Editing Organolithium reagent (section)

== Reactivity and applications==
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===

====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]]

===As base===
Organolithium reagents provide a wide range of [[basicity]]. [[tert-Butyllithium|''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|''n''-butyllithium]] and lithium dialkylamides (LiNR<sub>2</sub>). 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<sub>2</sub>) are widely used in [[enolate]] formation and [[aldol]] reaction.<ref name=Reich3 /> The reactivity and selectivity of these bases are also influenced by solvents and other counter ions.

====Metalation====
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. 
{{NumBlk|:|<chem title="Lithium hydrogen exchange">R-H + R'Li -> RLi + R'H</chem>|{{EquationRef|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.<ref name=Reich3 /> 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 [[heterocyclic compound|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.<ref name=Leroux>''The Preparation of Organolithium Reagents and Intermediates'' Leroux.F., Schlosser. M., Zohar. E., Marek. I., Wiley, New York. 2004. {{ISBN|978-0-470-84339-0}}</ref> [[Chiral]] organolithium reagents can be accessed through asymmetric metalation.<ref name=asymmetalation />

:[[File:Directed ortho metalation2.png|500px|Directed ortho metalation|center]]

[[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, [[carbamate]]s, [[sulfone]]s and [[sulfonamide]]s. 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.<ref name=Clayden>{{cite book| last = Clayden| first = Jonathan | chapter = Directed metallization of aromatic compounds| title = PATAI'S Chemistry of Functional Groups.| publisher = John Wiley & Sons, Ltd | year = 2009| isbn = 9780470682531 | doi = 10.1002/9780470682531.pat0306}}</ref>

====Superbases====
{{main|Superbase}}
Addition of potassium alkoxide to alkyllithium greatly increases the basicity of organolithium species.<ref name=Schlosser2>{{cite journal|last=Schlosser|first=M|title=Superbases for organic synthesis|journal=Pure Appl. Chem.|year=1988|volume=60|issue=11|pages=1627–1634|doi=10.1351/pac198860111627|doi-access=free}}</ref> The most common "superbase" can be formed by addition of KOtBu to butyllithium, often abbreviated as "LiCKOR" reagents. 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.<ref name=Roush>{{cite journal| title = Enantioselective synthesis using diisopropyl tartrate modified (E)- and (Z)-crotylboronates: Reactions with achiral aldehydes| author = Roush, W.R.| journal = Tetrahedron Lett.| year = 1988| volume = 29| issue = 44| pages = 5579–5582| doi = 10.1016/S0040-4039(00)80816-3 |display-authors=etal}}</ref>

:[[File:Superbase;.png|center|550px|Superbase]]

=====Asymmetric metalation=====
Enantioenriched organolithium species can be obtained through [[asymmetric synthesis|asymmetric]] metalation of prochiral substrates. Asymmetric induction requires the presence of a [[chiral]] ligand such as (−)-[[sparteine]].<ref name=asymmetalation>{{cite book| last1 = Hoppe | first1 = Dieter | last2 = Christoph | first2 = Guido| chapter = Asymmetric deprotonation with alkyllithium– (−)-sparteine| title = PATAI'S Chemistry of Functional Groups.| publisher = John Wiley & Sons, Ltd | year = 2009| isbn = 9780470682531 | doi = 10.1002/9780470682531.pat0313}}</ref> 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 trimethyltinchloride affords the opposite enantiomer.<ref name=NBocbenzylamines>{{cite journal| title = (−)-Sparteine-Mediated α-Lithiation of N-Boc-N-(p-methoxyphenyl)benzylamine: Enantioselective Syntheses of (S) and (R) Mono- and Disubstituted N-Boc-benzylamines| author = Park, Y.S.| journal = J. Am. Chem. Soc.| year = 1996| volume = 118| issue = 15| pages = 3757–3758| doi = 10.1021/ja9538804 |display-authors=etal}}</ref>

:[[File:Asymmetric synthesis with nBuLi and (-)-sparteine.png|600px|center|Asymmetric synthesis with nBuLi and (−)-sparteine]]

====Enolate formation====

Lithium [[enolate]]s 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]].

:[[File:Li enolate 2.png|center|750x125px|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.<ref name=valnotenolate />

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.<ref name=Ireland>{{cite journal| title = The ester enolate Claisen rearrangement. Stereochemical control through stereoselective enolate formation| author = Ireland. R. E.| journal = J. Am. Chem. Soc.| year = 1976| volume = 98| issue = 10| pages = 2868–2877| doi = 10.1021/ja00426a033 |display-authors=etal}}</ref>

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.<ref name=valnotenolate />

:[[File:Ireland model enolate1.svg|center|540px|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.<ref name=valnotenolate /> 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.<ref name=valnotenolate>{{cite book| last1 = Valnot | first1 = Jean-Yves | last2 = Maddaluno | first2 = Jacques| chapter = Aspects of the synthesis, structure and reactivity of lithium enolates| title = PATAI'S Chemistry of Functional Groups.| publisher = John Wiley & Sons, Ltd | year = 2009| isbn = 9780470682531 | doi = 10.1002/9780470682531.pat0345}}</ref>

=== Lithium–halogen exchange ===
{{main|Metal-halogen exchange#Lithium-halogen exchange}}

Lithium–halogen exchange involves heteroatom exchange between an organohalide and organolithium species.
{{NumBlk|:|<chem title="Lithium-Halogen exchange">R-Li + R'-X -> R-X + R'-Li</chem>|{{EquationRef|2}}}}
Lithium–halogen exchange is very useful in preparing new organolithium reagents. The application of lithium–halogen exchange is illustrated by the Parham cyclization.<ref name=parham>{{cite journal| title = Aromatic organolithium reagents bearing electrophilic groups. Preparation by halogen-lithium exchange| author = Parham, W.P.|author2=Bradsher, C.K.| journal = Acc. Chem. Res.| year = 1982| volume = 15| issue = 10| pages = 300–305| doi = 10.1021/ar00082a001}}</ref>

:[[File:Parham cyclization in MitoSpin'.png|center|580px|Parham cyclization in MitoSpin]]

===Transmetalation===
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.

{{NumBlk|:|<math chem title="Transmetalation">\ce{R-M} + \textit{n-}\ce{BuLi -> {R-Li} +}\ \textit{n-}\ce{BuM}</math>|{{EquationRef|3}}}}

Common types of transmetalation include Li/Sn, Li/Hg, and Li/Te exchange, which are fast at low temperature.<ref name=Reich3 /> The advantage of Li/Sn exchange is that the tri-alkylstannane precursors undergo few side reactions, as the resulting n-Bu<sub>3</sub>Sn byproducts are unreactive toward alkyllithium reagents.<ref name=Reich3>''Organolithium Reagents'' Reich, H.J. 2002 https://organicchemistrydata.org/hansreich/resources/organolithium/organolithium_data/orgli-primer.pdf</ref> In the following example, vinylstannane, obtained by [[hydrostannylation]] of a terminal alkyne, forms vinyllithium through transmetalation with n-BuLi.<ref name=stannane>{{cite journal| title = Useful new organometallic reagents for the synthesis of allylic alcohols by nucleophilic vinylation| author = Corey, E.J.|author2=Wollenberg, R.H.| journal = J. Org. Chem.| year = 1975| volume = 40| issue = 15| pages = 2265–2266| doi = 10.1021/jo00903a037}}</ref>

:[[File:Li Sn exchange.png|center|550px|Li Sn exchange]]

Organolithium can also be used in to prepare organozinc compounds through transmetalation with zinc salts.<ref name=organozinc>{{cite journal| title = An Improved Method for the Palladium Cross-Coupling Reaction of Oxazol-2-ylzinc Derivatives with Aryl Bromides| author = Reeder, M.R.| journal = Org. Process Res. Dev.| year = 2003| volume = 7| issue = 5| pages = 696–699| doi = 10.1021/op034059c |display-authors=etal}}</ref>

:[[File:Organozincfrom li.png|center|550px|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.<ref name=pathwayofcuprate>{{cite journal| title = Reaction Pathway of the Conjugate Addition of Lithium Organocuprate Clusters to Acrolein| author = Nakamura, E.| journal = J. Am. Chem. Soc.| year = 1997| volume = 119| issue = 21| pages = 4900–4910| doi = 10.1021/ja964209h |display-authors=etal}}</ref>

:[[File:1,4 cuprate addition.png|center|390px|1,4 cuprate addition]]