Process Design of Chemo-Enzymatic Synthetic Cascades

Chemo-enzymatic synthesis is a new method to achieve selective catalysis, with potential application to many classes of reactions where conventional approaches are difficult. A combination of enzymatic as well as heterogeneous and homogeneous catalysis will direct the reaction toward the desired products. Therefore, this new approach has a potential application in many biosynthetic processes as well as pharmaceutical processes. However, in many chemo-enzymatic synthesis processes, even a small reaction pathway, there are many alternative technologies. Some can be integrated together, some give the required yield and selectivity, some are difficult to implement and others are untested at scale (Boisen et al., 2008). Thus, this makes it very difficult to justify effort and resources on process design in the early stage of process development when the information is limited (Shaeri et al., 2006). Therefore, there is a need for a methodology capable of fast evaluation of different processes with limited information in order to reduce the number of potential process flowsheets. The purpose is to set targets for further improvement of the best process options for further improvement, and finally identify the optimal set of products and the best route for producing them (Sammons et al., 2007; Shaeri et al., 2006).

Here we propose a methodology of using a computer aided model framework for process design of chemo-enzymatic synthetic cascades. The first step in the methodology is to list all the possible process flowsheets, which involve all the alternative technologies and routes. After that, a fast process screening is performed. To do a fast process screening, process model (e.g., Software PRO/II) is used to obtain the mass and energy balance for different flowsheets. Based on the simulation results, the raw material and energy cost for producing 1 kg final product of different process options is estimated and compared to eliminate unattractive flowsheets and to select the most promising process flowsheets for further analysis. For the selected process flowsheets, sensitivity analysis together with the cost analysis is performed to identify the bottlenecks of the flowsheets and ways for improving the process. Furthermore, other criteria like environmental factors, technical feasibility, safety, scale-up possibilities are included to optimize the process and identify the most likely process. Finally, targets for catalyst and process improvements are set.

As an example, a case study of process design of chemo-enzymatic synthetic cascades from glucose is used to illustrate how to apply the proposed methodology in chemo-enzymatic synthetic process design. The study aims to produce  2,5-furandicarboxylic acid (FDA) from glucose via the intermediate 5-hydroxymethyl furfural (HMF) and employs a combination of chemical and enzymatic catalysis as well as novel reactor design. FDA is a new building block for the polymer industry with applications and properties similar to terephthalic acid, which is derived from fossil resources and is the main building block in polyethylene terephthalate based resins and fibers.

HMF is an important intermediate product, which can be converted to several valuable products, including oxidation to FDA. In aqueous media, HMF may also be hydrolyzed to levulinic acid and formic acid. Both FDA and levulinic acid are listed in the top 12 value-added chemicals for building blocks for industry (Werpy and Petersen, 2004). HMF can be obtained by dehydration of hexoses. The dehydration of fructose to HMF is reported to have good conversion and selectivity (Moreau et al., 2004). The dehydration of glucose to HMF is much harder than for fructose and thus gives poorer selectivity. However, glucose can be converted to fructose by the enzyme glucose isomerase. The process starts with glucose and involves isomerization, dehydration and oxidation to synthesize FDA. The reaction conditions for the three main reactions are listed in Table 1.

There are many alternative options and technologies in the route from glucose to FDA. One option is to run the three individual reactions separately. Even in this way, there are many options. For example, the second reaction involving dehydration fructose to HMF can be running in different media like water, organic solvent, biphasic system or ionic liquid (Kuster, 1990; Zhao et al., 2007). Furthermore, the dehydration reaction and the oxidation reaction can also be integrated together (Kröger et al., 2000). All the possible process alternatives thus give a big challenge for design engineers, especially at the early stage of the process design.

In this paper, the use of a computer-aided model framework to design and select a suitable scaleable process from glucose to FDA within economic constraints is described as an example to illustrate how to use the methodology. The complexity, challenges and opportunities in chemo-enzymatic process design are also emphasized. The methodology behind should be applied to a large range of chemo-enzymatic synthesis problems. In addition, it is also an example to show that computer aided modeling provides a testing ground for process design.

 

Table 1: Typical reaction conditions for three main reactions involved in synthesis FDA.

Reaction	Temperature (°C)	pH	Reaction media	Catalyst
Isomerization	50 – 60	7 – 8	water	Glucose isomerase
Dehydration	80- 200	acidic	Water/organic solvent/biphasic/ ionic liquid	Heterogeneous/  Homogeneous
Oxidation	25	basic	Water/organic solvent	Noble metal

REFERENCES

 

Boisen, A., Christiansen, T.B., Fu, W., Gorbanev, Y.Y., Hansen, T.S., Jensen, J.S., Klitgaard, S.K., Pedersen, S., Riisager, A., Ståhlberg, T. and Woodley, J.M., 2009, Process intergration for the conversion of glucose to 2,5-furandicarboxylic acid, Chemical Engineering Research and Design, submitted.

Kröger, M., Prüße, U. and Vorlop, K.-D., 2000, A new approach for the production of 2,5-furandicarboxylic acid by in situ oxidation of 5-hydroxymethylfurfural starting from fructose, Topics in Catalysis, 13: 237–242.

Kuster, B. F. M., 1990, 5-Hydroxymethylfurfural (HMF). A review focusing on its manufacture, Starch, 42(8): 314-321.

Moreau, C., Belgacem, M. N., Gandini, A., 2004, Recent catalytic advances in the chemistry of substituted furans from carbohydrates and in the ensuing polymers, Topics in Catalysis, 27(1–4): 11-30.

Sammons, N., Eden, M., Cullinan, H., Perine, L. and Connor, E., 2007, A flexible framework for optional biorefinery product allocation, Environmental Progress, 26:349 – 354.

Shaeri, J., Wohlgemuth, R., and Woodley J. M., 2006, Semiquantitative process screening for the biocatalytic synthesis of D-Xylulose-5-phosphate, Organic process research & development, 10: 605-610.

Werpy, T., Petersen, G., (Eds) 2004, Top value added chemicals from biomass, US Department of Energy, Office of Scientific and Technical Information, No. DOE/GO-102004-1992, http://www.nrel.gov/docs/fy04osti/35523.pdf

Zhao, H., Holladay, J.E., Brown, H., Zhang, Z. C., 2007, Metal chlorides in ionic liquid solvents convert sugars to 5-hydroxymethylfurfural, Science, 316: 1597-1600.