共老我白发The foundation of this methodology resides in the fact that the?uorous solvent has a low miscibility with common organic solvents.At a certain increased temperature,it is miscible with organic solvents but,when cooled,it splits into a biphasic system.A?uorous biphasic system can therefore,consist of a?uorous phase containing a?uorous-soluble reaction component and a second product phase, which may be any organic or non-organic solvent with limited solubility in the?uorous phase.40The?uorous biphasic reaction at the operating temperature can proceed either in the?uorous phase or at the interface of the two phases,depending on the solubilities of the reactants in the ?uorous phase.When the reaction is complete,simply cooling the system makes the?uorous solvent immiscible in the organic phase.The?uorous biphasic system therefore, combines the advantages of a one-phase reaction with biphasic product separation.
The?uorous biphasic concept has been successfully applied in stoichiometric chemical reactions utilising organic, inorganic,or organometallic?uorous-soluble reagents. Because of the nature of the?uorous media,the application of?uorous reagents is limited to apolar substrates,since the reactions of polar substrates may be too slow for practical applications.This concept has also found application in catalysis(where only transition-metal complexes have been converted into?uorous soluble entities through ligand modi?cation),in multistep organic synthesis and in combinatorial chemistry.41
The?uorous phase,together with ionic liquid approaches and supercritical?uid systems,offers a whole new repertoire of solvents that overcome many of the problems of volatile organics.
1.3.4.Aqueous solvents.In the most recent decades,the use of water as a reaction solvent or co-solvent has received much attention in synthetic organic chemistry,with some-times surprising and unforeseen results.42Despite the different advantages that the previous mentioned solvents can offer,water can still be considered as a unique solvent. Moreover,water is the‘solvent of Nature’and,therefore,its use in common chemistry can be regarded as biomimetic and biocompatible.There are many potential reasons to replace the classical organic solvents by water,such as cost, safety and environmental concern.In fact,aqueous procedures are often referred to as green,environmentally friendly,or benign.In addition,the unique solvation properties of water have been shown to have bene?cial effects on many types of organic reactions in terms of both the rate and selectivity.Furthermore,experimental pro-cedures may be simpli?ed,since isolation of organic products and recycling of water-soluble catalysts and other reagents can be achieved by simple phase separation. The main obstacle to the use of water as reaction solvent is the negligible solubility of the majority of organic compounds in water.This problem can be addressed by using aqueous organic solvents or phase-transfer agents.As will be shown in this review,aqueous-phase transition-metal catalysis,including asymmetric catalysis,has emerged as an important tool in the formation of carbon–carbon bonds.43
1.4.Reaction conditions
While some reactions occur spontaneously,most of them require activation.For carbon–carbon coupling reactions, chemical activation modes(i.e.,catalysis)are indispensable in order to make processes effective and selective.The association of several activation modes,however,emerges as a powerful synthetic strategy when the respective kinetic effects are convergent.Besides the classical thermal activation mode,new methods have emerged in the recent years,such as physical or physicochemical activation techniques,among others.Thus,microwaves and ultrasonic and high-pressure techniques have been added to the chemist’s repertoire as physical methods for accelerating chemical reactions.On the other hand,physicochemical activation results from interactions between the medium and the reactive molecules and can arise from the solvent or from added complexing molecules.Physicochemical activation can be applied through the action of solvophobic effects(microemulsions and vesicles),host–guest chemistry,etc.
F.Alonso et al./Tetrahedron61(2005)11771–1183511775
1.4.1.Physical activation.
1.4.1.1.Microwave.Microwaves are a form of electro-magnetic radiation.When molecules with a permanent dipole are placed in an electric?eld,they become aligned with that?eld.If the electric?eld oscillates,then the orientations of the molecules will also change in response to each oscillation.Most microwave ovens operate at
2.45GHz,wavelength at which oscillations occur4.9! 109times per second.Molecules subjected to this microwave radiation are extremely agitated as they align and realign themselves with the oscillating?eld,creating an intense internal heat that can escalate as quickly as108C per second.Non-polar molecules such as toluene,carbon tetrachloride,diethyl ether and benzene are microwave inactive,while polar molecules such as DMF,acetonitrile, dichloromethane,ethanol and water are microwave active. This technique proves to be excellent in cases where traditional heating has a low ef?ciency because of poor heat transmission and,hence,local overheating is a major inconvenience.44
Microwave-assisted synthesis is a relatively young science of increasing research interest,as evidenced by the number of papers and reviews appearing in the literature.45The most important advantage of microwave-enhanced chemistry is the reduction in the reaction times.Reactions that require hours or days of conventional heating may often be accomplished in minutes under microwave heating.More-over,reactions are not only faster,but proceed with higher purity and,consequently,higher yields.The dramatic acceleration and increased purity and yields of micro-wave-assisted reactions make them attractive to the increased demands in industry and,in particular,for combinatorial drug discovery.46In addition to being energy ef?cient,the possibility of employing milder and less toxic reagents and solvents,or even solvent-free systems,offers a further advantage of this heating technology.
1.4.1.
2.Ultrasound.Ultrasound generally designates acoustic waves with frequencies in the range of20–100MHz.This energy is insuf?cient to cause chemical reactions,but when ultrasound travels through media a series of compressions and rarefactions are created,the rarefaction of liquids leading to cavities.During rarefaction, the negative pressure developed by power ultrasound is enough to overcome the intermolecular forces binding the ?uid and tear it,producing cavitation bubbles.The succeeding compression cycle can cause the microbubbles to collapse almost instantaneously with the release of large amounts of energy.The enormous rise in local temperatures and pressures produces a dramatic bene?cial effect of reaction acceleration,with relatively short times being required for completing the reaction such that the decomposition of thermally labile products is minimised.47 The frequency of ultrasound has surprisingly little in?uence on the reactions within the range in which cavitation occurs. Of signi?cance is the fact that ultrasound affects both homogeneous and heterogeneous reactions.
1.4.1.3.High pressure.Pressure represents a mild non-destructive activation mode,generally respecting the molecular structure by limiting decomposition or further evolution of the products.Therefore,the speci?c effects of high pressure can be of important value for organic synthesis.48The kinetic pressure effect is primarily determined by the variation of volume due to changes in the nuclear positions of the reactants during the formation of the transition state.Related to volume requirements are steric effects since the bulkiness of the molecules involved in the transition state conditions the magnitude of the steric interactions.As a consequence,pressure affects volume changes and should have an effect on steric congestion. As a mild activation mode,pressure may be considered of value in the synthesis of thermally fragile molecules, permitting a lowering of the temperature.In addition,the selectivity is generally preserved or even improved under such conditions.
On the other hand,pressure can be combined with solvophobic effects.The effect of pressure on organic reactions in aqueous solutions is complex.The activation volume relative to hydrophobic effects is positive(meaning deceleration by pressure),whereas the activation volume due to hydrogen bonding is negative.In addition, electrostatic effects may also be involved in many reactions (negative activation mode).Nevertheless,the combination of pressure and solvophobic activation may be an interesting method to increase the reactivity of reluctant polar molecules.
1.4.
2.Physicochemical activation.
1.4.
2.1.Micellar solutions.Micelles are dynamic colloidal aggregates formed by amphiphilic surfactant molecules.These molecules can be ionic,zwitterionic,or non-ionic,depending on the nature of their head groups, their micelles being classi?ed in the same way.In dilute solutions,amphiphile molecules exist as inpidual species in the media and these solutions have completely ideal physical and chemical properties.As the amphiphile concentration increases,aggregation of monomers into micelles occurs and,as a consequence,these properties deviate gradually from ideality.This concentration is called the critical micellisation concentration.
During the formation of micelles,head group repulsions are balanced by hydrophobic attractions and for ionic micelles, also by attractions between head groups and counterions. Hydrogen bonds can be also formed between adjacent head groups.
It is well known that the rates and pathways of all kinds of chemical reactions can be altered by performing the reactions in micellar media instead of pure bulk solvents.49 Micelles are able to(a)concentrate the reactants within their small volumes,(b)stabilise substrates,intermediates or products and(c)orientate substrates so that ionisation potentials and oxidation–reduction properties,dissociation constants,physical properties,quantum ef?ciencies and reactivities are changed.Thus,they can alter the reaction rate,mechanism and the regio-and stereochemistry.For many reactions,rate increments of5–100-fold over the reactions in homogeneous solutions have been reported.In some cases,rate increments may be much higher and increments in the order of106-fold have been observed.
