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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, 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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 traxler type transition state the e enolate is favored due to an unfavorable syn pentane interaction in the z enolate transition state 55 ireland model for lithium enolate stereoselectivity in this example the e enolate is favored addition of polar additives such as hmpa or dmpu favors the formation of z enolates the ireland model argues that these donor ligands coordinate to the lithium cations as a result carbonyl oxygen and lithium interaction is reduced and the transition state is not as tightly bound as a six membered chair the percentage of z enolates also increases when lithium bases with bulkier side chains such as lihmds are used 55 however the mechanism of how these additives reverse stereoselectivity is still being debated there have been some challenges to the ireland model as it depicts the lithium species as a monomer in the transition state in reality a variety of lithium aggregates are often observed in solutions of lithium enolates and depending on specific substrate solvent and reaction conditions it can be difficult to determine which aggregate is the actual reactive species in solution 55 lithium halogen exchange edit main article metal halogen exchange lithium halogen exchange lithium halogen exchange involves heteroatom exchange between an organohalide and organolithium species r li r x r x r li displaystyle ce r li r x r x r li 2 lithium halogen exchange is very useful in preparing new organolithium reagents the application of lithium halogen exchange is illustrated by the parham cyclization 57 parham cyclization in mitospin transmetalation edit organolithium reagents are often used to prepare other organometallic compounds by transmetalation organocopper organotin organosilicon organoboron organophosphorus organocerium and organosulfur compounds are frequently prepared by reacting organolithium reagents with appropriate electrophiles r m n buli r li n bum displaystyle ce r m textit n ce buli r li textit n ce bum 3 common types of transmetalation include li sn li hg and li te exchange which are fast at low temperature 47 the advantage of li sn exchange is that the tri alkylstannane precursors undergo few side reactions as the resulting n bu 3 sn byproducts are unreactive toward alkyllithium reagents 47 in the following example vinylstannane obtained by hydrostannylation of a terminal alkyne forms vinyllithium through transmetalation with n buli 58 li sn exchange organolithium can also be used in to prepare organozinc compounds through transmetalation with zinc salts 59 organozinc reagents from alkyllithium lithium diorganocuprates can be formed by reacting alkyl lithium species with copper i halide the resulting organocuprates are generally less reactive toward aldehydes and ketones than organolithium reagents or grignard reagents 60 1 4 cuprate addition preparation edit most simple alkyllithium reagents and common lithium amides are commercially available in a variety of solvents and concentrations organolithium reagents can also be prepared in the laboratory below are some common methods for preparing organolithium reagents displacement of a leaving group edit in lithium halogen exchange reduction of alkyl halide with metallic lithium can afford simple alkyl and aryl organolithium reagents 36 r x 2 li r li li x displaystyle ce r x 2li r li li x 4 tert butyllithium or n butyllithium are the most commonly used reagents for generating new organolithium species through lithium halogen exchange lithium halogen exchange is mostly used to convert aryl and alkenyl iodides and bromides with sp2 carbons to the corresponding organolithium compounds the reaction is extremely fast and often proceed at 60 to 120 c 48 industrial preparation of organolithium reagents is achieved using this method by treating the alkyl chloride with metal lithium containing 0 5 2 sodium the conversion is highly exothermic the sodium initiates the radical pathway and increases the rate 61 the reduction proceeds via a radical pathway below is an example of the preparation of a functionalized lithium reagent using reduction with lithium metal 62 sometimes lithium metal in the form of fine powders are used in the reaction with certain catalysts such as naphthalene or 4 4 di t butylbiphenyl dtbb another substrate that can be reduced with lithium metal to generate alkyllithium reagents is sulfides reduction of sulfides is useful in the formation of functionalized organolithium reagents such as alpha lithio ethers sulfides and silanes 63 reduction with li metal metalation edit further information metalation reactivity and applications a second method of preparing organolithium reagents is a metalation lithium hydrogen exchange the relative acidity of hydrogen atoms controls the position of lithiation this is the most common method for preparing alkynyllithium reagents because the terminal hydrogen bound to the sp carbon is very acidic and easily deprotonated 36 for aromatic compounds the position of lithiation is also determined by the directing effect of substituent groups 64 some of the most effective directing substituent groups are alkoxy amido sulfoxide sulfonyl metalation often occurs at the position ortho to these substituents in heteroaromatic compounds metalation usually occurs at the position ortho to the heteroatom 36 64 transmetalation edit further information transmetalation applications the fourth method to prepare organolithium reagents is through transmetalation this method can be used for preparing vinyllithium shapiro reaction edit in the shapiro reaction two equivalents of strong alkyllithium base react with p tosylhydrazone compounds to produce the vinyllithium or upon quenching the olefin product handling edit organolithium compounds are highly reactive species and require specialized handling techniques they are often corrosive flammable and sometimes pyrophoric spontaneous ignition when exposed to air or moisture 65 alkyllithium reagents can also undergo thermal decomposition to form the corresponding alkyl species and lithium hydride 66 organolithium reagents are typically stored below 10 c reactions are conducted using air free techniques 65 the concentration of alkyllithium reagents is often determined by titration 67 68 69 organolithium reagents react often slowly with ethers which nonetheless are often used as solvents 70 approximate half lives of common lithium reagents in typical solvents solvent temp n buli s buli t buli meli ch 2 c oet li ch 2 c sime 3 li thf 40 c 338 min thf 20 c 42 min thf 0 c 17 h thf 20 c 107 min 15 h 17 h thf 35 c 10 min thf tmeda 20 c 55 h thf tmeda 0 c 340 min thf tmeda 20 c 40 min ether 20 c 480 min ether 0 c 61 min ether 20 c 153 h 30 min 17 d ether 35 c 31 h ether tmeda 20 c 603 min dme 70 c 120 min 11 min dme 20 c 110 min 2 min 2 min dme 0 c 6 min see also edit alkynylation grignard reagent hsab concept schlosser s base isotopes of lithium further reading edit reich h j borst j p dykstra r r green p d 1993 a nuclear magnetic resonance spectroscopic technique for the characterization of lithium ion pair structures in thf and thf hmpa solution j am chem soc 115 19 8728 8741 doi 10 1021 ja00072a028 references edit 1 2 zabicky jacob 2009 analytical aspects of organolithium compounds patai s chemistry of functional groups john wiley sons ltd doi 10 1002 9780470682531 pat0304 isbn 9780470682531 wietelmann ulrich steinbild martin 2014 lithium and lithium compounds ullmann s encyclopedia of industrial chemistry pp 1 38 doi 10 1002 14356007 a15_393 pub2 isbn 978 3 527 30385 4 eisch john j 2002 henry gilman american pioneer in the rise of organometallic chemistry in modern science and technology organometallics 21 25 5439 5463 doi 10 1021 om0109408 issn 0276 7333 rappoport z marek i eds 2004 the chemistry of organolithium compounds 2 parts john wiley sons ltd isbn 978 0 470 84339 0 1 2 3 4 5 6 7 8 9 stey thomas stalke dietmar 2009 lead structures in lithium organic chemistry patai s chemistry of functional groups john wiley sons ltd doi 10 1002 9780470682531 pat0298 isbn 9780470682531 1 2 3 4 5 6 7 8 9 10 reich hans j 2013 role of organolithium aggregates and mixed aggregates in organolithium mechanisms chemical reviews 113 9 7130 7178 doi 10 1021 cr400187u pmid 23941648 1 2 3 4 5 6 7 8 9 10 strohmann c et al 2009 structure formation principles and reactivity of organolithium compounds pdf chem eur j 15 14 3320 3334 doi 10 1002 chem 200900041 pmid 19260001 1 2 jemmis e d gopakumar g 2009 theoretical studies in organolithium chemistry patai s chemistry of functional groups john wiley sons ltd doi 10 1002 9780470682531 pat0297 isbn 9780470682531 1 2 streiwieser a 2009 perspectives on computational organic chemistry j org chem 74 12 4433 4446 doi 10 1021 jo900497s pmc 2728082 pmid 19518150 1 2 bickelhaupt f m et al 2006 covalency in highly polar bonds structure and bonding of methylalkalimetal oligomers ch3m n m li rb n 1 4 j chem theory comput 2 4 965 980 doi 10 1021 ct050333s pmid 26633056 weiss erwin november 1993 structures of organo alkali metal complexes and related compounds angewandte chemie international edition in english 32 11 1501 1523 doi 10 1002 anie 199315013 issn 0570 0833 fraenkel g qiu fayang 1996 observation of a partially delocalized allylic lithium and the dynamics of its 1 3 lithium sigmatropic shift j am chem soc 118 24 5828 5829 doi 10 1021 ja960440j fraenkel g et al 1995 the carbon lithium bond in monomeric arllithium dynamics of exchange relaxation and rotation j am chem soc 117 23 6300 6307 doi 10 1021 ja00128a020 power p p hope h 1983 isolation and crystal structures of the halide free and halide rich phenyllithium etherate complexes phli et2o 4 and phli et2o 3 libr journal of the american chemical society 105 16 5320 5324 doi 10 1021 ja00354a022 1 2 williard p g salvino j m 1993 synthesis isolation and structure of an lda thf complex journal of organic chemistry 58 1 1 3 doi 10 1021 jo00053a001 hilmersson goran granander johan 2009 structure and dynamics of chiral lithium amides patai s chemistry of functional groups john wiley sons ltd doi 10 1002 9780470682531 pat0342 isbn 9780470682531 1 2 collum d b et al 2007 lithium diisopropylamide solution kinetics and implications for organic synthesis angew chem int ed 49 17 3002 3017 doi 10 1002 anie 200603038 pmid 17387670 sekiguchi akira et al 2000 lithiosilanes and their application to the synthesis of polysilane dendrimers coord chem rev 210 11 45 doi 10 1016 s0010 8545 00 00315 5 collum d b et al 2008 solution structures of lithium enolates phenolates carboxylates and alkoxides in the presence of n n n n tetramethylethylenediamine a prevalence of cyclic dimers j org chem 73 19 7743 7747 doi 10 1021 jo801532d pmc 2636848 pmid 18781812 reich h j et al 1998 aggregation and reactivity of phenyllithium solutions j am chem soc 120 29 7201 7210 doi 10 1021 ja980684z mcgarrity j f ogle c a 1985 high field proton nmr study of the aggregation and complexation of n butyllithium in tetrahydrofuran j am chem soc 107 7 1805 1810 doi 10 1021 ja00293a001 1 2 reich h j 2012 what s going on with these lithium reagents j org chem 77 13 5471 5491 doi 10 1021 jo3005155 pmid 22594379 wardell j l 1982 chapter 2 in wilinson g stone f g a abel e w eds comprehensive organometallic chemistry vol 1 1st ed new york pergamon isbn 978 0080406084 strohmann c gessner v h 2008 crystal structures of n buli adducts with r r tmcda and the consequences for the deprotonation of benzene j am chem soc 130 35 11719 11725 doi 10 1021 ja8017187 pmid 18686951 collum d b et al 2007 lithium diisopropylamide solution kinetics and implications for organic synthesis angew chem int ed 46 17 3002 3017 doi 10 1002 anie 200603038 pmid 17387670 1 2 chalk a j hoogeboom t j 1968 ring metalation of toluene by butyllithium in the presence of n n n n tetramethylethylenediamine j organomet chem 11 615 618 doi 10 1016 0022 328x 68 80091 9 1 2 reich h j green d p 1989 spectroscopic and reactivity studies of lithium reagent hmpa complexes journal of the american chemical society 111 23 8729 8731 doi 10 1021 ja00205a030 williard p g nichols m a 1993 solid state structures of n butyllithium tmeda thf and dme complexes journal of the american chemical society 115 4 1568 1572 doi 10 1021 ja00057a050 collum d b 1992 is n n n n tetramethylethylenediamine a good ligand for lithium acc chem res 25 10 448 454 doi 10 1021 ar00022a003 bernstein m p collum d 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