Anatomy of Long-Lasting Love Affairs with Lithium Carbenoids: Past and Present Status and Future Prospects

DOI: 10.1002/chem.200902870 Anatomy of Long-Lasting Love Affairs with Lithium Carbenoids: Past and Present Status and Future Prospects Vito Capriati* and Saverio Florio*[a] 4152  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 178 Chem. Eur. J. 2010, 16, 4152 – 4162 MINIREVIEW reactivity relationship will be (re)considered in the light of literature recent advances. The authors hope this survey may further increase the interest toward these intriguing reactive species, stimulate new ideas and the scientific discussion around them, and promote at the same time more “surgical” stereoselective applications in the near future. Abstract: After a long adolescence, the chemistry of lithium carbenoids has currently been entering its maturity bringing a dowry of a more in-depth and less empirical knowledge of the structure and configurational stability of such double-faced intermediates; this, thanks in particular to the synergistic and harmonic cooperation between calculations and the most modern NMR techniques now at our disposal. Such knowledge has stimulated the development of fruitful stereoselective applications in the field of organic synthesis, providing in addition a rationale to observed selectivities. Such aspects together with the role played by aggregation and solvation on the structure–reactivity relationship are highlighted throughout this Minireview with selected examples extracted from recent literature. Structural Features of Lithium Carbenoids Structurally, a lithium carbenoid is a species such as 1 b (Scheme 1) carrying a lithium and a peculiar nucleofugal heterosubstituent on the same carbon atom. The “chame- Keywords: carbenoids · density functional calculations · lithium · NMR spectroscopy · stereochemistry Scheme 1. Conceivable resonance structures of the lithium carbenoid 1 b. Introduction In the “collection” of organolithium compounds available for the organic chemist, lithium carbenoids undoubtedly represent some of the most astonishing “precious stones”. Because of their intriguing ambiphilic behavior (nucleophilic and electrophilic reactivity), they are generally recognized as useful reagents capable of modifying their reactivity by “umpolung”. Over the years, their synthetic utility for carbon–carbon and carbon–heteroatom bond formation (e.g., cyclopropane formation from alkenes, CH insertion, reaction with RLi, alkynes and carbonyl compounds, etc.) has been amply demonstrated and the interest for their nature and structure has stimulated numerous theoretical studies and NMR investigations.[1] Curiously, the term “carbenoid” itself has been characterized by an intrinsic dichotomy over time: employed for the first time as an adjective by Friedman and Shechter[2] to describe a carbene-like reactivity, Closs and Moss[3] were later to suggest the appellation (as a noun) of “carbenoid” to those species capable of undergoing electrophilic reactions without necessarily being free carbenes. In this Minireview, some selected features of lithium carbenoids such as their structure and configurational stability, the stereochemistry of their coupling reactions with electrophiles as well as the influence of aggregation and solvation on the structure– leon-like” character becomes evident from a closer look at the resonance structures (1 a and 1 c) associated with 1 b; indeed, the extreme ionization of the polar bonds could lead, in principle, to the liberation of a carbanionic species (1 a) and a carbocation (1 c) from 1 b. Elongation of the CX bond: A common structural feature of lithium carbenoids is the elongation of the CX bond upon metalation, which enhances its p character; at the same time, the s character of the CLi bond is increased as well (Figure 1). Figure 1. Carbenoid carbon atom of Li/X carbenoids in the spectrum and conclusions thereof. C NMR This particular hybridization of the carbenoid carbon atom has been experimentally proven by recent X-ray structure analyses and multinuclear magnetic resonance investigations.[1a,b] Indeed, there is an increase in the value of the 13 C–6Li/7Li coupling constant, because of the Fermi-contact term involving s-orbital contributions from both atoms,[4] and, very often, also a deshielding of the 13C NMR chemical shift of the lithiated carbenoid center, because of the paramagnetic contribution of the s*CX orbital to the shielding constant.[1b,c] However, the presence of a “generic” acceptor substituent X at the anionic carbon atom is not sufficient to [a] Prof. V. Capriati, Prof. S. Florio Dipartimento Farmaco-Chimico, Universit di Bari “Aldo Moro” Consorzio Interuniversitario Nazionale Metodologie e Processi Innovativi di Sintesi C.I.N.M.P.I.S. Via E. Orabona 4, 70125 Bari (Italy) Fax: (+ 39) 080-5442231 E-mail: capriati@farmchim.uniba.it florio@farmchim.uniba.it Chem. Eur. J. 2010, 16, 4152 – 4162 13  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 179 www.chemeurj.org 4153 S. Florio and V. Capriati by Niecke et al.[12] Interestingly, in spite of the potential carbene-like reactivity this carbenoid would have (as shown by the strong deshielding experienced by the carbenoid 13C nucleus), it tends to undergo LiCl elimination only above 10 8C to give a l3-phosphirene. Most probably, the fact that the carbenoid center is a component of a delocalized pelectron framework extending over three atoms may enhance the kinetic stability of such a Li/Hal carbenoid. Another alkylidenecarbenoid that surprisingly revealed to be kinetically stable almost up to ambient temperature is (Z)-4 (Figure 2).[13] Apparently, the presence of a stationary substituent, such as the isopropyloxy group, hampers both the expected phenyl migration through a Fritsch–Buttenberg– Wiechell rearrangement and the 1,5-CH insertion into isopropyl CH3 groups as the temperature is increased; in addition, this intermediate does not even undergo a possible dimerization to furnish a butatriene. Although ab initio calcu- label the corresponding lithiated species as a carbenoid. In the first place, one should take into consideration that an important common feature of many polar organometallic compounds is, in contrast, the shortened CX bond compared with that of the corresponding nonlithiated species; this is the case, for instance, of a-lithiated sulfones, sulfoxides, thioethers, nitro compounds, and so on.[5] In the second place, not all those a-heterosubstituted lithiated species experiencing a lengthening of the CX bond can be regarded a priori as real carbenoids. For instance, the CO bond elongation also found for other classes of compounds such as alithiated carbamates[6] did not find confirmation in electrophilic reactivity. To date, compounds that have undoubtedly shown a remarkable electrophilic/nucleophilic character are lithiated alkyl[1b,c] and vinyl halides,[1d,e] lithio derivatives of ethers in general[7] and epoxides in particular,[8] and, very recently, also terminal and ring-fused lithiated aziridines.[9] Thermal lability: Another characteristic feature one would expect to find for a lithium carbenoid is thermal lability. However, this is not universally true. The first example of a Li/halide (Li/Hal) carbenoid (2, Figure 2), stable at room Vito Capriati obtained his M.Sc. degree with honours in Chemistry and Pharmaceutical Technology from the University of Bari in 1990. After working as a forensic chemist officer within the Carabinieris RIS (Scientific Investigation Department) of Rome and earning a two-year graduate fellowship within the National Research Council (CNR) centre “M.I.S.O.”, in 1993 he became Assistant Professor at the University of Bari before taking up his current position of Associate Professor of Organic Chemistry at the same University in 2002. His current research interests revolve around lithium chemistry and the elucidation of the structure–reactivity relationships, asymmetric synthesis of small-ring heterocycles and their functionalization, stereochemistry, and multinuclear magnetic resonance investigations on highly reactive intermediates aimed at solving their solution structures and dynamic behavior. Recently, he has been honoured for his work with the C.I.N.M.P.I.S. Prize “Innovation in Organic synthesis” awarded by the Interuniversities Consortium C.I.N.M.P.I.S. Figure 2. Thermally stable lithium carbenoids. Saverio Florio received his “Laurea” in Chemistry at the University of Bari (Italy). After being first Assistant Professor and then Associate Professor of Organic Chemistry in 1986, he was appointed Full Professor of Organic Chemistry at the University of Lecce. In 1990 he moved to the University of Bari on the chair of organic chemistry. Currently, he is Director of “Consorzio Interuniversitario sulle Metodologie e Processi Innovativi di Sintesi” (CINMPIS). President of the Division of Organic Chemistry of the Italian Chemical Society from 1997 to 2001, at present he acts as the vice president of the Italian Chemical Society. He is member of the Scientific Advisory Board of the Ischia IASOC School and member of the “Academy of Science and Arts of Salsburg”. Prof. Florios research interests are concerned with mechanistic studies, stereochemistry, asymmetric synthesis of small-ring heterocycles. He has published more than 200 papers and for his research work has been awarded with “Ziegler–Natta Lecture” from the German Chemical Society (GDCh) in 2005 and with the “Angelo Mangini Gold Medal” from the Division of Organic Chemistry of the Italian Chemical Society in 2007. temperature, has recently been reported by Le Floch and co-workers.[10] An X-ray analysis has revealed a strong stabilization occurring for the lithium cation provided by the two sulfur atoms and two molecules of diethyl ether that prevent LiCl elimination, thus accounting for the observed increase in thermal stability. Surprisingly, a shielding of d = 15.2 ppm was at the same time detected for the central 13C atom further to lithiation. This phenomenon, rather unusual for a lithium carbenoid, has been interpreted by the authors by noting that the central lithiated carbon possesses its lone pair in a pure p orbital, thereby being efficiently stabilized by negative (anionic) hyperconjugation[11] into the phosphorus antibonding orbitals; this leads to a rather strong CCl bond. The above peculiar structural characteristics have also been successfully exploited to transform the carbenoid into “carbene complexes” with electron-rich metal centers. A remarkable thermal stability has also been reported for the methylene(phosphoranylidene) carbenoid 3 (Figure 2) 4154 www.chemeurj.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 180 Chem. Eur. J. 2010, 16, 4152 – 4162 Lithium Carbenoids MINIREVIEW lations,[14] in line with experimental findings, proved the higher thermodynamic stability of the Z isomer with respect to the E isomer, in spite of the fact the former could not benefit from a stabilizing OLi chelation, the reluctance of 4 to display an electrophilic reactivity as the majority of alkylidenecarbenoids do remains to date unexplained. The first case of a chiral Li/O carbenoid undergoing a very slow isomerization to the corresponding ketone in ethereal solvents as the temperature is increased has recently been described by Capriati, Florio, and co-workers.[15] Oxazolinyloxiranyllithium 5 (Figure 2), generated by H/Li exchange, was successfully trapped with a deuterium source also at 25 8C in 85 % yield (> 98 % D) and 65 % yield (> 98 % D) starting from 0 and 78 8C, respectively. A multinuclear magnetic resonance investigation, jointly with IRspectroscopic studies, suggested that at least in a range of concentration of 0.08–0.3 m, 5 mainly exists as a monomeric h3-aza-allyl coordinated species rapidly equilibrating, on the NMR timescale, with a complex mixture of diastereomeric oxazoline-bridged dimeric species variously intra-aggregated. Here, too, as in the case of 2, intramolecular coordination of lithium seems to be a key factor in controlling the kinetic stability of such a lithium carbenoid in spite of its potential carbenoid reactivity, which is more apparent in nonpolar solvents; indeed, the carbenoid carbon atom is deshielded by 36.3 ppm in THF. At the same time, the bias that lithium has to be strongly coordinated by the iminic oxazoline moiety seems also to be a crucial factor in causing a fast racemization of 5 on the NMR timescale (t1/2 = 6.05 s, = 8.8 kcal mol1 at 130 8C in 3:2 THF/Et2O). An exDGenant 6¼ change mechanism by which the two enantiomeric monomers 5 and ent-5 (Figure 2) would interchange their Li atoms via an oxazoline-bridged dimeric species, detectable at NMR level, has been proposed.[15] studying the mechanism and the stereochemistry of reactions of chiral lithium carbenoids (in particular those of chiral cyclopropyl and vinyl lithium carbenoids) with nucleophiles.[17] By using stereochemistry as a probe they were able to distinguish between the carbenoid and carbene mechanisms. In order to explain the stereochemical results of the substitution reaction on such carbenoid species, the concept of “metal-assisted ionization” (MAI) was introduced (Figure 3). In practice, according to this model, as a consequence of a lithium-assisted partial ionization of the carbon–halogen bond, the car- Figure 3. Metal-assisted ionizabenoid species acquires a cer- tion (MAI) in a typical lithium/halogen carbenoid. tain carbocationic character, but still retaining its configuration because of the permanent coordination of lithium to the halogen. Thus, a nucleophile is allowed to attack the lithiated carbon atom from the backside giving rise to a product that, in the case of chiral cyclopropyl and vinyl lithium carbenoids, often (but not always) displays an overall inversion of configuration. The development of new pathways for the stereoselective generation of chiral nonracemic lithium carbenoids and their employment in asymmetric processes is an amazing goal that is being pursued more and more today. However, the question of configurational stability of these chiral intermediates under the conditions of their generation as well as the steric course of their coupling reactions with electrophiles (retentive or invertive pathways)[18] are important issues that need always to be preliminarily addressed before planning an asymmetric synthesis.[19] Configurational stability of a-haloorganolithiums: While chiral nonracemic a-oxygen and a-nitrogen-substituted lithium carbenoids are known to be nearly always configurationally stable at temperatures as low as 78 8C and during the time needed to generate and to trap them with electrophiles,[20] enantiomeric a-halolithium compounds still have not been deeply investigated.[1f, 21] However, the results reported to date are pleasingly surprising and encouraging for stereoselective transformations. The first racemic bromocarbenoid investigated was 6 (Figure 4).[22] Generated by a bromine–lithium exchange reaction from the corresponding dibromo derivative, it showed a remarkable configurational stability at 120 8C on a macroscopic timescale when sub- Influence of the leaving group: The influence of the leaving group on the structure and reactivity in the carbenoid series LiCH2X (X = Hal, OH) toward a “classic” cyclopropanation reaction has also been studied by Boche et al. from a theoretical point of view.[16] At the end of such an investigation, the authors concluded that there is no special halide effect in the reaction of the carbenoids LiCH2Hal with ethene, because the energy of the CHal bond cleavage in the transition states is essentially compensated by the energy of the LiHal bond formation; in contrast, the higher energy for the reaction of LiCH2OH (chosen as a model system of a Li/OR carbenoid) with ethene results from the high COH bond energy. Configurational Stability of Lithium Carbenoids and Stereochemistry of their Coupling Reactions with Electrophiles Stereochemistry has always been a recurring theme when dealing with lithium carbenoids that have a stereogenic lithium-bearing carbon atom. Walborsky et al. were pioneers in Chem. Eur. J. 2010, 16, 4152 – 4162 Figure 4. Chiral lithium halogen carbenoids.  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 181 www.chemeurj.org 4155 S. Florio and V. Capriati jected to the Hoffmann test, which is based on kinetic resolution. Likewise, diastereomeric 1-bromoalkyllithium compounds 7 and 8 (Figure 4), generated by bromine–lithium exchange, were found to be configurationally stable at 110 8C.[22] Interestingly, Hammerschmidt et al. have recently reported[23] that an enantiomerically enriched chloromethyllithium such as (S)-[D1]9 (Figure 4), generated by tin– lithium exchange, in spite of its chemical lability, is configurationally stable on both microscopic and macroscopic timescales up to the temperature of its rapid decomposition, which is 78 8C. Although its half-life at this temperature has been estimated in the range of seconds, it rather decomposes than racemizes! This suggests that the pathway of racemization (whenever it occurs) may not be as simple as predicted. In the case of the configurationally labile oxazolinyloxiranyllithium 5, for instance, an inverting tetrahedral configuration is very likely to take place rather than an inverting planar configuration,[15] the latter being the favorite racemization pathway radical intermediates usually follow. Therefore, a proper understanding of such an inversion occurring at a stereogenic lithium-bearing carbon atom of a carbenoid cannot disregard either the “cocktail” of components in which these reagents are formed and the reaction conditions or, above all, their aggregation states.[24] Terminal epoxides could be lithiated with lithium tetramethylpiperidide (LTMP) and trapped with boronic esters to give syn-1,2-diols with complete diastereoselectivity.[26] In addition, also in this case, the whole process could successfully be iterated, thus creating triols containing up to four stereogenic centers with total control over their relative and absolute stereochemistry. In the selected example depicted in Scheme 3, the iterative homologation of boronic acid pi- Scheme 3. Homologation of boronic esters using terminal lithiated epoxides. nacol ester 17 using (R)-butenoxide 16 is shown. It furnished first the b-silyloxy boronic ester 18 and then, after a second homologation and final oxidative workup, the stereodefined triol 19. When the above protocol was applied to lithiated styrene oxide, 1,2-diols bearing quaternary stereogenic centers could also be successfully generated. In a similar way, terminal N-Boc aziridines (Boc = tert-butyloxycarbonyl) have been stereospecifically b-lithiated and trapped in situ with boronic esters to give syn-b-amino alcohols as single enantiomers and with a complete control of the diastereoselectivity.[27] Lithiated carbamates 20, derived from primary alcohols and prepared in the presence of ()-sparteine (sp), proved to be effectively configurationally stable chiral lithium carbenoids able to react with both boranes or boronates 21 to give, through the collapse of ate complexes 22 and final oxidative workup, secondary alcohols 23 in good yield, high enantioselectivity and complete retention of configuration (Scheme 4).[28] Similarly, chiral nonracemic carbenoids derived from secondary alcohols have also been successfully employed by Aggarwal and co-workers to prepare highly enantiomerically enriched tertiary alcohols.[29] The most intriguing outcome of this reaction is that either enantiomer of the tertiary alcohol can be obtained with high level of stereocontrol from the same enantiomer of the secondary alcohol, simply depending on whether a borane or a boronic ester is used. The above versatile methodology, the power of which lies just in its potential iterative use, has recently been applied by Aggarwal and co-workers in natural product synthesis.[30] Thus, a stereocontrolled total synthesis of (+)-faranal 26 has been set up exploiting as key steps onepot iterative boronic ester homologations (which run without detriment to selectivity) between chiral lithiated carbamate 24 and boronic ester 25. The stereocontrolled addition Coupling reactions of stereodefined lithium carbenoids: An enantioenriched Li–carbenoid species such as (S)-10 (Scheme 2), generated by in situ sulfoxide-ligand exchange, Scheme 2. Homologation of boronic esters and iterative stereospecific reagent-controlled homologation. has recently been shown to undergo a coupling reaction under Barbier conditions with the boronate 11 to give the carbinol 12 in a remarkable 96 % ee and 70 % yield after oxidative workup, thus providing an interesting asymmetric route to homologate boronic esters.[25a] Under an optimized protocol, Blackmore et al. then set up a programmed synthesis of a stereodiad motif leading to targeted carbinols 15 by iteratively reacting chiral carbenoid 10 with boronate 13 interspersing a homologation step with chloromethyllithium 14 (Scheme 2).[25b] 4156 www.chemeurj.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 182 Chem. Eur. J. 2010, 16, 4152 – 4162 Lithium Carbenoids MINIREVIEW Scheme 6. Geminal difunctionalization of alkenylidene-type carbenoids and stereocontrolled approach to tetrasubstituted olefins. boronates 34 as single diastereomers with no trace of dicoupled products. Irrespective of the vinyl substituent R, the stereochemical outcome is always uniform. Further coupling reaction with another halide R2X allows the obtainment of tetrasubstituted ethenes 35 with overall complete stereocontrol (Scheme 6).[34] Now, what about the stereochemical integrity of an alkylidene Li/Hal carbenoid such as 32 when subjected to a 1,2metalate rearrangement? In an interesting survey that reports full details of the insertion reactions of 1-chloro-1-lithioalkenes into organozirconocenes, Whitby et al. investigated the stereochemistry of such a carbenoid insertion.[35 ] The insertion of 1-chloro-lithioalkenes 36 into organozirconocene chlorides 37 effectively provides a stereocontrolled synthesis of terminal dienes, trienes, dienynes, and other unsaturated systems (Scheme 7). To explain the experimental results in terms of stereochemistry, the proposed mechanism envisages a clean inversion of configuration at an sp2 center of an “ate” complex 38 with the formation of a new organozirconium species 39 which may be further elaborated (Scheme 7). Scheme 4. One-pot lithiation/borylation of carbamates and total synthesis of (+)-faranal through iterative boronic ester homologations. of successive groups to the growing chain finally leads to the insect pheromone 26 (Scheme 4). Simultaneous incorporation of two metals into organic substrates is a crucial and challenging task in organic synthesis in order to obtain multisubstituted target organic frameworks.[31] In particular, the preparation of novel gem-diborylated compounds has been successfully accomplished taking advantage of gem-diborylation of lithium carbenoids with diboron compounds. The synthesis of 1,1-diborylated cyclopropanes 29, for instance, has been performed by gem-diborylation of cyclopropylidene lithium carbenoids 27 with bis(pinacolato)diboron 28 (BpinBpin). Cyclopropanes 29 showed their synthetic utility as useful precursors of vic-diborylated methylenecyclopentenes 30 amenable to further functionalization by regioselective cross-coupling reactions with aryl halides to the corresponding derivatives 31 (Scheme 5).[32] Scheme 7. Insertion of 1-chloro-1-lithioalkenes into organozirconocene chlorides. However, only the insertion of b-monosubstituted 1-halo1-lithioalkenes strongly supports a concerted 1,2-migration mechanism, as depicted in Scheme 7, that finally leads to stereodefined unsaturated systems. Indeed, b,b’-dialkyl-substituted 1-lithio-1-alkenes also insert but with a loss of stereochemical integrity of the starting vinyl halide. The authors ascertained that such a loss of stereochemistry arises from a rapid isomerization of 36 into 37 that occurs prior to 1,2-metalated rearrangement on the zirconium and is most probably mediated by a “metal-assisted ionization”. Interestingly, Harada et al. have reported[36] that lithium carbenoids derived from 1,1-dibromoalkenes are configurationally stable at low temperature, whereas they undergo rapid iso- Scheme 5. Synthesis and application of 1,1-diborylated cyclopropanes. Analogously, geminal difunctionalization of stereodefined alkylidene-type carbenoids 32, by using interelement compounds such as 28, also serves as an efficient preparative method for the obtainment of 1,1-diboryl-1-alkenes 33[33] (Scheme 6). Palladium-catalized cross-coupling reaction of 33 with R1X proceeds stereoselectively to give (E)-alkenyl- Chem. Eur. J. 2010, 16, 4152 – 4162  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 183 www.chemeurj.org 4157 S. Florio and V. Capriati Seebach et al.[44] The 6Li,13C triplet observed in their C NMR spectra would be suggestive of a carbon coupled to only one lithium atom (6Li I = 1) such as would occur in monomeric structures. However, performing calculations on LiCH2F (40; Figure 5) (chosen as a model system), Boche merization at the carbenoid atoms in the presence of the unreacted starting dibromoalkenes probably through a rapid reversible bromine/lithium exchange. Substitution reactions promoted by organolithiums at unactivated 1-chloro-1-alkenes have been recently investigated by Knorr and coworkers;[37] an alkylidenecarbenoid chain reaction has been proposed to occur in the case of 2-(halogenomethylidene)1,1,3,3-tetramethylindan derivatives. Now, the questions needed to be addressed would be the following: what is the real “identity” of a lithium carbenoid responsible of a dichotomous reactivity according to the employed experimental conditions? What are the factors responsible of its configurational integrity/lability and that govern the stereochemistry of its coupling reactions with electrophiles? 13 The Influence of Aggregation and Solvation on the Structure–Reactivity Relationship The structure–reactivity relationship is an important feature of organolithium compounds to be always taken into consideration for both the elucidation of reaction mechanisms and an improved understanding of observed selectivities.[38] Lithium compounds, often schematically depicted as monomeric species (especially for educational purposes), are instead known to be typical self-assembling molecules par excellence, reputed to exhibit an astonishing array of structures;[39] lithium carbenoids are no exception. As a consequence, their solution structures tend to be much more complicated than expected, because of the formation of higher aggregates in which the metal may be associated with more than one carbanion center. Such rule-breaking structures, in Schleyers terminology,[40] illustrate the interplay of ionic and covalent bonding. Lithium carbenoids are similarly variously aggregated in solution and an understanding of their peculiar reactivity cannot leave out the consideration of their structure elucidation. In particular, some structural features are noteworthy when dealing with these reactive intermediates. As supported by X-ray analyses,[1c,d, 7] NMR investigations,[1c,d, 7] and calculations,[41] the presence of a heteroatom (e.g., halogen, O) in the organic framework of a lithiated system allows it preferentially to form bridged structures with the heteroatom bridging the carbon–lithium bond. In addition, in the case of bridged dimers[42] or higher aggregates,[43] it is not unusual that such architectures may differ in their basic structural features from those of the most common symmetric types, because of the presence of additional intramolecular coordinations that might induce a distortion of their geometries. This is particularly true also when solvation is considered: an ethereal solvent, competing with the heteroatom for coordination sites on lithium, might indeed increase both lithium–carbon and lithium–heteroatom bond lengths in a different way in a higher aggregate. In this context, NMR spectroscopic data, suggestive of a certain aggregation state of a lithium carbenoid, should always be treated with caution. Lets consider, for instance, the case of the Li/Hal carbenoids LiCHCl2 and LiCCl3 examined by 4158 www.chemeurj.org Figure 5. MP2/6-31G(d)//3-21G energies [kcal mol1] and bond lengths [pm] of bridged LiCH2F, LiCH2F·OH2, [LiCH2F]2 and [LiCH2F·OH2]2. et al.[7] found a more stable bridged dimer (LiCH2F)2 (41) with respect to the monomer in which the bridging lithium exhibited two different bond lengths to carbon. Solvation of Li in the monomer to form LiCH2F·OH2 (42) increased the difference even more in the corresponding disolvated dimer (LiCH2F·OH2)2 (43) (Figure 5). This implies that the above Li/Hal carbenoids, namely LiCHCl2 and LiCCl3, might indeed be themselves aggregated as dimers and the single 6 Li,13C coupling observed be just due to the large distance of the bridging 6Li to the carbenoid 13C atom. The controversy of the mechanistic dichotomy for carbenoid-promoted cyclopropanation reactions (that is, the methylene-transfer pathway and the carbometalation pathway; Scheme 8), has recently been deeply re-investigated by Zhao and co-workers[45] by means of DFT calculations taking into account both aggregation and solvation states for lithium carbenoids. These calculations reveal, first, that the carbometalation pathway cannot compete with the Scheme 8. The methylene-transfer mechanism and carbometalation mechanism for carbenoid-promoted cyclopropanation reactions.  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 184 Chem. Eur. J. 2010, 16, 4152 – 4162 Lithium Carbenoids MINIREVIEW methylene-transfer pathway once aggregation states are considered. Second, the aggregated lithium carbenoids are the most likely reactive species in the reaction systems; indeed, the reaction barrier of the methylene-transfer pathway for a lithium carbenoid such as 40 decreases from 16.0 kcal mol1 for the monomer to 10.1 kcal mol1 for the dimer (LiCH2F)2 (41), and to 8.0 kcal mol1 for the tetramer (LiCH2F)4. By investigating the solvation effect, introducing explicitly coordinating solvent molecules to the lithium ion of 40, it transpires that solvation helps make the methylene-transfer pathway even more favored than the carbometalation pathway. DFT calculations have also been employed to examine the possible formation of mixed aggregates (mixed dimers, trimers and tetramers) between halomethyllithium carbenoids and lithium halides in both the gas phase and THF solution. As highlighted by L. M. Pratt et al.,[46] these mixed aggregates, whenever formed, can affect the activation barrier of carbenoid reactions (e.g., that of cyclopropanation reactions) and may cause, at the same time, a change in the mechanism during the course of the same reaction. In addition, such mixed aggregates may also have a potential in synthetic reactions of lithium carbenoids. Similarly, aggregation and solvation proved to be crucial factors also for a proper elucidation of the dichotomous reactivity of a-lithiated ethers. As reported,[7] the carbenoid nature of a-lithiated ethers has always allowed them to react with nucleophiles like RLi. Moreover, whenever spectroscopic data are available, a-lithiated ethers have often been described as having bridged dimeric structures in solution. One of the rare exceptions is represented by the Li/O carbenoid 44 (Figure 6), which is a monomer in THF at 108 8C and has an ylide nature, with the lithium bound to oxygen; the stabilization of the negative charge at the anionic carbon is, most probably, the prerequisite for the removal of Li from this carbon. Curiously, attempts to react this monomeric species 44 in various solvents with RLi nucleophiles have always failed. A recent multinuclear magnetic resonance investigation performed by Capriati, Florio, and co-workers on a-lithiated [a,b-13C2] styrene oxide (also in an enantiomerically enriched form), nicely supported by both DFT and GIAO chemical shift calculations, showed that in [D8]THF at 173 K this oxiranyllithium is mainly present as a solvated monomeric species in equilibrium with a complex mixture of stereoisomeric dimeric aggregates (with/without OLi coordinations) as well as with a fluxional tetrameric aggregate.[47] The reduced symmetry of some aggregates, mainly because of the partial breaking of some CaLi bonds, complicates their NMR spectra even more. Thus, for a certain dimeric aggregate such as 45 (Figure 6), two diastereomers, namely 45 a·2 THF and 45 b·2 THF, under slow equilibration on the NMR timescale in absence of tetramethylethylenediamine (TMEDA), could be seen each one exhibiting a pair of diastereotopic lithiated carbons. Interestingly, DFT and GIAO chemical shift calculations suggested that the trisolvated monomeric aggregate 46·3 THF is very likely to exist in solution without any coordination between Li and the oxirane oxygen, thus exhibiting an almost tetra- Chem. Eur. J. 2010, 16, 4152 – 4162 Figure 6. Li/O carbenoid 44, selected aggregation states of lithiated styrene oxide (45–47), lithiated allenyl ether 48, and lithiated diphenylaziridines 49 and 50 in two different geometries and aggregation states according to the nature of the solvent. hedral arrangement around the carbanionic carbon. At the same time, bridged O-coordinated dimeric aggregates of the type of 47·2 THF are most probably the expression of a higher “carbene-like” reactivity of lithiated styrene oxide with respect to the monomer 46·3 THF (Figure 6). This supposition was supported by both natural bond analysis (NBA) and experimental results. Therefore, the dichotomous reactivity exhibited by lithium carbenoids may be properly rationalized on the basis of a close structure–reactivity relationship; aggregates are, indeed, the real species formed in solution—each one being preferred with respect to another one under certain experimental conditions and each one characterized by its own reactivity. A combined computational and 13C NMR study has been analogously used to determine the solution structures of a lithiated allenyl ether such as 1-methoxyallenyllithium (48; Figure 6).[48] The NMR spectra in THF, together with the calculated aggregation energies and chemical shifts, are consistent with a dimer–tetramer equilibrium, the dimer being favored by lower temperatures whereas the tetramer by higher temperatures. An opposite stereochemical course has been observed in different solvents by Florio and co-workers in the lithiation-trapping sequence of trans-N-alkyl-2,3-diphenylaziridines with electrophiles.[49] This phenomenon has recently been spectroscopically rationalized just in terms of a switch occurring between two differently configured lithiated intermediates according to the nature of the solvent em-  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 185 www.chemeurj.org 4159 S. Florio and V. Capriati ployed.[50] A monomeric species cis-49 (presumably solvated up to three molecules of THF), has been postulated in THF, whereas a trans-50, a homomeric dimer with TMEDA tightly bonded to lithium, is most probably the aggregate favored in toluene (Figure 6). Throughout the last three decades, the structural analysis of an organolithium compound has benefited a lot from the tremendous evolution of new NMR techniques. Today, in particular, the aggregate size of an organolithium intermediate may be deduced not only from NMR line multiplicities due to 13C,6, 7Li coupling,[51] but also from the measurements of diffusion constants (related to the individual lithiated species present in solution) by pulsed gradient spin-echo (PGSE) NMR methods. The incorporation of the PGSE sequence into a two-dimensional experiment leads to the socalled diffusion-ordered NMR spectroscopy (DODY).[52] Starting in the year 2000, many efforts have been made by Williard and co-workers to employ multinuclear DOSY techniques in the characterization of reactive organolithium aggregates in order to correlate solid-state crystal structures (determined by X-ray diffraction) with solution structures and also to discover the role of aggregate formation and solvation states in reaction mechanisms.[53] The combination of 7 Li NMR and PGSE methods also proved to be quite useful for recognizing both ion pairing and aggregation of organolithium species in THF.[54] tions) that may be responsible of the geometries of these clusters and in which a “lithium bond”[55] and/or close “agostic”-type Li···HC interactions[56] also might be playing an important role. Topological analysis of the charge densities from high resolution X-ray data exploiting the “atoms in molecules” (AIM) approach,[57] may shed some brighter light in unveiling such interactions.[11b] This type of knowledge is important not only in the field structure–reactivity relationships, but also because these higher ordered structures could also display an interesting chirality at the supramolecular level. This, in turn, could inspire the proper planning of an asymmetric synthesis as well as its optimization. As an example of a successful self-assembly in the organolithium field, suffice it to say that one of the simplest nonchiral organolithiums, methyllithium, in the presence of diethoxymethane, forms tetrameric (MeLi)4 units linked to each other through Li3C···Li intertetrameric long-range interactions, each tetramer also interacting completely with its eight adjacent tetramers, thus leading to a three-dimensional network characterized by hexagonal channels.[58] A further example of the formation of high-order supramolecular structures has been provided by Collum: an achiral lithium acetylide and a lithium ephedrate containing two stereogenic centers self-assemble into mixed tetramers containing up to 14 stereogenic centers with complete stereocontrol.[59] Studying the spontaneous or induced self-assembly of organolithiums[60] in order to get functional architectures at a supramolecular level may be one of the most challenging breakthroughs in the near future, because this would also smooth the way toward a proper understanding of the circumstances under which these “reagents” become able to “communicate” with each other or, better, they start to “live”! Summary and Outlook Organolithium compounds, in general, because of the predominantly ionic nature of their CLi bonds are often aggregated in solution, the molecular structure being affected by various factors such as solvent/cosolvent coordination of the lithium atom, (de)localization of the negative charge into the organic framework, and the steric demand around the lithiated carbon. Li carbenoids, in particular, because of additional coordination promoted by the heteroatom toward lithium (which compete with those arising from both the lithiated carbon and the solvent), may exhibit even more complex architectures in solution with a lower symmetry than expected. Any proposal for the solution structures of these aggregates should therefore result, preferentially, from a synergistic interaction between theoretical and experimental work. Solid-state structures (if any) may also be of further help for the interpretation of experimental results. A new synthesis making use of this class of compounds cannot disregard (particularly in terms of selectivity) the knowledge of the structure–reactivity relationship, which with these systems becomes particularly crucial; their dichotomous reactivity is indeed related to the different aggregates formed in solution. Such lithium aggregates can be considered, in all respects, as supramolecular entities in Lehns terminology, because they are the result not only of additive but also of cooperative interactions between monomeric units. The challenge from now on is to pay great attention to all of the “secondary interactions” (mainly noncovalent interac4160 www.chemeurj.org Acknowledgements This work was carried out under the framework of the National Project “Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni” and financially supported by the University of Bari and by the Interuniversities Consortium C.I.N.M.P.I.S. 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