Future directions?

Having surveyed the current landscape, the remaining challenges and some future opportunities for realising aerobic oxidation reactions for the production of speciality chemicals are discussed in this section. At smaller scale and higher margin, capital expenditure (Capex) is usually dwarfed by the operating expenditure (Opex) in the pharma and fine chemicals industry. Ideally, there needs to be certain flexibility in the design of the chemical plant, such that a variety of different chemical reactions can be implemented at the same site, i.e. highly modular units of operation, each with a small footprint, is preferred over dedicated facilities. Greater emphasis on the development and adaptation of continuous flow technology in the fine chemicals and pharmaceutical sectors bodes well for future applications of aerobic oxidation reactions, as it can overcome the explosive hazards currently hampering the wider implementation of this synthetic methodology. Conversely, it has been shown (as in the case of Amoco’s TA production) that it is possible to execute large-scale aerobic oxidation reactions in a homogeneous solution of flammable solvents, as long as the amount of O2 in the headspace can be managed by a good understanding of the underlying kinetics and mass transfer parameters.

As to future aspects, these may be broadly divided into Engineering and Chemistry challenges (listed in the following sections), although the issues tend to be highly interrelated. Thus, a coordinated and interdisciplinary approach is necessary to deliver truly innovative solutions.

6.1 Engineering challenges

1. Flammability of solvents and explosive hazards remain at the top of the agenda, which can be addressed by better control of reaction and process parameters. This will require a detailed study of the reaction kinetics involved, combined with a clear understanding of the fluid mechanics in the reaction vessel, allowing for the design of the appropriate residence time and holdup volume of the gas phase. This in turn causes, by design, the oxygen concentration to be below the flammability limit upon release into the head space of the vessel. With no excess oxidant in the system, the reaction will need to be able to operate under an O2-lean regime. Selectivity of the reaction must not be compromised, and any catalyst designed for such processes must not deactivate under these conditions.

2. Equally, heat release is effectively controlled by operating at the boiling point of the solvent. This could be tuned by adjustment of the reactor pressure, however, this will also directly affect oxygen solubility, autoignition temperatures and flammability limits (as discussed in section 3.2).

3. O2 delivery is critical to maintain process efficiency and safety. Ideally, the O2 is delivered at a rate that is comparable to the oxidation process. The use of membrane reactors can eliminate accumulation of excess O2 in the headspace, but this is currently limited by the availability of suitable materials that can maintain both a high flux of O2 and pressure differential (between the gas and mobile phases) at the same time.

4. Synthetic routes in the fine chemicals and pharmaceutical industry tend to be multistep. Hence it is desirable to operate the individual steps in tandem to minimise the need to isolate intermediates. This is best achieved by a continuous process with attendant continuous separation stage, for example: organic solvent nanofiltration,88continuous distillation,89 or continuous crystallization.90–92 The implementation of reliable online/inline process analytics and effective feedback control is critical for quality assurance – this is still a considerable challenge.

5. Handling and maintaining multiple phases in flow reactors is still somewhat difficult and should be avoided where possible. Particularly, if the reaction system results in the formation of solids, a batch reactor system may still be the better option (e.g. Amoco’s TA process), particularly if long residence times are involved.

6. Removal of homogeneous catalysts from the reaction mixture has always been a problem in process chemistry, which also hampers the development of tandem processes. Thus, development and adoption of heterogeneous catalysts for the synthesis of complex molecules needs to be further exemplified, particularly for more robust catalysts that can be incorporated into an appropriate flow reactor without losing efficiency. That said, catalyst leaching from heterogeneous catalysts (leading to contamination of the final product) is also an important issue seldom addressed in academic papers.

6.2. Chemistry challenges

1. There is a need to expand the scope of aerobic oxidation reactions with high selectivities. Currently, much of the research effort has been focussed on the oxidation of alcohols to aldehydes and ketones, typically benzyl alcohols to benzaldehydes. There needs to be more studies on the reaction scope of new catalysts, especially towards substrates with multiple functional groups. Conversely, other aerobic oxidation reactions (particularly type II) are also under-developed. An example is the epoxidation of alkenes, which is an important process for the fine chemicals/pharmaceutical sector. With the notable exception of silver-catalysed epoxidation of ethylene (achieved on an industrial scale in the gas phase at 220–280 °C),93 direct oxidation of alkenes by O2 (in the liquid phase) is unknown on industrial scale.

2. Certain aerobic oxidation reactions proceed via free-radical intermediates (e.g.oxidation of benzylic and allylic C–H bonds). Currently, these require high temperatures, and are thus generally difficult to control and often lead to low selectivity. This can be addressed by broadening the chemistry of singlet O2/photocatalysis94–100 (the artemisinin project showed that it is possible to scale-up such processes). Electrochemistry is another interesting possibility, e.g. O2 can be converted into effective oxidants using redox mediators.101–104 Photo- and electro-chemistry are generally performed at (sub-) ambient conditions therefore have great potential to deliver unique chemistry.

3. Ionic liquids (ILE’s)105,106 and CO2,107–109 have been employed in aerobic oxidation reactions, in order to circumvent the need for flammable solvents. However, the use of such unconventional reaction media may require specialised equipment to contain sc-CO2 and to recycle ILE, which may be too energy-intensive. In the context of pharmaceutical intermediates, there may be certain applications where the use of such reaction media, particularly sc-CO2 and perfluorinated solvents, may be uniquely advantageous: pure oxygen can be used with these non-flammable materials, and post-reaction separation can be easily achieved by a simple pressure reduction (employed in a continuous process the higher pressure required would not be as critical as in a batch process). The disadvantage here would be the formation of a multiphase system, which is more difficult to control .

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