Development of solvent-free synthesis of hydrogen-bonded supramolecular polyurethanes

A solvent free ball-milling method for the synthesis of small molecule and oligomeric carbamates is described that is applicable to supramolecular polymer synthesis.


GENERAL EXPERIMENTAL METHODS
All reactions were performed under a nitrogen atmosphere unless otherwise stated. Reagents were purchased from major suppliers and used without further purification unless otherwise stated. Anhydrous toluene, hexane, diethyl ether, tetrahydrofuran and chloroform were obtained from the in-house solvent purification system from Innovative Inc. PureSolv ® .
Anhydrous dimethylacetamide and 1,4-dioxane were obtained from Sigma Aldrich equipped with Sure/Seal™. Triethylamine was distilled from calcium hydride and was stored under nitrogen over potassium hydroxide pellets prior to use. 1-Propanol was distilled from calcium hydride directly before use. Poly(ethylene glycol)-block-poly(propylene glycol)-blockpoly(ethylene glycol) was heated at 60°C, over 4Å molecular sieves under vacuum for 6 hours prior to use. DABCO was recrystallized from petroleum ether and dried before use.
Prior to use, TBD was dried by stirring in tetrahydrofuran with calcium hydride, filtering and removing the solvent in vacuo. Analytical thin layer chromatography was performed on Merck Kiesegel 60 F 254 0.25 mm pre-coated aluminium plates. Product spots were visualised under UV light (λ max = 254 nm). Flash chromatography was carried out using Merck Kieselgel 60 silica gel. Nuclear magnetic resonance spectra were obtained using a Bruker AMD300 or Bruker DMX500 spectrometer operating at 300 MHz or 500 MHz for 1 H spectra and 75 MHz or 125 MHz for 13 C spectra as stated. Reactions followed by infra-red spectroscopy used a Perkin-Elmer FTIR spectrometer where absorption maxima (υ max ) are quoted in wavenumbers (cm -1 ) and only structurally relevant absorptions have been included.
High Resolution Mass Spectra (HRMS) were recorded on a Bruker Daltonics microTOF using electrospray ionisation (ESI).

General procedure for solution based carbamate synthesis
The alcohol (2.0 mmol) was stirred in the required dry solvent (20 mL) at the required temperature. The required amount of catalyst (10 mol%) was added in one portion and stirred for a further 10 minutes. Methylene diphenyl diisocyanate (0.25 g, 1.0 mmol) was added in one portion and the reaction mixture was stirred for a further 6 hours before removal of the solvent in vacuo. The recovered solid was purified by column chromatography.

General procedure for solid phase carbamate synthesis
The alcohol (1.85 mmol), the required amount of catalyst (10 mol%) and the isocyanate or diisocyanate (1.85 mmol or 0.93 mmol) were added in one portion to the reaction cups (stainless steel, 10 mL) and the reaction mixture was ball-milled for 3 minute intervals at 20 Hz. The recovered solid was subjected to crude 1 H NMR and LC-MS analysis. The Retsch Mixer Mill 200 was supplied by Retsch.
MDI (0.5 g, 2 mmol) was added in one portion and the reaction mixture was stirred for a further 6 hours before removal of the solvent in vacuo. The recovered solid was subjected to crude NMR analysis only.
Bulk Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (2 mL, 1 mmol), the required amount of catalyst (10 mol%) and MDI (0.5 g, 2 mmol) were added in one portion to the reactions cups (stainless steel, 10 mL) and the reaction mixture was milled for 5 minute intervals at 25 Hz, at which point small aliquots were removed for IR analysis.
The recovered solid was subjected to crude NMR analysis to confirm identity of the material and conversion. Bulk for 7a 5,6-dimethyl 2-aminobenzimidazole 4 (0.32 g, 2 mmol) was added to the product 3 obtained from the reaction of Poly(ethylene glycol)-block-poly(propylene glycol)-blockpoly(ethylene glycol) 1 with MDI 2 to the reactions cups (stainless steel, 10 mL) and the reaction mixture was milled for 5-minute intervals at 25 Hz. After satisfaction of NCO stretches by IR, the diotpic DAC 6 was added in one portion and the reaction mixture further milled at 5 min intervals for 20 min until a homogenous sample was obtained which was dried further in vacuo and subjected to NMR and IR analysis to confirm identity of the material.

Di-2-(2-ethoxyethoxy)ethyl 4,4'-methylenebis(4,1-phenylene)dicarbamate 9b
The compound was prepared following the same procedure as for 9a on a 2 mmol scale. A sample was purified by column chromatography eluting with (       Partial crude NMR (DMSO-d 6, 500 MHz). 1 equiv. of 2, 2 equiv. of 8a. Crude conversion was taken by integrating MDI protons in the desired product (doublets at 7.1ppm and 7.3ppm) against unreacted (6.5ppm and 6.8ppm) material. Fig. S12-demonstrating catalyst effect in toluene at room temperature for 6hr. Partial crude NMR (DMSO-d 6, 500 MHz); Crude conversion was taken by integrating MDI protons in the desired product (doublets at 7.1ppm and 7.3ppm) against unreacted (6.5ppm and 6.8ppm) and side product material. Reaction concentration 0.05 M, 10 mol% catalyst used, 1 equiv. of 2, 2 equiv. of 8b, toluene, rt. Fig. S17-demonstrating catalyst effect in toluene at room temperature for 6hr. Partial crude NMR (DMSO-d 6, 500 MHz); Crude conversion was taken by integrating MDI protons in the desired product (doublets at 7.1ppm and 7.3ppm) against unreacted (6.5ppm and 6.8ppm) and side product material. Reaction concentration 0.05 M, 10 mol% catalyst used, 1 equiv. of 2, 2 equiv. of 8b, toluene, 40°C.  S22-Overlaid partial IR spectra of the reaction between MDI 2 and diol terminated PEG-PPG-PEG 1 in toluene at 40 °C with Et 3 N catalysis for 6hr. In the reaction, -NCO functionality is retained, which is exhibited as a strong absorption at 2200cm -1 .   Differential Scanning Calorimetry (DSC) scans of supramolecular polymers formed synthesized in a ball mall solvent-free using a 2:1 NCO to OH ratio 7a (top) and 4:1 NCO to OH ratio 7b (bottom). Scans were conducted between -90 °C and 210 °C, at a heating and cooling rate of 10 deg min -1 after N 2 purge. Comparison is made to supramolecular polymers, which are synthesized using standard solution methodology.