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.
Figure 1: ThalesNano X-Cube
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
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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
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Deposition, M.T.Schaal, A.C. Pickerell, C. T. Williams, J.R. Monnier, J. Catal., 2008,
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