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 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 as Grignard and organolithium reagents. In 1848 Edward Frankland prepared the first organozinc compound, diethylzinc, by heating ethyl iodide in the presence of zinc metal.[5] 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 techniques. 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.[6]

Organozincs can be categorized according to the number of carbon substituents that are bound to the metal.[2][3]

  1. Diorganozinc (R2Zn): A class of organozinc compounds in which two alkyl ligands. These may be further divided into subclasses depending on the other ligands attached
  2. 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).
  3. Ionic organozinc compounds: This class is divided into organozincates (RnZn−) and organozinc cations (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]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]

In organozinc compounds, carbon and zinc atoms form a polar covalent bond. The bond is polarized toward carbon due to the differences in electronegativity values (carbon: 2.5 & zinc: 1.65),[2] but still about 85% covalent, comparable to a carbon-tin bond.[7]

Because zinc has a large atomic radius and low electron deficiency, organozinc compounds rarely saturate zinc's coordination sphere. Instead, they are usually two- or three-coordinate, reflecting strong donation from the carbanionic ligands. Diorganozinc species complex ethereal solvents only weakly, and bridging alkyl or aryl groups are rare. Exceptions are Ph2Zn and certain metal clusters:[2]

Organozinc complexes with formula R2Zn are monomeric and linear at the zinc atom,[8] generating sp-hybridization in the molecular orbitals. The symmetric molecules have no dipole moment, and dissolve easily in nonpolar solvents like cyclohexane. When a halogen ligand is added to the zinc atom, the molecule is polarized and both the acceptor and donor character of zinc is enhanced, allowing for aggregation.[2]

Synthesis

Several methods exist for the generation of organozinc compounds. Commercially available diorganozinc compounds are dimethylzinc, diethylzinc and diphenylzinc, but these reagents are expensive and difficult to handle.

From zinc metal

Frankland's original synthesis of diethylzinc involves the reaction of ethyl iodide with zinc metal. Similar to formation of a Grignard reagent, the zinc must be activated to facilitate this redox reaction,[5] and ethereal solvents accelerate the reaction by stabilizing the product.[9] One of such activated form of zinc employed by Frankland is zinc-copper couple:[5]

2 EtI + 2 Zn0 → Et
2Zn + ZnI
2

Alternatively, in situ reduction of ZnCl2 with potassium generates Riecke zinc, another activated form of zinc:[10]

In some cases, a weak Lewis acid, suffices to activate the zinc metal. For example, in the following synthesis, 1,2-dibromoethane and trimethylsilyl chloride catalyze formation of the final organozinc through transmetallation, but a key ingredient is lithium chloride, which quickly forms a soluble adduct with the bromoethylzinc intermediate, removing it from the metal surface:[11][12]

Formation of organozinc reagents is generally facilitated when alkyl or aryl halides bearing electron-withdrawing substituents, e.g., nitriles and esters;[13] these are the first step in the Reformatsky and Blaise reactions.

Zinc-halogen exchange

One of the most common zinc functional group interconversion reactions forms a complicated organozinc compound from exchange of an alkyl halide with a cheaper organozinc:

RI + ZnMe2 → R2Zn + MeI

The reaction requires either copper iodide (CuI) or base catalysis.

Transmetallation

A wide variety of organo-metal and organo-semimetal compounds admit transmetallation to organozincs. One example is the reaction of diphenylmercury with zinc metal to form diphenylzinc and metallic mercury:[9]: 8 

HgPh2 + Zn → ZnPh2 + Hg

As a practical matter, organozinc compounds are most commonly made from metal exchange between a cheap organozinc and organoboron compounds, the latter from an initial hydroboration:[14]

The benefit of transmetalation to zinc is improved functional group tolerance: organozincs are less reactive than many organometals, and consequently selective for the most reactive site in the molecule.

For example, zinc moderates various alkyllithium reagents:

  • 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 ester functionality in the subsequent coupling with methyl chlorooxaloacetate.[15]

Reactions

In many of their reactions organozincs appear as intermediates.

Absent additional activation, diorganozinc compounds are generally too nonpolar to react with carbonyl compounds, but do attack unpolarized C-C multiple bonds.[7]

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[17]

Organozinc compounds can be used in allylation, or other coupling reactions (such as Negishi coupling):[18]

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 trimethylsilylmethyl- (Me3SiCH2-), which is stabilized through negative hyperconjugation in silicon and does not transfer:[19]

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.[20] The benefits of the Reformatsky reaction over the conventional aldol reaction protocols is the following:

  1. Allows for exceedingly derivatized ketone substrates
  2. The ester enolate intermediate can be formed in the presence of enolizable moieties
  3. Well suited for intramolecular reactions

Below shows the six-membered transition state of the Zimmerman–Traxler model (Chelation Control, see Aldol reaction), in which R3 is smaller than R4.[21]

The Reformatsky reaction has been employed in numerous total syntheses such as the synthesis of C(16),C(18)-bis-epi-cytochalasin D:[22]

The Reformatsky reaction even allows for with zinc homo-enolates.[23] A modification of the Reformatsky reaction is the Blaise reaction.[21]

Simmons–Smith reaction

The 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.

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]

Titanium–zinc methylidenation

Organozinc compounds derived from methylene bromide or iodide can electrophilically add to carbonyl groups to form terminal alkenes.[24] The reaction is mechanistically related to the Tebbe reaction and can be catalyzed by various Lewis acids (e.g. TiCl4 or Al2Me6).[25] 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 reactions 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).[26] Either diorganic 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 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:[29]

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.[30]

A further example of this coupling method is the synthesis of (+)-biotin. In this case, the Fukuyama coupling takes place with the thiolactone:[31]

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.[21]

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 Danishefsky's synthesis of cycloproparadicicol. By using the organozinc addition reaction conditions the other functionality of the dienone and the alkyne are tolerated:[32]

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.[33] 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 reactions, hydrogenation, and pericyclic reactions.[34]

In the absence of ligands, the reaction is slow and inefficient. In the presence of chiral ligands, the reaction is fast and gives high conversion. Ryoji Noyori determined that a monozinc-ligand complex is the active species.[35]

Diastereoselectivity for addition of organozinc reagents into aldehydes can be predicted by the following model by Noyori and David A. Evans:[36]

Zinc-acetylides are used in the HIV-1 reverse transcriptase inhibitor Efavirenz as well as in Merck's ephedrine derivatives .[37]

Organozincates

The first organozinc ate complex (organozincate) was reported in 1858 by James Alfred Wanklyn,[38] an assistant to Frankland and concerned the reaction of elemental sodium with diethylzinc:

2 Na + 3 ZnEt2 → 2 NaZnEt3 + Zn

Organozinc compounds that are strongly Lewis acidic are vulnerable to nucleophilic attack by alkali metals, such as sodium, 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]

Synthesis

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]

Triorganozincates compounds are formed by treating a diorganozinc such as (Me3SiCH2)2Zn with an alkali metal (K), or an alkali earth metal (Ba, Sr, or Ca). One example is [(Me3SiCH2)3Zn]K. Triethylzincate degrades to sodium hydridoethylzincate(II) as a result of beta-hydride elimination:[39]

2 NaZnEt3 → Na2Zn2H2Et4 + 2 C2H4

The product is an edge-shared bitetrahedral structure, with bridging hydride ligands.

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.[3]

Organozinc(I) compounds

Low valent organozinc compounds having a Zn–Zn bond are also known. The first such compound, decamethyldizincocene, was reported in 2004.[40]

See also

References

  1. ^ Knochel, Paul; Millot, Nicolas; Rodriguez, Alain L.; Tucker, Charles E. (2004). Organic Reactions. doi:10.1002/0471264180.or058.02. ISBN 0471264180.
  2. ^ a b c d e f The Chemistry of Organozinc Compounds Archived 31 March 2017 at the Wayback Machine (Patai Series: The Chemistry of Functional Groups), (Eds. Z. Rappoport and I. Marek), John Wiley & Sons: Chichester, UK, 2006, ISBN 0-470-09337-4.
  3. ^ a b c d e Organozinc reagents – A Practical Approach, (Eds. P. Knochel and P. Jones), Oxford Medical Publications, Oxford, 1999, ISBN 0-19-850121-8.
  4. ^ 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
  5. ^ a b c E. Frankland, Liebigs Ann. Chem.,1849, 71, 171
  6. ^ Elschenbroich, C. "Organometallics" (2006) Wiley-VCH: Weinheim. ISBN 978-3-527-29390-2
  7. ^ a b Sklute, Genia; Cavender, Hannah; Marek, Ilan (2015). "Carbozincation reactions of carbon-carbon multiple bonds". In Denmark, Scott E. (ed.). Organic Reactions. Vol. 87. Wiley. p. 515. doi:10.1002/0471264180.or087.03.
  8. ^ John Bacsa; Felix Hanke; Sarah Hindley; Rajesh Odedra; George R. Darling; Anthony C. Jones; Alexander Steiner (2011). "The Solid State Structures of Dimethylzinc and Diethylzinc". Angewandte Chemie International Edition. 50 (49): 11685–11687. doi:10.1002/anie.201105099. PMC 3326375. PMID 21919175.
  9. ^ a b Markies, P; Schat, Gerrit; Akkerman, Otto S.; Bickelhaupt, F.; Spek, Anthony L. (1992). "Complexation of diphenylzinc with simple ethers. Crystal structures of the complexes Ph2Zn·glyme and Ph2Zn·diglyme". J. Organomet. Chem. 430: 1. doi:10.1016/0022-328X(92)80090-K.
  10. ^ Rieke, R. D. (1989). "Preparation of Organometallic Compounds from Highly Reactive Metal Powders". Science. 246 (4935): 1260–1264. Bibcode:1989Sci...246.1260R. doi:10.1126/science.246.4935.1260. PMID 17832221. S2CID 92794.
  11. ^ Krasovskiy, Arkady; Malakhov, Vladimir; Gavryushin, Andrei; Knochel, Paul (2006). "Efficient Synthesis of Functionalized Organozinc Compounds by the Direct Insertion of Zinc into Organic Iodides and Bromides". Angewandte Chemie International Edition. 45 (36): 6040–6044. doi:10.1002/anie.200601450. PMID 16900548.
  12. ^ In this example the arylzinc iodide continues to react with allyl bromide in a nucleophilic displacement
  13. ^ Negishi, Ei-Ichi (2002). "A genealogy of Pd-catalyzed cross-coupling". Journal of Organometallic Chemistry. 653 (1–2): 34–40. doi:10.1016/S0022-328X(02)01273-1.
  14. ^ Langer, Falk; Schwink, Lothar; Devasagayaraj, Arokiasamy; Chavant, Pierre-Yves; Knochel, Paul (1996). "Preparation of Functionalized Dialkylzincs via a Boron−Zinc Exchange. Reactivity and Catalytic Asymmetric Addition to Aldehydes". The Journal of Organic Chemistry. 61 (23): 8229–8243. doi:10.1021/jo961129n. ISSN 0022-3263. PMID 11667810.
  15. ^ Lu, Ping; Gu, Zhenhua; Zakarian, Armen (2013). "Total Synthesis of Maoecrystal V: Early-Stage C–H Functionalization and Lactone Assembly by Radical Cyclization". Journal of the American Chemical Society. 135 (39): 14552–5. Bibcode:2013JAChS.13514552L. doi:10.1021/ja408231t. PMC 4118676. PMID 24047444.
  16. ^ Kim, Jeung Gon; Walsh, Patrick J. (2006). "From Aryl Bromides to Enantioenriched Benzylic Alcohols in a Single Flask: Catalytic Asymmetric Arylation of Aldehydes". Angewandte Chemie International Edition. 45 (25): 4175–4178. doi:10.1002/anie.200600741. PMID 16721894.
  17. ^ Merck Index. Merck & Co. 2001. ISBN 9780911910131. Frankland–Duppa reaction.
  18. ^ Naka, H.; et al.New J. Chem., 2010, 34, 1700–1706
  19. ^ Knochel,P.; et al. Angel. Chem. Int. Ed. Engl. 1997, volume 36, 1496-1498
  20. ^ Fürstner, Alois (1989). "Recent Advancements in the Reformatsky Reaction". Synthesis. 1989 (8): 571–590. doi:10.1055/s-1989-27326. S2CID 94339252.)
  21. ^ a b c d Kurti, L.; Czako, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier: Burlington, 2005.
  22. ^ Vedejs, E.; Duncan, S. M. (2000). "A Synthesis of C(16),C(18)-Bis-epi-cytochalasin D via Reformatsky Cyclization". The Journal of Organic Chemistry. 65 (19): 6073–81. doi:10.1021/jo000533q. PMID 10987942.
  23. ^ Kumwaijima,I.; et al. J. Am. Chem. 1987, 109, 8056
  24. ^ Takai, Kazuhiko; Hotta, Yuji; Oshima, Koichiro; Nozaki, Hitosi (1980). "Wittig-type Reaction of Dimetallated Carbodianion Species as Produced by Zinc Reduction of gem-Polyhalogen Compounds in the Presence of Lewis Acids". Bulletin of the Chemical Society of Japan. 53 (6): 1698–1702. doi:10.1246/bcsj.53.1698.
  25. ^ Trost, Barry; Fleming, Ian; Schreiber, Stuart (1991). "Transformation of the Carbonyl Group into Nonhydroxylic Groups". Comprehensive Organic Synthesis Volume 1: Additions to CX π-Bonds, Part 1 (1st ed.). New York: Pergamon Press. pp. 749–751. doi:10.1016/B978-0-08-052349-1.00020-2. ISBN 9780080405926.
  26. ^ S. Sase, M. Jaric, A. Metzger, V. Malakhov, P. Knochel, J. Org. Chem., 2008, 73, 7380-7382
  27. ^ Nicolaou, K. C.; Bulger, Paul G.; Sarlah, David (2005). "Palladium-Catalyzed Cross-Coupling Reactions in Total Synthesis". Angewandte Chemie International Edition. 44 (29): 4442–4489. doi:10.1002/anie.200500368. PMID 15991198.)
  28. ^ McCann, L. C.; Hunter, H. N.; Cyburne, J. A. C.; Organ, M. G (2012). "Higher-Order Zincates as Transmetalators in Alkyl-Alkyl Negishi Cross-Coupling". Angew. Chem. Int. Ed. 51 (28): 7024–7027. doi:10.1002/anie.201203547. PMID 22685029.
  29. ^ Aïssa, Christophe; Riveiros, Ricardo; Ragot, Jacques; Fürstner, Alois (2003). "Total Syntheses of Amphidinolide T1, T3, T4, and T5". Journal of the American Chemical Society. 125 (50): 15512–20. Bibcode:2003JAChS.12515512A. doi:10.1021/ja038216z. PMID 14664598.
  30. ^ Tokuyama, Hidetoshi; Yokoshima, Satoshi; Yamashita, Tohru; Fukuyama, Tohru (1998). "A novel ketone synthesis by a palladium-catalyzed reaction of thiol esters and organozinc reagents". Tetrahedron Letters. 39 (20): 3189–3192. doi:10.1016/S0040-4039(98)00456-0.
  31. ^ Shimizu, Toshiaki; Seki, Masahiko (2000). "Facile synthesis of (+)-biotin via Fukuyama coupling reaction". Tetrahedron Letters. 41 (26): 5099–5101. doi:10.1016/S0040-4039(00)00781-4.
  32. ^ Yang, Zhi-Qiang; Geng, Xudong; Solit, David; Pratilas, Christine A.; Rosen, Neal; Danishefsky, Samuel J. (2004). "New Efficient Synthesis of Resorcinylic Macrolides via Ynolides: Establishment of Cycloproparadicicol as Synthetically Feasible Preclinical Anticancer Agent Based on Hsp90 as the Target". Journal of the American Chemical Society. 126 (25): 7881–9. Bibcode:2004JAChS.126.7881Y. doi:10.1021/ja0484348. PMID 15212536.
  33. ^ Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele, L.; Reider, P. J. Synthesis 1999, 1453-1458.
  34. ^ Soai, Kenso; Niwa, Seiji (1992). "Enantioselective addition of organozinc reagents to aldehydes". Chemical Reviews. 92 (5): 833–856. doi:10.1021/cr00013a004.
  35. ^ Noyori, Ryoji; Kitamura, Masato (1991). "Enantioselective Addition of Organometallic Reagents to Carbonyl Compounds: Chirality Transfer, Multiplication, and Amplification". Angewandte Chemie International Edition in English. 30: 49–69. doi:10.1002/anie.199100491.
  36. ^ Evans, D. (1988). "Stereoselective organic reactions: Catalysts for carbonyl addition processes". Science. 240 (4851): 420–6. Bibcode:1988Sci...240..420E. doi:10.1126/science.3358127. PMID 3358127.
  37. ^ Thompson, A. S.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 8937-8940
  38. ^ J. A. Wanklyn (1858). "Ueber einige neue Aethylverbindungen, welche Alkalimetalle enthalten". Liebigs Annalen. 108 (67): 67–79. doi:10.1002/jlac.18581080116.
  39. ^ Lennartson, Anders; Håkansson, Mikael; Jagner, Susan (2007). "Facile Synthesis of Well-Defined Sodium Hydridoalkylzincates(II)". Angewandte Chemie International Edition. 46 (35): 6678–6680. doi:10.1002/anie.200701477. PMID 17665387.
  40. ^ Schulz, Stephan (2010). "Low-Valent Organometallics-Synthesis, Reactivity, and Potential Applications" (PDF). Chemistry: A European Journal. 16 (22): 6416–28. doi:10.1002/chem.201000580. PMID 20486240.
This article is issued from Wikipedia. The text is available under Creative Commons Attribution-Share Alike 4.0 unless otherwise noted. Additional terms may apply for the media files.