View source for Organozinc chemistry

{{Use dmy dates|date=June 2023}}
[[File:OrganozincLogo.png|150px|right|thumb|Organozinc chemistry]]
'''Organozinc chemistry''' is the study of the physical properties, synthesis, and reactions of '''organozinc compounds''', which are [[organometallic compounds]] that contain [[carbon]] (C) to [[zinc]] (Zn) [[chemical bond]]s.<ref>{{cite book | doi = 10.1002/0471264180.or058.02| title = Organic Reactions| year = 2004| last1 = Knochel| first1 = Paul| last2 = Millot| first2 = Nicolas| last3 = Rodriguez| first3 = Alain L.| last4 = Tucker| first4 = Charles E.| isbn = 0471264180}}</ref><ref name= wiley>''[http://www.wiley.com/WileyCDA/WileyTitle/productCd-0470093374.html The Chemistry of Organozinc Compounds]'' (Patai Series: [http://www.wiley.com/WileyCDA/Section/id-11128.html The Chemistry of Functional Groups]), (Eds. Z. Rappoport and I. Marek), John Wiley & Sons: Chichester, UK, '''2006''', {{ISBN|0-470-09337-4}}.</ref><ref name=knochel>''Organozinc reagents – A Practical Approach'', (Eds. P. Knochel and P. Jones), Oxford Medical Publications, Oxford, '''1999''', {{ISBN|0-19-850121-8}}.</ref><ref>''Synthetic Methods of Organometallic and Inorganic Chemistry Vol 5, Copper, Silver, Gold, Zinc, Cadmium, and Mercury'', W.A. Herrmann Ed., {{ISBN|3-13-103061-5}}</ref>

Organozinc compounds were among the first organometallic compounds made. They are less reactive than many other analogous organometallic reagents, such as [[Grignard reaction|Grignard]] and [[organolithium reagent]]s. In 1848 [[Edward Frankland]] prepared the first organozinc compound, [[diethylzinc]], by heating [[ethyl iodide]] in the presence of zinc metal.<ref name= frankland>E. Frankland, Liebigs Ann. Chem.,1849, 71, 171</ref> This reaction produced a volatile colorless liquid that spontaneous combusted upon contact with air. Due to their [[pyrophoric]] nature, organozinc compounds are generally prepared using [[air-free technique]]s. They are unstable toward [[protic solvents]]. For many purposes they are prepared [[in situ]], not isolated, but many have been isolated as pure substances and thoroughly characterized.<ref>Elschenbroich, C. "Organometallics" (2006) Wiley-VCH: Weinheim. {{ISBN|978-3-527-29390-2}}</ref>

Organozincs can be categorized according to the number of carbon substituents that are bound to the metal.<ref name= wiley/><ref name="knochel"/>
# Diorganozinc ({{chem2|R2Zn}}): A class of organozinc compounds in which two alkyl ligands. These may be further divided into subclasses depending on the other [[ligands]] attached 
# Heteroleptic (RZnX): Compounds which an [[electronegative]] or monoanionic ligand (X), such as a [[halide]], is attached to the zinc center with another alkyl or aryl substituent (R).
# Ionic organozinc compounds: This class is divided into organozincates ({{chem2|R_{''n''}Zn−}}) and organozinc [[cations]] ({{chem|RZnL|''n''|+}}).

==Bonding==
In its [[coordination complexes]] zinc(II) adopts several coordination geometries, commonly [[octahedral]], [[tetrahedral]], and various pentacoordinate geometries. These structural flexibility can be attributed to zinc's [[electronic configuration]] [Ar]3d<sup>10</sup>4s<sup>2</sup>. The 3d orbital is filled, and therefore, [[ligand field]] effects are nonexistent. Coordination geometry is thus determined largely by electrostatic and steric interactions.<ref name= wiley/> Organozinc compounds usually are two- or three-coordinate, reflecting the strongly donating property of the carbanionic ligands.

Typical diorganozinc complexes have the formula R<sub>2</sub>Zn. Dialkylzinc compounds are monomeric with a linear coordination at the zinc atom.<ref>{{cite journal |author1=John Bacsa |author2=Felix Hanke |author3=Sarah Hindley |author4=Rajesh Odedra |author5=George R. Darling |author6=Anthony C. Jones |author7=Alexander Steiner | title = The Solid State Structures of Dimethylzinc and Diethylzinc | journal = [[Angewandte Chemie International Edition]] | year = 2011 | volume = 50 |issue=49 | pages = 11685–11687 | doi = 10.1002/anie.201105099|pmid=21919175 |pmc=3326375 }}</ref> A [[polar covalent bond]] exists between carbon and zinc, being polarized toward carbon due to the differences in [[electronegativity]] values (carbon: 2.5 & zinc: 1.65). The [[Molecular dipole moment|dipole moment]] of symmetric diorganozinc reagents can be seen as zero in these linear complexes, which explains their solubility in nonpolar solvents like [[cyclohexane]]. Unlike other binary metal alkyls, the diorganozinc species show a low affinity for complexation with [[ether]]eal solvent. Bonding in R<sub>2</sub>Zn is described as employing sp-[[Orbital hybridisation|hybridized]] orbitals on Zn.<ref name= wiley/>

These structures cause zinc to have two bonding d-orbitals and three low-lying non-bonding d-orbitals (see [[non-bonding orbital]]), which are available for binding. When zinc lacks electron donating ligands it is unable to obtain coordination saturation, which is a consequence of the large atomic radius and low electron deficiency of zinc. Therefore, it is rare for bridging alkyl or aryl groups to occur due to the weak electron deficiency of the zinc atom. Although, it does occur in some cases such as Ph<sub>2</sub>Zn (Shown below) and which halogens are the organozinc can form metal clusters (see [[cluster chemistry]]). When a [[halogen]] ligand is added to the zinc atom both the acceptor and donor character of zinc is enhanced allowing for aggregation.<ref name= wiley/>

[[File:Bridging aryl organozinc.png|400px|center|thumb|Saturated diorganozinc reagents with bridging aryl groups]]

==Synthesis==
Several methods exist for the generation of organozinc compounds. Commercially available diorganozinc compounds are [[dimethylzinc]], [[diethylzinc]] and diphenylzinc. These reagents are expensive and difficult to handle. In one study<ref>{{cite journal | doi = 10.1002/anie.200600741| title = From Aryl Bromides to Enantioenriched Benzylic Alcohols in a Single Flask: Catalytic Asymmetric Arylation of Aldehydes| journal = Angewandte Chemie International Edition| volume = 45| issue = 25| pages = 4175–4178| year = 2006| last1 = Kim| first1 = Jeung Gon| last2 = Walsh| first2 = Patrick J.| pmid=16721894| doi-access = free}}</ref><ref>In this [[one-pot reaction]] [[bromobenzene]] is converted to [[phenyllithium]] by reaction with 4 equivalents of [[N-Butyllithium|''n''-butyllithium]], then transmetalation with [[zinc chloride]] forms diphenylzinc which continues to react in an [[asymmetric reaction]] first with the [[MIB ligand]] and then with 2-naphthylaldehyde to the [[Alcohol (chemistry)|alcohol]]. In this reaction formation of diphenylzinc is accompanied by that of [[lithium chloride]], which unchecked, catalyses the reaction without MIB involvement to the [[racemic]] alcohol. The salt is effectively removed by [[chelation]] with [[tetraethylethylene diamine]] (TEEDA) resulting in an [[enantiomeric excess]] of 92%.</ref> the active organozinc compound is obtained from much cheaper [[organobromine compound|organobromine]] precursors:
{{NumBlk|:|<imagemap>File:DiphenylzincCarbonylAddition.png|400px|center|Addition of diphenylzinc to an aldehyde</imagemap>|{{EquationRef|2.1}}}}

===From zinc metal===
Frankland's original synthesis of [[diethylzinc]] involves the reaction of [[ethyl iodide]] with zinc metal. The zinc must be activated to facilitate this redox reaction. One of such activated form of zinc employed by Frankland is [[zinc-copper couple]].<ref name= frankland/>

{{NumBlk|:|2 EtI + 2 Zn<sup>0</sup> → {{chem|Et|2|Zn}} + {{chem|Zn|I|2}}|{{EquationRef|2.2}}}}

[[Rieke metals|Riecke zinc]], produced by in situ reduction of ZnCl<sub>2</sub> with potassium, is another activated form of zinc. This form has proven useful for reactions such as [[Negishi coupling]] and [[Fukuyama coupling]]. Formation of organozinc reagents is facilitated for alkyl or aryl halides bearing electron-withdrawing substituents, e.g., nitriles and esters.<ref>{{cite journal| author=Rieke, R. D.|title=Preparation of Organometallic Compounds from Highly Reactive Metal Powders|journal= [[Science (journal)|Science]]|year= 1989|volume= 246| pages= 1260–1264|doi=10.1126/science.246.4935.1260| pmid=17832221| issue=4935|bibcode = 1989Sci...246.1260R |s2cid=92794}}</ref><ref>{{cite journal | doi = 10.1016/S0022-328X(02)01273-1| title = A genealogy of Pd-catalyzed cross-coupling| journal = Journal of Organometallic Chemistry| volume = 653| issue = 1–2| pages = 34–40| year = 2002| last1 = Negishi| first1 = Ei-Ichi}}</ref>

{{NumBlk|:|<math chem title="Reicke zinc allows for an activated zinc species for oxidative addition">
\ce{{ZnCl2} + 2K ->[\ce{THF}][\ce{-2KCl}]} \overbrace\ce{Zn^0}^\ce{Riecke\ zinc} + \ce{R-X ->[\ce{THF}][20-60^\circ\ce C] R-Zn-I} \qquad
\begin{cases}
\mathbf{R}: &\text{Allyl, Aryl, Alkyl, Benzyl}\\
\mathbf{X}: &\text{Bromide, Iodide}
\end{cases}
</math>|{{EquationRef|2.3}}}}

{{NumBlk|:|<imagemap>File:Zinc coupling.png|320px|center|Using oxidative addition to get Negishi coupling precursors
desc bottom-left</imagemap>|{{EquationRef|2.4}}}}

===Functional group exchange===
The two most common zinc functional group interconversion reactions are with halides and boron, which is catalyzed by [[copper iodide]] (CuI) or base. The boron intermediate is synthesized by an initial [[hydroboration]] reaction followed by treatment with [[diethyl zinc]]. This synthesis shows the utility of organozinc reagents by displaying high selectivity for the most reactive site in the molecule, as well as creating useful coupling partners.<ref name="LangerSchwink1996">{{cite journal|last1=Langer|first1=Falk|last2=Schwink|first2=Lothar|last3=Devasagayaraj|first3=Arokiasamy|last4=Chavant|first4=Pierre-Yves|last5=Knochel|first5=Paul|title=Preparation of Functionalized Dialkylzincs via a Boron−Zinc Exchange. Reactivity and Catalytic Asymmetric Addition to Aldehydes|journal=The Journal of Organic Chemistry|volume=61|issue=23|year=1996|pages=8229–8243|issn=0022-3263|doi=10.1021/jo961129n|pmid=11667810}}</ref>

{{NumBlk|:|<imagemap>File:Functional group exchange.png|470px|center|Organozinc function group exchange with metals or boron reagents
desc top-left</imagemap>|{{EquationRef|2.5}}}}

This group transfer reaction can be used in [[allylation]], or other coupling reactions (such as Negishi coupling).<ref>Naka,H; et al.New J. Chem., 2010, 34, 1700–1706</ref>

{{NumBlk|:|<imagemap>File:Group Transfer Base Diagram.png|500px|center|Hiroshi Naka and coworkers utilized this group transfer reaction to get to the key intermediate</imagemap>|{{EquationRef|2.6}}}}

===β-Silyl diorganozinc compounds===
One of the major drawbacks of diorganozinc alkylations is that only one of the two alkyl substituents is transferred. This problem can be solved by using Me<sub>3</sub>SiCH<sub>2</sub>- (TMSM), which is a non-transferable group.<ref>Knochel,P.; et al. Angel. Chem. Int. Ed. Engl. 1997, volume 36, 1496-1498</ref>

{{NumBlk|:|<math chem title="Knochel and coworkers beta silyl group transfer addition">
\begin{array}{l}
{}\\
\ce{{R2Zn} + (TMSM)2Zn}\ \overset\ce{THF}\ce{<=>>} \ \ce{2R(TMSM)Zn}\\ {}\\
\ce{{RZnI} + (TMSM)Li ->[\ce{THF}][-80^\circ\!\ce C] {R(TMSM)Zn} + LiI}\\ {}
\end{array}
</math>
|{{EquationRef|2.7}}}}

===Transmetallation===
[[Transmetallation]] is similar to the interconversions displayed above zinc can exchange with other metals such as [[Mercury (element)|mercury]], [[lithium]], [[copper]], etc. One example of this reaction is the reaction of [[diphenylmercury]] with zinc metal to form [[diphenylzinc]] and metallic [[Mercury (element)|mercury]]:
{{NumBlk|:|HgPh<sub>2</sub> + Zn → ZnPh<sub>2</sub> + Hg|{{EquationRef|2.8}}}}

The benefit of transmetalling to zinc it is often more tolerant of other functional groups in the molecule due to the low reactivity which increases selectivity.<ref>{{cite journal | last1 = Markies | first1 = P | doi = 10.1016/0022-328X(92)80090-K | title = Complexation of diphenylzinc with simple ethers. Crystal structures of the complexes Ph<sub>2</sub>Zn·glyme and Ph2Zn·diglyme | year = 1992 | pages = 1–13 | volume = 430 | journal = [[J. Organomet. Chem.]] | last2 = Schat | first2 = Gerrit | last3 = Akkerman | first3 = Otto S. | last4 = Bickelhaupt | first4 = F. | last5 = Spek | first5 = Anthony L.}}</ref>
*In the synthesis of Maoecrystal V, a [[directed ortho metalation]] gives the initial aryl-lithium species, which is transmetallated to the desired arylzinc compound. The arylzinc compound is significantly less reactive than the aryl-lithium species and thus better tolerates the functionality in the subsequent coupling with methyl chlorooxaloacetate. [[Esters]] are significantly stable against organozinc reagents.<ref>{{cite journal | doi = 10.1021/ja408231t| pmid = 24047444| title = Total Synthesis of Maoecrystal V: Early-Stage C–H Functionalization and Lactone Assembly by Radical Cyclization| journal = Journal of the American Chemical Society| volume = 135| issue = 39| pages = 14552–5| year = 2013| last1 = Lu| first1 = Ping| last2 = Gu| first2 = Zhenhua| last3 = Zakarian| first3 = Armen| pmc=4118676}}</ref>

{{NumBlk|:|<imagemap>File:Maoecrystal V transmetallation.png|530px|center|Zakarian's synthesis of Maoecrystal V utilized an early stage zinc transmetallation to tolerate functionality</imagemap>|{{EquationRef|2.9}}}}

Organozinc can be obtained directly from zinc metal:<ref>{{cite journal | doi = 10.1002/anie.200601450| title = Efficient Synthesis of Functionalized Organozinc Compounds by the Direct Insertion of Zinc into Organic Iodides and Bromides| journal = Angewandte Chemie International Edition| volume = 45| issue = 36| pages = 6040–6044| year = 2006| last1 = Krasovskiy| first1 = Arkady| last2 = Malakhov| first2 = Vladimir| last3 = Gavryushin| first3 = Andrei| last4 = Knochel| first4 = Paul| pmid=16900548}}</ref><ref>In this example the arylzinc iodide continues to react with [[allyl bromide]] in a [[nucleophilic displacement]]</ref> 
{{NumBlk|:|<imagemap>File:OrganozincSynthesisbyDirectInsertion.png|400px|center|Organozinc Synthesis by Direct Insertion</imagemap>|{{EquationRef|2.10}}}}
:In this method zinc is activated by [[1,2-dibromoethane]] and [[trimethylsilyl chloride]]. A key ingredient is [[lithium chloride]] which quickly forms a soluble adduct with the organozinc compound thus removing it from the metal surface.

==Reactions==
In many of their reactions organozincs appear as intermediates.
* In the '''Frankland–Duppa reaction''' (1863) an [[oxalate]] ester (ROCOCOOR) reacts with an [[alkyl halide]] R'X, zinc and [[hydrochloric acid]] to the α-hydroxycarboxylic esters RR'COHCOOR<ref>{{cite book | title = Merck Index | year = 2001 | url = https://archive.org/details/merckindexency00onei | url-access = registration | publisher = Merck & Co. | isbn = 9780911910131 | id = Frankland–Duppa reaction}}</ref>

===Reformatsky reaction===
This organic reaction can be employed to convert α-haloester and [[ketone]] or [[aldehyde]] to a β-hydroxyester. Acid is needed to protonate the resulting [[alkoxide]] during work up. The initial step is an oxidative addition of zinc metal into the carbon-halogen bond, thus forming a carbon-zinc enolate. This C-Zn [[enolate]] can then rearrange to the Oxygen-Zinc enolate via coordination. Once this is formed the other carbonyl containing starting material will coordinate in the manner shown below and give the product after protonation.<ref>{{cite journal | doi = 10.1055/s-1989-27326| title = Recent Advancements in the Reformatsky Reaction| journal = Synthesis| volume = 1989| issue = 8| pages = 571–590| year = 1989| last1 = Fürstner| first1 = Alois| s2cid = 94339252}})</ref> The benefits of the [[Reformatsky reaction]] over the conventional [[aldol reaction]] protocols is the following:
# Allows for exceedingly derivatized ketone substrates 
# The ester [[enolate]] intermediate can be formed in the presence of enolizable moieties 
# Well suited for [[intramolecular reaction]]s
Below shows the six-membered transition state of the Zimmerman–Traxler model (Chelation Control, see [[Aldol reaction]]), in which R<sup>3</sup> is smaller than R<sup>4</sup>.<ref name=Kurti>Kurti, L.; Czako, B. ''Strategic Applications of Named Reactions in Organic Synthesis''; Elsevier: Burlington, 2005.</ref>

{{NumBlk|:|<imagemap>File:Reformatsky Rxn.png|600px|center|Basic mechanistic scheme of the Reformatsky reaction</imagemap>|{{EquationRef|3.1}}}}

The Reformatsky reaction has been employed in numerous total syntheses such as the synthesis of C(16),C(18)-bis-epi-cytochalasin D:<ref>{{cite journal | doi = 10.1021/jo000533q| pmid = 10987942| title = A Synthesis of C(16),C(18)-Bis-epi-cytochalasin D via Reformatsky Cyclization| journal = The Journal of Organic Chemistry| volume = 65| issue = 19| pages = 6073–81| year = 2000| last1 = Vedejs| first1 = E.| last2 = Duncan| first2 = S. M.}}</ref>

{{NumBlk|:|<imagemap>File:Reformatskytotsynth.png|650px|center|E. Vedejs total synthesis of C(16),C(18)-bis-epi-cytochalasin D uses a late stage Reformatsky reaction to access the natural product
desc bottom-left</imagemap>|{{EquationRef|3.2}}}}

The Reformatsky reaction even allows for with zinc homo-enolates.<ref>Kumwaijima,I.; et al. J. Am. Chem. 1987, 109, 8056</ref> A modification of the Reformatsky reaction is the [[Blaise reaction]].<ref name="Kurti"/>

{{NumBlk|:|<imagemap>File:Blaise Reaction.png|600px|center|Scheme for the organozinc Blaise reaction, which utilizes an alpha-haloester and a functionalized cyano group
desc top-left</imagemap>|{{EquationRef|3.3}}}}

===Simmons–Smith reaction===
The [[Simmons–Smith reaction|Simmons–Smith]] reagent is used to prepare cyclopropanes from olefin using [[methylene iodide]] as the methylene source. The reaction is effected with zinc. The key zinc-intermediate formed is a [[carbenoid]] (iodomethyl)zinc iodide which reacts with alkenes to afford the cyclopropanated product. The rate of forming the active zinc species is increased via ultrasonication since the initial reaction occurs at the surface of the metal.

{{NumBlk|:|<math chem title="Basic scheme for the Simmons-smith reaction">
2\, {\color{Red}\ce{CH2I2}} + 2\, {\color{Blue}\ce{Zn}} 
\ \ce{-> 2}\,  
{\color{Red}\ce{ICH2}}{\color{Blue}\ce{ZnI}} 
\ \ce{<=>}\  
{\color{Red}\ce{(ICH2)2}}{\color{Blue}\ce{Zn}} + {\color{Blue}\ce{Zn}}{\color{Red}\ce{I2}}
</math>|{{EquationRef|3.4}}}}

{{NumBlk|:|<imagemap>File:Butterfly ts.png|400px|center|The butterfly TS for the Barbier reaction</imagemap>|{{EquationRef|3.5}}}}

Although the mechanism has not been fully elaborated it is hypothesized that the organozinc intermediate is a metal-[[carbenoid]]. The intermediate is believed to be a three-centered "butterfly-type". This intermediate can be directed by substituents, such as alcohols, to deliver the cyclopropane on the same side of the molecule. [[Zinc-copper couple]] is commonly used to activate zinc.<ref name="Kurti"/>

{{NumBlk|:|<imagemap>File:Simmons-smith-example.png|370px|center|Directing groups aid in the selectivity of the Simmons–Smith reaction
desc top-right</imagemap>|{{EquationRef|3.6}}}}

===Titanium–zinc methylidenation===
Organozinc compounds derived from [[methylene bromide]] or [[diiodomethane|iodide]] can [[electrophile|electrophilically]] add to [[carbonyl]] groups to form terminal [[alkene]]s.<ref>{{cite journal|last1=Takai|first1=Kazuhiko|last2=Hotta|first2=Yuji|last3=Oshima|first3=Koichiro|last4=Nozaki|first4=Hitosi|title=Wittig-type Reaction of Dimetallated Carbodianion Species as Produced by Zinc Reduction of gem-Polyhalogen Compounds in the Presence of Lewis Acids|journal=Bulletin of the Chemical Society of Japan|date=1980|volume=53|issue=6|pages=1698–1702|doi=10.1246/bcsj.53.1698|doi-access=free}}</ref> The reaction is mechanistically related to the [[Tebbe's reagent#Scope|Tebbe reaction]] and can be catalyzed by various [[Lewis acids]] (e.g. [[Titanium tetrachloride|TiCl<sub>4</sub>]] or [[Trimethylaluminium|Al<sub>2</sub>Me<sub>6</sub>]]).<ref>{{cite book|last1=Trost|first1=Barry|last2=Fleming|first2=Ian|last3=Schreiber|first3=Stuart|chapter=Transformation of the Carbonyl Group into Nonhydroxylic Groups|title=Comprehensive Organic Synthesis Volume 1: Additions to CX π-Bonds, Part 1|date=1991|publisher=Pergamon Press|location=New York|isbn=9780080405926|pages=749–751|edition=1st|doi=10.1016/B978-0-08-052349-1.00020-2}}</ref> The reaction is used to introduce [[deuterium]] into molecules for [[isotopic labeling]] or as an alternative to the [[Wittig reaction]].

===Negishi coupling===
This powerful carbon-carbon bond forming [[cross-coupling reaction]]s combines an organic halide and an organozinc halide reagent in the presence of a nickel or [[palladium catalyst]]. The organic halide reactant can be [[alkenyl]], [[aryl]], [[allyl]], or [[propargyl]]. Alkylzinc coupling with alkyl halides such as bromides and chlorides have also been reported with active catalysts such as Pd-PEPPSI precatalysts, which strongly resist beta-hydride elimination (a common occurrence with alkyl substituents).<ref>S. Sase, M. Jaric, A. Metzger, V. Malakhov, P. Knochel, J. Org. Chem., 2008, 73, 7380-7382</ref> Either diorganic{{typo help inline|reason=similar to disorganic|date=November 2019}} species or organozinc halides can be used as coupling partners during the transmetallation step in this reaction. Despite the low reactivity of organozinc reagents on organic electrophiles, these reagents are among the most powerful metal nucleophiles toward palladium.<ref>{{cite journal | doi = 10.1002/anie.200500368| pmid = 15991198| title = Palladium-Catalyzed Cross-Coupling Reactions in Total Synthesis| journal = Angewandte Chemie International Edition| volume = 44| issue = 29| pages = 4442–4489| year = 2005| last1 = Nicolaou| first1 = K. C.| last2 = Bulger| first2 = Paul G.| last3 = Sarlah| first3 = David}})</ref>

Alkylzinc species require the presence of at least a stoichiometric amount of halide ions in solution to form a "zincate" species of the form RZnX<sub>3</sub><sup>2−</sup>, before it can undergo transmetalation to the palladium centre.<ref>{{cite journal | last1 = McCann | first1 = L. C. | last2 = Hunter | first2 = H. N. | last3 = Cyburne | first3 = J. A. C. | last4 = Organ | first4 = M. G | year = 2012 | title = Higher-Order Zincates as Transmetalators in Alkyl-Alkyl Negishi Cross-Coupling| doi = 10.1002/anie.201203547 | journal = Angew. Chem. Int. Ed. | volume = 51 | issue = 28| pages = 7024–7027 | pmid=22685029}}</ref> This behavior contrasts greatly with the case of aryl zinc species. A key step in the [[catalytic cycle]] is a [[transmetalation]] in which a zinc halide exchanges its organic substituent for another halogen with the metal center.

An elegant example of [[Negishi coupling]] is Furstner's synthesis of amphidinolide T1:<ref>{{cite journal | doi = 10.1021/ja038216z| pmid = 14664598| title = Total Syntheses of Amphidinolide T1, T3, T4, and T5| journal = Journal of the American Chemical Society| volume = 125| issue = 50| pages = 15512–20| year = 2003| last1 = Aïssa| first1 = Christophe| last2 = Riveiros| first2 = Ricardo| last3 = Ragot| first3 = Jacques| last4 = Fürstner| first4 = Alois}}</ref>
{{NumBlk|:|<imagemap>File:Amphidinolide T1 Negishi.png|700px|center|Negishi Cross coupling reaction in the total synthesis of Amphidinolide T1</imagemap>|{{EquationRef|3.7}}}}

===Fukuyama coupling===
[[Fukuyama coupling]] is a palladium-catalyzed reaction involving the coupling of an aryl, alkyl, allyl, or α,β- unsaturated [[thioester]] compound. This thioester compound can be coupled to a wide range of organozinc reagents in order to reveal the corresponding ketone product. This protocol is useful due to its sensitivity to functional groups such as [[ketone]], [[acetate]], aromatic halides, and even aldehydes. The chemoselectivity observed indicates ketone formation is more facile than oxidative addition of palladium into these other moieties.<ref>{{cite journal | doi = 10.1016/S0040-4039(98)00456-0| title = A novel ketone synthesis by a palladium-catalyzed reaction of thiol esters and organozinc reagents| journal = Tetrahedron Letters| volume = 39| issue = 20| pages = 3189–3192| year = 1998| last1 = Tokuyama| first1 = Hidetoshi| last2 = Yokoshima| first2 = Satoshi| last3 = Yamashita| first3 = Tohru| last4 = Fukuyama| first4 = Tohru}}</ref>

{{NumBlk|:|<imagemap>File:Fukuyama Coupling.png|350px|center|Basic scheme for Fukuyama coupling of thioesters
desc top-right</imagemap>|{{EquationRef|3.8}}}}

A further example of this coupling method is the synthesis of (+)-[[biotin]]. In this case, the Fukuyama coupling takes place with the thiolactone:<ref>{{cite journal | doi = 10.1016/S0040-4039(00)00781-4| title = Facile synthesis of (+)-biotin via Fukuyama coupling reaction| journal = Tetrahedron Letters| volume = 41| issue = 26| pages = 5099–5101| year = 2000| last1 = Shimizu| first1 = Toshiaki| last2 = Seki| first2 = Masahiko}}</ref>
{{NumBlk|:|<imagemap>File:(+)-Biotin Fukuyama Coupling.png|600px|center|Total synthesis of (+)-biotin using Fukuyama coupling
desc top-right</imagemap>|{{EquationRef|3.9}}}}

===Barbier reaction===
The [[Barbier reaction]] involves [[nucleophilic addition]] of a carbanion equivalent to a carbonyl. The conversion is similar to the Grignard reaction. The organozinc reagent is generated via an oxidative addition into the alkyl halide. The reaction produces a primary, secondary, or tertiary alcohol via a [[1,2-addition]]. The Barbier reaction is advantageous because it is a one-pot process: the organozinc reagent is generated in the presence of the carbonyl substrate. Organozinc reagents are also less water sensitive, thus this reaction can be conducted in water. Similar to the Grignard reaction, a [[Schlenk equilibrium]] applies, in which the more reactive dialkylzinc can be formed.<ref name="Kurti"/>

{{NumBlk|:|<imagemap>File:Barbier Reaction.png|470px|thumb|center|Basic scheme of the Barbier reaction
desc top-left</imagemap>|{{EquationRef|3.10}}}}

The mechanism resembles the [[Grignard reaction]], in which the metal alkoxide can be generated by a radical stepwise pathway, through [[single electron transfer]], or [[concerted reaction]] pathway via a cyclic transition state. An example of this reaction is in [[Samuel Danishefsky|Danishefsky]]'s synthesis of cycloproparadicicol. By using the organozinc addition reaction conditions the other functionality of the dienone and the alkyne are tolerated:<ref>{{cite journal | doi = 10.1021/ja0484348| pmid = 15212536| title = New Efficient Synthesis of Resorcinylic Macrolides via Ynolides: Establishment of Cycloproparadicicol as Synthetically Feasible Preclinical Anticancer Agent Based on Hsp90 as the Target| journal = Journal of the American Chemical Society| volume = 126| issue = 25| pages = 7881–9| year = 2004| last1 = Yang| first1 = Zhi-Qiang| last2 = Geng| first2 = Xudong| last3 = Solit| first3 = David| last4 = Pratilas| first4 = Christine A.| last5 = Rosen| first5 = Neal| last6 = Danishefsky| first6 = Samuel J.}}</ref>

{{NumBlk|:|<imagemap>File:Barbier-Cycloproparadicicol.png|650px|center|Samuel Danashefskey's total synthesis of cycloproparadiciciol utilizes an early stage Barbier reaction to access the key intermediate
desc top-left</imagemap>.|{{EquationRef|3.11}}}}

===Zinc acetylides===
The formation of the zinc [[acetylide]] proceeds via the intermediacy of a dialkynyl zinc (functional group exchange). Catalytic processes have been developed such as Merck's [[ephedrine]] process.<ref>Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele, L.; Reider, P. J. Synthesis 1999, 1453-1458.</ref> Propargylic alcohols can be synthesized from zinc acetylides. These versatile intermediates can then be used for a wide range of chemical transformations such as [[cross-coupling reaction]]s, [[hydrogenation]], and [[pericyclic reactions]].<ref>{{cite journal | doi = 10.1021/cr00013a004| title = Enantioselective addition of organozinc reagents to aldehydes| journal = Chemical Reviews| volume = 92| issue = 5| pages = 833–856| year = 1992| last1 = Soai| first1 = Kenso| last2 = Niwa| first2 = Seiji}}</ref>

{{NumBlk|:|<imagemap>File:ZnPropargylic alcohols.png|400px|center|Synthesis of zinc propargylic alcohols
desc top-right</imagemap>|{{EquationRef|3.12}}}}

In the absence of ligands, the [[chemical reaction|reaction]] is slow and inefficient. In the presence of [[Asymmetric Addition of Alkynylzinc Compounds to Aldehydes|chiral ligands]], the reaction is fast and gives high conversion. [[Ryoji Noyori]] determined that a monozinc-ligand complex is the active species.<ref>{{cite journal | doi = 10.1002/anie.199100491| title = Enantioselective Addition of Organometallic Reagents to Carbonyl Compounds: Chirality Transfer, Multiplication, and Amplification| journal = Angewandte Chemie International Edition in English| volume = 30| pages = 49–69| year = 1991| last1 = Noyori| first1 = Ryoji| last2 = Kitamura| first2 = Masato}}</ref>

{{NumBlk|:|<imagemap>File:Mono zinc reactive.png|500px|center|Mono zinc is the most reactive species</imagemap>|{{EquationRef|3.13}}}}

[[Diastereoselectivity]] for addition of organozinc reagents into [[aldehydes]] can be predicted by the following model by Noyori and [[David A. Evans]]:<ref>{{cite journal | doi = 10.1126/science.3358127| pmid = 3358127| title = Stereoselective organic reactions: Catalysts for carbonyl addition processes| journal = Science| volume = 240| issue = 4851| pages = 420–6| year = 1988| last1 = Evans| first1 = D.| bibcode = 1988Sci...240..420E}}</ref>

{{NumBlk|:|<imagemap>File:Favored conformer.png|500px|center|Favored conformer for organozinc aldehyde addition</imagemap>|{{EquationRef|3.14}}}}
*The α-[[stereocenter]] of the ligand dictates observed [[stereochemistry]] of the propargylic alcohols
*The [[steric effects]] between the [[aldehyde]] substituent and the ligand are less important but still dictate the favored conformation

Zinc-acetylides are used in the [[HIV-1]] [[reverse transcriptase]] inhibitor [[Efavirenz]] as well as in Merck's [[ephedrine]] derivatives .<ref>Thompson, A. S.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 8937-8940</ref>

{{NumBlk|:|<imagemap>File:Effavirenz & ephedrine.png|350px|center|Merck's Effavirenz and ephedrine derivative synthesized via zinc acetylide</imagemap>|{{EquationRef|3.15}}}}

==Organozincates==
The first organozinc [[ate complex]] ('''organozincate''') was reported in 1858 by [[James Alfred Wanklyn]],<ref>{{cite journal | author = [[J. A. Wanklyn]] | title = Ueber einige neue Aethylverbindungen, welche Alkalimetalle enthalten | journal = [[Liebigs Annalen]] | year = 1858 | volume = 108 | issue = 67| pages = 67–79 | doi = 10.1002/jlac.18581080116 | url = https://zenodo.org/record/1427111}}</ref> an assistant to Frankland and concerned the reaction of elemental [[sodium]] with [[diethylzinc]]:
{{NumBlk|:|2 Na + 3 ZnEt<sub>2</sub> → 2 NaZnEt<sub>3</sub> + Zn|{{EquationRef|4.1}}}}

Organozinc compounds that are strongly [[Lewis acid]]ic are vulnerable to nucleophilic attack by [[alkali metals]], such as [[sodium]], and thus form these 'ate compounds'. Two types of organozincates are recognized: tetraorganozincates ([R<sub>4</sub>Zn]M<sub>2</sub>), which are dianionic, and triorganozincates ([R<sub>3</sub>Zn]M), which are monoanionic. Their structures, which are determined by the ligands, have been extensively characterized.<ref name="knochel"/>

===Synthesis===
'''Tetraorganozincates''' such as [Me<sub>4</sub>Zn]Li<sub>2</sub> can be formed by mixing Me<sub>2</sub>Zn and MeLi in a 1:2 molar ratio of the reactants. Another example synthetic route to forming spriocyclic organozincates is shown below:<ref name="knochel"/>

{{NumBlk|:|<imagemap>File:Tetraorganozincates.png|600px|center|Spirocyclic tetraorganozincate synthesis</imagemap>|{{EquationRef|4.2}}}}

'''Triorganozincates''' compounds are formed by treating a diorganozinc such as (Me<sub>3</sub>SiCH<sub>2</sub>)<sub>2</sub>Zn with an [[alkali metal]] (K), or an [[alkali earth metal]] (Ba, Sr, or Ca). One example is [(Me<sub>3</sub>SiCH<sub>2</sub>)<sub>3</sub>Zn]K.
Triethylzincate degrades to sodium hydridoethylzincate(II) as a result of [[beta-hydride elimination]]:<ref>{{cite journal | doi = 10.1002/anie.200701477| title = Facile Synthesis of Well-Defined Sodium Hydridoalkylzincates(II)| journal = Angewandte Chemie International Edition| volume = 46| issue = 35| pages = 6678–6680| year = 2007| last1 = Lennartson| first1 = Anders| last2 = Håkansson| first2 = Mikael| last3 = Jagner| first3 = Susan| pmid=17665387}}</ref>
{{NumBlk|:|2 NaZnEt<sub>3</sub> → Na<sub>2</sub>Zn<sub>2</sub>H<sub>2</sub>Et<sub>4</sub> + 2 C<sub>2</sub>H<sub>4</sub>|{{EquationRef|4.3}}}}
The product is an edge-shared bitetrahedral structure, with [[bridging ligand|bridging]] [[hydride ligand]]s.

===Reactions===
Although less commonly studied, organozincates often have increased reactivity and selectivity compared to the neutral diorganozinc compounds. They have been useful in stereoselective alkylations of ketones and related carbonyls, ring opening reactions. Aryltrimethylzincates participate in vanadium mediated C-C forming reactions.<ref name="knochel"/>

{{NumBlk|:|<imagemap>File:Organozincate rxn.png|400px|center|One useful organozincate reaction
desc top-left</imagemap>|{{EquationRef|4.4}}}}

==Organozinc(I) compounds==
Low valent organozinc compounds having a Zn–Zn bond are also known. The first such compound, [[decamethyldizincocene]], was reported in 2004.<ref>{{cite journal|doi=10.1002/chem.201000580|pmid=20486240|title=Low-Valent Organometallics-Synthesis, Reactivity, and Potential Applications|year=2010|last1=Schulz|first1=Stephan|journal=Chemistry: A European Journal|volume=16|issue=22|pages=6416–28|url=https://duepublico2.uni-due.de/servlets/MCRFileNodeServlet/duepublico_derivate_00073020/Accepted_Manuscript_Chem_EurJ_2010_16_6416.pdf }}</ref>

== See also ==
* [[Compounds of zinc]]

==References==
{{reflist|30em}}

==External links==
*[http://www.chem.wisc.edu/areas/reich/orgmet/zinc.htm Zinc in organic synthesis]
*[http://www.rznx.basf.com Organozinc Compounds produced by BASF Corporation]
{{ChemicalBondsToCarbon}}

[[Category:Organozinc compounds| ]]