Switching Chemoselectivity: Using Mechanochemistry to Alter Reaction Kinetics

Abstract A reaction manifold has been discovered in which the chemoselectivity can be altered by switching between neat milling and liquid assisted grinding (LAG) with polar additives. After investigation of the reaction mechanism, it has been established that this switching in reaction pathway is due to the neat mechanochemical conditions exhibiting different kinetics for a key step in the transformation. This proof of concept study demonstrates that mechanochemistry can be used to trap the kinetic product of a reaction. It is envisaged that, if this concept can be successfully applied to other transformations, novel synthetic processes could be discovered and known reaction pathways perturbed or diverted.


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H, 19 F and 13 C NMR spectra were obtained on Bruker 400 Ultrashield TM and Bruker 500 MHz spectrometers with chloroform-d as deuterated solvent. The obtained chemical shifts δ are reported in ppm and are referenced to the residual solvent signal. Spin-spin coupling constants J are given in Hz.
High resolution mass spectral (HRMS) data were obtained on a Thermo Scientific LTQ Orbitrap XL by the EPSRC UK National Mass Spectrometry Facility at Swansea University or on a Waters MALDI-TOF mx in Cardiff University.
Infrared spectra were recorded on a Shimadzu IR-Affinity-1S FTIR spectrometer. Peaks of medium or higher intensity are reported.
Melting points were measured using a Gallenkamp apparatus and are reported uncorrected.
The ball mill used was an InSolidoTech IST500 mixer mill. Unless otherwise stated, mechanochemical reactions were performed in 14 mL stainless steel jars with one stainless steel ball of mass 4 g at a milling frequency of 30 Hz.
All chemicals were obtained from commercial sources and used without further purification unless stated otherwise.

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General Procedure for mechanochemical reactions Liquid Assisted Grinding (LAG) Screen 2,2-difluoro-1,3-diphenylpropane-1,3-dione (0.065 g, 0.25 mmol.), diphenyl disulfide (0.055 g, 0.25 mmol.), cesium carbonate (0.244 g, 0.75 mmol.) and the liquid additive were added to a 14 mL stainless steel jar and a ball added. The mixture was milled for one hour and the resulting mixture transferred into a flask by manually removing the material with a spatula and washing with ethyl acetate (approximately 40 mL). The insoluble material was removed by gravity filtration. α,α,α-trifluorotoluene (0.020 mL, 0.16 mmol) was added as a standard and 19 F NMR was taken of the crude mixture to determine the yields of different products.
2,2-difluoro-1,3-diphenylpropane-1,3-dione (0.065 g, 0.25 mmol.), cesium carbonate (0.244 g, 0.75 mmol), diphenyl disulfide (0.055 g, 0.25 mmol) and DMSO (0.050 mL) were added to a 14 mL stainless steel jar and charged with one stainless steel ball (10 mm, 4.1 g). The reaction mixture was milled at 30 Hz for one hour. The resulting mixture was transferred into a flask by manually removing the material with a spatula and washing with ethyl acetate (approximately 40 mL). The insoluble material was removed by gravity filtration. α,α,α-trifluorotoluene (0.020 mL, 0.16 mmol) was added as a NMR standard and 19 F NMR was taken of the crude reaction mixture and the yield determined to be 62%. The mixture was then added to a separating funnel with distilled water (40 mL). The aqueous layer was extracted with ethyl acetate (2 x 40 mL), the organic layers combined, washed with brine (50 mL), dried (MgSO4), and the solvent removed under reduced pressure to yield the crude product. This material was purified by flash column chromatography with gradient elution (0 -10% ethyl acetate in petroleum ether) to yield the product as a colourless oil (0.038 g, 0.14 mmol., 56%).
α,α,α-trifluorotoluene (0.020 mL, 0.16 mmol) was added as a NMR standard and 19 F NMR was taken of the crude reaction mixture and the yield determined to be 88%. The mixture was then added to a separating funnel with distilled water (40 mL). The aqueous layer was   were added to a 14 mL stainless steel jar and charged with one stainless steel ball (10 mm, 4.1 g). The reaction mixture was milled at 30 Hz for one hour. The resulting mixture was transferred into a flask by manually removing the material with a spatula and washing with ethyl acetate (approximately 40 mL). The insoluble material was removed by gravity filtration. α,α,α-trifluorotoluene (0.020 mL, 0.16 mmol) was added as a NMR standard and 19 F NMR was taken of the crude reaction mixture to determine the yields. To measure the quantity of benzoic acid (for the LAG case), the residue was then transferred into a separating funnel, washing with dichloromethane (30 mL) and water (30 mL). The layers were separated and the aqueous layer further extracted with dichloromethane (2 x 30 mL).
The aqueous phase was acidified to pH 1 with HCl (1 M) then extracted with dichloromethane (3 x 30 mL). This organic phase was dried (MgSO4), filtered and the solvent removed under reduced pressure to yield benzoic acid (0.011 g, 0.09 mmol., 36%).

Effect of time on yield for LAG reaction
The reactions were run as in GP1 but for different times.

Effect of time on yield for neat grinding reaction
The reactions were run as in GP2 but for different times.

Effect of quantity of DMSO on LAG reaction
The reactions were run as in GP1 but for 10 minutes with different added quantities of DMSO. Yield 4 S11 Solution comparison for different times 2,2-difluoro-1,3-diphenylpropane-1,3-dione (0.520 g, 2 mmol.), cesium carbonate (1.952 g, 6 mmol), diphenyl disulfide (0.440 g, 2 mmol) and DMSO (10 mL) were added to a flask, which was stirred at room temperature. α,α,α-trifluorotoluene (0.160 mL, 1.3 mmol) was added as a NMR standard. After stirring for the desired time, a sample was removed from the reaction mixture and filtered through cotton wool into an NMR tube. 19 F NMR was taken of this mixture and the yields determined.
The mixture was milled for one hour. The residue was then transferred into a separating funnel, washing with ethyl acetate (30 mL) and water (30 mL). The layers were separated and the aqueous layer further extracted with ethyl acetate (2 x 30 mL). The combined organic phase was dried (MgSO4), filtered and the solvent removed under reduced pressure. This reaction and workup procedure was repeated ten times and the crude material combined and purified by flash column chromatography with gradient elution (0 -10% ethyl acetate in petroleum ether) to yield the product as a yellow oil (0.240 g, 0.77 mmol., 62%).