COST research action on high pressure tuning of chemical and biochemical processes

Brussels, 23 September 2002

Full text of Document 260/02

20 September 2002

Memorandum of Understanding for the implementation of a European Concerted Research Action designated as COST Action D30 "High Pressure Tuning of Chemical and Biochemical Processes"

Attached is the text of the abovementioned Memorandum of Understanding, signed in Brussels on 9 September 2002 by Poland, on 10 September 2002 by Croatia and on 11 September 2002 by Belgium, Finland, Germany, the Netherlands, Spain and the United Kingdom.

The Signatories to this Memorandum of Understanding, declaring their common intention to participate in the concerted Action referred to above and described in the Technical Annex to the Memorandum, have reached the following understanding:

1. The Action will be carried out in accordance with the provisions of document COST 400/01 "Rules and Procedures for Implementing COST Actions", the contents of which the Signatories are fully aware of.

2. The main objective of the Action is to stimulate the tuning of chemical and biochemical processes through the application of high pressure as a physical variable, in order to achieve lower energy consumption, less pollution and higher selectivity in chemical and biochemical transformations, and production of new materials with better properties.

3. The economic dimension of the activities carried out under the Action has been estimated, on the basis of information available during the planning of the Action, at Euro 90 million in 2002 prices.

4. The Memorandum of Understanding will take effect on being signed by at least five Signatories.

5. The Memorandum of Understanding will remain in force for a period of five years, calculated from the date of the first meeting of the Management Committee, unless the duration of the Action is modified according to the provisions of Chapter 6 of the document referred to in Point 1.

A. BACKGROUND

A1. Why a COST Action for this topic?

Recent initiatives within the European Research Area have been made to stimulate research in such fields as life sciences, chemical catalysis, nano-science and nano-technology, and have been supported by the alliance for chemical sciences and technologies in Europe (AllChemE). These initiatives are predicted to have a global impact and will promote sustainable development as well as defining new roles for chemistry and chemical engineering. Within this concept, the tuning of chemical and biochemical processes through the exploration/investigation/use/application of pressure as a physical variable can play an important and decisive role.

High pressure is an important tool in the development of a range of disciplines, and warrants interest both in terms of its fundamental science and in the development of new methods in applied research. In chemistry, two different approaches can be considered: Solution Chemistry (inorganic, organic chemistry and biochemistry) and Solid State Chemistry (novel materials, nano-tubes, supramolecular chemistry).

In fluid phase chemistry the application of high pressure kinetic and thermodynamic techniques has often been a key element in the elucidation of chemical reaction mechanisms. Clarification of such mechanisms enables a systematic tuning of processes for synthetic application in areas such as the development of new contrast agents for magnetic imaging (MRI), homogeneous catalysis, enantio-selective synthesis, drug design and preparation of new compounds. Knowing the mechanism allows systematic electronic and steric modifications of the participating molecules. Reactions often exhibit a characteristic pressure dependence, which can be exploited to tune not only the reactivity, but also reversibility and product distribution of the process. The know-how developed in this area is in the hands of a few well-equipped laboratories in Europe; these laboratories provide the potential for new technological developments and hold world-wide leadership in this area. In addition, pressure tuning applied to gaseous or liqid reaction media can result in unique solvent properties coupled to high chemical turnover and selectivity.

It should be noted that reactions involving biopolymers, viruses and cells often show effects that are absent in the reactions of small molecules. Among these, protein denaturation is an important topic.

Changes in the conformation of proteins may give rise to several important structures that are of biotechnological relevance. Protein-protein interaction is certainly one of the most important effects which have recently been related to several molecular diseases. Fundamental differences have been observed between the effects of temperature and pressure, knowledge which may be lead to useful applications especially in the pharmaceutical and the medical fields. The exploration of the effects of pressure in the developing fields of genomics, proteomics and metabolomics is only at the beginning.

In Materials Chemistry, high pressure plays an important role both in chemical bonding and on the adopted structure. Consequently, for the same chemical composition the resulting physical properties of the material are strongly pressure dependent.

The new results achieved recently in the fields of high pressure research, methodology and industrial applications, require concentrated efforts in order to achieve efficient exploitation. The envisaged integration of research laboratories developing and applying high pressure techniques in a European Network, will strengthen this development and enhance the accessibility of the available know-how within the European context....

B. OBJECTIVES, BENEFITS AND SCIENTIFIC PROGRAMME

B1. Objectives and Benefits

The main objective of the Action is to stimulate the tuning of chemical and biochemical processes through the application of high pressure as a physical variable, in order to achieve lower energy consumption, less pollution and higher selectivity in chemical and biochemical transformations, and production of new materials with better properties. The Action will build on existing knowledge on the effect of pressure on chemical and biochemical processes, in order to systematically tune the desired properties of such systems for selective applications in industrial, environmental and biological processes. It is envisaged that multi-disciplinary teams will be formed to develop specific activities in areas of common interest, with the goal to investigate and further develop the application of pressure tuning technology. Such an approach will strengthen the overall output of the COST Action and especially promote the ability to handle topics of multi-disciplinary interest.

A research area in which such an approach could be very fruitful is for instance the pressure tuning of enzymatic reactions for which model chemical catalysts have been developed. In this way a systematic comparison of chemical and biochemical results could lead to possible industrial applications. A further objective will also be the pressure tuning of the synthesis of fine chemicals and pharmaceutical products. This is currently a market for specialists and is open for the application of techniques that could improve the yield and selectivity of chemical processes. From available information in the literature, it is well-known that many such reactions exhibit a characteristic pressure dependence, which could be employed as a tuning device for the overall reaction. In addition, matrix effects such as the introduction of a supercritical or fluorous phase, could add considerably to the competitiveness of the developed process. Close collaboration with the fine chemical and pharmaceutical industry should be sught.

The network of groups working under the D30 COST Action would organise high pressure research and the use of related techniques by supplying information, affording measurements and providing training to people outside the D30 collaboration.

It is also intended to develop methods for the combination of chemical reaction and separation processes in a single reactor by the control of phase equilibria and solubility through the selective tuning of catalysts, ligands, temperature, pressure and reaction media. The adaptation of catalysts to reach optimised reaction and recycling conditions as a function of the mentioned variables will form a crucial part of the work. Catalyst activity could be controlled by phase boundary effects such as found in micro-emulsions and ionic liquids, in which transport phenomena play an important role.

Catalyst design will include the introduction of fluorinated ligands to improve catalyst solubility in supercritical CO2, H2O and NH3. It will throughout be the goal to develop environmentally friendly ("green") processes. Examples of suitable processes to be studied are for instance hydroformylation reactions in supercritical CO2 and oxidation reactions of aldehydes by dioxygen in supercritical fluids where a much higher solubility of dioxygen can be reached. Multi-phase systems will be used to separate reactants and products, and to recycle the catalyst species. A systematic exploration of the physical parameters, i.e. temperature, pressure and medium composition, will be employed to assist the separation procedures by controlling the phase equilibria as well as phase phenomena. A strong interaction with partners from the chemical industry is envisaged.

In the "life sciences" applications, the relation between protein unfolding and protein aggregation created a new domain of research, which attracted considerable interest because of its role in several neuro-degenerative processes.. Tissue deposition of insoluble aggregates formed by water-soluble proteins was shown to be the initiating factor in several conformational diseases ("prion diseases") like hereditary and acquired amyloidosis and Alzheimer's disease. These amyloid aggregates are sometimes formed by mutant forms of the native protein as in e.g. lysozyme which can cause hereditary amyloidosis. In some cases, however, mutation is not needed and the formation of aggregates is induced by other (so far rather unknown) factors (like in bovine spongiform encephalophaty and in its human variant CJD). Partial refolding of proteins after pressure denaturation can serve as model object for studying the aggregation of slightly destabilized protein structures.

From the point of view of basic science, pressure tuning of the intermolecular forces acting between proteins can change the formation of aggregates into the direction of the disaggregation.

Application of high pressure on proteins can therefore be used for tuning the supermolecular organisation of biomolecules, and proteins in particular. Moderate pressures (~ 2-3 kbar) have also been proven to prevent aggregation of proteins. Pressure was also shown to disrupt the intermolecular hydrogen bonding network formed by destabilised proteins. Pressure can therefore be a useful tool in the characterization of the strength of these aggregates. Since the intermolecular forces are more sensitive to pressure variables than the intramolecular ones, the pressure required for the tuning of intermolecular aggregation is far lower than that which is needed for complete denaturation. It follows that pressure may be useful for the production of vaccines against viruses.

Pressure may also be used as a tool for the prevention of unwanted protein aggregation in pharmaceutical preparations. Recovery of proteins from inclusion bodies is yet another possible application.

At a higher level of complexity, research on the cell as a molecular factory has proven that high pressure is a useful tool for studying a number of cell-mediated processes, the most important being those of gene expression and metabolic dynamics. In order to exploit these effects to a maximum of benefit, a thorough understanding of cellular processes is needed at the molecular level.

A COST Action focused on the research in this field will be an important investment for improving interdisciplinary collaboration between chemists involved in different areas (organic, inorganic, solid state) and also biochemists. Such an objective will benefit a better knowledge on chemical processes ­ in particular for improving solvothermal reactions.

Solvothermal reactions are important in different sectors e.g. synthesis, shaping (crystal-growth, divided materials, dense ceramics).

We are now at the edge of marketing of "safe food" produced by high pressure processing (Ultra High Pressure ­UHP- or "pressure cooked" food). There is an urgent need for both basic and applied research to improve the UHP food production.

Consequently such a COST Action will be an important tool in terms of scientific exchange at the interface between different research areas or development axes (?). Another important gain from such a COST Action will be the exchange of technical solutions in different domains involving high pressure technology. This feed-back is an important challenge for Europe in order to develop a scientific network of high pressure competence in Chemical and Biochemical processes.

Other objectives include:

- Setting up a European Network for training, supplying measurements and services and providing information on the use of high pressure techniques.

- The development in Europe of competence in Chemical and Biochemical Processes involving High Pressures will be important also for the high pressure community involved in physics.

- Development of high pressure analytical techniques for the majority of the physico-chemical methods (particularly spectroscopic ones such as NMR, IR, UV-visible, electrochemistry, flow methods, etc.) - Development and use of the high pressure facilities at the European large scale instrumentation facilities.

- Development and use of high pressure molecular computer modelling in close collaboration with and as a feedback to ongoing experimental approaches.

- The Action will be open to all research groups dealing with catalyst modifications, application of high pressure techniques, and the use of supercritical fluids to control chemical reactivity and selectivity.

- All the techniques used may find new applications in other fields.

- Training of young scientists in a strong interdisciplinary field of research. (From small molecules, to macromolecules to cells)

- Enhancing scientific exchange and cooperation with Newly Associated States, where a considerable potential in high pressure chemistry and biochemistry is present.

- The application of high pressure conditions in chemical transformations can lead to a more effective control over chemical syntheses, product selectivity, and chemical reactivity. New synthetic processes, new materials and an improved understanding of chemical reactivity are to be expected.

- The application of supercritical conditions can lead to new separation technologies, non- organic solvent processes, milder reaction conditions, improved phase transport phenomena, higher turnover numbers in heterogeneous catalytic systems, improved hazardous waste treatment processes, and improved solubilities.

- It is also planned to especially collaborate with medium-size industry with the ability to produce appropriate instrumentation to make high pressure techniques available to more research groups in all areas of chemistry.

B2. Scientific Programme

The scientific programme will depend on the projects submitted by individual research teams. The successful projects will be selected according to the objectives outlined above. At this stage there is no specific scientific programme suggested for this Action in order to place no limitations on the invited proposals. The selection will strictly occur according to the outlined objectives....

D. TIMETABLE

The Action will have a duration of five years and comprise the following four stages:

Stage 1: After the first meeting of the Management Committee a detailed inventory of on-going research and existing plans of the participating groups to begin joint projects will be made. This will result in a discussion document which will allow further planning to occur.

Stage 2: It will be evident which projects are closely related and would benefit from joint activities.

Researchers (and co-workers) will set up (and continue) joint collaborative projects, and exchange their recent research results. It may be appropriate to explore wider collaboration with other European countries during this stage. Organisation and development of the European Network of the research laboratories using High Pressure Techniques.

Stage 3: An intermediate progress report will be prepared after 3 years for review by the COST Technical Committee for Chemistry and by the COST Senior Officials Committee.

Stage 4: This final phase will begin after 4 years and will involve the evaluation of the results obtained. It may include the organisation of a symposium for all the participants and co-workers....

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