RICERCA ITALIANA     

Design and development of molecular or nano-structured catalysts and sustainable (high yield and selectivity) synthetic strategies for the synthesis of complex molecular compounds from eco-friendly building blocks.

Università degli Studi di Bari

Abstract

This Project is aimed at developing new synthetic methodologies of complex-multifunctional molecules for which there is a need of developing new strategies responding to the basic principles of sustainability. The new syntheses will:
• avoid the use of toxic products,
• reduce the use of organic solvents (avoiding halogenated solvents),
• introduce the concept of solvent-reagent in order to simplify the reaction system,
• operate at the lowest possible temperature in order to save energy,
• be driven by efficient nano-structured or novel-concept molecular catalysts able to organize the sequential reaction of several substrates.
As a result, syntheses characterized by high yield and selectivity are expected, which will have a lower environmental impact of those on stream while producing higher benefits to Industry. The target molecules are either fine chemicals or intermediates or products used by the Chemical and/or Pharmaceutical Industry. They have been selected among those that already have a large market, under further expansion because of new uses of the product, and need an urgent innovation of the synthetic technologies because those on stream cause a negative environmental impact, being based on the use of toxic compounds (banned in several Countries) or produce large amounts of toxic waste.
The goals of this Project are to develop syntheses that:
• avoid the use of phosgene in the synthesis of organic carbonates, carbamates, isocyanates and ureas;
• use direct methodologies in the synthesis of complex and multifunctional molecules such as lactones, lactames, O- or N-heterocycles bearing substituents conferring particular properties;
• synthesise acrylic acids possibly from olefins and carbon dioxide;
• synthesise carboxylates by direct carboxylation of organic substrates under mild conditions avoiding low-atom-efficiency technologies;
• convert in one pot nitrobenzenes into alkylated anylines using the solvent alcool as reagent;
• hydro-de-halogenate polyhalogenated aromatics to afford aromatic or saturated hydrocarbons.
The Project will also promote fundamental studies to support applied catalysis.
The Partners of the Project will use advanced methodologies and technologies for running their research. Theoretical studies will be combined with experiments in order to have a better characterization of the reactive systems in terms of reaction mechanism and sequence of reactive steps. Advanced techniques (microtests-autoclaves with many compartments for fast analyses, supercritical fluids as solvents and, eventually, reagent, ionic liquids as solvents) will be used for speeding the research and innovative approaches (combinatorial science, catalyst design, reaction modelling, spectroscopic studies in the “OPERANDO” mode) will help to make choises among possible solutions. The catalysts and products will be characterized using advanced techniques (solution multinuclear NMR, solid state NMR, X-rays, XPS, among others) and kinetics under the reaction conditions (FTIR combined with optic fibers, NMR under pressure) will be run to gather information on the reactive systems.
This Project will operate in strict cooperation with two EU FP6 Projects, namely the: IP Project “TOPCOMBI: Towards optimized chemical processes and new materials by combinatorial science", and ERANET "ACENET-Applied catalysis". <<<

Principal Investigator

Michele Aresta Università degli Studi di BARI

Research Objectives

The increased pressure on manufacturers to produce chemicals meeting the Kyoto Protocol [1] and the EU Policies for the Chemical Industry and the Protection of Human Health [2] has led to an urgent demand for alternative environmentally friendly processes. New approaches to catalysis (key to over 80% of the actual chemical production) are based on the key issues categorized below.
• Development of new, highly efficient catalysts characterized by excellent selectivity and long lifetime.
• Utilization of new reaction means, alternative to conventional solvents, with total elimination of chlorinated solvents.
• New synthetic methodologies characterized by low carbon-intensity.
• Substitution of toxic compounds with less noxious ones.
• Reduction of production costs by reducing the amount of raw-materials and energy, using single-step syntheses.
The implementation of such concepts can help to generate more efficient chemical syntheses with higher yields, near-to-zero-waste production for safer and more energy-efficient processes. The experimental space to be explored is immense, expanding from thinking discovering and testing new reactions, to scale up of most successful ideas. In order to be effective it is necessary to develop focused strategies that must address the efficiency issue at various levels, namely:
• atom-efficiency at nano-scale through an “intelligent” activation and reaction of substrates, improving catalyst efficiency;
• Energy-efficiency, favouring low temperature processes;
• Cost-efficiency by
• enhancing the reaction effectiveness (higher selectivity, reduced separation costs, less waste),
• reducing the capital investment (processes run in mild conditions with less dangerous compounds and new reactor concept), and
• lowering the production cost (plant flexibility).
Improving the feedstock diversification, with larger use of secondary raw materials.
As a consequence of the change in production, companies will produce at lower costs and be encouraged to invest in research, markets will be more dynamic, end-users will have better and cheaper products, with an overall step forward towards sustainability.
In order to implement the concepts described above, the Partners of this Project aim at developing new synthetic strategies based on:
• Development of new molecular or nano-structured enzyme-like catalysts, able to drive an ordered sequence of “activation-reaction steps”, selecting substrates by “recognition” and combining them in the correct order.
• Process innovation, through the substitution of conventional organic solvents with water or supercritical fluids or ionic liquids or a combination of the latter two.
• Implementation of the concept “solvent-reagent”, for simplifying the reactive system.
• New syntheses which do not use toxic compounds and are based on low-cost easily-available raw materials.
• One-pot reactions, with a well specified reaction sequence-driven by the catalyst.
• Carbon recycling and conversion of by-products or waste into useful chemicals.
Such concepts will be applied to the synthesis of a number of target-compounds selected by the partners on the basis of national-EU needs or international markets. They are:
• Organic carbonates, carbamates, isocyanates, ureas and carboxylates.
• Products for the pharmaceutical industry, namely heterocyclic compounds containing O,N heteroatoms.
• Lactones and lactames bearing substituents which may confer special properties.
• Acrylic acids prepared by direct coupling of olefins and CO2 or other clean technologies.
• Alkylanilines prepared by direct reduction of nitrobenzene in alcohol.
• Cyclohexanes obtained by dehalogenation of polyhalobenzenes and subsequent hydrogenation.
• Optically active organics for special applications.
The new syntheses will be investigated by combining computational and experimental studies. Such integration will allow to identify Transition States and their energy, that will help to design effective catalysts. Solution spectroscopic techniques under “catalytic-conditions” will whenever possible be used in order to identify intermediates for a cross-check with theoretical data. Stable intermediates will be isolated and characterized.
New catalysts will be synthesized and characterized also during their use, whenever possible. Catalysts will be tuned by strong- (with the ligands) or weak-interactions (with the solvent or other secondary or supramolecular tuning agents).
The correct development of this Project requires the complementary, qualified competence of the five Partners for the synthesis of the metal systems (soluble in organic solvents or in supercritical carbon dioxide or in ionic-liquids, or intercalated in or anchored to hydrophilic polymeric matrices) and their characterization in solution or in the solid state; for the modulation of their activity through the ligands; for the study of the reaction kinetics and mechanism also under high pressure; for the characterization of intermediates. Partners have the competence, use the methodological approach, and make available laboratory facilities required by the Project, and will be supported by the collaborations they have at EU and International level.
The Partners of the Project have specific competence which will be integrated in the Project. They will adopt the same synthetic strategy for the synthesis of their target chemicals. In some cases they will work at the synthesis of the same product using complementary approaches so that the Project will produce several protocols which may be compared for their cost and efficiency. The integrated approach will, eventually, bring to the definition of a "protocol for a strategy for the selective synthesis of a product", which is the ultimate goal of this Project.
Advanced techniques will be of common use. A confrontation of the researchers from the partner institutions will be promoted in order to make the knowledge developed within the Project of common use, promoting the development of high level skills.
Also, this Project will strive to structure the European Research Area (ERA) by interacting and co-operating with the EU FP6 Projects: “TOPCOMBI-Towards Optimized Chemical Processes and New Materials by Combinatorial Science” and ERANET “ACENET-Applied Catalysis” in which the Co-ordinator of this Project is involved.
This will allow all Partners of this Project to:
• use highly innovative EU-focused technological services,
• promote Chemical Science,
• develop high level skills for National and European Academia and Industry,
• establish a common system of scientific references and
• promote young researchers in Science.
New concepts developed in this Project will be disseminated through various routes, as Seminars, International and National Conferences, publications in international journals, scientific meetings, teaching in advanced PhD Courses.
The Partners of this Project have a long lasting collaboration and have achieved excellent results as shown by the acceptance by the International Scientific Community, by the many invited papers and lectures delivered by the partners at top international events and scientific institutions.
Objective of the Project is also high formation (PhD, Post-Docs) to which a substantial part of the budget is devoted. <<<

Timescale

24 months

National and international background

Research in catalysis has the difficult task of finding practical solutions for innovating the chemical industrial production, making sustainable the Chemical Industry. This can be achieved by mastering complexity, either process- or product-complexity, by implementing the principles of “sustainability”. The innovative approach must be integrated at the level of the synthetic methodology, reagents, catalysts, and reaction medium unified in a single strategy mimetic of “enzymatic catalysis”. Such a “new” global approach to problem solving requires the collaboration of various expertise with the combination of efforts and an exchange of information that may reinforce the potential of each partner. The Partners of this Research Project collaborate since a decade within National and International Programmes and have already very successfully run National Projects in the last years with the application at the national level of principles already accepted at the EU level. The objective of this Programme is the “definition of a synthetic strategy that may allow to master the process/product complexity ending with the catalytic synthesis of molecular compounds characterized by multiple functionalities”.
The selected target species are:
• Organic carbonates, carbamates, isocyanates, ureas and carboxylates.
• Products for the pharmaceutical industry, namely saturated or unsaturated heterocyclic compounds containing O,N heteroatoms.
• Lactones and lactames bearing substituents which may confer special properties.
• Acrylic acids and their derivatives prepared by direct coupling of olefins and CO2 or by using other clean technologies.
• Alkylanilines prepared by direct reduction of nitrobenzene in alcohol.
• Cyclohexanes obtained by dehalogenation of polyhalobenzenes.
• Bi- and ter-phenyls and congeners.
• Optically active organics for special applications.
The above mentioned compounds are worldwide recognized as chemicals that have an expanding market because of new applications: they are either intermediates or useful synthons or fine chemicals. Processes on stream cannot guarantee that future market needs will be covered, because of the existing environmental constraints to their expansion. In order to cover the market needs, the development of sustainable technologies must be favoured, with a total re-thinking of the synthetic strategies, trying to find an approach to problem solving that can be adapted to various circumstances. In general, the existing technologies are mostly destructive and non convergent to a unique synthetic design, they also are energy and material intensive, with large waste production at source, or based on the use of toxic species. As a matter of fact, several of the existing processes are not catalytic. In fact,
• carbonates, carbamates, ureas and isocyanates use phosgene, a toxic species banned in several countries, as building block. [3]
• Carboxylates are produced by oxidation of hydrocarbons [4] or using cyanides,[5] techniques characterized by a low atom efficiency (50-60% at the best).
• Acrylic acids are obtained by cyanation of acetone (metacrylic acid and esters) [6] or other not efficient routes.
• Lactones and lactames are prepared by long synthetic paths with large waste production. [7]
• Alkylanilines are obtained by methylation of aniline, often using toxic alkylating agents such as dimethylsulphate or methyliodide (only recently dimethylcarbonate has been introduced, with alternate fortune).
• Alogenated aliphatic and aromatic compounds are common pollutants which need to be detoxified using innovative technologies as their oxidation does not assure ecocompatible results.
• Optically active compounds are produced with low optical purity in many cases.
Therefore, there is a great interest in the international scientific community to discover and implement new synthetic technologies, which respond to the sustainability criteria. It must be also taken into account that the target compounds mentioned above are complex molecules: this means that several steps are necessary in the conventional way, or using catalysis for their synthesis, they require the reaction, according to a pre-ordered sequence, of two or more substrates, which have different properties, like carbon oxides and small organic molecules. Alternatively, the synthesis may require the activation in two different ways of the same substrate (see below). This makes more complex the solution to existing problems, as for the synthesis may proceed, the substrates need to be activated in the proper order by an “organizer”, like a metal system or a metal-enzyme or any other promoter. The new synthetic strategy cannot be a simple optimization of the existing technologies: it must respond to the "atom economy" and ”waste reduction” principles, with “energy saving”, being "eco-efficient". This is only possible if different aspects of the synthetic complexity are fully mastered, as specified below. By molecular engineering, “organizers” of reactive sequences characterized by high chemio-, regio-, and, eventually, stereo-selectivity must be produced. New-concept molecular catalysts or nano-structured catalytic systems, “Nature inspired”, are the best candidates: their reaction centre will have enzyme-like properties so that may be able to regulate the selectivity of access of substrates and the repetition of reactive sequences. Catalysts will be tuned by strong- (ligands) or weak-interactions (with the solvent or other secondary or supramolecular tuning agents). The "organizer" must regulate the activation of substrates with an intelligent "start-stop" discrete action, in order to control the various aspects of system-complexity and produce, in an effective way, the target molecular species. The utilization of supercritical solvents or ionic liquids or two- or three-phase systems will allow to improve the reaction selectivity and rate. The study of the supramolecular dimension of catalysts, either at the level of multiple interactions with substrates and reagents or at the level of nanometric dimensions generated using various techniques is a tool for an effective control of the reaction rate, and of the chemio-, regio- and stereo-selectivity.
As an example of the dimension of the problems that need to be solved, a few selected cases are discussed below.
i) Carbonates, carbamates, ureas, isocyanates.
Organic carbonates (as well as carbamates ureas and isocyanates) are prepared today by using phosgene (route A). The phosgene-free synthesis of carbonates can be achieved by oxidative carbonylation of alcohols using either CuCl2 [ENIChem process, 8] or Pd/NO [UBE process, 9] catalysts.

In the series of reactions A-C, alcohol is a common reagent, but going from route A to B and C the energy content of the reaction partner (COCl2, CO+O2, CO2) decreases so that while the phosgene route does not require any catalyst, the direct carboxylation of alcohol (C) needs an efficient catalyst. Moreover, if one looks at the molecular structure of an organic linear carbonate can easily understand that the activation of the alcohol must be carried out in two different modes:
• activation with an acid to generate the alkyl cation (R+),
• activation with a base to produce the alkoxo group RO- which can react with CO2 to afford the emicarbonate anion, ROC(O)O- that then reacts with R+ to afford (RO)2CO.
This exemplifies how complex can be the re-design of a technology and the difficulties to overcome. In fact, the direct carboxylation of alcohols needs engineerized catalysts which should be able to perform a bifunctional catalysis.
ii) The oxidative carboxylation of olefins.
The oxidative carboxylation (Eq. 1) of olefins [10] allows the synthesis of cyclic carbonates that can be converted into linear ones by transesterification (Eq. 2) [11].


Reaction 1 requires a strict control of the radical cleavage of the olefinic double bond caused by O2 and the promotion of the "one-oxygen"transfer to the olefin in order to generate the epoxide, precursor of the carbonate.
The synthetic strategies described in (i) and (ii) meet the EU IP "TOPCOMBI-Towards Optimized Chemical Processes and New Materials by Combinatorial Science" in which the co-ordinator of this Project is partner.

iii) Synthesis of acrylic acid derivatives
Acrylic acids can be synthesised by direct interaction of olefins with CO2 with 100% atom efficiency. (Eq. 3)

Although such reaction has been studied in the lab since the '80s, so far has produced either metalla-cycles (Eq. 4, [12]) or hydrido-acrylate complexes (Eq. 5, [13]) in stoichiometric amounts.

A recent combined theoretical-experimetal study carried out by the OU-Aresta [14,15] has allowed to inequivocally identify the reaction steps of the reaction and to estimate the energy barriers of the TS. This allows to design catalysts which may prompt the elimination of acrylic acid from the metal complex with regeneration of the catalyst.

iv) Synthesis of lactones and butenolides
Lactones are heterocyclic derivatives with important application in many fields. The lactone core is, in fact, present in many natural products and in several pharmacologically active molecules. The classical syntheses of functionalized lactones usually involve expensive procedures, based on several different steps. By contrast, transition-metal catalyzed carbonylation reactions of suitably functionalyzed substrates may allow a direct, one-step synthesis of lactones in a highly atom-economic fashion. In this context, several innovative approaches to the high efficient, one-step synthesis of lactones have been developed by some Partners of this project, as exemplified in Scheme 1:


v) Phosgene-free synthesis of diarylureas in sc-CO2 as solvent.
The synthesis of diarylureas is subject to many drawbacks both from the ecological and the technical point of view as it is based on the use of phosgene. Partners of this Project [16] have recently found that some para-substituted diarylureas such as the para-methoxy derivatives can be prepared with high yield (&gt; 85%) and TON (&gt; 5000) by reacting substituted anilines with carbon monoxide in carbon dioxide as solvent under the catalytic action of K2PdI4 in the presence of air (Eq. 6).


vi) One-pot synthesis of condensed heterocycles.
Several pharmaceutical compounds are being prepared according to conventional procedures, involving many separate steps. An example is offered by the synthesis of phenanthridinones, which, even in their last improved synthetic version (2003), require a laborious procedure [17]. Our procedure allows to obtain the same type of compounds starting from readily available substrates in one-pot reaction that involves an ordered sequence of steps, as shown below (Scheme 2).


vii) Functionalisation of aromatic oxygenates.
The synthesis of functionalized aromatic oxygenates, such as phenols, requires the use of multistep and time consuming techniques with production of large amounts of waste. In this Project a new synthetic strategy will be developed based on the use of phenols as nucleophiles toward activated olefins that brings to a one-step functionalization of the parent molecule with high atom efficiency.

viii) Detossification of polihalo-aromatics and -aliphatics.
Perhalo-aromatics and -aliphatics are persistent compounds due to their chemical inertness. They are not easily biodegraded. Their thermal destruction causes the formation of very toxic compounds such as halobenzofurans and congeners. The reductive hydrodehalogenation is a safe route to their conversion into useful compounds. In fact, the catalysts we intend to use are able to afford a total hydrogenation to saturated linear (aliphatic) or cyclic (aromatic) hydrocarbons with high environmental and economic advantages.

The correct development of this Project requires, thus, complementary, qualified competence for the synthesis of the metal systems (soluble in organic solvents or in supercritical carbon dioxide or in ionic-liquids, or anchored to hydrophilic polymeric matrices) and their characterization in solution or in the solid state; for the modulation of their activity through the ligands; for the study of the reaction kinetics and mechanism also under high pressure; for the characterization of intermediates.

Theoretical studies and modelling of the metal systems, combined with experimental studies, will make possible a "catalyst design", for achieving the best efficiency and selectivity in the synthetic processes. The integrated approach will, eventually, bring to the definition of a "protocol for a strategy for selective syntheses", which is the ultimate goal of this Project.
Partners provide the necessary expertise and complement of competence, both from the methodological point of view and the availability and use of laboratory and analysis techniques, as specified in the following sections. <<<