Organozinc chemistry is the study of the physical properties, synthesis, and reactions oforganozinc compounds, which areorganometallic compounds that containcarbon (C) tozinc (Zn)chemical bonds.[1][2][3][4]
Organozinc compounds were among the first organometallic compounds made. They are less reactive than many other analogous organometallic reagents, such asGrignard andorganolithium reagents. In 1848Edward Frankland prepared the first organozinc compound,diethylzinc, by heatingethyl iodide in the presence of zinc metal.[5] This reaction produced a volatile colorless liquid that spontaneous combusted upon contact with air. Due to theirpyrophoric nature, organozinc compounds are generally prepared usingair-free techniques. They are unstable towardprotic solvents. For many purposes they are preparedin situ, not isolated, but many have been isolated as pure substances and thoroughly characterized.[6]
Organozincs can be categorized according to the number of carbon substituents that are bound to the metal.[2][3]
In itscoordination complexes zinc(II) adopts several coordination geometries, commonlyoctahedral,tetrahedral, and various pentacoordinate geometries. These structural flexibility can be attributed to zinc'selectronic configuration [Ar]3d104s2. The 3d orbital is filled, and therefore,ligand field effects are nonexistent. Coordination geometry is thus determined largely by electrostatic and steric interactions.[2] Organozinc compounds usually are two- or three-coordinate, reflecting the strongly donating property of the carbanionic ligands.
Typical diorganozinc complexes have the formula R2Zn. Dialkylzinc compounds are monomeric with a linear coordination at the zinc atom.[7] Apolar covalent bond exists between carbon and zinc, being polarized toward carbon due to the differences inelectronegativity values (carbon: 2.5 & zinc: 1.65). Thedipole moment of symmetric diorganozinc reagents can be seen as zero in these linear complexes, which explains their solubility in nonpolar solvents likecyclohexane. Unlike other binary metal alkyls, the diorganozinc species show a low affinity for complexation withethereal solvent. Bonding in R2Zn is described as employing sp-hybridized orbitals on Zn.[2]
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. Nevertheless, organic bridge ligands occur in Ph2Zn (shownbelow) and certain metal clusters (seecluster chemistry) with organozinc halides. When ahalogen ligand is added to the zinc atom both the acceptor and donor character of zinc is enhanced allowing for aggregation.[2]
Several methods exist for the generation of organozinc compounds. Commercially available diorganozinc compounds aredimethylzinc,diethylzinc and diphenylzinc. These reagents are expensive and difficult to handle. In one study[8][9] the active organozinc compound is obtained from much cheaperorganobromine precursors:
 | 2.1 |
Frankland's original synthesis ofdiethylzinc involves the reaction ofethyl iodide with zinc metal. The zinc must be activated to facilitate this redox reaction. One of such activated form of zinc employed by Frankland iszinc-copper couple.[5]
| 2 EtI + 2 Zn0 →Et 2Zn +ZnI 2 | 2.2 |
Riecke zinc, produced by in situ reduction of ZnCl2 with potassium, is another activated form of zinc. This form has proven useful for reactions such asNegishi coupling andFukuyama coupling. Formation of organozinc reagents is facilitated for alkyl or aryl halides bearing electron-withdrawing substituents, e.g., nitriles and esters.[10][11]
| 2.3 |
 | 2.4 |
The two most common zinc functional group interconversion reactions are with halides and boron, which is catalyzed bycopper iodide (CuI) or base. The boron intermediate is synthesized by an initialhydroboration reaction followed by treatment withdiethyl 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.[12]
 | 2.5 |
This group transfer reaction can be used inallylation, or other coupling reactions (such as Negishi coupling).[13]
 | 2.6 |
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 Me3SiCH2- (TMSM), which is a non-transferable group.[14]
| 2.7 |
Transmetallation is similar to the interconversions displayed above zinc can exchange with other metals such asmercury,lithium,copper, etc. One example of this reaction is the reaction ofdiphenylmercury with zinc metal to formdiphenylzinc and metallicmercury:
| HgPh2 + Zn → ZnPh2 + Hg | 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.[15]
 | 2.9 |
Organozinc can be obtained directly from zinc metal:[17][18]
 | 2.10 |
In many of their reactions organozincs appear as intermediates.
This organic reaction can be employed to convert α-haloester andketone oraldehyde to a β-hydroxyester. Acid is needed to protonate the resultingalkoxide 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-Znenolate 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.[20] The benefits of theReformatsky reaction over the conventionalaldol reaction protocols is the following:
Below shows the six-membered transition state of the Zimmerman–Traxler model (Chelation Control, seeAldol reaction), in which R3 is smaller than R4.[21]
 | 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:[22]
 | 3.2 |
The Reformatsky reaction even allows for with zinc homo-enolates.[23] A modification of the Reformatsky reaction is theBlaise reaction.[21]
 | 3.3 |
TheSimmons–Smith reagent is used to prepare cyclopropanes from olefin usingmethylene iodide as the methylene source. The reaction is effected with zinc. The key zinc-intermediate formed is acarbenoid (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.
| 3.4 |
 | 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.[21]
 | 3.6 |
Organozinc compounds derived frommethylene bromide oriodide canelectrophilically add tocarbonyl groups to form terminalalkenes.[24] The reaction is mechanistically related to theTebbe reaction and can be catalyzed by variousLewis acids (e.g.TiCl4 orAl2Me6).[25] The reaction is used to introducedeuterium into molecules forisotopic labeling or as an alternative to theWittig reaction.
This powerful carbon-carbon bond formingcross-coupling reactions combines an organic halide and an organozinc halide reagent in the presence of a nickel orpalladium catalyst. The organic halide reactant can bealkenyl,aryl,allyl, orpropargyl. 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).[26] Either diorganic[check spelling] 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.[27]
Alkylzinc species require the presence of at least a stoichiometric amount of halide ions in solution to form a "zincate" species of the form RZnX32−, before it can undergo transmetalation to the palladium centre.[28] This behavior contrasts greatly with the case of aryl zinc species. A key step in thecatalytic cycle is atransmetalation in which a zinc halide exchanges its organic substituent for another halogen with the metal center.
An elegant example ofNegishi coupling is Furstner's synthesis of amphidinolide T1:[29]
 | 3.7 |
Fukuyama coupling is a palladium-catalyzed reaction involving the coupling of an aryl, alkyl, allyl, or α,β- unsaturatedthioester 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 asketone,acetate, aromatic halides, and even aldehydes. The chemoselectivity observed indicates ketone formation is more facile than oxidative addition of palladium into these other moieties.[30]
 | 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:[31]
 | 3.9 |
TheBarbier reaction involvesnucleophilic 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 a1,2-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, aSchlenk equilibrium applies, in which the more reactive dialkylzinc can be formed.[21]
 | 3.10 |
The mechanism resembles theGrignard reaction, in which the metal alkoxide can be generated by a radical stepwise pathway, throughsingle electron transfer, orconcerted reaction pathway via a cyclic transition state. An example of this reaction is inDanishefsky's synthesis of cycloproparadicicol. By using the organozinc addition reaction conditions the other functionality of the dienone and the alkyne are tolerated:[32]
 | 3.11 |
The formation of the zincacetylide proceeds via the intermediacy of a dialkynyl zinc (functional group exchange). Catalytic processes have been developed such as Merck'sephedrine process.[33] Propargylic alcohols can be synthesized from zinc acetylides. These versatile intermediates can then be used for a wide range of chemical transformations such ascross-coupling reactions,hydrogenation, andpericyclic reactions.[34]
 | 3.12 |
In the absence of ligands, thereaction is slow and inefficient. In the presence ofchiral ligands, the reaction is fast and gives high conversion.Ryoji Noyori determined that a monozinc-ligand complex is the active species.[35]
 | 3.13 |
Diastereoselectivity for addition of organozinc reagents intoaldehydes can be predicted by the following model by Noyori andDavid A. Evans:[36]
 | 3.14 |
Zinc-acetylides are used in theHIV-1reverse transcriptase inhibitorEfavirenz as well as in Merck'sephedrine derivatives .[37]
 | 3.15 |
The first organozincate complex (organozincate) was reported in 1858 byJames Alfred Wanklyn,[38] an assistant to Frankland and concerned the reaction of elementalsodium withdiethylzinc:
| 2 Na + 3 ZnEt2 → 2 NaZnEt3 + Zn | 4.1 |
Organozinc compounds that are stronglyLewis acidic are vulnerable to nucleophilic attack byalkali metals, such assodium, and thus form these 'ate compounds'. Two types of organozincates are recognized: tetraorganozincates ([R4Zn]M2), which are dianionic, and triorganozincates ([R3Zn]M), which are monoanionic. Their structures, which are determined by the ligands, have been extensively characterized.[3]
Tetraorganozincates such as [Me4Zn]Li2 can be formed by mixing Me2Zn and MeLi in a 1:2 molar ratio of the reactants. Another example synthetic route to forming spriocyclic organozincates is shown below:[3]
 | 4.2 |
Triorganozincates compounds are formed by treating a diorganozinc such as (Me3SiCH2)2Zn with analkali metal (K), or analkali earth metal (Ba, Sr, or Ca). One example is [(Me3SiCH2)3Zn]K.Triethylzincate degrades to sodium hydridoethylzincate(II) as a result ofbeta-hydride elimination:[39]
| 2 NaZnEt3 → Na2Zn2H2Et4 + 2 C2H4 | 4.3 |
The product is an edge-shared bitetrahedral structure, withbridginghydride ligands.
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.[3]
 | 4.4 |
Low valent organozinc compounds having a Zn–Zn bond are also known. The first such compound,decamethyldizincocene, was reported in 2004.[40]
Compounds ofcarbon with other elements in the periodic table | |
|---|---|
| Legend |
|
