Stereoregular functionalized polysaccharides via cationic ring-opening polymerization of biomass-derived levoglucosan

We report the facile synthesis and characterization of 1,6-α linked functional stereoregular polysaccharides from biomass-derived levoglucosan via cationic ring-opening polymerization (cROP). Levoglucosan is a bicyclic acetal with rich hydroxyl functionality, which can be synthetically modified to install a variety of pendant groups for tailored properties. We have employed biocompatible and recyclable metal triflate catalysts – scandium and bismuth triflate – for green cROP of levoglucosan derivatives, even at very low catalyst loadings of 0.5 mol%. Combined experimental and computational studies provided key kinetic, thermodynamic, and mechanistic insights into the cROP of these derivatives with metal triflates. Computational studies reveal that ring-opening of levoglucosan derivatives is preferred at the 1,6 anhydro linkage and cROP proceeds in a regio- and stereo-specific manner to form 1,6-α glycosidic linkages. DFT calculations also show that biocompatible metal triflates efficiently coordinate with levoglucosan derivatives as compared to the highly toxic PF5 used previously. Post-polymerization modification of levoglucosan-based polysaccharides is readily performed via UV-initiated thiol–ene click reactions. The reported levoglucosan based polymers exhibit good thermal stability (Td > 250 °C) and a wide glass transition temperature (Tg) window (<−150 °C to 32 °C) that is accessible with thioglycerol and lauryl mercaptan pendant groups. This work demonstrates the utility of levoglucosan as a renewably-derived scaffold, enabling facile access to tailored polysaccharides that could be important in many applications ranging from sustainable materials to biologically active polymers.

and Omnirad 2100 was sandwiched between two polished NaCl plates. Once the sample was exposed to UV light, spectra were recorded every 20 ms at an average of 1 scan with a spectral resolution of 16 cm −1 . To calculate poly(3) ene conversion due to UV irradiation (OmniCure S1500 Curing System, 100 mW/cm 2 ), the intensity reduction of C=C double bond peak at 925 cm −1 as compared to the initial peak was calculated. The double bond peak area was normalized to the non-reactive CH2 stretches at 2976 cm −1 for the thioglycerol mixture, and 2926 cm −1 for the lauryl mercaptan mixture respectively.

Preparation and Characterization of 3
Two synthetic routes were investigated for 3 as described below.

Synthetic Route 1
In a 250 mL round-bottom flask, levoglucosan ( After 120-hour reaction, the aqueous layer was extracted with diethyl ether (3 x 200 mL).
The organic layer was dried over Na2SO4 and the filtrate was then concentrated via rotary evaporation. The crude mixture was subjected to column chromatography on silica gel (4:1 Hexanes:EtOAc) to isolate 3 as a yellow oil (Yield = 75%).
After 24-hour reaction, the aqueous layer was extracted with dichloromethane (3 x 100 mL). The organic layer was dried over Na2SO4 and the filtrate was then concentrated via rotary evaporation. The crude mixture was subjected to column chromatography on silica gel (4:1 Hexanes:EtOAc) to isolate 3 as a yellow oil (Yield = 36%).

Representative polymerization procedure of 2 in 100% CH2Cl2 or MeCN
In a nitrogen-filled glovebox, the required amount of catalyst (e.g. 0.01 mmol for 2 mol% catalyst loading) was weighed out in an 8 ml scintillation vial. A Teflon coated stir bar was added to this vial. 2 (0.5 mmol) was dissolved in CH2Cl2 or MeCN (e.g. 500 μL for initial monomer concentration of 1M) and added to the vial containing the catalyst. The vial was sealed with a Teflon lined cap and the polymerization solution was stirred at RT inside the glovebox. After 72 hours, the vial was removed from the glovebox. The polymerization was quenched with methanol (100 μL) or tert-butyl alcohol (100 μL) and stirred for an additional 10 mins. The crude reaction mixture was analyzed by 1 H NMR spectroscopy to determine conversion. The polymer was then precipitated twice into cold methanol. The methanol was removed, and the polymer was dried under vacuum overnight. Typical poly(2) yield ranged from 65 to 90%.

Representative polymerization procedure of 2 in a mixed solvent system
In a nitrogen-filled glovebox, the required amount of Sc(OTf)3 (e.g. 0.01 mmol for 2 mol% catalyst loading) was weighed out in an 8 ml scintillation vial. MeCN (e.g. 50 μL for 10% MeCN) was added to the vial containing Sc(OTf)3, along with a Teflon coated stir bar. 2 (0.5 mmol) was dissolved in CH2Cl2 (e.g. 450 μL for 90% CH2Cl2 and for total initial monomer concentration of 1M) and added to the vial containing Sc(OTf)3. The vial was sealed with a Teflon lined cap and the polymerization solution was stirred at RT inside the glovebox. After 72 hours, the vial was removed from the glovebox. The polymerization was quenched with methanol (100 μL) or tertbutyl alcohol (100 μL) and stirred for an additional 10 mins. The crude reaction mixture was analyzed by 1 H NMR spectroscopy to determine conversion. The polymer was then precipitated twice into cold methanol. The methanol was removed, and the polymer was dried under vacuum overnight. Typical poly(2) yield ranged from 37 to 68%.
Monomer conversion was determined by 1 H NMR analysis of the crude polymerization mixture.
For this purpose, the C1 anomeric proton was used which is labeled using a purple circle in the monomer 2 and crude polymerization mixture spectra. The conversion was calculated as follows.
! corresponds to the integration of polymer repeat unit proton and " corresponds to the integration of the anomeric proton in 2.

Representative polymerization procedure of 3 in 100% CH2Cl2
In a nitrogen-filled glovebox, the required amount of catalyst (e.g. 0.017 mmol for 5 mol% catalyst loading) was weighed out in an 8 ml scintillation vial. A Teflon coated stir bar was added to this vial. 3 (0.354 mmol) was dissolved in CH2Cl2 (354 μL for initial monomer concentration of 1M) and added to the vial containing the catalyst. The vial was sealed with a Teflon lined cap and the polymerization solution was stirred at RT inside the glovebox. After 72 hours, the vial was removed from the glovebox. The polymerization was quenched with tert-butyl alcohol (100 μL) and stirred for an additional 10 mins. The crude reaction mixture was analyzed by 1 H NMR spectroscopy to determine conversion. The polymer was precipitated into a cold mixture of 50:50 water : methanol. The precipitation solvent was then removed, and the isolated polymer was redissolved in CH2Cl2. Water was removed by drying over Na2SO4, followed by rotary evaporation of the filtrate and finally drying the polymer under vacuum overnight. Typical poly(3) yield ranged from 38 to 91%.

Representative polymerization procedure of 3 in a mixed solvent system
In a nitrogen-filled glovebox, the required amount of Bi(OTf)3 (e.g. 0.017 mmol for 5 mol% catalyst loading) was weighed out in an 8 ml scintillation vial.

Overall cROP kinetics of monomer 2
In a nitrogen-filled glovebox

Determination of rate law for cROP of 2
Based on the results of the previous study, it was decided that conversion data between 0 and 4 h will be utilized to evaluate the reaction order for cROP of 2. To obtain sufficient time points within this region, the kinetic study was repeated in duplicate for a total reaction time of 3 h. In a nitrogen-filled glovebox, 5.13 mg of Sc(OTf)3 (0.0104 mmol for 0.5 mol% catalyst loading) was weighed out in an 8 ml scintillation vial. A Teflon coated stir bar was added to this vial. 900 mg of 2 (2.08 mmol) was dissolved in CH2Cl2 (1040 μL for initial monomer concentration of 2M) and added to the vial containing the catalyst. The vial was sealed with a Teflon lined cap and the polymerization solution was stirred at RT inside the glovebox. At each specified time point, an aliquot was taken from this reaction mixture inside the glovebox and was quenched by adding isopropanol. The crude reaction mixture was analyzed by 1 H NMR spectroscopy to determine conversion.

Fitting plots to determine rate law for cROP kinetics of 2
To investigate whether the cROP of 2 follows zero, first or second order kinetics with respect to monomer concentration, the following plots were constructed.

Zero Order Kinetics
For zero order kinetics, a plot of For cROP of 2, kobs could not be calculated and it is hypothesized that the cROP kinetics for 2 may follow more complex rate laws.

Overall cROP kinetics of monomer 3
In a nitrogen-filled glovebox, 28 mg of Bi(OTf)3 (0.043 mmol for 1 mol% catalyst loading) was weighed out in an 8 ml scintillation vial. A Teflon coated stir bar was added to this vial.

Fitting plots to determine rate law for cROP kinetics of 3
To investigate whether the cROP of 3 follows zero, first or second order kinetics with respect to monomer concentration, the following plots were graphed as described in section 5.3.

Synthesis and Purification of poly(4)
In a 4 mL vial, poly ( in ethanol was then added to the vial containing thioglycerol and further mixed by vortexing at room temperature. The formulation was irradiated with UV light (OmniCure S1500 Curing System, 100 mW/cm 2 ) for 10 min to synthesize poly(4). poly(4) was isolated from the crude mixture via a two-step purification method. In the first step, the crude mixture was redissolved in excess water and extracted thrice with dichloromethane to remove unreacted poly(3). The aqueous layer was then dialyzed in water (1 kDa RC dialysis tubing) to remove any unreacted thioglycerol. The purified polymer was concentrated by rotary evaporation and finally the polymer was dried under vacuum for 48 h.

Synthesis and Purification of poly(5)
In a 4 mL vial, poly ( Figure S22. FTIR spectra for poly(3)-thioglycerol as a function of irradiation time. Figure S23. FTIR spectra for poly(3)-lauryl mercaptan as a function of irradiation time.           Figure S40. SEC trace of poly(2).

Computational Methods
Extensive conformational analysis of reactants and products was carried out using  Figure S45. Optimized ring-opening transition state structures of allyl and benzyl substituted levoglucosan derivatives catalyzed by various Lewis acids (Bi(OTf)3, Sc(OTf)3 and PF5) and their respective free energy of activations (kcal/mol) with respect to I1 are provided in the parenthesis. Distances are in Å.

Nucleophilic Addition of Monomer to I2
The carbenium intermediate I2, is formed after the ring opening of allyl or benzyl derivatives of levoglucosan step. Subsequently, The nucleophilic addition of another monomer to the carbenium intermediate generates new C-O linkage through TS structure TS2. The nucleophilic addition step can occur either backside attack (TS2a) or frontside attack (TS2β) ( Figure S46). We have considered a variety of conformations for this nucleophilic addition (TS2a and TS2β) step using Bi(OTf)3 for allyl and benzyl monomers ( Figure S47). Interestingly, the computed energetics evident that the formation of intermediate I3 (1,6-a linkage) through TS2a is preferred over I4 through TS2β (1,6-β linkage).  Figure S48. Alternative Possible Pathways for the cationic ring-opening polymerization of Levoglucosan derivatives catalyzed by Lewis acids. The free energy of activations (ΔG ‡ in kcal/mol) with respect to I1 are provided.