼ 1.05) (Fig. S3, ESI †) although secondary alcohols are generally recognized to be unsuitable for rapid initiation. 29We assumed that the initiation rate of OTP, even by secondary alcohols, is signicantly faster than the propagation rate, thus leading to the low PDI.Furthermore, umethoxy-capped polyethylene oxide (mPEO) was also used as a macroinitiator for the synthesis of a block copolymer.The polymerization resulted in mPEO-b-poly(OTP) with narrow MWDs (P8 and P9) (Fig. S4 and S5, ESI †).These well-dened amphiphilic block copolymers with narrow MWDs would  We then examined whether OTP is polymerized in a living/ controlled manner.The polymerization kinetics of poly(OTP) were measured by 1 H NMR and SEC (Fig. 1).We could observe a linear relationship between M n versus the conversion ratio and a decrease in the PDI (M w /M n ) as the reaction progressed.Also, by plotting Àln([M]/[M] 0 ) versus reaction time, we could obtain a strict linear relationship, which suggests that the polymerization rate is proportional to the OTP concentration in the rst order.
We also performed one-pot post-polymerization with additional OTP feed to prove the livingness of the polymeric end group.First, we conducted polymerization at a [M]/[I] ratio of 25 for 24 h, where the full conversion of the monomer was conrmed by 1 H NMR. The solution was further stirred without quenching for an additional 24 h.There was still no sign of backbiting or peak broadening in the SEC chromatogram even aer 24 h from monomer depletion (Fig. 2a, black curve).Then, we added the second monomer solution feed ([M]/[I] ¼ 25) to the unquenched polymer solution and stirred the mixture for an   additional 48 h.We conrmed the second full consumption of the monomer by 1 H NMR. The SEC chromatogram clearly showed the peak shi with an almost 2-fold increase of M n from 3.63 kDa to 6.56 kDa, as well as the maintenance of the low PDI < 1.05 (Fig. 2a, red curve), which implies that the chain end of poly(OTP) is still "living".
The results above encouraged us to attempt a successive ring-opening polymerization of 3CL and OTP in a one-pot manner for the preparation of poly(3CL)-b-poly(OTP).Aer the rst polymerization of the poly(3CL) block at a [3CL]/[I] ratio of 30 for 24 h, where the full conversion of 3CL was conrmed by 1 H NMR, the second OTP monomer was injected rapidly at an [OTP]/[I] ratio of 30.Aer the second polymerization proceeded for 48 h, we could observe that the SEC peak had shied from the initial peak of poly(3CL) and that M n showed an increase of 4.5 kDa (Fig. 2b).The PDI value was also maintained below 1.09 during the successive one-pot polymerization.In addition, the peak corresponding to the methylene proton at the chain end (-CH 2 OH) of poly(3CL) at 3.65 ppm (ref.25) shied to 4.15 ppm corresponding to those next to ester (-CH 2 OOC-) in the 1 H NMR spectrum aer the polymerization (see the ESI †), implying the successful one-pot post-polymerization with OTP from poly(3CL).
The disulde backbone of poly(OTP) is expected to have degradability responding to various chemical and physical stimuli.As a representative chemical stimulus to trigger the disulde metathesis in poly(OTP), we chose D,L-dithiothreitol (DTT), a reagent well known to induce thiol-disulde exchange reactions by forming a stable intramolecular cyclic disulde while reducing other disulde substrates. 30P3 (M n ¼ 11.2 kDa) was dissolved in chloroform and DTT was added to the solution at a molar ratio of 1 : 1 relative to the disulde content of P3.Aer incubation at ambient temperature for 24 h, the backbone of poly(OTP) was almost completely degraded to oligomers, as shown in the SEC chromatogram in Fig. 3a.Poly(OTP) showed the characteristic degradability of disulde polymers responding to the reducing conditions.Then, we also examined the backbone degradation of poly(OTP) by UV irradiation, which is known to facilitate disulde metathesis by generating thiyl radicals via the homolytic cleavage of disulde. 2Aer irradiation with UV light (l max ¼ 357 nm, 5 W cm À2 ), the initial peak of P2 (M n ¼ 5.71 kDa) in the SEC chromatogram gradually decreased in intensity with an increase in retention time, while small peaks appeared with increasing intensity in the oligomer region (Fig. 3b).The results clearly exhibit the UVresponsive degradability of the poly(OTP) backbone.In addition, the disulde bonds in the poly(OTP) backbone are quite stable even at 100 C, where the broadening of the MWD was observed probably due to transesterication, but start to show exchange reactions to produce a mixture of head-to-head, headto-tail and tail-to-tail disulde bonds with larger broadening of the MWD at 120 C (Fig. S11 and S12, ESI †).

Conclusions
In summary, we have demonstrated the rst example of controlled living polymerization of disulde-backbone polymers with narrow MWDs (PDI < 1.1).We could successfully synthesize poly(OTP)s from various alcohol initiators and their block copolymers with PEO and poly(3CL) through the combination of a newly designed 7-membered disulde-containing lactone, OTP, and a lactone-activating catalyst unreactive to disuldes.The poly(OTP)s showed characteristic degradability of disulde-bearing compounds under exposure to thiols and UV irradiation.Thanks to the simple introduction of a poly(-disulde) backbone with a controlled length, the OTP polymerization can be a very useful tool for the development of smart materials with stimuli-responsive reversible degradability, especially in the biomedical elds.More importantly, we believe that poly(OTP)s can be applicable to supramolecular chemistry for formation of delicate nanostructures requiring narrow MWDs of the components, where the application of poly(disulde)s with attractive stimuli-responsiveness has been difficult due to broad MWDs until now.

Fig. 3
Fig. 3 Stimuli-responsive degradability of poly(OTP)s.(a) The change of the SEC chromatogram of poly(OTP) (P3) before and after treatment with DTT (1 eq. of the disulfide bonds in P3).(b) The change of the SEC chromatogram of poly(OTP) (P2) before and after UV irradiation (5 W cm À2 ).The black curves indicate the molecular weight distributions of poly(OTP)s before stimuli-triggering.

Table 1
Polymerization of OTP at various monomer (M) to initiator (I) ratios and with various initiators c1.04 c form controllable polymeric nanostructures with disuldebased responsiveness for future applications.