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1967, über, adamantan, und, dessen, stellung, substituierte, 575, 1135, cccc19670570, 570, czechoslovak, communications, yamataka, hiroshi, pat0310, ashby, noding, 1979, compound, 4377, jo01338a026, 4371, carey, francis, kindle, springer, 387, 44899, advanced, bailey, facile, alkyn, yllithiums, 3904, 99279, 3901, baskaran, müller, 2010, germany, verlag, gmbh, kgaa, ch1, living, polymerizations, heinz, brandt, wolfgang, nentwig1, nicola, rooney, laflair, ute, wolf, duffy, judit, puskas, gabor, kaszas, mark, drewitt, stephan, glander, rubber, rubbers, 2011, o23_o02, fananas, francisco, sanz, roberto, pat0341, seebach, 1654, 198816241, 1624, pinacolone, peptides, difficulties, opportunities, afforded, bernstein, dependent, metalations, understanding, krel, 8010, ja00071a011, 8008, 454, ar00022a003, 448, nichols, 1572, ja00057a050, 1568, 8731, ja00205a030, 8729, 111, chalk, hoogeboom, 1968, toluene, 618, 0022, 328x, 80091, 615, organomet, gessner, adducts, tmcda, consequences, benzene, 11725, 18686951, ja8017187, 11719, 130, wardell, chapter, wilinson, stone, abel, 1st, pergamon, 0080406084, comprehensive, vol, 2012, going, 5491, 22594379, jo3005155, 5471, mcgarrity, ogle, 1985, field, complexation, 1810, ja00293a001, 1805, 7210, ja980684z, 7201, 7747, 18781812, 2636848, jo801532d, 7743, phenolates, carboxylates, prevalence, sekiguchi, akira, 2000, lithiosilanes, s0010, 8545, 00315, 210, coord, hilmersson, goran, granander, johan, pat0342, salvino, jo00053a001, power, hope, rich, etherate, 5324, ja00354a022, 5320, 105, 1995, arllithium, relaxation, rotation, 6307, ja00128a020, 6300, 117, qiu, fayang, observation, partially, delocalized, sigmatropic, shift, 5829, ja960440j, 5828, weiss, erwin, november, organo, alkali, 1523, 0570, 0833, 199315013, 1501, angewandte, chemie, international, edition, bickelhaupt, covalency, bonding, methylalkalimetal, ch3m, 980, 26633056, ct050333s, 965, theory, comput, streiwieser, 4446, 19518150, 2728082, jo900497s, 4433, perspectives, 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anolithium reagents it was originally proposed that lower aggregates such as monomers are more reactive in alkyllithiums 23 however reaction pathways in which dimer or other oligomers are the reactive species have also been discovered 24 and for lithium amides such as lda dimer based reactions are common 25 a series of solution kinetics studies of lda mediated reactions suggest that lower aggregates of enolates do not necessarily lead to higher reactivity 17 also some lewis bases increase reactivity of organolithium compounds 26 27 however whether these additives function as strong chelating ligands and how the observed increase in reactivity relates to structural changes in aggregates caused by these additives are not always clear 26 27 for example tmeda increases rates and efficiencies in many reactions involving organolithium reagents 7 toward alkyllithium reagents tmeda functions as a donor ligand reduces the degree of aggregation 5 and increases the nucleophilicity of these species 28 however tmeda does not always function as a donor ligand to lithium cation especially in the presence of anionic oxygen and nitrogen centers for example it only weakly interacts with lda and lihmds even in hydrocarbon solvents with no competing donor ligands 29 in imine lithiation while thf acts as a strong donating ligand to lihmds the weakly coordinating tmeda readily dissociates from lihmds leading to the formation of lihmds dimers that is the more reactive species thus in the case of lihmds tmeda does not increase reactivity by reducing aggregation state 30 also as opposed to simple alkyllithium compounds tmeda does not deaggregate lithio acetophenolate in thf solution 6 31 the addition of hmpa to lithium amides such as lihmds and lda often results in a mixture of dimer monomer aggregates in thf however the ratio of dimer monomer species does not change with increased concentration of hmpa thus the observed increase in reactivity is not the result of deaggregation the mechanism of how these additives increase reactivity is still being researched 22 reactivity and applications edit the c li bond in organolithium reagents is highly polarized as a result the carbon attracts most of the electron density in the bond and resembles a carbanion thus organolithium reagents are strongly basic and nucleophilic some of the most common applications of organolithium reagents in synthesis include their use as nucleophiles strong bases for deprotonation initiator for polymerization and starting material for the preparation of other organometallic compounds as nucleophile edit carbolithiation reactions edit as nucleophiles organolithium reagents undergo carbolithiation reactions whereby the carbon lithium bond adds across a carbon carbon double or triple bond forming new organolithium species 32 this reaction is the most widely employed reaction of organolithium compounds carbolithiation is key in anionic polymerization processes and n butyllithium is used as a catalyst to initiate the polymerization of styrene butadiene or isoprene or mixtures thereof 33 34 anionic polymerization of styrene initiated by sec butyllithium another application that takes advantage of this reactivity is the formation of carbocyclic and heterocyclic compounds by intramolecular carbolithiation 32 as a form of anionic cyclization intramolecular carbolithiation reactions offer several advantages over radical cyclization first it is possible for the product cyclic organolithium species to react with electrophiles whereas it is often difficult to trap a radical intermediate of the corresponding structure secondly anionic cyclizations are often more regio and stereospecific than radical cyclization particularly in the case of 5 hexenyllithiums intramolecular carbolithiation allows addition of the alkyl vinyllithium to triple bonds and mono alkyl substituted double bonds aryllithiums can also undergo addition if a 5 membered ring is formed the limitations of intramolecular carbolithiation include difficulty of forming 3 or 4 membered rings as the intermediate cyclic organolithium species often tend to undergo ring openings 32 below is an example of intramolecular carbolithiation reaction the lithium species derived from the lithium halogen exchange cyclized to form the vinyllithium through 5 exo trig ring closure the vinyllithium species further reacts with electrophiles and produce functionalized cyclopentylidene compounds 35 a sample stereoselective intramolecular carbolithiation reaction addition to carbonyl compounds edit nucleophilic organolithium reagents can add to electrophilic carbonyl double bonds to form carbon carbon bonds they can react with aldehydes and ketones to produce alcohols the addition proceeds mainly via polar addition in which the nucleophilic organolithium species attacks from the equatorial direction and produces the axial alcohol 36 addition of lithium salts such as liclo 4 can improve the stereoselectivity of the reaction 37 liclo4 increase selectivity of t buli when the ketone is sterically hindered using grignard reagents often leads to reduction of the carbonyl group instead of addition 36 however alkyllithium reagents are less likely to reduce the ketone and may be used to synthesize substituted alcohols 38 below is an example of ethyllithium addition to adamantone to produce tertiary alcohol 39 li add to adamantone organolithium reagents are also better than grignard reagents in their ability to react with carboxylic acids to form ketones 36 this reaction can be optimized by carefully controlling the amount of organolithium reagent addition or using trimethylsilyl chloride to quench excess lithium reagent 40 a more common way to synthesize ketones is through the addition of organolithium reagents to weinreb amides n methoxy n methyl amides this reaction provides ketones when the organolithium reagents is used in excess due to chelation of the lithium ion between the n methoxy oxygen and the carbonyl oxygen which forms a tetrahedral intermediate that collapses upon acidic work up 41 li add to weinreb organolithium reagents also react with carbon dioxide to form after workup carboxylic acids 42 in the case of enone substrates where two sites of nucleophilic addition are possible 1 2 addition to the carbonyl carbon or 1 4 conjugate addition to the β carbon most highly reactive organolithium species favor the 1 2 addition however there are several ways to propel organolithium reagents to undergo conjugate addition first since the 1 4 adduct is the likely to be the more thermodynamically favorable species conjugate addition can be achieved through equilibration isomerization of the two product especially when the lithium nucleophile is weak and 1 2 addition is reversible secondly adding donor ligands to the reaction forms heteroatom stabilized lithium species which favors 1 4 conjugate addition in one example addition of low level of hmpa to the solvent favors the 1 4 addition in the absence of donor ligand lithium cation is closely coordinated to the oxygen atom however when the lithium cation is solvated by hmpa the coordination between carbonyl oxygen and lithium ion is weakened this method generally cannot be used to affect the regioselectivity of alkyl and aryllithium reagents 43 44 1 4vs1 2 addition organolithium reagents can also perform enantioselective nucleophilic addition to carbonyl and its derivatives often in the presence of chiral ligands this reactivity is widely applied in the industrial syntheses of pharmaceutical compounds an example is the merck and dupont synthesis of efavirenz a potent hiv reverse transcriptase inhibitor lithium acetylide is added to a prochiral ketone to yield a chiral alcohol product the structure of the active reaction intermediate was determined by nmr spectroscopy studies in the solution state and x ray crystallography of the solid state to be a cubic 2 2 tetramer 45 merck synthesis of efavirenz s n 2 type reactions edit organolithium reagents can serve as nucleophiles and carry out s n 2 type reactions with alkyl or allylic halides 46 although they are considered more reactive than grignard reagents in alkylation their use is still limited due to competing side reactions such as radical reactions or metal halogen exchange most organolithium reagents used in alkylations are more stabilized less basic and less aggregated such as heteroatom stabilized aryl or allyllithium reagents 6 hmpa has been shown to increase reaction rate and product yields and the reactivity of aryllithium reagents is often enhanced by the addition of potassium alkoxides 36 organolithium reagents can also carry out nucleophilic attacks with epoxides to form alcohols sn2 inversion with benzyllithium as base edit organolithium reagents provide a wide range of basicity tert butyllithium with three weakly electron donating alkyl groups is the strongest base commercially available pka 53 as a result the acidic protons on oh nh and sh are often protected in the presence of organolithium reagents some commonly used lithium bases are alkyllithium species such as n butyllithium and lithium dialkylamides linr 2 reagents with bulky r groups such as lithium diisopropylamide lda and lithium bis trimethylsilyl amide lihmds are often sterically hindered for nucleophilic addition and are thus more selective toward deprotonation lithium dialkylamides linr 2 are widely used in enolate formation and aldol reaction 47 the reactivity and selectivity of these bases are also influenced by solvents and other counter ions metalation edit metalation with organolithium reagents also known as lithiation or lithium hydrogen exchange is achieved when an organolithium reagent most commonly an alkyllithium abstracts a proton and forms a new organolithium species r h r li rli r h displaystyle ce r h r li rli r h 1 common metalation reagents are the butyllithiums tert butyllithium and sec butyllithium are generally more reactive and have better selectivity than n butyllithium however they are also more expensive and difficult to handle 47 metalation is a common way of preparing versatile organolithium reagents the position of metalation is mostly controlled by the acidity of the c h bond lithiation often occurs at a position α to electron withdrawing groups since they are good at stabilizing the electron density of the anion directing groups on aromatic compounds and heterocycles provide regioselective sites of metalation directed ortho metalation is an important class of metalation reactions metalated sulfones acyl groups and α metalated amides are important intermediates in chemistry synthesis metalation of allyl ether with alkyllithium or lda forms an anion α to the oxygen and can proceed to 2 3 wittig rearrangement addition of donor ligands such as tmeda and hmpa can increase metalation rate and broaden substrate scope 48 directed ortho metalation directed ortho metalation is an important tool in the synthesis of regiospecific substituted aromatic compounds this approach to lithiation and subsequent quenching of the intermediate lithium species with electrophile is often better than the electrophilic aromatic substitution due to its high regioselectivity this reaction proceeds through deprotonation by organolithium reagents at the positions α to the direct metalation group dmg on the aromatic ring the dmg is often a functional group containing a heteroatom that is lewis basic and can coordinate to the lewis acidic lithium cation this generates a complex induced proximity effect which directs deprotonation at the α position to form an aryllithium species that can further react with electrophiles some of the most effective dmgs are amides carbamates sulfones and sulfonamides they are strong electron withdrawing groups that increase the acidity of alpha protons on the aromatic ring in the presence of two dmgs metalation often occurs ortho to the stronger directing group though mixed products are also observed a number of heterocycles that contain acidic protons can also undergo ortho metalation however for electron poor heterocycles lithium amide bases such as lda are generally used since alkyllithium has been observed to perform addition to the electron poor heterocycles rather than deprotonation in certain transition metal arene complexes such as ferrocene the transition metal attracts electron density from the arene thus rendering the aromatic protons more acidic and ready for ortho metalation 49 superbases edit main article superbase addition of potassium alkoxide to alkyllithium greatly increases the basicity of organolithium species 50 the most common superbase can be formed by addition of kotbu to butyllithium referred to as schlosser s base or lickor lic denoting the alkylithium kor deonting the potassium alkoxide superbases these superbases are highly reactive and often stereoselective reagents in the example below the lickor base generates a stereospecific crotylboronate species through metalation and subsequent lithium metalloid exchange 51 superbase organolithium reagents in asymmetric synthesis edit chiral organolithium reagents can be accessed through asymmetric metalation 52 they have also been applied in asymmetric synthesis in the pharmaceutical industry 53 asymmetric induction requires the presence of a chiral ligand such as sparteine 52 the enantiomeric ratio of the chiral lithium species is often influenced by the differences in rates of deprotonation in the example below treatment of n boc n benzylamine with n butyllithium in the presence of sparteine affords one enantiomer of the product with high enantiomeric excess transmetalation with trimethyltin chloride affords the opposite enantiomer 54 asymmetric synthesis with nbuli and sparteine enolate formation edit lithium enolates are formed through deprotonation of a c h bond α to the carbonyl group by an organolithium species lithium enolates are widely used as nucleophiles in carbon carbon bond formation reactions such as aldol condensation and alkylation they are also an important intermediate in the formation of silyl enol ether sample aldol reaction with lithium enolate lithium enolate formation can be generalized as an acid base reaction in which the relatively acidic proton α to the carbonyl group pk 20 28 in dmso reacts with organolithium base generally strong non nucleophilic bases especially lithium amides such lda lihmds and litmp are used thf and dmso are common solvents in lithium enolate reactions 55 the stereochemistry and mechanism of enolate formation have gained much interest in the chemistry community many factors influence the outcome of enolate stereochemistry such as steric effects solvent polar additives and types of organolithium bases among the many models used to explain and predict the selectivity in stereochemistry of lithium enolates is the ireland model 56 in this assumption a monomeric lda reacts with the carbonyl substrate and form a cyclic zimmerman trax...
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