Editing Organolithium reagent (section)

===As nucleophile===

====Carbolithiation reactions====
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.<ref name=Intracarbolithiation>{{cite book| last1 = Fananas | first1 = Francisco | last2 = Sanz | first2 = Roberto| chapter = Intramolecular carbolithiation reactions| title = PATAI'S Chemistry of Functional Groups.| publisher = John Wiley & Sons, Ltd | year = 2009| isbn = 9780470682531 | doi = 10.1002/9780470682531.pat0341}}</ref> This reaction is the most widely employed reaction of organolithium compounds. Carbolithiation is key in anionic polymerization processes, and [[n-butyllithium|''n''-butyllithium]] is used as a catalyst to initiate the polymerization of [[styrene]], butadiene, or isoprene or mixtures thereof.<ref name=Hsieh>Heinz-Dieter Brandt, Wolfgang Nentwig1, Nicola Rooney, Ronald T. LaFlair, Ute U. Wolf, John Duffy, Judit E. Puskas, Gabor Kaszas, Mark Drewitt, Stephan Glander "Rubber, 5. Solution Rubbers" in Ullmann's Encyclopedia of Industrial Chemistry, 2011, Wiley-VCH, Weinheim. {{doi|10.1002/14356007.o23_o02}}</ref><ref name=anionicpolymer>
{{cite book| last1 = Baskaran | first1 = D.| last2 = Müller | first2 = A.H.| chapter = Anionic Vinyl Polymerization| title = Controlled and living polymerizations: From mechanisms to applications| publisher = Wiley-VCH Verlag GmbH & Co. KGaA| location = Weinheim, Germany| year = 2010| doi = 10.1002/9783527629091.ch1| isbn = 9783527629091}}</ref>

:[[File:Anionic polymerization of styrene initiated by sec-BuLi.png|450px|Anionic polymerization of styrene initiated by ''sec''-butyllithium|center]]

Another application that takes advantage of this reactivity is the formation of carbocyclic and heterocyclic compounds by [[Intramolecular reaction|intramolecular]] carbolithiation.<ref name=Intracarbolithiation /> 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.<ref name=Intracarbolithiation /> 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.<ref name=intra18>{{cite journal| title = Preparation and facile cyclization of 5-alkyn-1-yllithiums| author = Bailey, W.F.| journal = Tetrahedron Lett.| year = 1989| volume = 30| issue = 30| pages = 3901–3904| doi = 10.1016/S0040-4039(00)99279-7 |display-authors=etal}}</ref>

:[[File:Intramolecular carbolithiation'.png|470px|A sample stereoselective intramolecular carbolithiation reaction|center]]

====Addition to carbonyl compounds====
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.<ref name=Carey>{{cite book| last = Carey | first = Francis A. | chapter = Organometallic compounds of Group I and II metals| title = Advanced Organic Chemistry: Reaction and Synthesis Pt. B| publisher = Springer| edition = Kindle| year = 2007| isbn = 978-0-387-44899-2}}</ref> Addition of lithium salts such as LiClO<sub>4</sub> can improve the stereoselectivity of the reaction.<ref name=Ashby>{{cite journal|last=Ashby|first=E.C.|author2=Noding, S.R.|title=The effects of added salts on the stereoselectivity and rate of organometallic compound addition to ketones|journal=J. Org. Chem.|year=1979|volume=44|issue=24|pages=4371–4377|doi=10.1021/jo01338a026}}</ref>

:[[File:LiClO4 increase selectivity.png|500px|center|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.<ref name=Carey /> However, alkyllithium reagents are less likely to reduce the ketone, and may be used to synthesize substituted alcohols.<ref name=Yamatakaddorgli>{{cite book| last = Yamataka | first = Hiroshi | chapter = Addition of organolithium reagents to double bonds| title = PATAI'S Chemistry of Functional Groups.| publisher = John Wiley & Sons, Ltd | year = 2009| isbn = 9780470682531 | doi =  10.1002/9780470682531.pat0310}}</ref> Below is an example of ethyllithium addition to adamantone to produce tertiary alcohol.<ref name=adamantone>{{cite journal| title = Über adamantan und dessen derivate IX. In 2-stellung substituierte derivate| author = Landa, S.| journal = Collection of Czechoslovak Chemical Communications| year = 1967| volume = 72| issue = 2| pages = 570–575| doi = 10.1135/cccc19670570 |display-authors=etal}}</ref>

:[[File:Li add to adamantone.png|350px|center|Li add to adamantone]]

Organolithium reagents are also better than Grignard reagents in their ability to react with carboxylic acids to form ketones.<ref name=Carey /> This reaction can be optimized by carefully controlling the amount of organolithium reagent addition, or using trimethylsilyl chloride to quench excess lithium reagent.<ref name=carey114>{{cite journal| title = Preparation of methyl ketones by the sequential treatment of carboxylic acids with methyllithium and chlorotrimethylsilane| author = Rubottom, G.M.|author2=Kim, C| journal = J. Org. Chem.| year = 1983| volume = 48| issue = 9| pages = 1550–1552| doi =  10.1021/jo00157a038}}</ref> A more common way to synthesize ketones is through the addition of organolithium reagents to [[Weinreb amide]]s (''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.<ref name=weinreb>{{cite journal| title = A One-Pot Synthesis of Ketones and Aldehydes from Carbon Dioxide and Organolithium Compounds | author = Zadel, G.|author2=Breitmaier, E.| journal = Angew. Chem. Int. Ed.| year = 1992| volume = 31| issue = 8| pages = 1035–1036| doi = 10.1002/anie.199210351}}</ref>

:[[File:Li add to weinreb.png|450px|center|Li add to weinreb]]

Organolithium reagents also react with [[carbon dioxide]] to form, after workup, [[carboxylic acids]].<ref name=liaddtocbx>{{cite journal| title = Methoxymethyl ethers. An activating group for rapid and regioselective metalation| author = Ronald, R.C.| journal = Tetrahedron Lett.| year = 1975| volume = 16| issue = 46| pages = 3973–3974| doi = 10.1016/S0040-4039(00)91212-7}}</ref>

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.<ref name=14conjugate>{{cite journal| title = Michael addition of organolithium compounds. A Review| author = Hunt, D.A.| journal = Org. Prep. Proc. Int.| year = 1989| volume = 21| issue = 6| pages = 705–749| doi = 10.1080/00304948909356219}}</ref><ref name=12vs14>{{cite journal| title = Regioselectivity of Addition of Organolithium Reagents to Enones: The Role of HMPA| author = Reich, H. J.|author2=Sikorski, W. H.| journal = J. Org. Chem.| year = 1999| volume = 64| issue = 1| pages = 14–15| doi = 10.1021/jo981765g| pmid = 11674078}}</ref>

:[[File:1,4vs1,2_addition1.svg|center|480px|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.<ref name=MerckDupont>{{cite journal| title = NMR Spectroscopic Investigations of Mixed Aggregates Underlying Highly Enantioselective 1,2-Additions of Lithium Cyclopropylacetylide to Quinazolinones| author = Collum, D.B.| journal = J. Am. Chem. Soc.| year = 2001| volume = 123| issue = 37| pages = 9135–9143| doi = 10.1021/ja0105616 | pmid = 11552822|display-authors=etal}}</ref>

:[[File:Merck synthesis of Efavirenz.png|center|700px|Merck synthesis of Efavirenz]]

====S<sub>N</sub>2 type reactions====
Organolithium reagents can serve as nucleophiles and carry out S<sub>N</sub>2 type reactions with alkyl or allylic halides.<ref name=inversionSn2>{{cite journal| title = Stereospecific coupling reactions between organolithium reagents and secondary halides| author = Sommmer, L.H.|author2=Korte, W. D.| journal = J. Org. Chem.| year = 1970| volume = 35| pages = 22–25| doi = 10.1021/jo00826a006}}</ref>
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.<ref name=Reich /> 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.<ref name=Carey /> Organolithium reagents can also carry out nucleophilic attacks with [[epoxides]] to form alcohols.

:[[File:SN2 inversion with benzyllithium.png|550px|center|SN2 inversion with benzyllithium]]