Acid-Base Bifunctional Shell Cross-Linked Micelle Nanoreactor for One-pot Tandem Reaction

Transcription

1 Supporting Information Acid-Base Bifunctional Shell Cross-Linked Micelle Nanoreactor for One-pot Tandem Reaction Li-Chen Lee, a# Jie Lu, b# Marcus Weck, b * Christopher W. Jones a * a School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA , United States b Molecular Design Institute and Department of Chemistry, New York University, New York, NY , United States # These authors contributed equally to this work. Corresponding Authors: cjones@chbe.gatech.edu; marcus.weck@nyu.edu Table of Contents Materials Measurements Synthesis Typical preparation of SCMs Hydrolysis of ester functional groups for triblock copolymers/scms Boc-deprotection for triblock copolymers/scms General procedure for Deacetalization-Henry reaction Table S1 Table S2 Figure S1, S2 Characterizations Figure S3, S4 Figure S5, S6 Figure S7 Figure S8 References S2 S2 S3 S4 S4 S5 S5 S6 S7 S8 S8 S9 S10 S11 S12 S13 S1

2 Materials Methyl 3-(oxazol-2-yl)propionate (EsterOx, monomer A) 1, 2-(3-butenyl)-1,3-oxazoline (AlkeneOx, monomer B) 2, and 2-nonyl-2-oxazoline (NOx, monomer C) 3 were synthesized based on adapted literature procedures. All reagents were purchased from standard suppliers and used as received unless otherwise stated. 2-Methyl-2-oxazoline, acetonitrile and chlorobenzene were distilled over CaH 2 and stored under dry argon and molecular sieves (4 Å). Methyl triflate was distilled over barium oxide and stored under dry argon at 4 C. Dichloromethane was dried by passing through columns of activated alumina. The ph 7.0 buffer solution was prepared by potassium dihydrogen phosphate / disodium hydrogen phosphate. The anhydrous CH 3 NO 2 was purchased from Sigma-Aldrich with over molecular sieve (H 2 O 0.01%). Flash column chromatography was performed using silica gel 60 Å ( mesh) purchased from Sorbent Technologies. Measurements 1 H NMR and 13 C NMR spectra were recorded at 25 C on a Bruker AC 600 MHz and Bruker DRX-400 spectrometers. All chemical shifts are reported in parts per million (ppm) with reference to solvent residual peaks. Gel-permeation chromatography (GPC) was carried out using a Shimadzu pump coupled to a Shimadzu RI detector. A 0.03 M LiCl solution in N,Ndimethylformamide was used as eluent at a flow rate of 1 ml/min at 60 C. A set of Polymer Standards columns (AM GPC gel, 10 μm, precolumn, 500 Å and linear mixed bed) was used. M app w, M app n, and Ð represent the apparent weight-average molecular weight, apparent numberaverage molecular weight, and dispersity index, respectively. Commercially available poly (styrene) standards were used for calibration. A 3.5K MWCO membrane was used to purify the triblock copolymers and SCMs in dialysis. Hydrodynamic diameters and size distributions (% S2

3 PD: percentage of polydispersity) of micelles and SCMs were determined at 25 o C by dynamic light scattering (DLS) using a Protein Solution DynaPro instrument with a 663 nm laser module. The thiol-ene click addition was irradiated by Rayonet Chamber Reactor, RMR-600 model. Synthesis Scheme S1. Synthesis of polymer I Polymer I: A typical procedure for the cationic ring-opening polymerization was as follows: Methyl triflate (28.29 μl, 0.25 mmol) was added to a solution of monomer A EsterOx (1.65 ml, 12.5 mmol) in chlorobenzene (12 ml) and acetonitrile (2 ml). The mixture was stirred for 48 h at 70 C and was monitored by 1 H NMR based on the disappearances of the monomer peaks at 3.8 and 4.2 ppm as well as the appearances of the side chain peaks (Figure S2 and S3). After monomer A was completely consumed, monomer B AlkeneOx (0.64 ml, 2.5 mmol) and chlorobenzene (1 ml) was added to the polymer solution under an argon atmosphere. The mixture was stirred for eight hours at 70 C. After monomer B was fully consumed, monomer C NOx (0.52 ml, 2.5 mmol) were added. The solution was stirred at 70 C for an additional 36 h. S3

4 After monomer C was fully consumed, the polymerization was terminated via the addition of Boc-protected tris(2-aminoethyl) amine 4 (174 mg, 0.5 mmol) and stirred at room temperature for 4 h. The polymer was purified by dialysis against DCM and isolated by freeze-drying from dioxane. The repeat units for A EsterOx (a = 50), B AlkeneOx (b = 13), and C NOx (c = 10) were determined by 1 H NMR spectroscopy end group analysis (Figure S3 and S4). The molecular weight distributions were determined by GPC using DMF as the eluent: M app n = 12,500 g/mol, D = 1.13 (Fig. S5). Typical preparation of SCMs The triblock copolymer I (50 mg) was dissolved in methanol (10 ml), and the solution was filtered by passing through a 0.2 µm PTFE syringe filter. 1,5- Pentanedithiol (2.7 µl, 0.02 mmol) and 2,2 -dimethoxy-2-phenylacetophenone (25.6 mg/10 ml in methanol, 20 μl, 0.2 μmol) were added into micelle methanol solution. The micelle solution was thoroughly degassed by bubbling through nitrogen before being transferred into a 20 ml sample glass vial. The solution was irradiated in a Rayonet photoreactor for ca. 10 h until most alkenic protons in polymer I were consumed. The organic solvents were removed by rotary evaporation and the residue was washed by hexane to give a light yellowish powder (50 mg). The micelle formation was confirmed by DLS at 25 C (Figure S8). The stable hydrodynamic radius of the SCM in different solvents proved the success of crosslinking. Hydrolysis of ester functional groups for triblock copolymers/scms Triblock copolymer/scm (200 mg) was dissolved in 5 ml methanol, and 5 ml of NaOH (0.1 M) solution was added into methanol solution. The mixed solution was stirred at 60 0 C. After 12 h, solvent was removed under reduced pressure, and the residue was redissolved in 5 ml water, HCl (0.1 M) was added in to water solution to adjust the ph to 7. The polymers/scms were purified by S4

5 dialysis against DI-water. Final pure powder (200 mg) could be collected by removing water under reduced pressure. Boc-deprotection for triblock copolymers/scms Triblock copolymers/scms (200 mg) was dissolved in CHCl 3 (10 ml) with excess TFA and stirred at room temperature for overnight. CHCl 3 and TFA were removed by rotary evaporation and the residue was redissolved in methanol and adjust ph to 7 by K 2 CO 3 / MeOH saturated solution. The polymers/scms were purified by dialysis against methanol. Final pure powder (192 mg) could be collected by removing MeOH under reduced pressure. General Procedure for Deacetalization-Henry reaction Regarding the optimization of the experimental conditions, we used excess water instead of a catalytic amount of water in the reaction because SCMs are only very soluble in an aqueous environment. However, water has some acidity and is able to catalyze the deacetalization in the absence of other catalysts. Also, a large excess of water could catalyze the Henry reaction as well. To reduce the background conversion of the reactions, we used ph=7 buffer and pure, anhydrous CH 3 NO 2 to replace the distilled water and as-received CH 3 NO 2. Generally, benzaldehyde dimethyl acetal (37.5 µl, 0.25 mmol) and SCMs (8 mg, roughly 10 mol% of acid and 0.2 mol% of base) were dissolved in 0.2 ml H 2 O (ph=7 buffer) and 1.0 ml anhydrous CH 3 NO 2 mixed solution. The mixed solution was transferred into Schlenk flask and went through a freeze-pump-thaw process to remove oxygen. The reaction was conducted under nitrogen and stirred at 90 0 C. After 24 h, the wet mixed solution was dried by MgSO 4 and CH 3 NO 2 was removed under reduced pressure. The yield of the product was determined by 1 H NMR spectroscopy. For further investigations of the catalytic activity of TREN in the micelle core, we used another set of experimental conditions to limit the S5

6 background signal that was caused by the presence of excess water in the Henry reaction (Table S1). The reaction did not proceed in the absence of TREN (Table S1, entry 1 and 2). In contrast, TREN either in the SCM core or in an uncrosslinked polymer, showed high catalytic performance (Table S1, entry 3 and 4). Table S1. Nitroaldol reaction catalyzed by various catalysts. Entry a Catalyst Yield of 3 [%] b 1 None N.R. 2 P-P N.R. 3 P-TREN 86 4 Polymer II mol% TREN >99 6 COOH-P N.R. 7 COOH-TREN 32 8 Polymer III mol% AcOH N.R mol% AcOH mol% TREN 7 a Reaction conditions: 0.25 mmol of benzaldehyde, 8 mg of micelle (or polymer), 0.01 ml H 2 O (ph=7 buffer) and 1.0 ml anhydrous CH 3 NO 2 at 90 0 C under N 2 for 24 h. b The reaction yield was determined by 1 H NMR spectroscopy. S6

7 Table S2. Optimizations of one pot deacetalization-nitroaldol reaction cascade. Entry a Catalyst Temp ( 0 C) H 2 O (µl) Conv. Of Yield of Yield of 1 [%] b 2 [%] b 3 [%] b 1 P-P COOH-P P-P COOH-P None mol% AcOH > mol% AcOH+0.2 mol% TREN > P-P COOH-P COOH-TREN P-P COOH-P COOH-TREN a Reaction conditions: 0.25 mmol of benzaldehyde dimethyl acetal, 8 mg of micelle, certain amount of ml H 2 O (ph=7 buffer) and 1.0 ml anhydrous CH 3 NO 2 under N 2 for 24 h. b The reaction yield was determined by 1 H NMR spectroscopy. S7

8 Figure S1. Reaction conditions: 0.25 mmol of benzaldehyde dimethyl acetal, 8 mg of catalysts, 0.2 ml H 2 O (ph=7 buffer) and 1.0 ml anhydrous CH 3 NO 2 at 90 0 C under N 2 for certain time. And, the reaction yield was determined by 1 H NMR spectroscopy. S8

9 Characterization Figure S2. 1 H NMR spectra of the three 2-substituted-2-oxazoline monomers. Figure S3. 1 H NMR spectra of each block during the triblock copolymer synthesis. S9

10 driu Figure S4. 1 H NMR spectrum of triblock copolymer I time (min) Figure S5. Normalized gel-permeation chromatogram of triblock copolymer I. S10

11 Figure S6. The thiol-ene addtion and Boc deprotection were monitored by 1 H-NMR (CDCl 3 ). Figure S7. The hydrolysis of the ester was monitored by 1 H-NMR (D 2 O). S11

12 DLS Sample Solvent Size (nm) A Polymer I Water 37 ± 6 B Polymer I DMF 2.5 ± 0.4 C P-P SCM Water 30 ± 3 D P-P SCM DMF 32 ± 3 E COOH-TREN SCM Water 18 ± 3 F COOH-TREN SCM DMF 19 ± 2 Figure S8. DLS profiles of A) polymer I in water; B) polymer I in DMF and C) P-P SCM in water; D) P-P SCM in DMF; E) COOH-TREN SCM in water and F) COOH-TREN SCM in DMF. S12

13 References 1 Zarka, M. T., Nuyken, O. & Weberskirch, R. Chem. Eur. J. 2003, 9, Puts, R. D. & Sogah, D. Y. Tetrahedron Lett. 1994, 35, Bodner, T., Ellmaier, L., Schenk, V., Albering, J. & Wiesbrock, F. Polym. Int. 2011, 60, Kim, C.; Shah, B. P.; Subramaniam, P.; Lee, K. B. Mol. Pharm. 2011, 8, S13