III.2 Title: Continuous Catalytic Oxidation in Pharmaceutical Processing
Participants: B. Frank Gupton, John Monnier
Motivation: The ability to carry out the selective oxidation of highly functionalized molecules continues to be a major challenge in pharmaceutical process development. Many of the reaction conditions which have been established require the use of stoichiometric quantities of reagents or rely on homogeneous catalysts which can be expensive and difficult to separate from the reaction products, making them impractical for commercial operations. Some specific examples of these reactions are provided in Scheme 1.
Scheme 1: Oxidation Reactions
Swern Oxidation Jones Oxidation
TEMPO Oxidation
Amide bond forming reactions represent a second class of chemical transformations that are widely used but lack atom economy. These reactions usually employ a reagent to activate a carboxylic acid followed by addition of an amino group to form the amide. An example of these reaction types is provided in Scheme 2.
Scheme 2: Amide Bond Forming Reaction
Several examples of catalytic oxidation of primary alcohols to aldehydes as well as the conversion of alcohols and amines into amides using oxygen as the oxidizing agent have been reported and are provided in Scheme 3.
Scheme 3: Catalytic Oxidation of Alcohols
However, the use of O2 as an oxidizing agent in large scale batch operations has been generally discouraged due to its incompatibility with organic solvents and the prospect of safety issues associated with ignition upon heating. Recent advances in flow reactor technology provide the opportunity to carry out these types of O2-enriched reactions safely using short path, continuous processing conditions. This continuous approach also provides the ability to carry out these reactions under kinetically-controlled reaction conditions by minimizing both O2 concentration (unlike batch reactors the O2 is constantly renewed in flow reactors) and residence time in the reaction zone, thus limiting the possibility of over-oxidation and byproduct formation. Heterogeneous oxidation catalysts are especially well-suited for these applications; in particular, bimetallic catalysts that combine the ability to simultaneously activate both molecular oxygen and the proper functional group of the substrate alcohol are appealing candidates.
Hypothesis: Coupling intelligent catalyst design with continuous process capabilities will provide an effective platform for the safe, selective and efficient oxidation of alcohols.
Research Plan: We will focus on the continuous oxidation of primary and secondary alcohols using bimetallic compositions that would include Group IB metals (Cu, Ag, and Au) paired with Group VIII metals such as Pd and Pt. Bimetallic catalysts prepared by electroless deposition would be selected from those already prepared by the Monnier group using for selective We will use factorial design of experiments to evaluate critical process parameters (independent variables) such as reaction temperature, pressure, flow rate and catalyst concentration to optimize reaction selectivity and conversion (dependent variables). Initial catalysts to be evaluated include monometallic Pd and Pt catalysts and bimetallic catalysts containing variable coverages of Cu, Ag, and Au on either Pd or Pt particles.
The common feature between the alcohol oxidation and the amide forming reaction is the aldehyde that is produced from the initial alcohol oxidation, which is also a transient intermediate in the formation of the amide. Using modular flow rectors we will be able to optimize the reaction conditions for each of these reactions independently and telescope them into a single discrete process as shown in Scheme 3.
Scheme 3: Telescoped Oxidations in Flow
We will use a ThalesNano flow reactor system (Figure 1) to conduct both the individual optimization experiments as well as the telescoping experiments. The instrument can accommodate up to two separate packed columns with individual temperature control. The unit also contains two piston pumps that can be easily configured to meet the individual requirements of each of the three scenarios depicted in Scheme 3.
First year milestone: Reactor and analytical systems will be constructed and several families of bimetallic compositions will be evaluated with a variety of primary and secondary alcohols. Results will be used to refine our computational model. A continuous oxidation unit will be developed which will allow us to evaluate the chemical diversity of the oxidation reactions with a series of aromatic and aliphatic alcohols. An in-line gas sample loop added to the end of the flow system will be used to quantitatively analyze low molecular weight off-gases, such as CO2, water vapor, and light hydrocarbons from non-selective oxidation and decomposition of the substrate alcohols.
Cost: $60,000 for year one
References
1. Supported Ruthenium Catalyst for the Heterogeneous Oxidation of Alcohols with Molecular OxygenK. Yamaguchi, N. Mizuno; Angew. Chem. Int. Ed. 2002, 114, 4720-4723
2. Powerful Amide Synthesis from Alcohols and Amines under Aerobic Conditions Catalyzed by Gold or Gold/Iron, -Nickel or Cobalt NanoparticlesJ. Soule, H. Miyamura, S. Kobayashi; J. Am. Chem. Soc.. 2011, 133 , 18550-18553
3. (a) Homogeneous Catalysis: The Application of Catalysis by Soluble Transition Metal Complexes, G. Parshall, G. W. Wiley: New York, 1980. (b) Metal-Catalyzed
Oxidations of Organic Compounds, R. Sheldon, J. Kochi, Academic Press: New York, 1981.
4. Recent Advances in Transition Metal Catalyzed Oxidation of Organic Substrates with Molecular Oxygen, T. Punniyamurthy, S. Velusamy, J. Iqbal, Chem. Rev. 2005, 105, 2329.
5. Recent Advances in Transition-Metal Catalyzed Reactions Using Molecular Oxygen as an Oxidant, Z. Shi, C. Zhang, C. Tang, N. Jiao, Chem. Soc. Rev., 2012, 41, 3381.
6. Room Temperature Swern Oxidation Using a Microscale Flow System, T. Kawaguchi, H. Miyata, K. Ataka, K. Mae, J. Yoshida, Angew. Chem., Int. Ed. 2005, 44, 2413.
7. Fluoride Ion Complexation by a Cationic Borane in Aqueous Solution, S. Kobayashi, H. Miyamura, R. Akiyama, T. J. Ishida, Am. Chem. Soc. 2005, 127, 9251.
8. A Basic Oxidation of Alcohols to Aldehydes and Ketones Using a Simplified Packed-bed Microreactor, A. Bogdan, D. T. McQuade, Beilstein J. of Org. Chem. 2009, 5, 1.
9. Oxidation of Alcohols with Molecular Oxygen on Solid Catalysts, T. Mallat, A. Baiker, Chem. Rev. 2004, 104, 3037.
10. Theoretical and Experimental Studies of Ag-Pt Interactions for Supported Ag- Pt Bimetallic Catalysts, M. T. Schaal, M.P. Hyman, M. Rangan, S. Ma, C.T. Williams, J.R. Monnier, J.W.Medlin, Surf. Sci., 2009, 603, 690.
11. Characterization and Evaluation of Ag-Pt/SiO2 Catalysts Prepared by Electroless Deposition, M.T.Schaal, A.C. Pickerell, C. T. Williams, J.R. Monnier, J. Catal., 2008, 254, 131.