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1.4.
2.2.Microemulsions.When water is mixed with an organic liquid immiscible with water and an amphiphile, generally a turbid milky emulsion is obtained which,after some time,separates again into an aqueous and an organic phase.On the water-rich side,the mixtures consist of stable dispersions of oil droplets in water,which coagulate with rising temperature.A spongelike structure is obtained if the mixtures contain approximately equal amounts of water and oil.On the oil-rich side,dispersed water droplets are found, which coagulate with decreasing temperature.The size of the domains is a function of the amphiphile concentration and the volume fractions of water and oil.50
Since microemulsions contain both a polar component (water)and a non-polar component(oil),they are capable of solubilising a wide spectrum of substrates.The mechanism of solubilisation is similar to that in micellar solutions.The micelles are replaced by the oil domains,which are capable of solubilising all kinds of hydrophobic substances.The solubilisation of polar substances takes place analogously through the aqueous domains of the microemulsion.The solubilisation capacity of microemulsions is generally superior to that of the micellar solutions and can therefore, affect the rate and course of a certain reaction.
1.4.3.Electrochemical activation.Electrochemistry represents a convenient synthetic method in which electrons constitute clean and energetically ef?cient reactants.The development of the potentialstat turned electrochemistry into a common tool for organic synthesis.51In spite of the procedural simplicity,absence of side products derived from reagents and high ability for accomplishing selective oxidoreductions under very mild conditions,electro-synthesis still appears to be undervalued,even though some industrial-scale work has demonstrated its appealing features.
The apparatus required for electrosynthesis can be as simple as a beaker containing a pair of electrodes connected to a direct-current voltage source.A stirrer,thermometer,jacket, inert gas inlet,or any combination,can be added.For some reactions,the separation of the electrodes by a diaphragm is mandatory to prevent the products from one electrode diffusing to the other and being destroyed.A proper solvent and supporting electrolyte will be also required.
In some cases,chemical techniques turn out to be quite dif?cult in the preparation of certain organometallic species. Electrochemistry can,however,provide an easy way to generate a desired oxidation state of a metal complex that becomes the active catalytic species for an organic reaction. In the particular case of redox processes,the active catalytic species can be recycled continually by the electrode oxidation or reduction reactions.In these processes,the electrons are consumed stoichiometrically with respect to the substrate.Therefore,it is the electrons that are used as clean,controlled and non-polluting redox agents.In non-redox reactions,electrochemistry is used only to generate the catalytic system.It has been observed that electro-generated species can be more reactive than their chemically prepared analogues.521.5.Miscellaneous non-conventional techniques
The techniques mentioned below are rather speci?c and so far have only been described for a limited number of examples.
1.5.1.Nano?ltration.It is important to recognise that the total ef?ciency of synthesis is also conditioned by the ability to separate the products from the unchanged starting materials,excess reagents and catalysts.Within the green chemistry context,it is also interesting to develop techniques that enable the separation and re-use of catalysts and reagents.Thus,separation protocols additional to those described above(i.e.,per?uorinated systems,sc?uids,ionic liquids,solid-phase supported reagents and catalysts,etc.), which are easily automated to enable rapid puri?cation by simple operations,are welcome.53
In the?eld of homogeneous catalysis,separation of the catalyst from the product mixture is rather complicated, preventing large-scale industrial processes.An interesting and promising development in the area of homogeneous catalyst recycling is the attachment of homogeneous catalysts to soluble organic supports.In this way, macromolecular catalysts anchored on soluble supports such as polymers and dendrimers are created,which can be recovered by ultra-or nano?ltration techniques and re-used again.
Recently,solvent-stable ultra-and nano?ltration mem-branes have been introduced showing high retentions for medium-sized soluble molecules.54In the?eld of mem-brane?ltration,ultra-and nano?ltration techniques are de?ned to retain macromolecules with dimensions between 8–800and0.5–8nm,respectively.
1.5.
2.Microreactors.Microreactor devices consist of a network of micron-sized channels(10–300m m),with a high surface-area-to-volume,etched into a solid substrate.55For solution-based chemistry,the channel networks are con-nected to a series of reservoirs containing chemical reagents and products to form the complete device with overall dimensions of a few cm.Reagents can be brought together in a speci?c sequence,mixed and allowed to react for a speci?ed time in a controlled region of the channel network using electrokinetic(electro-osmotic and electrophoretic)or hydrodynamic pumping.For electrokinetically driven systems,electrodes are placed in the appropriate reservoirs to which speci?c voltage sequences can be delivered under automated computer control.This control offers an effective method of moving and separating reagents within a microreactor,without the need for moving parts.Hydro-dynamic pumping uses conventional,or microscale,pumps to manoeuvre solutions around the channel network,but, this technique has the disadvantage of requiring either large external pumps or complex fabrication of small moving parts.
Many reactions have been demonstrated to show altered reactivity,product yield and selectivity when performed in microreactors,as compared with conventional benchtop glassware.In fact,the desired product is often produced in higher yield and purity and more quickly.Process
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parameters such as pressure,temperature,residence time and?ow rate are more easily controlled,thus minimising risk and side reactions.Furthermore,solvent-free mixing, in situ reagent generation and integrated separation techniques can all help to make the chemistry greener.56 One of the immediate applications is therefore in drug and process discovery,where the generation of compounds with different reagents under variable conditions is an essential factor and also allows,in a short time and with greater safety,a process to be transferred to the pilot and production scale.57
1.5.3.Ball-milling conditions.Ball-mill chemistry is of interest because of the mild conditions under which it operates and also the absence of any solvent and easy work up.This technique has,however,been scarcely studied and applied to very few reactions.58Apparently,the rotation of the steel balls creates a high pressure in contact with the walls of the container,allowing the reagents to interact and promoting the process.
2.Objectives and organisation
In principle,we wanted to present in this report the application of recent non-conventional methodologies to the transition metal-catalysed carbon–carbon coupling reaction.Heck,Suzuki,Sonogashira,Stille,Negishi and Kumada reactions,among others,were the reactions originally to be covered.Because of the abundant literature found on this topic,however,we decided to dedicate this ?rst part only to the Heck reaction,whereas the rest of the reactions will be studied in the second part in due course.
Nonetheless,the above introduction is common for any of the parts of the review.Other carbon–carbon bond forming reactions such as the transition-metal catalysed coupling reactions through the activation of carbon–hydrogen bonds, nucleophilic substitution(Tsuji–Trost reaction),or acyla-tion of carbon nucleophiles are beyond the scope of this review.Some of the reports dealing with the perse topics to be tackled here have been previously and properly reviewed elsewhere and will not be covered to their full extent.Instead,a summary together with the more recent contributions until2004will be provided.The review is organised according to the sub-headings presented in the general introduction,taking into account the different components and variety of conditions involved in the Heck reaction.Many of the contributions to this review are also analysed from a critical point of view,with the aim of discussing the advantages and disadvantages that the different techniques offer and trying to select the best choice,when possible.A short conclusion can be found at the end of each section.
3.Introduction to the Heck reaction
The Heck reaction is broadly de?ned as Pd(0)-mediated coupling of an aryl or vinyl halide or sulfonate with an alkene under basic conditions.Since its discovery,this methodology has been found to be very versatile and applicable to a wide range of aryl species and a perse range of ole?ns(Scheme2).59The major steps of the general and traditional mechanism for the Heck reaction are depicted in Scheme3.60
4.Substrates
4.1.Alternative arylating agents
In all the Heck reactions described in Scheme2,a stoichiometric amount of base is required to neutralise the acid that is formed during the reaction(see Scheme3).As a consequence,the corresponding equivalent amount of halide salt is obtained as waste.In the search for a cheap aryl source that does not lead to the formation of halide salts,de Vries et al.introduced the use of aromatic carboxylic anhydrides as the arylation source.61For instance,heating benzoic anhydride and n-butyl acrylate in a N-methylpyrrolidinone(NMP)solution containing PdCl2and NaBr at1608C for90min,led to the formation of(E)-n-butyl cinnamate with high conversion,90% selectivity and good yield.Although a catalytic amount of a chloride or bromide was necessary for optimal activity, phosphane ligands were not required.p-Methoxybenzoic anhydride and2-furanoic acid anhydride were also successfully used as arylation agents.A variety of ole?ns were arylated under similar conditions at140–1908C (Scheme4).Ole?ns with electron-withdrawing groups gave better yields,although,due to the relatively high reaction temperature,double-bond isomerisations and
