Organocatalyzed chemoselective ring-opening polymerizations

A novel metal-free and protecting-group-free synthesis method to prepare telechelic thiol-functionalized polyesters is developed by employing organocatalysis. A scope of Brønsted acids, including trifluoromethanesulfonic acid (1), HCl.Et2O (2), diphenyl phosphate (3), γ-resorcylic acid (4) and methanesulfonic acid (5), are evaluated to promote ring-opening polymerization of ε-caprolactone with unprotected 6-mercapto-1-hexanol as the multifunctional initiator. Among them, diphenyl phosphate (3) exhibits great chemoselectivity and efficiency, which allows for simply synthesis of thiol-terminated poly(ε-caprolactone) with near-quantitative thiol fidelity, full monomer conversion, controlled molecular weight and narrow polydispersity. Kinetic study confirms living/controlled nature of the organocatalyzed chemoselective polymerizations. Density functional theory calculation illustrates that the chemoselectivity of diphenyl phosphate (3) is attributed to the stronger bifunctional activation of monomer and initiator/chain-end as well as the lower energy in hydroxyl pathway than thiol one. Moreover, series of tailor-made telechelic thiol-terminated poly(δ-valerolactone) and block copolymers are efficiently generated under mild conditions.


Results and Discussion
The primary requirements for broad applications of thiol-functionalized polymers are quantitative thiol fidelity, controlled molecular weight and narrow polydispersity, which have not yet been achieved by the previous methods [30][31][32][33][34][35] . To address these challenges, a scope of Brønsted acids, including trifluoromethanesulfonic acid (1), HCl. Et 2 O (2), diphenyl phosphate (3), γ-resorcylic acid (4) and methanesulfonic acid (5), were investigated respectively in ε-caprolactone (CL) polymerizations initiated by 6-mercapto-1-hexanol (MH) as the multifunctional initiator. The polymerization results were summarized in Table 1. Under the initial conditions ([CL]:[MH]:[Cata lyst] = 50:1:0.5, [CL] = 2 mol/L), all acids enabled full monomer conversions for different reaction temperatures and times. The fractions of desirable thiol-terminated polymer in the product, defined as thiol fidelity, were ranged between 69% and 96%. The molecular weights (M n,NMR ) according to NMR analysis agreed with the theoretical values (M n,theo ) and the molecular weight distributions (Ð M ) were very narrow (<1.10). It was noteworthy that no large distinction was observed between the strong acid and weak acid (1 vs 5, 2 vs 4) with respect to the reaction temperature, time, thiol fidelity, molecular weight and polydispersity. As the acidity decreased from 1 to 5, moderate acid of 3 exhibited relative higher chemoselectivity (96% thiol fidelity) ( Table 1, run 4). It might be correlated with the structure of diphenyl phosphate (3).
Subsequently, diphenyl phosphate (3) was chosen as the model investigation organic acid. The kinetics studies elucidated the linear increases between -ln(1-conversion) and reaction time, which indicated polymerization rate to be first order in monomer concentration (Fig. 2a). Linear dependences of molecular weight (M n,NMR ) and monomer conversion were plotted in Fig. 2b, while the molecular weight distributions (Ð M ) kept narrow. To  feed ratio to produce thiol-terminated poly(ε-caprolactone) (PCLSH) with varied molecular weights. M n,NMR increased as the elevating monomer feed ratio from 3000 to 10000 g/mol with narrow molecular weight distributions (Ð M < 1.10) ( Table 1, run 3-6). All thiol fidelities were near-quantitative, which cannot be done by the previous enzyme or metal catalysis [30][31][32][33][34][35] . The chemical structures of PCLSH were characterized by NMR, MALDI TOF MS and SEC. In Fig. 3a, besides the f eature proton signals in PCL backbone, the appearance of quartet peak at around 2.5 ppm (H w ) revealed the presence of thiol as polymer end group, which was assigned to the methylene proton signals adjacent to the thiol. The other end group of hydroxyl could be validated by the triplet peak at 3.6 ppm (H a ). Thiol fidelity was obtained to be 96% for PCL (Table 1, run 4) by the integral comparison between H w and H a . M n,NMR were calculated to be 5400 g/mol, which agreed with the theoretical values. The proton signals of thiol (H x ) and others in initiator were overlapped by those of polymer backbones. The direct evidence was supplied by 1 H-1 H COSY ( Figure S1a). The coupling signals of area B and C confirmed the presence of H x and H v . 13 C NMR ( Figure S2a) showed that all signals were fully assigned and no thiolester and disulfide structure existed. MALDI TOF MS provided detailed polymer information of molecular weight. As depicted in Fig. 4a, two series of main peaks cationized by Na + and K + were clearly observed with separation of 114 (CL unit). The molecular weights were consistent with the theoretical values of PCLSH. Signals corresponding to the disulfide structure were not detected. The molecular weight distributions were measured by SEC. The symmetrical monomodal SEC traces of PCLSH elucidated their narrow polydispersities (Fig. 5a).
Our next concern was the chemoselective polymerization mechanism. According to the reports of of Penczek 36 , Kakuchi 41 , and Bourissou 42 , Brønsted acids catalyzed CL polymerization initiated by unprotected MH was assumed to obey activated monomer mechanism. In the last decade, ring-opening polymerization process has been explored by using computational studies [43][44][45][46][47][48][49] . To get better understanding of the great chemoselectivity of diphenyl phosphate (3), we carried out DFT calculations to compare two model reactions of CL ring-opening with methanol (CH 3 -OH) or methanthiol (CH 3 -SH) ( Fig. 6 and details in Figure S3). Cooperative bifunctional activation of initiator and monomer was involved in transition state TS 1 for the nucleophilic addition step. It was clearly seen that OH in methanol was closer to carbonyl of CL than SH (O 5 -C 1 1.92 Å vs S-C 1 2.30 Å). The distance of hydrogen bond between P=O and OH was shorter than that between P=O and SH (O 4 -H 1.51 Å vs O 4 -H 1.55 Å), which indicated stronger initiator/chain-end activation by diphenyl phosphate (3) in the presence of methanol as the initiator. Energy of TS 1 (OH pathway) was lower by about 18 kcal/mol than that of SH pathway. Ring-opening of CL proceeded via transition state TS 2 . Accompanied with proton transfer from acid to the endocyclic oxygen, endocyclic C-O bond was cleaved.   Lower energy of TS 2 in OH pathway was obtained in comparison with SH (14.09 Kcal/mol vs 21.91 kcal/mol). Therefore, it was proposed that the great chemoselectivity of diphenyl phosphate (3) was resulted from the stronger bifunctional activation of monomer and initiator/chain-end and lower energy in OH pathway than SH route.  Then, our attention was paid on the application of this metal-free and protecting-group-free green synthetic approach. By using diphenyl phosphate (3) as the organic acid catalyst, the monomer was extended into δ-valerolactone (VL). Under similar reaction conditions, well-defined thiol-terminated poly(δ-valerolactone) (PVLSH) were prepared with quantitative thiol fidelity, broad molecular weight range and narrow polydispersities ( Table 2). The linear increases between -ln(1-conversion) and reaction time were recorded in Fig. 2a. The apparent polymerization rate constant of VL (K app = 0.14205 min −1 ) was larger than that of CL (K app = 0.01876 min −1 ), which was consistent with the previous reports 41,42 .The molecular weight (M n,NMR ) increased linearly with the monomer conversion (Fig. 2c). The chemical structure of PVLSH was demonstrated by 1 H NMR (Fig. 3b), 1 H-1 H COSY ( Figure S1b), 13 C NMR ( Figure S2b), MALDI TOF MS (Fig. 4b) and SEC (Fig. 5b). To further confirm the living/controlled nature of diphenyl phosphate (3) Figure S4) and 13 C NMR ( Figure S5) illustrated the chemical structures of block copolymers. The polyesters with thiol functionality enabled multiple promising applications [22][23][24][25] . The resultant PCLSH (M n,NMR = 5400 g/mol, Ð M = 1.09, thiol fidelity = 96%) protected silver nanoparticles were prepared through two phase method 25 . Well-dispersed silver nanoparticles were clearly shown in TEM (Fig. 8), which was promising in biospecific labeling.

Conclusions
A novel metal-free and protecting-group-free green synthetic approach to thiol-functionalized polymers was developed by the utility of organocatalysis. Trifluoromethanesulfonic acid (1), HCl.Et 2 O (2), diphenyl phosphate (3), γ-resorcylic acid (4) and methanesulfonic acid (5) all showed chemoselective activity toward hydroxyl and thiol. Diphenyl phosphate (3) achieved relative higher quantitative chemoselectivity in synthesis of well-defined thiol-terminated homo-and block-polyesters. Density functional theory calculations explained that it was attributed to stronger bifunctional activation of monomer and initiator/chain-end and lower energy Metal nanoparticle preparation. The silver nanoparticles were prepared by two-phase method. 5 mL (0.10 mol/L) (n-C 8 H 17 ) 4 NBr in toluene and 5 mL (0.05 mol/L) aqueous solution of AgNO 3 was mixed under rapid stirring. Thiol-terminated PCL (M n,NMR = 5400, Ð M = 1.09) (0.2650 g, 0.05 mmol) in 5 mL toluene was added followed by slow addition of 5.0 mL freshly prepared aqueous solution of NaBH 4 (0.25 mol/L). The organic phase of reaction mixture was separated and concentrated by evaporation at room temperature and finally dissolved in chloroform.
Computational details. All calculations were performed using the Gaussian 03 program 51 . The hybrid functional B3LYP was employed at the DFT level of theory. Sulfur, nitrogen, carbon, oxygen and hydrogen atoms were described with a 6-31 G(d,p) double-z basis set. Phosphorus atoms were treated with LANL2DZ. Geometry  optimizations were carried out under extremely tight criteria without any symmetry restrictions, and the nature of the extrema was verified with analytical frequency calculations. Thermal correction to Gibbs free energies was obtained at 298.2 K and 1.013 × 10 5 Pa. The reference energy has been set to zero for the most stable ternary adduct of reactants.
Characterizations. NMR spectra were recorded on a Bruker (400 MHz) in CDCl 3 with tetramethylsilane (TMS) as the internal reference. Size exclusion chromatography (SEC) was performed on Wyatt system equipped with a SSI 1500 pump and a Waters Styragel HR 2.5 μm, 300 mm × 7.8 mm column by using THF (0.7 mLmin −1 ) as eluent at room temperature. Matrix assisted laser desorption ionization time of flight mass spectra (MALDI TOF MS) were recorded at 25 kV on the Bruker mass spectrometer (ultraextreme). The polymer and the matrix 2,5-dihydroxybenzoic acid (DHB) were dissolved in CH 2 Cl 2 . 1 μl of the sample solution was piped onto the thin NaI crystal layer and dried in air. All mass spectra were collected by employing 500 individual laser shots. Transmission electronic microscopy (TEM) was conducted on a JEM-200cx operating at 200 kV. The sample was prepared by dipping the TEM copper grid to a dilute dispersion of silver nanoparticles in chloroform and solvent was evaporated at room temperature.