Reactivity of Polar Organometallic Compounds in ...szolcsanyi/education/files/Organicka chemia...

MICROREVIEW

DOI: 10.1002/ejoc.201500757

Reactivity of Polar Organometallic Compounds in Unconventional ReactionMedia: Challenges and Opportunities

Joaquin García-Álvarez,*[a] Eva Hevia,*[b] and Vito Capriati*[c]

Dedicated to the memory of Dr. Guy Lavigne

Keywords: Organometallic compounds / Water chemistry / Deep eutectic solvents / Ionic liquids / Reactivity / Greenchemistry

Developing new green solvents in designing chemical prod-ucts and processes or successfully employing the already exi-sting ones is one of the key subjects in green chemistry andis especially important in organometallic chemistry, which isan interdisciplinary field. Can we advantageously also useunconventional reaction media in place of current harsh or-ganic solvents for polar organometallic compounds? This

1. Introduction

“There are times when one can sense a sea change, a shiftin the order of things that is profound and fundamental”.[1]

A silent revolution is taking place in the way of thinkingand practising organometallic chemistry (OC) by academicand industrial groups worldwide, driven mainly by new in-sights, needs and evidence on the horizon. OC plays an es-sential role across a wide spectrum of science, technology,medicine and industry, with a heavy impact on the environ-ment, and still remains a core subject for timely topics (e.g.,energy, materials, medicine) on which priorities and policyoften focus.

International strategies launched by institutions and or-ganisations, such as The American Chemical Society’s(ACS’s) Green Chemistry Institute Pharmaceutical Round-table (GCIPR), are directed towards the need to replaceconventional hazardous volatile organic compounds

[a] Laboratorio de Compuestos Organometálicos y Catálisis,Departamento de Química Orgánica e Inorganica (IUQOEM),Instituto Universitario de Química Organometálica “EnriqueMoles”, Facultad de Química, Universidad de Oviedo33071 Oviedo, SpainE-mail: [email protected]://www.unioviedo.es/comorca/Joaquin%20ingles.htm

[b] WestCHEM, Department of Pure and Applied Chemistry,University of Strathclyde,Glasgow, G1 1XL, UKE-mail: [email protected]

[c] Dipartimento di Farmacia-Scienze del FarmacoUniversità di Bari “Aldo Moro”, Consorzio C.I.N.M.P.I.S.Via E. Orabona 4, 70125 Bari, ItalyE-mail: [email protected]

Eur. J. Org. Chem. 2015, 6779–6799 © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 6779

microreview critically analyses the state of the art with re-gard to this topic and showcases recent developments andbreakthroughs that are becoming new research directions inthis field. Because metals cover a vast swath of the PeriodicTable the content is organised into three sections discussingthe reactivity of organometallic compounds of s-, p- and d-block elements in unconventional solvents.

(VOCs) in favour of safe, green and biorenewable reactionmedia that are not based on crude petroleum.[2] One largearea of consumption of petroleum-based chemicals inchemical transformations is, indeed, solvents used as reac-tion media, which account for 80–90% of mass utilisationin a typical pharmaceutical/fine chemical operational pro-cess. Thus, the solvent itself is often a critical parameter,especially in drug product manufacturing, and is also re-sponsible for most waste generated in the chemical indus-tries and laboratories.[3]

Following these considerations, some most critical andintriguing questions arise. Can we remove the need fortraditional organic solvents from organometallic reac-tions?[4] Can we also use recyclable, biodegradable andcheap unconventional solvents for polar organometalliccompounds? Answering these questions would not onlymean breaking new ground in the search for sustainablesolutions to the aforementioned challenges, but it could alsobe rewarding from an intellectual point of view in order toinvestigate to what extent a particular organometallic com-pound does not react with the unconventional solvent inquestion and, if that is the case, to explain why this occurs.

In this microreview, we seek to give an overview of somerecent contributions on the impact of unconventional sol-vents (e.g., water, deep eutectic solvents, ionic liquids andsupercritical CO2) on the chemistry of compounds of s-, p-and d-block elements, but seminal references have also beencritically analysed. As will emerge from the discussion thatfollows, especially in the case of highly reactive organo-metallic compounds and in contrast to what has been ob-

J. García-Álvarez, E. Hevia, V. CapriatiMICROREVIEWserved in the case of compounds of d- and p-block ele-ments, no protic solvent such as water has yet been ableto replace organic solvents entirely, although stoichiometricamounts have been shown to be crucial in redirecting reac-tions in interesting ways: for example, by speeding up thereaction rate or by influencing the stereochemistry of a cer-tain synthetic route. On the other hand, bio-based eutecticmixtures have also proved to be excellent surrogates of con-ventional solvents for reactions promoted by Grignard andorganolithium reagents, whereas unexpected reactivity/out-comes have sometimes been observed when ionic liquids areemployed (vide infra).

The contents are organised into three main sections withsubheadings according to the nature of the metal–carbon(M–C) bond. Topics that have recently been reviewed arenot further detailed here.

2. Organometallic Compounds of s-BlockElements

In the Periodic Table, the s-block elements are the 14elements contained in the first two columns (Groups 1Aand 2A), plus helium. Except for helium, they are unifiedby the fact that their valence electrons are in each case inan s orbital, and are very reactive due to highly polar M–

Joaquín García Álvarez studied chemistry at the University of Oviedo and received his PhD degree in 2005 under thesupervision of Prof. José Gimeno and Dr. Victorio Cadierno, studying the coordination of iminophosphorane–phosphaneand bis(iminophosphorane)methane ligands in (arene)RuII fragments. Then he joined the group of Prof. Robert E. Mulveyat the University of Strathclyde in Glasgow (Scotland, United Kingdom) working for two and a half years in the field ofmain-group chemistry (alkali-metal-mediated metallation). He returned to the University of Oviedo in 2008, where he iscurrently a “Ramón y Cajal” postdoctoral researcher. The current focuses of his research are: (i) the study of syntheticorganic reactions mediated by highly polarised organometallic compounds in green and biorenewable reaction media (e.g.,Deep Eutectic Solvents, DESs), and (ii) the application of transition-metal complexes (e.g., Ru, Re, Pd, Au, Cu, Ag)containing iminophosphorane ligands in homogeneous catalysis in environmentally friendly solvents (water, ionic liquids,glycerol and DESs) as reaction media. He is co-author of 45 publications and eight book chapters in the field of organome-tallic chemistry and green chemistry.

Eva Hevia received her MSci degree in chemistry from the Universidad de Oviedo (Spain) in 1998. She obtained herPhD degree from the same institution in 2002 under the supervision of Victor Riera and Julio Pérez. Next she wasawarded a Marie Curie Fellowship held at the University of Strathclyde under the direction of Prof. Robert Mulvey. In2006 she took up a Royal Society University Research Fellowship at the University of Strathclyde, where she is currently aProfessor of Inorganic Chemistry. Her research interests include s-block-metal-mediated transformations with a particularemphasis on metal–metal cooperativity and synergistic effects.

Vito Capriati obtained his MSci degree in chemistry and pharmaceutical technology (summa cum laude) from the Univer-sity of Bari “Aldo Moro” (Italy) in 1990. After working as a forensic chemist officer in the Carabinieri’s RIS (ScientificInvestigation Department) of Rome and earning a two-year graduate fellowship within the Italian National ResearchCouncil (CNR Centre MISO, then merged into ICCOM-CNR), in 1993 he became Assistant Professor before in 2002taking up his present appointment as Associate Professor of Organic Chemistry at the University of Bari, where he leadsthe Bioorganic and Organometallic group. He has been Visiting Scientist at The Ohio State University (USA, Prof.Fraenkel’s group, 2001) and Visiting Professor at the Gothenburg University (Sweden, 2003). He is co-founder of theacademic spin-off SYNCHIMIA srl and departmental coordinator of three Erasmus Programmes. His current researchinterests revolve around functionalised organolithium compounds (structure elucidation, dynamic stereochemistry of chiralcompounds, and the discovery of new reactions), synthesis and reactivity of new heterocycles, new sustainable chemicalprocesses using unconventional reaction media, organofluorine and organoboron chemistry, and the development of newdrugs for rare diseases. He has published over 90 articles in peer-reviewed journals, six book chapters and seven reviews.He was the recipient of the CINMPIS Prize for “Innovation in Organic Synthesis” (2009), of the Award of the ItalianChemical Society (Organic Division) for “Mechanistic and Theoretical Aspects of Organic Chemistry” (2014) and theItalian coordinator of an international Italian-German bilateral Vigoni Project (2012–2013). He was also co-editor of“Lithium Compounds in Organic Synthesis – From Fundamentals to Applications”, published by Wiley-VCH (2014).

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C bonds. In this section we deal with the reactivity oforganolithium and Grignard (organomagnesium) reagentsin unconventional solvents.

2.1. Reactivity in Protic Reaction Media (Water and DeepEutectic Solvents)

Organolithium and Grignard reagents are among themost useful and versatile organometallic compounds inchemical synthesis, and functionalised organometallic spe-cies are very useful intermediates for the synthesis of manyorganic non-natural and natural products.[5] Opening chap-ters in classic organic textbooks, however, emphasise theneed for the strict control of anhydrous conditions and theuse of water-free reaction media for the successful handlingof organometallic compounds with highly polarised M–Cbonds. Thus, at first sight, it might seem ridiculous to thinkof a protic solvent (e.g., water) as a potential “additive”(or, even worse, as a full component) for reaction media forcarrying out s-block-metal-mediated organic transforma-tions, because these organometallics are extremely sensitiveto traces of air and moisture.[6] Nevertheless, a perusal ofrecent and present-day literature reveals, from time to time,papers (vide infra) that highlight the unexpected outcomesof some chemical transformations run in the presence of

Reactivity of Organometallic Compounds in Unconventional Reaction Media

water. These deserve consideration and still need an expla-nation.

One of the first examples reported is the following. Inthe course of producing labelled aromatics by hydrolysis oforganometallic intermediates with tritiated water (T2O),Taylor made the observation that the most convenientmethod for the preparation of tritiated arenes was the ad-dition of nBuLi to a mixture of a bromoarene and wetted(T2O) sodium-dried Et2O. This result is consistent with alithium/bromine exchange reaction surprisingly occurring“at least as fast and most probably faster” than the ex-pected reaction between nBuLi and T2O (Scheme 1).[7] Therelative rates of deprotonation and of halogen/lithium ex-change by organolithium compounds, however, have been amatter of controversy in the following years.[8]

Scheme 1. Preparation of 9-tritium-labelled anthracene.

Lithium carboxylates 1 are known to react with organo-lithium compounds 2 in Et2O to give high yields of thecorresponding ketones 3 only after considerable reactiontimes at reflux (at least 24 h). Under these conditions, terti-ary alcohols 5 are usually not formed. Conversely, Grignardreagents react with lithium salts of carboxylic acids, giving,after a 24 h reaction time, mixtures of both ketones andtertiary alcohols, the latter also being the major products.If the time at reflux is kept shorter (e.g., 30 min), however,mixtures of ketones 3 and tertiary alcohols 5 are insteadalso produced, upon quenching with H2O, in the case oforganolithium compounds. This unexpected finding is con-sistent with a slow reaction between the lithium carboxylateand the organolithium compound, combined with a slowhydrolysis of the reaction intermediate 4. Thus, the excessorganolithium 2 still present reacts with a proportion of theformed ketone 3 competitively with its hydrolysis by water(Scheme 2).[9]

Scheme 2. Preparation of ketones and tertiary alcohols by treat-ment of organolithium compounds with lithium carboxylates.

In general, Lewis-basic solvents increase the reactivity oforganolithium compounds, because they become an inte-gral part of the organolithium aggregate and, once used asadditives or ligands, they have sometimes proved to be ef-fective in contributing to the optimisation of organolithiumreactions.[10]

For instance, in the asymmetric LDA-mediated synthesisof the anticancer agent Lonafarnib (8), a unique water ef-

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fect on the enantioselectivity was discovered. In the key alk-ylation step, an LDA·THF complex in cyclohexane wasadded to a toluene solution containing the tricyclic sub-strate 6, the chiral norephedrine-based mediator and thealkylating agent 7. Counterintuitively, the highest ee (95 %)and the best yield (95%) of 8 were achieved when 1 equiv.of water was added to the above reaction mixture and thencompensated for with an additional equivalent of LDA. Inthe absence of water, both the ee and the yield in 8 dramati-cally dropped to 50% (Scheme 3).[11] As an additional ex-ample, carboalumination of alkynes has been shown to oc-cur within minutes at –23 °C (and is fast even at –70 °C)in the presence of stoichiometric amounts of water, leadingstereoselectively to alkenes.[12]

Scheme 3. Stereoselectivity achieved in the key alkylation step byadding water.

We have always been taught about the crucial role playedby water in life sciences. Among its properties, it is worthmentioning its extraordinary capability to engage in strongintermolecular hydrogen bonding with a plethora of Lewis-acidic and -basic sites, thereby promoting self-organisationin supramolecular ordered structures. What about the “roleof water” in the reactions of organometallic compounds ofs-block metals? The hydrolysis of organolithium com-pounds by water or other proton donors is often assumedto be a very simple process, yielding quantitatively the cor-responding organic acid and LiOH.[13] As a matter of fact,it may not be as simple as is commonly believed. The ratesof protonation of Et2O solutions of PhLi and PhCH2Li andtheir O-deuterated analogues by water or alcohols, for in-stance, show small isotope effects (1.0–1.5), which impliesthat the rate-determining step is the displacement of Et2Ofrom the organolithium compound by the oxygen atom ofthe “acid”.[14] Could water act as a polar ligand towardsLi+ centres? The first lithiated organic compound contain-ing water as a ligand was reported by Wright and co-workers (Refcode: JEFTAP).[15] Lithiation of 2-mercapto-benzoxazole, in the presence of N,N,N�,N�-tetramethylethyl-enediamine (TMEDA) and H2O (either adventitious or de-liberately added to the reaction mixture) produced the mo-nomeric complex 9 (Figure 1) exhibiting strong hydrogenbonding between one proton of a coordinated H2O mol-ecule and the polarised sulfur centre of the organic anion,rather than a protonated Li–OH···SH species.

J. García-Álvarez, E. Hevia, V. CapriatiMICROREVIEW

Figure 1. Molecular structure of the complex 9 formed betweenlithiated 2-mercaptobenzoxazole and TMEDA.

Such a molecular structure, as suggested by the authors,can be viewed as a model for how hydrolysis of organo-lithium compounds might take place. Analogously to whathas been ascertained in the case of organoalanes (vide in-fra), this process might also proceed through preliminarycomplex formation between the organolithium and water,followed by proton transfer to the carbanion. The relativerates of these processes, however, might also be influencedby the nature of the aggregates involved, because of thestrong structure/reactivity relationship in organolithiumcompounds.[5b,5c] These findings were then also extended toalkaline-earth metal complexes,[16] with the synthesis ofaqua complexes carried out by “assembling” H2O ligands

Figure 2. Molecular structure of the 1:1:1 complex 10 formed from lithiated malonodinitrile, TMEDA and H2O.


from solid metal hydroxides in a hydrocarbon solvent andin the presence of a Lewis base.

The first structural characterisation of an H2O-contain-ing complex of a lithium salt of an organic molecule con-taining an acidic C–H bond was also reported (CSD-55645).[17] The three-dimensional polymeric structure 10 de-picted in Figure 2 reveals an intriguing complex of lithiatedmalonodinitrile, TMEDA and H2O in a 1:1:1 molar ratio.What is remarkable here is (a) the lack of TMEDA–Li in-teractions, which is unprecedented in lithium chemistry, es-pecially if it is considered that TMEDA, unlike water, is abidentate ligand, which should favour complexation to thelithium atom, and (b) the ability of each water molecule toengage simultaneously in hydrogen bonding (Figure 2) totwo TMEDA molecules (donor function) and to two lith-ium atoms (acceptor function).

The intrinsic reactivity of a series of monomeric all-ylmetal reagents with water and carbonyl compounds hasbeen recently addressed in a theoretical study.[18] Interest-ingly, calculations suggest that intrinsic kinetic preferencefor allylation over hydrolysis correlates quite well with thereactivity of hydrolysis. That is, a higher activation energyof hydrolysis corresponds to a higher kinetic preference forallylation. However, the polarity of the C–M bond does notsolely in itself fully account for the reactivity of hydrolysis,but both the nucleophilicity of the allylmetal and thermo-dynamic driving forces are likely to contribute significantlyto the barrier of hydrolysis. Data relating to the organome-tallic compounds of the s-block elements also suggest thatboth π complexes of Li and polarised σ complexes ofMgBr2 may hydrolyse or allylate preferentially, dependingon the employed experimental conditions. In particular, cal-culations for the reactions between allylMgBr and water oracetone show that the two activation energies, of hydrolysis(4.5 kcal mol–1) or allylation (5.7 kcal mol–1), are quite sim-


ilar. This competition was later experimentally investigatedby Madsen and Holm.[19] When allylMgBr was treated witheither acetone or PhCHO in the presence of water (inverseaddition), the yields of the corresponding addition productswere found to be 91 and 75%, respectively. Grignard rea-gents are complex mixtures of the Schlenk components alk-yl(aryl)magnesium halide, dialkyl(diaryl)magnesium, andmagnesium halide salt, solvated by an ethereal solvent, andundergoing very fast chemical exchange in solution(Scheme 4).[5g]

Scheme 4. The Schlenk equilibrium.

The position of the equilibrium is influenced by solvent,temperature, and the nature of the substituents. It is shiftedfrom left to right in strongly donating solvents (e.g., THFor dioxane) because the stabilisation due to the interactionwith solvent molecules decreases in the order MgX2 �RMgX � R2Mg, that is, according to the Lewis acidity ofthe various components.[20] Thus, the above results wouldseem to indicate that water preferentially coordinates mag-nesium, the complexation energy with one water moleculebeing –23.1 kcalmol–1.[18] It may be that “coordinated”water is less reactive in the protonation reaction, thereforeallowing the addition reaction to take place more competi-tively. The possible existence of a “scavenging” effect to-ward water promoted by any electrophilic magnesium com-pound present in solution was supported by an experimentin which allylMgBr was added to an acetone/water mixturein the presence of an extra equivalent of MgBr2. In thatcase, the yield of the addition product was quantitative.Benzylmagnesium chloride also proved to react sufficientlymore rapidly with acetone and benzaldehyde rather thanbeing quenched with water, whereas butylmagnesium brom-ide yielded only traces of the expected addition products.

During the investigation of the directing ability of thetetrahydrofuranyl moiety in promoting regioselective ortho-lithiation/functionalisation of diaryltetrahydrofurans, anunexpected reactivity was observed by Capriati and co-workers in a screening for electrophiles.[21] Whereas no reac-tion was detected upon addition of acetone to a dry Et2Osolution of the putative ortho-lithiated intermediate 11-Li[generated by lithiation of the parent precursor 11-H withtBuLi at 0 °C for 10 min (direct addition)], the expectedhydroxyalkylated adduct 12 could instead be isolated in30 % yield if an Et2O solution of 11-Li was added to anacetone/water mixture (6 equiv. each) at room temperature(inverse addition). It was ascertained, however, that waterdid not apparently boost any “rate acceleration” of the re-action, because a similar yield was obtained under neat con-ditions, that is, in the absence of water, which simply acts asa bystander (Scheme 5).

The potential impact of protic solvents in the above func-tionalisations was further investigated by employing the so-called “deep eutectic solvents” (DESs). The concept ofDESs was first introduced by Abbott and co-workers todescribe the formation of a liquid eutectic mixture (m.p.


Scheme 5. ortho-Lithiation/functionalisation of diphenyltetra-hydrofuran with acetone.

12 °C) by starting from two solid materials with high melt-ing points: choline chloride (ChCl, m.p. 133 °C) and urea(m.p. 302 °C) in a 1:2 ratio (1ChCl/2 urea).[22] DESs are to-day generally defined as combinations of two or three safeand inexpensive components that are able to engage inhydrogen-bonding interactions with one another to formeutectic mixtures with melting points lower than those ofany of the individual components.[23] ChCl, in particular, isnowadays one of the most widespread ammonium saltsused for the synthesis of DESs. Also known as vitamin B4,it is produced on the scale of a million metric tonnes peryear (ca. 2 j kg–1) as an additive for chicken feed and hasmany other applications. Thanks to their shallow ecologicalfootprint and attractive low price, DESs have now becomeof growing interest both at academic and at industriallevels, in particular for their unusual solvent properties. Itis worth noting that the concept of DESs is quite differentfrom that of traditional ionic liquids (ILs, vide infra), be-cause DESs are not entirely composed of ionic species, andcan also be obtained from non-ionic species.[23]

Both nucleophilic additions (acetone and benzophenone)and substitutions (chlorodiphenylphosphine) proved to beeffective in different eutectic mixtures, providing the ex-pected adducts 12–14 in good yields and competitively withprotonolysis (Scheme 6).[21] Adducts 12–14 could be ob-tained only in lower yields in Et2O (up to 60%), whereasbetter yields (up to 90 %) could be achieved in cyclopentylmethyl ether (CPME) as an alternative environmentallyfriendly reaction medium. Remarkably, when a commercialpentane solution of tBuLi (1.9 equiv.) was rapidly spreadout over a mixture of 11-H (1 equiv.) in CPME and ChCl/Gly (1:2), at 0 °C, under air, and with vigorous stirring, andquenched after 1 min of reaction time with neat DMF(2 equiv.), the formylated adduct 15 could be isolated in90 % yield (Scheme 6).

o-Tolyl-substituted tetrahydrofuran derivatives 16-Hhave recently been found to undergo an unprecedentedhighly regioselective intramolecular C–O bond-breaking re-action, triggered by the corresponding benzylically lithiatedintermediates 16-Li, ending up with the formation of func-


Scheme 6. Regioselective preparation of adducts 12–15 through or-tho-lithiation/electrophilic interception of 11-H in DES mixtures.

tionalised primary alcohols 17 featuring incorporation intheir skeletons both of a second equivalent of base andof an electrophile (if any) at a tertiary carbon atom(Scheme 7).[24]

Scheme 7. Site-selected benzylic lithiation/ring-opening of 16-Hand the regioselective preparation of functionalised alcohols 17 viaintermediates 16-Li.

This new organic transformation can also be conve-niently run directly in a glycerol-containing eutectic mix-ture, as a benign reaction medium, competitively withprotonolysis. As a general reaction procedure, a commercialhydrocarbon solution of the organolithium compound(sBuLi, iPrLi, tBuLi) was added by rapidly spreading it outover a mixture of 16-H in CPME and ChCl/Gly (1:2), at0 °C, under air, and with vigorous stirring, and quenchedwith the electrophile after a 3 min reaction time to givealcohols 17 in yields up to �98%. The scope, limitation andmechanistic aspects of this reaction, which pioneers“greener” alkylative THF ring-opening processes, have beendiscussed.[24] Interestingly, sBuLi was found to promotefaster deprotonation than tBuLi, and ortho-lithiation seri-ously competes with benzylic lithiation only in the case ofsubstrates possessing an ethyl group in an ortho position atone of the two aromatic rings.


The chemoselective nucleophilic addition of organo-lithium and Grignard reagents to ketones in ChCl-basedeutectic mixtures was investigated in depth by Hevia,García-Álvarez and co-workers.[25] A range of such rea-gents – compounds 19 – could successfully be added, underair and at room temperature, to aromatic and aliphaticketones 18 in both ChCl/Gly (1:2) and ChCl/H2O (1:2) mix-tures, thereby affording the corresponding tertiary alcohols20 in good yields (up to 90%) and competitively with pro-tonolysis (Scheme 8).

Scheme 8. Chemoselective addition of Grignard and organolithiumreagents to ketones in ChCl-based eutectic mixtures.

A comparison of the reactivity profiles of these organo-metallic reagents in DESs with those in pure water suggeststhat a kinetic activation takes place in the former case, mostprobably due to the formation of more nucleophilic halide-rich magnesiate or lithiate species further to reaction be-tween the alkylating reagent and ChCl. Thus, ChCl may beplaying a double role in these processes, as a componentboth of the DES mixtures and of the new “ate” complexes.This conclusion was supported by X-ray crystallographicstudies, multinuclear magnetic resonance investigations and1H DOSY NMR experiments.

In a recent paper, Song showed as well that catalyticamounts of Bu4NCl in THF solutions of Grignard reagentsenhanced the efficiency of addition reactions to carbonylcompounds, producing tertiary alcohols in excellent yieldswhile minimising the formation of enolisation and re-duction products[26] The authors proposed that the presenceof this ammonium salt should help to shift the Schlenkequilibrium of Grignard reagents in solution (Scheme 4) tothe side corresponding to the dimeric species, which wouldfavour the addition reaction thanks to the 2:1 complex in-volved in the six-membered transition state.

2.2. Reactivity in Ionic Liquids

In general, the term “ionic liquids” (ILs) refers to liquidscomposed of weakly coordinated ions and having meltingpoints below 100 °C.[27] At least one ion has a delocalisedcharge, and one component is organic; this prevents the for-mation of a stable crystal lattice. ILs have recently attractedgreat interest as “greener” alternative to conventional or-ganic solvents because of their thermal stability, non-flammability, ease of recycling, low vapour pressures, andcatalytic properties.[28] Their use as solvents for reactionsinvolving organometallic compounds of s-block elements,however, is still in its infancy. One of the most extensivelystudied class of ILs is based on imidazolium cations with


appropriate counter anions (ImILs), which are known tosupport many organic transformations.[28]

Because of the presence of the acidic hydrogen atom atthe C-2 position, ImILs 21 have been shown to react underbasic conditions to produce N-heterocyclic carbenes(NHCs) 22, which are neutral, highly reactive, six-electronspecies, each possessing a dicoordinate carbon atom withtwo nonbonding electrons, and are responsible for manyside reactions (Scheme 9).

Scheme 9. Formation of NHC species 22 from imidazolium cations21.

This problem was overcome by Clyburne and co-workers,who showed that dried phosphonium ILs 23 are inerttowards reactions with strong bases and are not reducedeven by potassium metal, thus representing the first suitablesolvents for Grignard chemistry.[29] Commercially availableTHF solutions of PhMgBr, once dissolved in 23 (THF/23,1:3), proved cleanly to promote carbonyl additions, benzynereactions, halogenation, hydroxy(alkylation)arylation, andcoupling reactions. Most importantly, competitive depro-tonation of 23 to produce the phosphoranes 24 did not takeplace (Scheme 10). The inertness of phosphonium cationstowards Grignard solutions appears to have a primarily ki-netic basis and to be anion-dependent; small bases are morelikely to deprotonate 23, whereas large bases are more reluc-tant. Several other factors, however, also seem to contributeto this inertness; they include the bulkiness and flexibilityof the cation as well as its electrochemical robustness rela-tive to unsaturated ions.[30]

Scheme 10. Possible formation of phosphoranes 24 by deproton-ation of 23.

The introduction of an ether oxygen atom on the sidearm of a phosphonium salt, as in 25, contributes to stabilis-ing the organomagnesium reagent, thereby improving thecapability of the corresponding IL to act as a solvent evenfor reactions mediated by aliphatic Grignard reagents (Fig-ure 3).[31]

Figure 3. Phosphonium ILs containing ether functionalities.


Walsby and co-workers also demonstrated that, whereasin molecular solvents Grignard reagents react according tonucleophilic pathways, ILs are ideal reaction media for pro-moting electron-transfer processes.[32] The Kumada–Corriureaction, which involves the coupling of Grignard reagentswith aryl halides mediated by transition metal catalysts(typically nickel or palladium), has been successfully carriedout between PhMgBr and aryl halides in the phosphoniumIL 26 in the presence of an Ni0 complex of NHC 27 toafford biaryl derivatives 28 with yields up to 88%, therebysupporting the in situ generation of carbene species(Scheme 11). Remarkably, such a reaction even facilitatesthe activation of C–F bonds.

Scheme 11. Kumada–Corriu cross-coupling in the phosphonium IL26.

As well as phosphonium ILs, some imidazolium-basedILs can also withstand the strong basicity of Grignard rea-gents. These include ImILs with either a phenyl substitu-ent[33] or an isopropyl group[34] at the vulnerable C-2 posi-tion. ILs 29 and 30 (Figure 4) have both been successfullyemployed as suitable solvents in reactions involving the ad-dition of aliphatic and aromatic Grignard reagents to alde-hydes, ketones and esters, affording the expected hydroxy-alkylated adducts in good yields (68–83%). These ImILscan be recycled and reused several times without appreci-able loss of the IL.

Figure 4. ILs employed as alternative reaction media for Grignardreagents.

All attempts, however, to generate Grignard reagents inILs had failed until 2006, when Chan and co-workers re-ported the first example of an organomagnesium speciesgenerated directly in the pyridinium-based IL 31, with tetra-fluoroborate as a counterion (Figure 4).[35] The reactivitypattern towards carbonyl compounds shown for reactionsrun in 31, however, was different from that exhibited byGrignard reagents in conventional organic solvents. For ex-ample, both a radical transfer leading to a pinacol deriva-tive and the formation of an iodo compound were observed

J. García-Álvarez, E. Hevia, V. CapriatiMICROREVIEWon treating EtMgI with PhCHO, with the yields of thesetwo adducts also being critically dependent on the molarratio of the reagents and the presence of additives in thereaction mixture. It was suggested that in the absence of acoordinatedligand(ashappensinthecaseofanIL),theorgano-magnesium compound is likely to have an oligomeric struc-ture, which is most probably responsible for the distinct re-activity observed. New alkylpyridinium and tetralkylphos-phonium ILs 32 and 33, respectively, each possessing anether functionality to provide stabilisation to the Grignardreagent, were prepared by Scammells and co-workers andevaluated as solvents for Grignard reactions.[36] Interest-ingly, different outcomes were observed, according to thepresence or otherwise of an ethereal co-solvent. When ad-dition reactions to carbonyl compounds were run in ILs32, an unusual reduction of aldehydes to the correspondingprimary alcohols (probably mediated by a hydride transferfrom a dihydropyridine intermediate) was observed in theabsence of Et2O, whereas the expected addition productswere obtained in the presence of this solvent. Conversely,in the phosphonium-based ILs 33, aldehydes reacted withthe Grignard reagent, affording the corresponding additionproducts, only when Et2O was present as a co-solvent.

To the best of our knowledge, analogous reactions oforganolithium compounds run in ILs have always produceddecomposition and unidentified products. Because of thebroad use of organolithium and Grignard reagents in thepharmaceutical and fine chemicals industry, a judiciouschoice of reaction solvent is crucial from both safety andenvironmental standpoints. In this context, 2-MeTHF (de-rived from a renewable source) and CPME (directly obtain-able from cyclopentene) are emerging “greener” alternativesto the common Et2O and THF for organometallic reac-tions, and have also proved to be more effective in im-proving product yield and in suppressing side reactions.[37]

The challenge will be the use of commercially preparedGrignard and organolithium solutions directly in the abovesolvents.

3. Organometallic Compounds of d-BlockElements

As has been outlined in the Introduction, OC has be-come a cornerstone of modern organic synthesis, and nowa-days hardly any total synthesis endeavour can be envisionedwithout a key step involving the use of polarised organome-tallic compounds containing d-block elements, that is, thetransition metals.[38] These fundamental reagents (mostcommonly organozinc and organocopper compounds) areable to deliver carbon residues (M–C bonds) from zinc[39]

or copper[40] to carbon halides or pseudohalides (C–X), toform new C–C bonds. However, the chemoselectivity ofthese processes can be seriously compromised by: (i) the for-mation of undesired products, (ii) the use of low tempera-tures (ranging from 0 to –78 °C), and (iii) the need to em-ploy dry, hazardous ethereal solvents and inert-gas proto-cols (to avoid fast degradation of the polar reagents). All


of these experimental restrictions hinder the synthetic appli-cation of these polarised species under environmentallyfriendly reaction conditions (i.e., at room temperature andin the absence of protecting gas)[1,3,41] and their use in thepresence of unconventional solvents [e.g., water, ILs, super-critical CO2 (scCO2) or perfluorinated solvents] as reactionmedia.[42] Despite all these drawbacks, during the last dec-ades the chemistry of polarised organometallic compoundscontaining d-block elements has crossed the frontiers be-tween their application in modern synthetic organic chemis-try and the growing area related to the employment of un-conventional solvents. Since the synthesis of the first polar-ised organozinc compound (ZnEt2) by Wanklyn in 1848,[43]

it has been well known that these basic compounds are ableto react with several unconventional solvents (such as wateror scCO2).

This section covers the progress made in the applicationof the aforementioned unconventional solvents as reactionmedia in a variety of organozinc-, organocopper-, and or-ganogold-mediated organic reactions. In particular, thefollowing reactions are surveyed: (i) Reformatsky- andBarbier-type reactions, (ii) addition of organozinc deriva-tives to α,β-unsaturated carbonyl compounds, (iii) cross-coupling reactions between organozinc reagents generatedin situ and organic halides (Negishi coupling), (iv) poly-merisation reactions, (v) organogold reactions, and (i) irid-ium-promoted C–H bond activation reactions.

3.1. Reformatsky Reaction in Unconventional Solvents

The Reformatsky reaction,[44] which involves the treat-ment of a halo ester with a carbonyl compound (ketone oraldehyde) in the presence of Zn (Scheme 12), was the firstexample of addition of polarised organometallic reagentscontaining d-block elements to carbonyl compounds. Sinceits discovery in the 19th century, it was believed that thisZn-mediated addition reaction could only take place undera protective gas (with use of Schlenk techniques) and withemployment of dry organic solvents.[45] However, several ex-amples showing such reactions between carbonyl com-pounds and organic halides, mediated by reactive d-blockmetals (Zn, Cu), both in wet solvents and in pure waterwere then reported in the literature.[46]

Scheme 12. Reformatsky reaction between halo esters and carbonylcompounds in the presence of Zn.

In 1990, Chan, Li and co-workers lit the way by studyingthe direct Reformatsky-type conversion between benzalde-


hyde and α-bromopropiophenone, mediated by metalliczinc, in pure water as the solvent (Scheme 13).[47] Both theyield (82%) and the ratio of the two diastereomeric prod-ucts (34; erythro/threo, 2.5:1) obtained in this aqueous reac-tion are comparable to those achieved with preformed orga-nometallic reagents under anhydrous conditions. After thisseminal work, several groups demonstrated that this pion-eering idea could be extended to a variety of carbonyl sub-strates and different halo esters. This chemistry has beensummarised in previous reviews,[46,48] so it is not furtherdetailed here.

Scheme 13. Reformatsky-type reaction between benzaldehyde andα-bromopropiophenone in water.

Not only water, but also other unconventional solventssuch as ILs have been employed as reaction media for Re-formatsky-type reactions. As previously discussed in Sec-tion 2.2 of this microreview, ILs have received much atten-tion as a new class of unconventional solvents during thelast decades.[28] To the best of our knowledge, the first Re-formatsky reactions in a variety of ILs were reported byKitazume and co-workers (Scheme 14).[49] The authorsstudied the Reformatsky reaction: (i) between aromatic, ali-phatic or alkenyl aldehydes 35 and different halo esters 36,(ii) mediated by metallic Zn, and (iii) in the ILs [EtDBU]-[OTf] (8-ethyl-1,8-diazabicyclo[5.4.0]undec-7-enium tri-fluoromethanesulfonate), [BMIM][BF4] (1-butyl-3-methyl-imidazolium tetrafluoroborate) and [BMIM][PF6] (1-butyl-3-methylimidazolium hexafluorophosphate). At room tem-perature, only a moderate yield (52%) of the desired com-pound 37 was achieved in the IL [EtDBU][OTf]. However,upon heating of the reaction mixture to 50 °C, an almostquantitative conversion of 93% to 37 was reached. As hasbeen pointed out in Section 2.2, one of the major advan-tages associated with the use of ILs as solvents is the pos-sibility of reusing the IL after a simple extraction of thedesired organic product 37 with organic solvents.[28,42] Inthis case, however, the recyclability of the system proved tobe the major limitation. Indeed, the IL could only be recy-cled for up to three consecutive cycles with moderate levelsof conversion ranging from 62 to 56 %. This experimental

Scheme 14. Reformatsky reaction in ILs.


fact may be the result of the need to heat the reaction mix-tures above room temperature.

3.2. Barbier Reaction in Unconventional Solvents

The Barbier reaction,[50] which involves the reaction be-tween an organic halide and a carbonyl compound in thepresence of magnesium, aluminium, zinc, indium, tin ortheir salts, is one of the most important methods for creat-ing C–C bonds and has widespread synthetic applicationsin organic chemistry.[51] The reaction proceeds through nu-cleophilic attack by the organometallic compound, gener-ated in situ, on the carbonyl electrophile (generally an alde-hyde). Since its discovery, considerable attention has beendevoted to the development of this Zn-mediated reaction inwater.[52] In fact, the allylation of aldehydes and ketonesunder Barbier conditions usually occurs more rapidly andgives rise to higher yields when water is used as the (co)-solvent.[53] In this context, Li and Chan reported one of thefirst and most innovative approaches to allylation reactionsof carbonyl compounds promoted by Zn in water(Scheme 15).[54] Again, the presence of water was critical tothe success of the coupling step for the formation of com-pounds 38. Thus, when the reactions were performed in dryconventional ethereal solvents (e.g., Et2O or THF), poorformation of compounds 38 was observed.

Scheme 15. Zn-mediated Barbier reaction in water.

Nowadays, a plethora of methods for Zn-mediated allyl-ation of different electrophiles (e.g., aldehydes, ketones,acetals or dioxolanes) under aqueous conditions is knownin the literature, allowing the direct synthesis of homoallylicalcohols under environmentally friendly reaction condi-tions.[55,56] Recently, the spectrum of unconventional sol-vents available to accomplish this Zn-mediated allylation re-action under green conditions has been enlarged by Leekeand co-workers. These authors reported the employment ofsubcritical CO2/H2O (30 °C/80 bar) as a renewable solventmixture to improve the desired allylation reaction with avariety of aryl aldehydes.[57,58]

In recent years, Li and co-workers have expanded thescope of these Barbier-type reactions to include the morechallenging carbonyl alkylations[59] and arylations[60] withnon-activated halides in water. In both the examples cited,the desired aromatic aldehyde undergoes the correspondingalkylation or arylation in water, mediated by stoichiometricamounts of Zn dust and catalysed by InCl or [Rh(acac)-(CO)2] (acac = acetylacetonate), respectively (Scheme 16).These processes allowed the mild and straightforward syn-thesis of benzyl alcohols 39 and arylmethanols 40, therebyunlocking one of the last challenges in the field of Barbier-type reactions in water.


Scheme 16. Barbier-type alkylation and arylation of aldehydes inwater.

Amines could also be conveniently prepared by direct ad-dition of zinc organometallic reagents to imines in the pres-ence of water. Savoia, Umani-Ronchi and co-workers firstdeveloped the enantioselective synthesis of homoallylicamines by addition of (allyl)ZnBr reagents (generated insitu) to imines in a THF/H2O mixture.[61] More recently,Naito and co-workers reported the Zn-mediated additionof alkyl iodides to imines in the absence of VOCs by usinga saturated aqueous NH4Cl solution as the solvent.[62]

Nitrones 41 can also undergo Barbier-type alkylation inpure water as the solvent and at room temperature, yieldingthe corresponding hydroxylamines 42 (Scheme 17).[63]

Scheme 17. Synthesis of hydroxylamines through Barbier-type alk-ylation of nitrones in water.

3.3. Conjugate Addition of Organozinc Derivatives to α,β-Unsaturated Carbonyl Compounds in Water

The conjugate 1,4-addition of organometallic com-pounds to electron-deficient olefins represents one of themost powerful tools to create new C–C bonds currently be-ing exploited. Among the various methods available, themost commonly employed strategies involve the use of or-ganometallic species such as Grignard reagents (RMgX) ororganolithium (RLi) compounds. However, the use of thesehighly reactive organometallic derivatives can lead to unde-sired side reactions (e.g., Wurtz coupling, reduction of thecarbonyl compounds, hydrolysis, competitive 1,2-additionetc.).[64] Thus, dialkylzinc reagents have dominated the fieldof copper-mediated enantioselective conjugate additionsince their first application in the mid-1990s.[65] From that


point onwards there appeared several reports demonstrat-ing that the addition of stoichiometric or substoichiometricquantities of water increases the rate and/or the enantio-selectivity of this organic transformation.[66]

Delapierre and co-workers reported the dramatic benefi-cial effect of addition of water (0.5 equiv.) in the asymmetricaddition of diethylzinc to cyclohex-2-enone (43) catalysedby CuI in the presence of chiral ligands (Scheme 18).[67]

Thus, when the reaction was performed in dry CH2Cl2, onlya 55 % yield of the desired cyclohexanone 44 was achieved,with 45% ee. However, formation of the desired carbonylcompound in higher yield (76%) and enantiomeric excess(61%) was observed upon addition of substoichiometricamounts of water. The authors proposed that the in situformation of Zn(OH)2 (which is a stronger and more effec-tive Lewis acid) activates the carbonyl moiety. This sugges-tion was confirmed by direct addition of Zn(OH)2 to thereaction mixture, which provided results analogous to thoseobserved with water.[68] Similarly, the addition of sub-stoichiometric amounts of water (0.3–0.33 equiv.) to lithiumdimethylcuprate (LiCuMe2) generated a more reactive andstereoselective reagent for conjugate addition to linear α,β-enones.[69] More recently, Lipshutz and co-workers reportedthe conjugate addition of organocopper reagents, generatedin situ, to enones[70] in water and at room temperaturethrough the use of small amounts of commercially availableamphiphiles (TPGS-750-M, polyoxyethanyl-α-tocopherylsuccinate) that are able to form nanomicelles in water.

Scheme 18. CuI-catalysed conjugate 1,4-addition of Et2Zn tocyclohex-2-enone (43) accelerated in the presence of water.

Conjugate 1,4-addition of alkyl halides (R–X) to α,β-un-saturated aldehydes, ketones, esters, amides[71] or nitriles[72]

can be mediated in EtOH/H2O or THF/H2O mixtures bythe combination of Zn and Cu under sonication conditions.It is worth noting that this methodology has been fruitfullyapplied to the synthesis of: (i) a variety of vitamin D3 deriv-atives,[73] (ii) dioxolanes,[73d] (iii) oxazolidinones[73h] and(iv) sinefungin analogues.[74] Finally, the intramolecular ver-sion of this 1,4-addition reaction mediated by Zn/CuI al-lowed the straightforward synthesis of the lupinine ana-logues 45 (Scheme 19).[75,76] Thus, the 1,4-conjugate ad-dition of alkyl halides to α,β-unsaturated carbonyl com-

Scheme 19. Synthesis of lupidine analogue 45 mediated by Zn/CuIunder sonication conditions in the presence of water.


pounds mediated by Zn/Cu mixtures in aqueous mediaproved to be the key step in the total synthesis of a varietyof natural products.

3.4. Cross-Coupling between Organozinc ReagentsGenerated in situ and Organic Halides (Negishi Coupling)in Unconventional Solvents

Metal-catalysed cross-coupling reactions between or-ganic electrophiles (typically an organic halide) and organicnucleophiles have developed into a standard component ofthe synthetic chemist’s toolbox for the formation of C–Cand C–heteroatom bonds.[77] Palladium-catalysed reactions,which can generally be carried out under milder conditionsand with a wider range of substrates than reactions pro-moted by other metals, clearly dominate the field. The or-ganic halide can be an sp-, sp2-, or sp3-hybridised carbonatom with any halogen or pseudo-halogen leaving group.Different organometallic nucleophiles (e.g., organoboron,organotin, organozinc, organomagnesium) and organic nu-cleophilic reagents (such as amines, alkenes or alkynes) areroutinely used in different cross-coupling reactions. In thissection, attention is mainly focused on the Pd-catalysed Ne-gishi coupling (with reference to the cross-coupling reac-tions of polarised organozinc reagents with organic hal-ides),[78] in different unconventional solvents such as water,ILs and perfluorinated solvents.

Lipshutz and co-workers have effectively dominated thefield of aqueous Negishi-type cross-coupling reactions bydescribing a new technology that allows Pd-catalysed Zn-mediated cross-couplings to be conducted in water and atroom temperature, without the need to preform the corre-sponding organozinc reagent RZnX.[79,80] Lipshutz’s ap-proach uses homogeneous micellar catalysis within catalyticnanoreactors formed spontaneously upon dissolution ofdifferent surfactants (PTS, TPGS, Brij 30, Solutol, SPGS)in water. The scope of this process has been studied in Pd-catalysed coupling between: (i) alkyl halides and aryl or het-eroaryl halides (Scheme 20),[79a,79f–79i] (ii) alkyl or benzylhalides and alkenyl halides,[79b,79e,79h] and (iii) benzyl hal-ides and aryl or heteroaryl halides.[79c,79d] More recently,Lipshutz and co-workers reported the reduction of alkylhalides[81] and nitroaromatics[82] in water and at room tem-perature with the aid of Zn dust in the presence of nano-micelles composed of the aforementioned surfactants.

Scheme 20. Representative example of Negishi-type coupling inwater at room temperature under the Lipshutz conditions.

Pd-catalysed Negishi-type coupling in ILs has also beenreported. At the beginning of this millennium Knochel and


co-workers described cross-coupling between preformedaryl- or benzylzinc halides (RZnX) and various aryl iodidesin the IL [BDMIM][BF4] (BDMIM = 1-butyl-2,3-dimethyl-imidazolium), with use of the mixture formed by [Pd-(dba)2] and ionic phosphine 46 as catalytic system(Scheme 21).[83a] In most cases the reactions proceeded atroom temperature within minutes, leading to the desiredproducts in almost quantitative yields. The workup is re-markably simple, because the IL phase containing the palla-dium catalyst can be separated from the organic productsimply by extraction with toluene. Attempts to reuse thepalladium catalyst showed that after the third cycle, a sig-nificant decrease in the yield was observed. The same au-thors enlarged the scope of unconventional solvents thatcould be used in the Negishi reaction by describing the Pd-catalysed cross-coupling of organozinc bromides with aryliodides in perfluorinated solvents.[83b]

Scheme 21. Pd-catalysed Negishi-type coupling between preformedorganozinc reagents and aryl halides in the ionic liquid[BDMIM][BF4].

3.5. Application of Lithium Organozincates forChemoselective Anionic Polymerisation

Highly coordinated dianion-type zincates (Li2ZnR4) werereported in the mid-1990s by Uchiyama and co-workers asa new type of zincate complexes, and added a new dimen-sion to organozincate reagents, because they were able topromote bromine/zinc exchange and carbozincation reac-tions.[84] In this regard, dilithium tetra-tert-butylzincate[Li2Zn(tBu)4] turned out to be a highly crowded and bulkyzincate with excellent anionic polymerisation ability, even inthe presence of acidic protons.[85] Uchiyama and co-workersstudied the anionic polymerisation of N-isopropylacryl-amide (NIPAm) with use of Li2Zn(tBu)4 as initiator in bothorganic solvents and water (Scheme 22).[86] Surprisingly, aninteresting solvent effect was found in this polymerisationreaction; in THF as the reaction medium, only an 8 % yieldof the desired polymeric material 47 was obtained after24 h, whereas the polymer 47 could be isolated in highyields (92–76%) after only 3 h when protic solvents (suchas H2O or MeOH) were used instead. On monitoring thetime/yields profile of this polymerisation reaction in water,the authors noticed that polymer 47 could be obtained in92% yield after 15 min. The nature of the organometalliccompound proved to be crucial, with no polymerisation re-action taking place when Li2Zn(tBu)4 was replaced by

J. García-Álvarez, E. Hevia, V. CapriatiMICROREVIEWtBuLi, ZnCl2, LiCl or LiOH. This Zn-mediated anionicpolymerisation in water could also be extended to otheracryl acid derivatives, such as N,N-dimethylacrylamide(DMA, 74% yield), acrylamide (AM, 84% yield) and 2-hydroxyethyl methacrylate (HEMA, 92 % yield). One of themain drawbacks of this Li2Zn(tBu)4-mediated polymerisa-tion in aqueous media is the impossibility of inducing thepolymerisation of styrene (one of the most important syn-thetic polymers). In this case, deprotonation of the solventtook place before polymerisation.[87]

Scheme 22. Li2Zn(tBu)4-catalysed anionic polymerisation of N-iso-propylacrylamide (NIPAm) in water.

Recently, Higashihara and co-workers reported anotherpossibility for application of zincate Li2Zn(tBu)4 in poly-merisation reactions, through an exchange-cross-couplingprocess.[88] Thus, when 2-bromo-3-hexyl-5-iodothiophene(48) was treated with Li2Zn(tBu)4, the iodine/zinc exchangereaction took place selectively. Upon being heated to 60 °Cin the presence of the nickel catalyst [Ni(dppe)Cl2] {dppe =1,2-bis(diphenylphosphanyl)ethane}, the resultant zincate49 polymerised in a controlled manner, affording poly(3-n-hexylthiophene) (50) in high yield (80–85 %) and with lowpolydispersion (PDI � 1.2). As analogously observed in theanionic polymerisation of N-isopropylacrylamide (NIPAm)in water,[86] the high-molecular-weight polymer 50 could beobtained in a THF solution containing a small amount ofwater (Scheme 23). In this case, the addition of just 1 equiv.of water, rather than complete replacement of the bulkTHF, benefited the polymerisation reaction, allowing theachievement of satisfactory results.

Scheme 23. Halogen exchange reactions and catalyst-transfer poly-condensation for the synthesis of polymer 50 with the aid ofLi2Zn(tBu)4 in the presence of water.

3.6. Organogold(I) Compounds in Palladium-CatalysedCross-Coupling Reactions in Aqueous Media

As previously discussed in Section 3.4, Pd-catalysedcross-coupling reactions are usually run with polarised or-ganometallic nucleophiles (e.g., organoboron, organotin,organozinc, organomagnesium) in VOCs as solvents. How-ever, Sarandeses and co-workers have recently expanded thescope of this transformation, by being the first to employ


organogold(I)–phosphane derivatives (RAuPPh3) as orga-nometallic nucleophiles in water. Under these conditions,reactions between isolated aryl-, alkenyl- or alkynylgold(I)–phosphanes and aryl halides or triflates were shown to pro-ceed at room temperature (or at 80 °C) in water/THF mix-tures.[89] These Pd-catalysed reactions delivered the corre-sponding coupling products in good yields and with highchemoselectivity, being compatible with free amino orhydroxy groups present in the electrophile. As a proof ofconcept, this methodology was then also successfully ap-plied to the preparation of substituted phenylalanine estersunder protic conditions (Scheme 24).

Scheme 24. Synthesis of 4-substituted phenylalanines in a THF/water mixture.

3.7. Iridium-Promoted C–H Bond Activation in Water

Encapsulation of a variety of organometallic complexesin the internal cavities of hydrophilic supramolecular struc-tures constitutes an innovative way to solubilise organo-metallic derivatives in aqueous media.[90] In this context,Raymond and co-workers have incorporated the cationiciridium complexes [(Cp*)(PMe3)Ir(Me)(η2-olefin)][OTf](η2-olefin = ethylene or cis-but-2-ene) into a supramolec-ular [Ga4L6] tetrahedral assembly [L = 1,5-bis(2,3-di-hydroxybenzoylamino)naphthalene; Scheme 25]. These spe-cies formed the host–guest complexes 51 and 52, stabilisedboth by hydrophobic effects and by π–π interactions be-tween the coordinated olefin and the π-basic naphthalenewalls of the host.[91] The resulting water-soluble host–guestsystems 51 and 52 were then tested in the C–H activationof aldehydes in aqueous media. In order to generate theactive iridium species, preliminary decoordination of theolefin was required. Simple heating of the host–guest com-plexes (45 °C for 51 and 75 °C for 52) facilitated olefindissociation, thereby allowing the C–H bond activation ofthe desired aldehyde. Interestingly, evidence for both sizeand shape selectivity was observed. Small aldehydes (e.g.,acetaldehyde) are readily activated, whereas large aldehydes(e.g., benzaldehyde) are too large to fit inside the cavity.Also, the shape of the aldehyde proved to influence the re-activity of the encapsulated host–guest complex. For exam-ple, the host–guest complex reacted with isobutyraldehydewith a lower diastereoselectivity than with butyraldehyde.This experimental evidence was attributed to the morespherical shape of the isobutyraldehyde complex in com-parison with the butyraldehyde one. The employment of or-ganic solvents and energy to create the required ligands,however, is always required beforehand.[92] Thus, this repre-sents a much more subtle balance in terms relating to thePrinciples of Green Chemistry.[41]


Scheme 25. C–H activation of aldehydes in aqueous media promoted by the water-soluble host–guest complexes 51 and 52.

4. Organometallic Compounds of p-BlockElements

Amongst the vast family of organometallic compounds,and within the subgroup of the p-block metals (elementswith their valence electrons in the p orbitals), organoalumi-nium[93] and organotin[94] members play a pivotal role inorganic synthesis, finding widespread applications in amyriad of C–C bond-forming processes. Although most ofthese reactivity studies have been performed with conven-tional VOCs, the potential of also using these commodityorganometallic reagents in unconventional media (includ-ing ILs, DESs, scCO2 and, recently, also in neat water) hasalready been hinted at by several intriguing studies dis-cussed in this section. In addition to these two importantfamilies of p-block metal reagents, the chemistry and appli-cations of organoindium compounds are receiving increas-ing attention from the synthetic community, and are thusbeing rapidly developed. Possessing exceptional functional-group tolerance and distinctive mild reactivity profiles,these compounds can provide unique chemoselectivities inseveral C–C bond-forming reactions that are difficult toachieve with more polar reagents such as organolithium ororganomagnesium reagents. Intriguingly, and contrastingwith the typical extreme moisture sensitivity of these polarorganometallics, organoindium reagents can be utilised inaqueous media, which allows the functionalisation of water-soluble substrates such as carbohydrates, as well as the de-velopment of greener synthetic methodologies. This uniquebehaviour was first reported by Li and Chan in 1991 in aseminal study assessing the allylation reactions of aldehydesand ketones under Barbier conditions in water,[95] and now-adays it constitutes a signature attraction of organoindiumchemistry. The chemistry of these reagents and their appli-


cations for the functionalisation of organic molecules (someof them in aqueous media) have recently been summarisedin a comprehensive review by Loh and co-workers.[96] Thus,they are not covered in this overview.

4.1. Applications of Group 13 Organometallic Reagents

Organoaluminium reagents have received considerableattention in recent years, not only due to their high chemo-selective reactivity and exceptional functional-group toler-ance, but also because of their relative cheapness, readyavailability and comparatively low toxicity. The polarity ofAl–C bonds makes these commodity reagents extremely air-and moisture-sensitive, and they usually have to be manipu-lated with use of strict inert-gas techniques. Careful, sys-tematic and controlled hydrolysis studies of kinetically sta-bilised Group 13 trialkyl compounds performed by Roeskyand co-workers, supported by spectroscopic and crystallo-graphic evidence, however, have led to the isolation and thestructural characterisation of interesting intermediate oligo-meric compounds that eventually result in the final poly-condensed metalloxane clusters.[97] More recent work re-vealed the synthesis of organoaluminium hydroxides[98] andof three-in-one clusters,[99] consisting in each case of twotetranuclear aluminophosphate units and a tetrameric alu-mino hydroxide unit. These examples attest that water canalso promote intermolecular interactions and extensive self-assembly, contributing to the coordination sphere of themetal atom, in the case of these sensitive organometalliccompounds.

Although at present most of their applications requirethe use of dry organic solvents, some promising studies havealready glimpsed the potential of applying these com-pounds in ILs as an alternative reaction media. In 2003,

J. García-Álvarez, E. Hevia, V. CapriatiMICROREVIEWTaddei and co-workers reported the multistep synthesis ofisoxazolines by use of the IL [BMIM][BF4], in which oneof the key synthetic steps involved the transformation of anester into an amide via an aluminium amide. This specieswas generated in situ by adding a solution of AlMe3 in tolu-ene to a solution of the ester 53 and benzylamine to furnish54 in 79% yield (Scheme 26).[100]

Scheme 26. Ester amidination of isoxazoline 53 with AlMe3 in theIL [BMIM][BF4].

More recently, Chen and Liu have shown that aluminiumalkyl and aryloxy compounds, used widely in polymerisa-tion processes, can effectively catalyse the conversion ofglucose into HMF [5-(hydroxymethyl)furfural] in the IL 1-ethyl-3-methylimidazolium chloride ([EMIM]Cl, 55).[101] Inan attempt to shed some light on the constitution of theactive Al species involved in this transformation, (alkyl)-(aryloxy)aluminium MeAl(OAr)2 56 (OAr = 2,6-di-tert-butyl-4-methylphenoxide) was mixed with 55 under thesame glucose conversion conditions, and this enabled theisolation and subsequent structural elucidation of the newmixed imidazolium aluminate {ENIM}+{Me(Cl)Al-(OAr)2}– 57, in which the chloride is now attached to Al(Scheme 27).

Scheme 27. Formation of imidazolium aluminate 57 by combiningaluminium complex 56 with IL 55.

As already alluded to, indium can mediate Barbier-typereactions in water.[95,96] Interestingly, metallic gallium canalso be used to promote the allylation of aldehydes andketones with allyl bromide in water, affording the relevanthomoallyl alcohols in high yields.[102] Similarly, the cou-pling of indoles and pyrroles with allyl halides can be ac-complished in a mixture of water and DMF in the presenceof Ga metal by use of Bu4NBr as an additive.[103] Thismethod for achieving access to C3-allylated indole species58 represents a main-group-metal-mediated alternative toother approaches in which Pd catalysts are employed. Inter-estingly, the choice of solvent is crucial for the success ofthis transformation, because mixtures of products resultwhen acetonitrile or THF are used. The effect of Bu4NBris also remarkable; indeed, the employment of other metalbromides such as MgBr2 or KBr inhibits the coupling pro-cess (Scheme 28).


Scheme 28. Gallium-mediated allylation of indoles with the aid ofan H2O/DMF mixture.

Oshima has shown that allylgallium reagents, generatedin situ by salt metathesis of GaCl3 and allylmagnesiumbromide, promote radical allylation of α-iodo and α-bromocarbonyl compounds in the presence of BEt3 and under air,when a mixture of THF (2 mL), hexane (1 mL) and water(1 mL) is used (Scheme 29).[104] Interestingly, on assessingsolvent effects, it was found that without use of water as aco-solvent [that is, a THF (2 mL)/hexane (1 mL) solution]the yields in the formation of 59 were lowered significantly.Although the exact nature of this favourable solvent effectis unclear, the authors suggest the possible involvement ofallylgallium hydroxide intermediates, which may be morereactive towards the radical allylation process.

Scheme 29. Triethylborane-induced radical allylation of α-halocarbonyl compounds with allylgallium reagent in aqueous media.

Significantly, indium-mediated allylation reactions can-not only be accomplished by using water as the solvent.[96]

Alternative reaction media such as ILs[105] and scCO2[106]

can be employed too. Indeed, Gordon and Ritchey reportedthe use of indium metal and allyl bromide for the allylationof a wide range of aldehydes and ketones with use of the IL[BMIM][BF4]. These reactions can be carried out at roomtemperature with stoichiometric amounts of In to afford therelevant homoallylic alcohols in yields ranging from 37 to92 %, comparable, in general, with those reported with useof organic solvents or water.[105a] Interestingly, this studyreveals that, at the end of the reaction, addition of water toquench the putative indium alkoxide intermediate is essen-tial in order to achieve the above yields for the relevanthomoallylic alcohols. With this approach for the allylationof 2-methoxycyclohexanone (60), the level of diastereoselec-tivity towards the syn product 61 was greater (61/62, 18.6:1)than those obtained with pure water or a THF/water mix-ture (Scheme 30).

Related to these studies is the work of Chan and co-workers, who compared the ability of In, Sn or Zn to medi-ate the allylation of carbonyl compounds in the ILs[BMIM][BF4] and [EMIM][BF4]. This study revealed thatunder ambient-temperature conditions each metal can ef-fectively promote the formation of the relevant homoallylic


Scheme 30. Indium-mediated allylation of 2-methoxycyclohexan-one (60) in the IL [BMIM][BF4].

alcohols in these solvent systems, although the best levelsof conversion were observed with Sn.[105b]

The same group has also shown that aldimines can un-dergo nucleophilic addition with allylindium reagents, gen-erated in situ from In and allyl bromide in a mixture of theILs [bpy][BF4]/[bpy][Br] (bpy = N-butylpyridine) to affordhomoallylic amines 63 in good yields (66–99 %; Scheme 31).Mechanistic studies have revealed that in these reaction me-dia allylindium(I) and allylindium(III) dibromide are inequilibrium, with the former being the most reactivetowards imines in the formation of 63. Interestingly, the useof bromide ion as an additive (in the form of the IL[bpy][Br]) shifts the position of this equilibrium towards anInI species, which promotes the selective formation of63.[105c]

Scheme 31. Indium-mediated allylation of imines in [bpy][BF4]/[bpy][Br].

From the perspective of greater cost-effectiveness, Hira-shita has reported the efficient allylation of carbonyl com-pounds in ILs by use of catalytic amounts of In, which canbe generated in situ by reduction of InCl3 (10 mol-%) withstoichiometric amounts of aluminium. Notably, these reac-tions occur more rapidly when water is added to the IL[BMIM][PF6], although it should be noted that when thesame approach was employed with neat water as the sol-vent, the allylation process was completely shut down.[105d]

In addition, if In-mediated aldehyde allylation processes arecarried out in liquid CO2 as the solvent, the relevant homo-allylic alcohols can be isolated in 38–82% yields.[106] Thismethod represents a cleaner and efficient alternative to con-ventional organic solvents, in which excess CO2 can be sep-arated by depressurisation and subsequently reused.

4.2. Applications of Organotin Reagents

Finding widespread applications in cornerstone syntheticmethods (Stille coupling, radical reactions, allylations etc.),organotin compounds are a family of versatile organome-tallic reagents. Part of their popularity stems from theirthermal stability and relatively straightforward preparation,


combined with their robustness to hydrolysis and oxidation.Furthermore, these reagents are also compatible with amyriad of organic functional groups, showing an excellentbalance between stability and reactivity. However, despitesuch an impressive synthetic background, one of their maindrawbacks is related to their toxicity and the difficulties as-sociated with the removal of residues from the final prod-ucts. Some of the strategies developed to try to overcomethis limitation include the use of organotin reagents sup-ported by ILs.[107] These reagents can be easily prepared bytreating imidazole derivative 65 with EtBr (or with MeI) toform the IL-supported tin reagent 66 that, in turn, can beused in Stille cross-coupling reactions, under solvent-freeconditions and without the addition of additives or ligands,thereby affording a range of bis(aryl) compounds of type67 in good yields (Scheme 32).

Scheme 32. Synthesis of the IL 66 and its application in a Stillecross-coupling reaction to give the biaryl derivative 67.[107f]

Furthermore, it is possible to recycle the tin compound/catalyst system at the end of the reaction by extracting theorganic products with an organic solvent. By treating theIL phase containing the halogenotin-supported IL 68 withPhLi, it is possible to regenerate the arylating starting mate-rial 66 (Figure 5).

Figure 5. Recycling of the IL-supported tin reagent 66.

These organotin reagents can also be used as effectivecatalysts for the reductive amination of aldehydes andketones with the aid of PhSiH3. Reactions can also be car-ried out under solvent-free conditions, which facilitate thepurification of the final products and minimise problemscaused by tin contamination.[107c]

It should also be noted that allylation reactions and Stillecouplings, two of the most powerful synthetic applicationsof organotin reagents, have also been investigated with re-gard to the use of ILs as alternative reaction media to or-

J. García-Álvarez, E. Hevia, V. CapriatiMICROREVIEWganic solvents. Successful methods for allylation of alde-hydes and ketones under these conditions with the aid ofseveral tin reagents, including Sn metal, SnCl2 or tetraall-yltin, have been reported. These reactions offer an excellentsubstrate scope and can be carried out at room temperature.Even more importantly, in many cases the IL can be ef-ficiently recycled without any further purification, thusmaking these protocols environmentally more benign.[108]

Moreover, by using tetraallyltin it is possible to activate allfour allyl groups for transfer to the carbonyl substrates,thereby maximising the atom economy of the process.[108a]

Related to this work is that by Kobayashi and co-workers,who described a silica-gel-supported scandium system withan IL acting as a heterogeneous catalyst for efficient pro-motion of several C–C bond-forming processes, includingthe allylation of ketones with tetraallyltin (Scheme 33).[109]

Intriguingly, this study shows that the key to the success ofthis new approach is the combination of a silica-gel-sup-ported metal catalyst with an IL, which creates a hydro-phobic reaction environment in water.

Scheme 33. Organotin-mediated allylation reaction catalysed by sil-ica/Sc/IL in water.

Stille couplings of organostannanes catalysed by Pd com-plexes in ILs have also been studied.[110] Pioneering workby Handy and Zhang[111] indeed showed that Stille couplingreactions can be successfully carried out in [BMIM][BF4] asthe reaction medium, thus allowing the effective recyclingof the solvent and the catalyst without significant activityloss. Notably, these processes are particularly sensitive tothe structure of the IL employed.[112] For example, as illus-trated in Scheme 34, if nucleophilic ILs such as [BMIM][Br]are used for the coupling of iodobenzene and tributyl-(vinyl)stannane under Pd(OAc)2 catalysis conditions, com-pound 69 is isolated in very low yields. Conversely, theemployment of ILs with N-containing anions such as[NTf2]– [NTf2 = bis(trifluoromethylsulfonyl)imide] allowedhigher levels of conversion (up to 94 %) under ligand-freereaction conditions (Scheme 34). This dramatic differencein the IL performance has been attributed by Chiappe andco-workers to the nucleophilic assistance by the NTf2

–

Scheme 34. Ligand-free Stille cross-coupling of iodobenzene with tributyl(vinyl)stannane in different ILs.


anion in the transmetallation step of the coupling reaction,which allows the coordination expansion of tin.[113] On thecontrary, a similar type of activation would be less likelyto occur in [BMIM][Br], due to the stronger cation–anioninteractions present in this IL. Notably, and despite thehigher reactivity observed in these NTf2-based ILs, the sta-bility of the catalyst is very low, which precludes the effec-tive recycling of the system.

This drawback can be overcome by using Pd nanopar-ticles as catalysts rather than molecular palladium spe-cies.[114] The versatility and tuneability of ILs allows thestabilisation of nanoparticles, protecting them from ag-glomeration while increasing the robustness to oxidationand hydrolysis of the nanoscale catalyst surface, thanks tothe formation of a protective shell. In these reactions, Pdnanoparticles act as catalyst reservoirs, while the activecatalytic species are molecular Pd complexes, which can beleached out from the surface of the nanoparticle.[115] A widerange of ILs, containing a variety of cations (e.g., pyridin-ium, imidazolium, tetraalkylammonium), have been as-sessed for this type of Stille coupling. Notably, Dysonshowed that the use of nitrile-functionalised ILs signifi-cantly improved the stability of the catalytic systems, al-lowing their efficient recycling and minimising catalystleaching.[114b] Employing Pd nanoparticles stabilised bytetraalkylammonium salts bearing long alkyl chains as cata-lysts, Nacci and co-workers reported efficient Suzuki andStille cross-couplings involving a wide range of aryl halides,including aryl chlorides, the applications of which in thesetype of processes can be particularly challenging due totheir reduced reactivity.[114c]

DESs have also been successfully employed in Stille alk-ylations and biaryl synthesis. König and co-workers havereported that with the aid of low-melting mixtures ofsugars, urea and inorganic salts as solvents it is possible topromote the fast and efficient Pd-catalysed alkyl transfer oftetraalkyltin reagents (Scheme 35).[116] In conventional or-ganic solvents, the transfer of simple alkyl groups insteadrequires special conditions including the use of toxic sol-vents such as HMPA or DMF. The smooth formation ofcoupling products 70 (Scheme 35) by this alternativemethod has been attributed to the high polarity and nucleo-philic character of the DES combinations employed. Bi-aryls 71 can also be prepared in almost quantitative yieldsby this approach, which works well with both electron-poorand electron-rich aryl bromides (Scheme 35). Interestingly,the catalyst load can be reduced to 0.001 mol-%, and thecatalyst/solvent mixture can be recycled up to three times.An added advantage to this approach is the simple workupand the ease with which products are isolated with employ-


ment of these melt mixtures; indeed, upon addition ofwater, the organic products precipitate as amorphous solidsand can be separated by filtration.

Scheme 35. Stille couplings in sugar/urea/salt melts (DMU = di-methylurea).

Although Stille couplings are traditionally carried out inorganic solvents, the stability that arylstannanes exhibit toair and moisture has allowed the development of alternativemethods that use water as the solvent.[117] For example,Wolf has reported an effective Stille cross-coupling method-ology using a wide range of aryl chlorides and aryl brom-ides. With the aid of an air-stable and water-soluble Pd–phosphinous acid catalyst, the synthesis of several bis(aryl)compounds can be accomplished in good to high yields, inneat water as the solvent and without the need for an or-ganic co-solvent.[117d]

Interestingly, the catalyst can be recycled up to four runswith just a slight decrease in the observed yields (from 96 %to 84%). These recycling studies also show the straightfor-ward isolation and purification of the coupling products,which can be separated from the water-soluble catalyst byextraction. Nevertheless, it should be noted that in thismethod reactions need to be carried out at high tempera-tures (135–140 °C) and over long periods of time (up to24 h). Milder reaction conditions for these couplings usingdendrimer-encapsulated Pd nanoparticles, which can cata-lyse Stille reactions in water at room temperature, have beenreported.[118] However, the substrate scope of these ap-proaches is relatively limited.

In this regard, Lipshutz and Lu have developed an alter-native strategy that builds on their previous work on Pd-catalysed Negishi cross-couplings in water (Scheme 20).[82]

The use of TPGS-750M as a surfactant (able to undergoself-assembly in water to form nanomicelles) and aPd[P(tBu)3]2/DABCO (DABCO = 1,4-diazabicyclo[2.2.2]-octane) combination as a catalyst enables the efficient cou-pling of an impressive range of aryl and alkenyl halides tobe conducted at room temperature with water as the onlyreaction medium.[119] These reactions not only take place inhigh yields but, in some cases, they also offer greater anddifferent stereoselectivities than when conventional solventsare used, as shown in Scheme 36 for the formation of 72.

A simple and efficient one-pot methodology using wateras the solvent has been developed by Duan and co-workers;with Pd(PPh3)4 as a catalyst, effective cross-coupling of a


Scheme 36. Stille couplings with a (Z)-alkenyl triflate using (a)NMP as the solvent and (b) under aqueous micellar conditions.

variety of aryl and heteroaryl bromides/iodides could be ac-complished.[120] This method requires the use of microwaveirradiation and involves sequential stannylation followed bya Stille cross-coupling process, as depicted in Scheme 37 forthe synthesis of 73.

Scheme 37. One-pot stannylation/Stille cross-coupling sequentialreactions.

5. Conclusions

In a world with dwindling petroleum resources, organo-metallic scientists are slowly but firmly nurturing their ownability to improve the environmental friendliness of chemi-cal processes so as to produce the best and original “greenorganometallic chemistry”. From the examples discussed inthis microreview, it is evident that the employment of un-conventional reaction media in the chemistry of polar orga-nometallic compounds is taking the stage today. In the caseof water, although it is increasingly being used (both in mix-tures with organic solvents or in bulk) in the chemistry ofd- and p-block elements, its employment in the chemistryof s-block elements is still limited to stoichiometricamounts. This, however, surprisingly redirects reactions ininteresting ways: for example, by increasing the reactionrate, by favouring a lithium/halogen exchange reaction, orby affecting the stereochemistry of a certain synthetic route.

On the other hand, major benefits are expected from theuse of DESs in the chemistry of polar organometalliccompounds, as attested by the recent results obtained evenfor the reactions of Grignard and organolithium rea-

J. García-Álvarez, E. Hevia, V. CapriatiMICROREVIEWgents.[21,24,25] ILs, although demonstrated to be useful aspotential alternative neoteric solvents for the reactions ofboth d- and p-block elements, still experience restricted ap-plications in the chemistry of Grignard reagents (often of-fering complementary chemistry because of the dominanceof electron-transfer processes) and are currently ineffectivefor carrying out organolithium reactions.

All in all, even if from the reactions described here ittranspires that in many cases the organic solvent cannot becompletely removed and the catalyst recyclability still ap-pears to be a recurrent problem, there can be no doubt thatthe change in thinking will be the key to shifting our ownparadigms and convictions definitively in order to revealnew and intriguing transformations. This will require acomplete redesign of the experimental conditions, a deeperunderstanding of organometallic mechanisms and reactivit-ies, and a close collaboration between theoreticians and ex-perimental inorganic and organic researchers. In addition,fostering stronger industry/academic partnerships will expe-dite the transfer of new knowledge and emerging “greenertechnologies” to the marketplace, ultimately to see whathad not long previously been simply considered “fragile andvisionary ideas” being brought to fruition in topical areasof science.

Now that the first seeds are being planted, it would beexpected and desirable that this infant field should grow upand develop quickly beyond our present concepts, and thatthe lion’s share of organometallic transformations (stoichio-metric, catalytic and asymmetric applications) be designedand carried out mainly according to “Green Chemistry”principles. Until this point in time, we have developed anextraordinary ability to adapt the world to our expectations.It is time now to adapt our expectations to fit environmentneeds, in the hope that this may also lead to new scientificfindings and to the discovery of new and unpredictable as-pects of organometallic reactivity in the years to come!

Acknowledgments

This research was supported by the Italian Ministero dell’Univer-sità e della Ricerca (MIUR) in financing the PON01_00862 Pro-ject, the Ateneo Italo-Tedesco (VIGONI programme 2012-2013,code E65E06000080001) and the Interuniversities ConsortiumCINMPIS. J. G.-A. is indebted to the MINECO of Spain (ProjectsCTQ2010-14796/BQU and CTQ2013-40591-P), the Gobierno delPrincipado de Asturias (Project GRUPIN14-006) and the COSTaction SIPs-CM1302 for financial support. J. G.-A. also thanks theMINECO and the European Social Fund for the award of a“Ramón y Cajal” contract. E. H. thanks the European ResearchCouncil (ERC) for generously supporting this work.

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Received: June 8, 2015Published Online: September 2, 2015

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