Transfer Hydrogenation of Asymmetric Ketones using Transition Metal Catalysts Katie Cornish Student Scholarship Day

Introduction Transfer hydrogenation is often used on a large scale in the making of commodity chemicals or pharmaceutical compounds. There is a drive for environmentally and economically “safe” reactants; companies are researching ways to avoid using toxic reactants, and reactions that require extreme conditions like high temperatures and pressures. Lowering the toxicity of the reactants used often means by-products are more eco-friendly and conditions for workers are safer.

Procedure 1 A hydrogen acceptor and a hydrogen donor (and solvent if needed) were added to a 10 mL round rottom flask containing a transition metal catalyst at room temperature (18°C) The solution was stirred constantly and refluxed at 70°C for 30 minutes Both the starting mixture and the product mixture were filtered and analyzed via 1 H NMR, 13 C NMR, and IR

Procedure 2 Reactants were added to a flask similarly to procedure 1 A balloon attached to the reflux tube that was attached to the flask, creating a closed system Hydrogen gas was added to the flask through a septum port until the balloon reached 10 cm diameter The flask was stirred without and then with heat (70°C) for a total of 30 minutes The starting and product mixtures were analyzed similarly

2-butanone Reactions Experiment:137 Date: Hydrogen Donor/Solvent: Cyclohexene H 2 /CH 2 Cl 2 Hydrogen Acceptor: 2-butanone Ratio (d/s:a:c):20:1:1 300:5:1 Amounts used:0.034g 2-butanone 1.00mL cyclohexene 0.050g Pd/C 5% 0.071g 2-butanone 2.00mL cyclohexene 0.100g Pd/C 5% 2.00mL CH 2 Cl 2 Reflux time::311: g cyclohexanone 0.020g Pd/C 5% Notes:Doubled all quantities

More 2-butanone reactions Experiment:81213 Date: Hydrogen Donor/Solvent: InositolMannitolCyclohexene Hydrogen Acceptor: 2-butanone Ratio (d/s:a:c):1:1:11:4:2201:1.3:17 Amounts used:0.824g inositol 0.035g 2-butanone 0.049g Pd/C 5% g mannitol g 2-butanone 0.509g Pd/C 5% 1.50mL cyclohexene 1.068g 2-butanone 0.101g Ru/C 5% Reflux time::302:301:00 Notes:added hydrogen gas via addition port; added 4mL D2O Ran in Parr reactorAdded 1mL CDCl 3

Results: No change forseen Experiments 3 and 9 show that doubling the quantity of certain reactants, changing the reaction time, changing the reaction temperature, and increasing the ratio of donor to acceptor to catalyst did not affect the outcome of the reaction Activating the catalyst and varying the hydrogen donor (cyclohexene, dichloromethane/H 2, inositol, mannitol), acceptor (2-butanone, cyclohexanone, acetophenone), and solvent also did not produce any different results Addition of a hydroxide base did not aid progress, rather it inhibited absorption of cyclohexene on the catalyst

Changing the catalyst Varying between catalysts of Rh/C, Ru/C, and Pd/C in each of the reactions did not aid in reaction progression; Pd/C, however, is noted to be the most reactive Acetophenone, Mg(OH) 2, Rh/C Acetophenone, Mg(OH) 2, Ru/C

Mystery products Cyclohexene reacts with itself to form benzene and cyclohexane in a 3:1:2 molar ratio, shown in the 1 H NMR of an experiment using acetophenone as the hydrogen acceptor

A successful reaction Used an activated Pd/C 5% catalyst with 2-butanone (acceptor) and mannitol (donor) in experiment 12 Run in a Parr 1340 reactor at high temperature, pressure, and rpm (220psi, 105˚C, 200 rpm, 1h, and 310 psi, 100˚C, 200rpm, 2h) Peaks that indicate presence of 2-butanol are shown at 1.40 ppm, 0.85 ppm and possibly 3.70 ppm (overlapped by mannitol hydroxyl peaks) Lack of cyclohexene peaks shows that the donor was absorbed very well onto the catalyst, but blocked access of the acceptor to the catalyst to complete the reduction process

A successful reaction Experimental 1 H NMR, showing peaks at 1.40 ppm and 0.85 ppm Reference 1 H NMR, showing peaks representing both ketone and alcohol

What about diols? Reactions were run using 1,3- cyclohexanediol (CHD) as a hydrogen donor, deuterated water as a solvent, 2-butanone as a hydrogen acceptor, and transition metal catalysts noted previously Reactant mixtures were activated with hydrogen gas and run similarly to procedure 1 for 2 hours, then analyzed at times of 2 hours and 5 days No reduced products were present in product spectra, and CHD did not absorb well on Ru/C or Pd/C catalysts

Conclusions Making slight changes to a host of variables, including reactants, quantities, temperature, and reaction length did not produce a reduced product The one experiment that yielded an alcohol product was run under extreme conditions, which is not conducive to green chemistry Other variables that may affect the outcome of the reaction include the pH, reactant stereochemistry, and reactant functional groups The results from the butanone reactions will be used when establishing the reversibility of reduction and oxidation of alcohols and asymmetric ketones.

Future work Isolate conditions for the formation of an alcohol product that are similar to normal atmospheric pressure, temperature and pH Investigate the mechanism by tracing how hydrogen is transferred from a donor like 2-butanone to the metal surface and then to the acceptor using deuterated compounds Examine the enantiomeric excess of the product and how its stereochemistry relates to that of the hydrogen donor and acceptor using a chiral column in HPLC

References Berkessel, Albrecht. "Hydrogenation without a Transition-Metal Catalyst: On the Mechanism of Base-Catalyzed Hydrogenation of Ketones." Journal of the American Chemical Society (2002): SciFinder Scholar. CAS. Grand Valley State University. June Hayes, et al. "A Class of Ruthenium(II) Catalyst for Asymmetric Transfer Hydrogenations of Ketones." Journal of the American Chemical Society (2005): SciFinder Scholar. CAS. Grand Valley State University. June Sandoval, et al. "Mechanism of Asymmetric Hydrogenation of Ketones Catalyzed by BINAP/1, 2-Diamine-Ruthenium(II) Complexes." Journal of the American Chemical Society (2003): May 2005.