Palladium-catalyzed hydrogenations in dichloromethane

Abstract Dichloromethane is shown to be a useful solvent in catalytic hydrogenation reactions of easily reduced functional groups (alkenes, alkynes, imines, and nitroarenes) using palladium on carbon as the catalyst under mild conditions (ambient pressure and temperature). Graphical Abstract


Introduction
The most commonly used solvents for reductions of alkenes via catalytic hydrogenation using palladium on carbon as the catalyst include ethanol, methanol, isopropyl alcohol, and ethyl acetate. [1,2] Less commonly employed solvents include tetrahydrofuran, 2methyltetrahydrofuran, isopropyl acetate, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and acetone. All the above-mentioned solvents are flammable. A recent publication compared the pyrophoricity of palladium on carbon catalysts filtered from these 11 solvents. [3] Self-ignition was observed with methanol, ethanol, and isopropyl alcohol.
Compounds being used in conjunction with another of our research projects had limited solubility in the above-mentioned hydrogenation solvents but were readily soluble in dichloromethane (DCM). DCM has previously been used in hydrogenation reactions with palladium on carbon catalysts, most often in mixed solvent systems and at high pressures and/or temperatures. [4][5][6][7][8][9][10][11][12][13] It has been reported that DCM is dehydrohalogenated at sufficiently high pressures and temperatures (6 bar, 80 C), liberating hydrogen chloride. [14] The possibility of this decomposition may be one reason DCM has been infrequently used as a single solvent for hydrogenation reactions at low pressures and ambient temperatures. [15][16][17][18][19] Other factors, including the toxicity of DCM and restrictions on its commercial use, may also play a part. Nevertheless, DCM seemed to us underutilized as a hydrogenation solvent given the factors in its favor: high solvent ability, ease of removal, and lack of flammability. [20] We carried out a survey of hydrogenation reactions in DCM with commercial palladium on carbon catalysts at ambient pressure and temperature and present the results in Table 1.
Many of the substrates examined in this study have previously been reduced via catalytic hydrogenation using palladium on carbon catalysts in one or more of the traditionally employed solvents listed in the introduction. We observed comparable or higher isolated yields employing DCM as solvent vs. published methods that used flammable solvents (e.g., see the literature references cited in Table 1). We observed no loss of solvent volume over the course of our experiments. We assume the product mixtures that arose from attempted reductions of trans-cinnamaldehyde and 3-phenylpropanal were due to the intermediacy of tautomeric intermediates. In molecules with two or more reducible functional groups, easily reduced functional groups (carbon-carbon double and triple bonds, carbon-nitrogen double bonds, nitroarenes) were rapidly reduced, while functional groups that are more resistant to reduction (carbon-oxygen double bonds, carbon-nitrogen triple bonds, carbon-halogen bonds) were either not reduced or Ethanol, 1 atm 96 [28] (continued) minimally affected under the mild reaction conditions (1 atmosphere, ambient temperature) employed here.

Conclusion
The results reported herein, together with its high solvent ability, ease of removal, and lack of flammability, suggest that DCM should be considered when planning catalytic hydrogenation reactions to reduce alkenes, alkynes, imines, nitroarenes, and other easily reduced functional groups using palladium on carbon as the catalyst, especially when considering large scale reactions. [38] Experimental

General experimental
Dichloromethane was used as supplied by the commercial source (Fisher, assay 99.5% min, water 0.02% max). 10% Palladium on carbon was used as supplied by the commercial sources (Sigma-Aldrich, Lot MKCQ402; Acros Organics, Lot B0144254). Substrates were commercially obtained and were purified before use as necessary or were prepared by the literature methods indicated. Reactions were carried out at an ambient temperature in flasks equipped with magnetic stir bars under hydrogen gas at ambient atmospheric pressure using doubled balloons. Workup consisted of filtration of reaction mixtures with the aid of Celite, washing of the Celite/catalyst with DCM, and removal of volatiles by rotary evaporation. Analytical thin-layer chromatography (TLC) was carried out on pre-coated silica gel 60 F-254 plates, and plates visualized with UV light, anisaldehyde stain, or 10% phosphomolybdic acid solution in 95% EtOH. In some cases, column chromatography was performed using silica gel 60 (flash 32-63 mm, gravity 70-230 mm). Melting points (uncorrected) were measured on an Electrothermal melting point apparatus. 1 H NMR and 13 C NMR spectra were recorded on an Automated NEO-500 NMR spectrometer (500 MHz for 1 H NMR and 126 MHz for 13 C NMR). Chemical shifts (d) are expressed in ppm, and are internally referenced (0.00 ppm for tetramethylsilane for 1 H NMR and 77.16 ppm for CDCl 3 for 13 C NMR). NMR spectra of products were consistent with published data (references appear in the Supplementary Information).

Supplementary Information
Full experimental detail, 1 H and 13 C NMR spectra of products, and literature references for characterization data of known compounds can be found via the "Supplementary Information" section of this article's webpage.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
This work was supported in part by award 55503-ND7 from the Petroleum Research Fund, administered by the American Chemical Society.