ORFEO - Project Overview

Summary
Description of the activity programme
A - New ligands
B - Metallic precursors
C - Reactivity studies
D - Assessment of the catalytic activity of new catalysts in the presence of model organic substrates
E - Preparation of new substrates
F - Catalytic reactions
G - Reactions in non-conventional media
H - Recovery and recycling of catalysts
I - Pilot plants

Development of organometallic moieties for the selective functionalization of organic molecules

SUMMARY

The overall purpose of this proposal is to develop novel organometallic moieties that are effective in the selective functionalization of organic molecules. The proposal has a marked technological motivation. At the end of the research process we wish to put in the market our molecules and synthetic procedures. In order to reach this objective, we will create a Technological Advisory Board. This committee will be formed by experts of relevant chemical industries such as: Asturpharma, S. A., Dominion Pharmakine, Ltd., Faes Farma, S. A., Ferrer Grupo, S. A., Henkel, Janssen-Cilag, S. A., Lilly, S. A., Medalchemy, S. L., Pharma Mar, S. A., Repsol-YPF and Trade Corporation International. Its function will be to advise to the Team Committee. The experimental work of the proposal will be developed through a synchronized procedure of simultaneous multisteps, taking advance of the interdisciplinary nature of the Team. The steps involve work in both stoichiometric and catalytic programmes. The stoichiometric studies include the preparation of new types of ligands, which will be used to synthesize new metallic precursors including, in addition to catalysts, anticancer compounds, and bio-organometallic systems. The catalytic activity of selected metallic precursors will be evaluated in several reactions of interest, using model organic substrates. On the basis of kinetic studies, spectroscopic investigations, and theoretical calculations, catalytic cycles will be established. Those metallic precursors with a better prospective will be assayed as reagents to induce the catalytic transformation of target relevant organic substrates with the goal of obtaining highly valuable products in a practical and rapid manner. The catalytic studies will include: Polymerization and co-polymerization of α-olefins, C(sp3)-C(sp3) and C(sp3)-C(sp2) bond formation by cross-coupling of functionalized secondary halides, metathesis reactions, cycloaddition and cyclization reactions, enantioselective additions, asymmetric allylic substitution, hydroamination, and asymmetric reductions. The processes that can compete in the market will be scaled up to pilot plant level.

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DESCRIPTION OF THE ACTIVITY PROGRAMME

Owing to the increasing demand for products of organic synthesis, the development of highly efficient and selective synthetic methods is one of the most urgent tasks for chemists. Increasing emphasis is placed upon atom economy in order to utilize raw materials more effectively and to minimize waste products. In this respect, the formation of carbon-carbon and carbon-heteroatom bonds mediated by transition metal complexes has emerged on its own right over the last years as an important step in organic synthesis (See for example: Trost, B. M. et al. Angew. Chem. Int. Ed. 2005, 44, 6630).

The overall purpose of this proposal is to develop novel organometallic moieties that are effective in the formation, à la carte, of carbon-carbon and carbon-heteroatom bonds; i. e., that are effective in the selective functionalization of organic molecules.

The proposal has a marked technological motivation. At the end of the research process, we wish to put in the market our molecules and synthetic procedures. In order to reach this objective, we will create a Technological Advisory Board. This committee will be formed by experts of relevant chemical industries. Their function will be to advise to the Team committee.

Within these general goals a summarized planning of the research activity program is depicted in Figure 1. The central point is going to be achieved by combining the production of new catalysts with the understanding of the reaction mechanism of the organometallic entities generated and the deepening in the theoretical modeling of these processes by computational procedures. The fact is that concomitantly to the discovery of these methods an important contribution to the advance of basic knowledge will be achieved. The quality and generality of the methods developed will be tested in the field of the reactivity of densely functionalized molecules from which a good feed-back will be obtained to improve the materials and reagents produced.

The success in this endeavor will translate in technology transfer to diverse sectors such as pharmaceuticals, agrochemical, polymers, and related chemical industries. It should be remarked that apart from the technical benefits, this project will produce a considerable advance in the knowledge, especially due to its transversal character and the synergy between the components of the research groups.

Figure 1. Summarized planning of the research

It is known that the R&D expenditure is growing as a consequence of the efforts promoted by public institutions and private companies. However, the number of novel molecular entities in industrial or commercial use does not follow the same trend. For instance, Figure 2 includes a representation of the R&D expenditure and the number of approved novel chemical entities (NCE’s) in the pharmaceutical industry during the 1994-2003 period. As it can be seen, the number of NCE’s in this area has diminished during the mentioned time interval. In this context, it should be noted that one of the leitmotivs of this proposal is the enhancement in the generation of novel molecular entities of high added value. This goal will be achieved by means of the synergistic interaction among the research groups possessing complementary expertise in different disciplines: Organic Synthesis (Valencia (G.2), Santiago (G.5), Barcelona-6 (G.6), Madrid (G.9), Alicante (G.10)), Inorganic Synthesis (Zaragoza (G.1), Oviedo (G.3), Castilla-La Mancha (G.7), Sevilla (G.8), York (G.11)), NMR (G.11, G.6), Theoretical Calculations (Barcelona-4 (G.4), G.9), Chemical Kinetic and Mechanisms (G.1, G.3, G.6), Bio-organometalllics (G.9), Nanoscience (G.6), Medicinal Chemistry (G.8), Material Science (G.9, G.6) and Catalysis including processes in water (G.3, G.5), supercritic CO₂ (G.2), in perfluorinated solvents (G.6) and a wide range of reactions such as olefin polymerization (G.7, G.1), metathesis (G.6, G.1, G.5, G.9), enantioselective additions (G.10, G.6, G.9), hydroamination (G.1), asymmetric reductions (G.8), etc. Furthermore, the group of Alicante has experience on the study of the processes at the pilot plant level, and the group Barcelona-6 offers an additional expertise in the technological transfer area through the direct participation, as a member of the group, of the Director of the Research Park of the UAB.

Figure 2 (Taken from Chem & Eng News). R&D expenditure and number of new molecular entities approved in the pharmaceutical sector during the period 1994-2003

The work will be developed through a synchronized procedure of simultaneous multi-steps (See Scheme 1), taking advantage of the interdisciplinary nature of the Team. The steps will involve work in both stoichiometric and catalytic programmes. The stoichiometric studies include the preparation of new types of ligands, which will be used to synthesize new metallic precursors including, in addition to catalysts, anticancer compounds, and bio-organometallic systems, among others. Because the knowledge of the reactivity of the candidate metallic species to catalysts is essential in order to develop new catalysts, and since we wish to functionalize non-activated organic molecules, both C-H bond activation and C-C and C-heteroatom coupling reactions will be studied. According to the results of the stoichiometric programme, the catalytic activity of selected metallic precursors will be evaluated in several reactions of our interest, using model organic substrates. On the basis of kinetic studies, spectroscopic investigations, and theoretical calculations, catalytic cycles will be established. In the context of the spectroscopic studies, it should be pointed out that one the groups included in the Team, headed by S. Duckett, is a world leader in NMR spectroscopy. Certainly, the use of parahydrogen NMR and the coupled laser-photolysis-NMR techniques (without experts in Spain) by the York group will increase the ability to identify and study the kinetic evolution of key catalytic intermediates. Those metallic precursors with a better prospective will be assayed as reagents to induce the catalytic transformation of target-relevant organic substrates with the goal of obtaining highly valuable products in a practical and rapid manner. The synthesis of such precursors will be carried out by the organic groups of the Team. The processes that can compete in the market will be scaled up to pilot plant level.

Scheme 1

The groups of the Team have a wide training experience. Thus, since 2001, around 100 Ph. D. theses have been defended. Although a lot of disciplines are used to develop the research proposal, the project presents an overall view of all of them. Certainly, this environment is very convenient for the training of new doctors. In addition, the contribution of the industry to the Team allow us to look at the problems from a real point of view and to be aware of the main private sector’s needs, which undoubtedly enhances the quality of the University training. Furthermore, in order to implement the training of our young research members, the Team will create a Training Secretary, which will develop specific training actions, including the school “Frontiers in Organometallic Chemistry”, lecture cycles, Ph. D. student exchange programs, and knowledge and technology transfer training.

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A – New ligands

The preparation of new species of the following types of ligands will be developed:

i) N-heterocyclic carbene (NHC).

ii) Heteroscorpionate.

iii) Cyclopentadienyl ligands with a chiral pendant group.

iv) Bis-cyclopentadienyl.

v) Hoveyda-type ligands.

vi) Bifunctional chiral ligands.

This task will be carried out by the groups G.1, G.2, G.3, G.5, G.6, G.7, G.8, G.9, and G.10. The work will be coordinated by G. Asensio.

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B – Metallic precursors

In order to enlarge the range of metal starting materials and catalysts that we have already in hand, new families of precursors, mainly, active in catalysis, but also with anticancer properties, and useful to study electron transfer reactions in biological processes will be prepared.

B₁ – Intrinsic interest 

Within this group of compounds we will study the preparation, characterization, and reactivity of, among others, new metallacycles with aromatic properties and polyhydrides with non-classical interactions. This task will be carried out by the groups G.1, G.4, G.6, G.7, G.8, and G.11. The work will be coordinated by A. Lledós.

B₂ – New catalysts

The following types of catalysts will be developed:

i) Early metal complexes for the catalytic hydroamination of alkynes, olefins and allenes, and for the polymerization of a-olefins.

ii) 14-valence-electron complexes of late transition metals. Since the most active transition metal catalysts are those containing the lowest number of valence electrons (van Leeuwen, P. W .N. M. Homogeneous Catalysis: Understanding the Art; Kluwer Academic Publishers: Dordretch, The Netherlands, 2004), we wish to develop novel 14-valence electron complexes of late transition metals for the reactions shown in Section F. The new compounds of this family will be mainly based on two types of skeletons: metal-NHC, and metal-[bis(imino)pyridine].

iii) Carbene complexes. In order to develop new types of catalysts for C-C coupling reactions we will prepare novel group 8 and 9 carbene complexes of different types, based on our previous experience. Novel methods to prepare vinylidene (M=C=CR₂) and allenylidene (M=C=C=CR₂) derivatives will be also developed.

iv) Oxime- and di-2-pyridylamine-palladium derivatives. This type of complexes will be prepared and used as catalysts in cross-coupling carbon-carbon (Mizoraki-Heck, Suzuki-Miyaura, Ullmann, Sonogashira, sila-Sonogashira, Glasser) and carbon-heteroatom forming reactions, such as Hiyama reaction, the Hartwig-Buchwald amination, the aryl halide cyanation, the enolate arylation, the Ullman ether formation, and the acylation of boronic acids and acetylenes.

v) Complexes containing macrocyclic ligands. The group G.6 will contribute its expertise on the preparation of macrocycles. These ligands will be used to prepare group 9-11 metal catalysts for reactions such as Suzuki cross coupling, telomerization, Mizoroki-Heck reaction, allylation of nucleophiles (the Tsuji-Trost reaction) and hydroarylation of alkynes .

vi) Metals in the form of nanoparticles, free or entrapped in aerogels. The entrapment of metal nanoparticles in silica, carbon aerogels or dendrimers is an emerging method of stabilization of nanoparticles. In this context, palladium, ruthenium, and gold catalysts, among others, will be prepared.

This task will be carried out by the groups G.1, G.3, G.6, G.7, G.8, and G.10. The work will be coordinated by C. Nájera.

B₃ – Organometallic anticancer compounds

We aim to design and synthesize new organometallic mono- and dinuclear compounds, which can be used as anticancer drugs. So, we will prepare ruthenium- and osmium-arene compounds. The presence of polar substituents in the arene will facilitate their solubility in water, which could increment the compatibility with the physiological ambient. Also remarkable is the participation of Prof. Peter Sadler as a member of the Team. He is a well-known prestigious researcher in Medicinal Chemistry, with well-established cooperations with industry and research centers for the study of the biological properties and the mechanisms of activity of potentially anticancer drugs. This will make affordable not only the study of the chemical properties of these compounds, but also the test of the activity of the best candidates towards different tumor types.

This task will be carried out by the groups G.1 and G.8. The work will be coordinated by M. Paneque.

B₄ – Bio-organometallic systems

Until recently, biology and organometallic chemistry were opposite an incompatible research fields. However, the last ten years have demonstrated that both disciplines are not only compatible but from their fusion a new field has emerged: the bio-organometallic chemistry. This research area is devoted to prepare biologically relevant compounds in which the M-C bond is the key feature. We have previously studied the electron transfer between an external donor and a monometallic acceptor, chemically, electrochemically, and photochemically. We are currently anchoring an organometallic fragment into densely functionalized molecules, which will produce bio-organometallic systems and will allow us to discover novel reaction pathways that are induced by electron transfer reactions. Some of the species being studied are shown in Chart 1:

Chart 1

Two different approaches to bio-organometallic compounds will be studied based on these premises: i) synthesis of Taylor-Made Polymetallic Cavities and ii) synthesis of Natural Product Hybrids and Chimeras.

This task will be carried out by the groups G.8 and G.9. The work will be coordinated by M. A. Sierra.

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C – Reactivity studies

The new prepared compounds capacity to promote stoichiometric s-bond activation and C-C and C-heteroatom coupling reactions will be investigated. This task will be carried out by the groups G.1, G.3, G.4, G.8, and G.9. The work will be coordinated by A. M. López.

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D – Assessment of the catalytic activity of new catalysts in the presence of model organic substrates

In general the catalytic mechanisms involve multistep reactions, where the intermediates are connected by equilibria that are highly dependent on the electronic properties and steric requirements of the catalyst ligands, as well as on the characteristic of the substrates. Small modifications of these factors can totally change the direction of the equilibria and, therefore, the contributions of a particular species to the overall catalytic processes. Thus, today, it is assumed that is only possible to propose a sensible catalytic cycle on the bases of kinetic, spectroscopic and theoretical studies of the reactions.

Kinetic studies. We will determine the reaction order with regard to each component of the catalysis (law rate), and the kinetic parameters for the most prominent cases. In particular, since kinetics on catalytic processes in non-conventional media have been scarcely studied we will devote attention to this type of transformations specially those using aqueous media such as those involving isomerization of allylic alcohols and tandem processes.

Spectroscopic studies.In order to detect and characterize reaction intermediates, we will insist upon: 

a) Nuclear magnetic resonance studies in solution with single substrates, including the application of hyperpolarized NMR methods which include parahydrogen technique and dynamic nuclear polarization approaches to the study of reaction intermediates, in order to determine the structure of the organometallic species, monitor fluxional or/and rotational processes which may impact on selectivity, and determine the kinetic and thermodynamic parameters that govern them.

b) Nuclear magnetic resonance studies under catalytic conditions in solution, including the application of hyperpolarized NMR methods which include the parahydrogen technique and dynamic nuclear polarization approaches to the study of reaction intermediates, in order to identify key organometallic species and determine the kinetic significance including mapping thermodynamic parameters that govern this.

c) Nuclear magnetic resonance studies on the stoichiometric elemental steps of the catalysis, in order to determine the kinetic and thermodynamic parameters governing these single reactions.

d) Structural and dynamics studies by modern solid-state NMR experiments.

e) Self-diffusion NMR experiments to study ion-pairing behavior and to obtain important information about molecular sizes and aggregation states. Identification of intermediate products and poly-metalated complexes.

f) Use of intra- and intermolecular homo- and heteronuclear NOE experiments. Particular application on ³¹P and ¹⁹F NMR spectroscopy.

g) Analysis of complex mixtures, characterization of crude reactions or identification of minor components and impurities by using the first hyphenated and fully automated LC-NMR-SPE-MS 600MHz system installed in Spain, equipped with a cryogenically cooled probe and available in the NMR Service at the UAB. The high sensitivity of the system also allows detect small amounts of material (50-100 mg dissolved in 60-120 ml of solvent) and can found wide application on mass-limited, low-concentrated and insoluble compounds without previous chemical separation.

Theoretical studies.For a long time computational chemistry has largely contributed to the understanding of the fundamental aspects of chemical systems, but nowadays it constitutes a powerful tool in practical chemistry. As has been previously mentioned, reaction cycles are usually multistep complicated processes, difficult to characterize experimentally. In many cases computational chemistry can be the only way to access to a detailed knowledge of the reaction mechanism, which is a fundamental piece of information in the optimization and design of new processes and catalysts. Calculations give a molecular picture of the organometallic reactivity. Theoretical studies can give accurate measures at the molecular level and will constitute a valuable technique in most of the tasks of the network. The major goal of the computational studies will be obtaining information about molecular properties: structural (geometries), thermodynamic (stabilities, product distribution) and reactivity (reaction barriers and mechanisms).

This task will be carried out by the groups G.1, G.3, G.4, G.6 and G.11. The work will be coordinated by S. Duckett.

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E – Preparation of new substrates

In order to develop the catalytic reactions collected in section F, new species of the following types of organic molecules will be prepared:

i) Diene and enyne for metathesis.

ii) Alkylidenecyclopropane derivatives for metal-catalyzed cycloaddition reactions.

iii) Amines and carbonyl groups tethered to unsaturated units in order to investigate intramolecular hydroamination reactions and others catalytic cyclization chemistry involving unsaturated units.

iv) Organic dihalides including alkyl-alkenyl, alkyl-alkynyl and alkenyl-alkynyl units in order to study the comparative reactivity in cross-coupling reactions.

v) Carbonyl and imino compounds in order to study the stereoselective addition of organometallic compounds to the prostereogenic center.

vi) Allylic systems including alcohols, carbonates, carbamates, ureas and halides in order to study asymmetric allylic substitution reactions.

This task will be carried out by the groups G.2, G.5, G.6, G.9, and G.10. The work will be coordinated by C. Nájera.

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F – Catalytic reactions

The complexes prepared according to Section B₂ and studied according to Section D, which show a better prospective will be assayed as catalysts to induce the following reactions:

F₁ – Polymerization of a-olefins

Studies about the catalytic activity and selectivity of group 4-metal ansa-metallocene complexes, with MAO as co-catalyst, will be carried out. We have a particular interest on the reactions involving ethylene and propylene. Because from an industrial point of view gas phase reactions have the advantage of existing heterogeneous polymerization plant infrastructure, and thus avoiding costly modification need in incorporating homogeneous system, the new single site catalysts will be immobilized on a solid support.

This task will be carried out by the groups G.1 and G.7. The work will be coordinated by A. Otero.

F₂– Cross-coupling reactions

Both activated and non-activated halides are interesting substrates in order to develop new methodologies for C-C bond formation, but the activated ones are even more interesting in organic synthesis because of the presence of the functional group. Consequently, we have selected for this proposal the study of the reactivity in palladium-catalyzed cross coupling reactions of secondary halides containing or not a coordinating substituent that can prevent from the competing b-hydride elimination.

This task will be carried out by the groups G.2, G.4, G.6, and G.11. The work will be coordinated by G. Asensio.

F₃   Metathesis

In order to build relevant polycarbocyclic products by means of tandem metathesis processes the new carbene complexes developed in the Team will be tested in the presence of elaborated polienyne natural products such as Taxol or dolastanes.

Although rhodium, iridium, ruthenium, and osmium catalysts for the alkyne metathesis have not been reported, we will also explore the catalytic properties of the carbyne complexes of these metals in this kind of reactions.

This task will be carried out by the groups G.1, G.5, G.6, G.8, and G.9. The work will be coordinated by A. Vallribera.

F₄ –  Cycloadditions

On the basis of recent achievements on the development of palladium and ruthenium catalyzed [3+2] cycloadditions of alkylidenecyclopropanes, we wish to expand this chemistry to accomplish other type of annulations, such as [3+4], [3+5], and [5+2] cycloadditions (See Scheme 2).

Scheme 2

The developments in this area, as well as in new catalytic cyclizations, should lead to rapid and competitive methods to prepare a variety of polycycles, even in an enantioselective manner, owing to the possibility of using chiral ligands developed by the Team.

This task will be carried out by the groups G.4, G.5, G.6, G.9, and G.11. The work will be coordinated by J. L. Mascareñas.

F₅ –  Enantioselective additions

The addition of functionalized organozinc compounds (R¹ZnX) to carbonyl compounds in the presence of hydroxysulfonamides as chiral ligands and a titanium compound leading to secondary and tertiary alcohols will be also studied (Scheme 3). An important aspect is to know which functional groups of the zinc reagent are tolerated in these processes. The starting organozinc compounds could be prepared by transmetallation of the corresponding boron, titanium or lithium derivatives.

Scheme 3

This task will be carried out by the groups G.4, G.6, G.10, and G.11. The work will be coordinated by M. Yus.

F₆–  Asymmetric allylic substitution

The new chiral complexes of Ti, Zr, Ru, Os, Rh and Ir, among others, will be studied as catalysts for the asymmetric allylic substitution reaction of different allylic esters and halides. C‑, N‑ and O‑ nucleophiles will be used among which, N‑nucleophiles would lead to the formation of enantiomerically enriched allyl amines as important building blocks for the enantioselective synthesis of amino acids.

This task will be carried out by the groups G.1 and G.5. The work will be coordinated by J. L. Mascareñas.

F₇–Hydroamination

Our effort will go into developing new and more efficient catalysts based both on early-transition-metal and late-transition-metal complexes that promote this kind of process. In connection with the development of new cyclization reactions we will investigate the potentiality of the discovered catalysts to induce the cyclization of alkynyl and alkenylamines and imines. We will also synthesize aminoenyne precursors that could provide in a single reaction highly complex azapolycyclic products owing to possibility of exploiting for tandem process the aminocarbene functionality generated in a first alkyne hydroamination reaction.

This task will be carried out by the groups G.1, G.5, and G.8. The work will be coordinated by A. M. López.

F₈ –  Asymmetric reductions

We propose the study and application of Rh, Ir, Ru, and Os catalysts, among others, based on chiral phosphine-phosphites in the reduction by hydrogenation and hydrogen transfer of several substrates of interest. For instance, it will be studied the hydrogenation of aryl- enol ethers, as the products of these reactions are of great interest for the pharmaceutical industry. This task will be carried out by group G.8.

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G – Reactions in non-conventional media

The use of chemical processes compatible with the principles of Green Chemistry is an important issue of modern chemical industries. This part of the project deals with the development of new efficient and “clean” catalytic approaches in organic synthesis. In addition, the new proposed methodologies allow the use of strategies to recycle the catalysts overcoming the main drawback of the homogeneous catalysis.

G₁–Reactions in water

We will mainly study tandem processes since they are still scarcely explored in aqueous media. Thus, among other transformations, we will investigate: i) reduction of allylic alcohols into the corresponding saturated alcohols through the initial isomerization of the allylic alcohol and subsequent transfer hydrogenation of the resulting carbonyl compound, ii) cross-coupling reactions between allylic alcohols and aldehydes, and iii) “tandem” allylic alcohol isomerization/Knoevenagel condensation in order to achieve the direct transformation of allylic alcohols into activated alkenes.

This task will be carried out by the groups G.3, G.4, G.5, G.8, G.10, and G.11. The work will be coordinated by J. Gimeno.

G₂ – Reactions in ionic liquids

We will devote special attention to the examples for which we found low efficiency in aqueous media of the type described above. For instance, the reduction of allylic alcohols into saturated alcohols via isomerization using hydrogenation instead of hydrogen transfer reactions might be an appropriate alternative to improve the low rates observed in previous results. In addition, the selection of the appropriate ionic liquid among the wide series of commercially available will allow using higher reaction temperature than that used in aqueous media.

This task will be carried out by the groups G.1 and G.3. The work will be coordinated by J. Gimeno.

G₃–Reactions in supercritic CO₂ 

The main goal of this part of the proposal is to design an efficient synthetic methodology by mixing the advantages of supercritical CO₂ and the use of supported catalysts in flow-through processes. This task will be carried out by group G.2.

G₄– Reactions in perfluorinated solvents

We plan to apply this procedure to macrocyclic complexes containing perfluorinated chains and to metal nanoparticles stabilized by highly fluorinated compounds. This task will be carried out by group G.6.

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H – Recovery and recycling of catalysts

The anchoring of the homogeneous precursors on the surface of a solid phase will be investigated in order to get easy recovery of the metal catalysts. Among others, boomerang-type supported group 8 carbene complexes (based on Hoveyda ligands) and cumulene complexes stabilized with NHC ligands will be tested as recoverable catalysts in metathesis reactions of dienes and enynes. Furthermore, metal doped silica and carbon aerogels will be used as recoverable heterogeneous catalysts of reactions promoted by Pd(0) (Mizoroki-Heck), and Eu(III) (Michael addition). This task will be carried out by group G.6.

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I – Pilot plant

In addition to the infrastructure of the industries of the Technical Advisory Board, the Team has his own pilot plant located in the campus at the University of Alicante. It is fully equipped to carry out all type of processes in reactors from one to 300 litres under ISO9001:2000, ISO14001:2004 normative and conditions of complete traceability. The main purpose of the plant is to scale-up reactions previously studied at the level of laboratory, developing both new products and processes of interest in fine chemistry at the industrial level. The pilot plant is supervised by the staff of the Department of Organic Chemistry and the Institute of Organic Synthesis, both belonging to the University of Alicante, and is controlled by qualified personnel.  The studies at this level will be coordinated by M. Yus.

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