Zinc Chloride1

ZnCl2

[7646-85-7]  · Cl2Zn  · Zinc Chloride  · (MW 136.29)

(used in the preparation of organozinc reagents via transmetalation;1 a mild Lewis acid useful for promoting cycloaddition,2 substitution,3 and addition reactions,4 including electrophilic aromatic additions;5 has found use in selective reductions6)

Physical Data: mp 293 °C; bp 732 °C; d 2.907 g cm-3.

Solubility: sol H2O (432 g/100 g at 25 °C), EtOH (1 g/1.3 mL), glycerol (1 g/2 mL).

Form Supplied in: white, odorless, very deliquescent granules; principal impurities are H2O and zinc oxychloride.

Analysis of Reagent Purity: melting point.

Purification: reflux (50 g) in dioxane (400 mL) in the presence of Zn0 dust, then filter hot and allow to cool to precipitate purified ZnCl2. Also, anhydrous material may be sublimed under a stream of dry HCl, followed by heating to 400 °C in a stream of dry N2.

Handling, Storage, and Precautions: very hygroscopic; store under anhydrous conditions; moderately irritating to skin and mucous membranes.

Organozinc Reagents.

The transmetalation of organomagnesium, organolithium, and organocopper reagents is an important and versatile method of preparing useful zinc reagents.1a Alternatively, ZnCl2 may be employed for direct insertion of Zn0 into carbon-halogen bonds using Mg0/ultrasound7 or prior reduction with K0.8 The addition of the resulting allylic and propargylic or allenic zinc reagents to carbonyl compounds, imines, and iminium salts represents an important method of selective carbon-carbon bond formation.9,11 These reactions are generally guided by chelation and the Zimmerman-Traxler transition state10 to control the relative stereochemistry about the new carbon-carbon bond (eq 1),12 as well as with respect to preexisting stereocenters (eq 2).13 Anions derived from propargylic deprotonation add to carbonyl compounds with a high degree of regiochemical integrity in the presence of ZnCl2, i.e. allenic organozinc intermediates cleanly afford the propargylic product (eq 3).11b

Alkylzinc reagents, often in the presence of copper salts, effectively participate in conjugate addition reactions14 and clean SN2 reactions (eq 4).15

Organozinc reagents are superior species for palladium- and nickel-catalyzed coupling reactions.16 This offers an exceptional method for the selective formation of sp2-sp3 (eq 5),17 sp2-sp2 (eqs 6 and 7),18,19 and sp2-sp (eq 8)20 carbon-carbon bonds. In addition, the palladium-catalyzed coupling reactions of sp and sp2 halides with vinylalanes (eq 9),21 vinylcuprates,22 vinylzirconium (eq 10)23 and acyliron species24 often proceed more effectively in the presence of ZnCl2. This effect has been noted in other metal-mediated carbon bond formations,25 though the role of this ZnCl2 catalysis is not understood at present.

Organozinc reagents have been successfully exploited in asymmetric carbon bond formation.26 Chiral glyoxylate esters engage organozinc species derived from Grignard reagents in selective addition reactions to afford enantiomerically enriched a-hydroxy acids (eq 11).27 Enantioselective addition reactions of Grignard reagents have been achieved by sequential addition of ZnCl2 and a chiral catalyst to afford secondary alcohols (eq 12).28

Zinc Enolates.

Zinc enolates can be prepared by deprotonation of carbonyl compounds using standard bases, followed by transmetalation with ZnCl2.1b These enolates offer important opportunities for stereoselective aldol condensations, including higher yields and stereochemical selection for threo crossed-aldol products (eq 13).29 Both of these consequences are the result of the reversible formation of a six-membered zinc chelate intermediate (1) which favors the anti disposition of its substituents. Though their use has been mostly replaced by kinetically controlled aldol methodology, zinc enolates sometimes present advantages in specific cases.30 For example, chelated zinc enolates derived from a-amino acids have been shown to be of value in the stereoselective synthesis of b-lactams (eq 14).31 Controlled monoalkylation of unsymmetrical ketones has been accomplished via treatment of zinc enolates with a-chlorothio ethers (eq 15),32 and mild allylation of b-dicarbonyl compounds may be realized through exposure of the corresponding zinc enolate to an allyl alcohol in the presence of a palladium catalyst (eq 16).33

Homoenolates.

Readily available mixed Me3Si/alkyl acetals are converted into zinc homoenolates in high yield through exposure to ZnCl2 in Et2O (eq 17).34 These mildly reactive species, which tolerate asymmetry a to the carbonyl, are useful for a variety of bond-forming reactions. In the presence of Me3Si activation they undergo addition to aldehydes and, when admixed with CuBr.DMS (see Copper(I) Bromide), can be allylated or conjugatively introduced to a,b-unsaturated ketones (eq 18).35 Copper salts are not required for conjugate addition to propargylic esters (eq 19).36 These zinc species also participate in useful palladium-catalyzed bond-forming processes (eq 20).37

Cycloaddition Reactions.

Catalysis by ZnCl2 is often a powerful influence on cycloaddition reactions.2 In addition to improving the rate of Diels-Alder reactions, enhanced control over regioselectivity (eq 21)2c and stereochemistry (eq 22)2e may be observed. An exceedingly important application of ZnCl2 catalysis is found in the reaction of electron-rich dienes with carbonyl compounds.2a,b Intensive mechanistic studies on these reactions has uncovered two mechanistic pathways that afford stereochemically contrasting products, depending upon which Lewis acid is employed (eq 23).38 It was concluded that cycloaddition reactions catalyzed by ZnCl2 proceed via a classical [4 + 2] concerted process, whereas Lewis acids such as Boron Trifluoride Etherate and Titanium(IV) Chloride afford products through sequential aldol/cyclization processes. Examples abound wherein advantage has been taken of the predictable Cram-Felkin selectivity of this ZnCl2 catalysis to exploit asymmetric variants of this reaction to synthesize a variety of natural products (eq 24).39 The selective cycloaddition of electron-rich dienes with imines has also been catalyzed by ZnCl2 (eq 25).40

Activation of C=X Bonds.

The mild Lewis acid character of ZnCl2 is frequently exploited to promote the addition of various nucleophiles to carbon-heteroatom double bonds.4 The well-established Knoevenagel condensation and related reactions have been effectively catalyzed by ZnCl2 (eq 26).41 The addition of enol ethers and ketene acetals to aldehydes and ketones has been noted (eq 27),42 though ZnCl2 has been used less widely in these aldol-type condensations than other Lewis acids, including TiCl4, Magnesium Bromide, and Tin(IV) Chloride, to name a few.4 In some instances, excellent levels of stereocontrol have been observed (eq 28).43 Analogous additions to imines have been noted as well.4e-g,44 Some conjugate addition reactions may also benefit from ZnCl2 catalysis (eq 29).45

The formation of cyanohydrins using Cyanotrimethylsilane and Isoselenocyanatotrimethylsilane has been effectively catalyzed by ZnCl2 (eq 30),46 as has Strecker amino acid synthesis via the treatment of imines with Me3SiCN/ZnCl2.47 The combination of carbonyl compounds with Acetyl Chloride or Acetyl Bromide may be promoted by ZnCl2 to afford protected vicinal halohydrins (eq 31).48

It is noteworthy that the treatment of carbonyl compounds with Chlorotrimethylsilane/ZnCl2 results in a useful synthesis of Me3Si enol ethers which, in turn, may be useful for other carbon bond-forming processes (eq 32).49

Activation of C-X Bonds.

The activation of C-X single bonds toward nucleophilic substitution is also mediated by the Lewis acidic character of ZnCl2.3 Benzylic (eq 33),50 allylic (eq 34),3d,51 propargylic,52 and tertiary halides (eq 35)53 undergo substitution with mild carbon and heteroatom3e nucleophiles.

In a similar fashion, acetals (eq 36)54 and orthoesters (eq 37)55 may be used as electrophiles in substitution reactions with electron-rich alkenic nucleophiles. The combination of ZnCl2 with co-catalysts has sometimes proven advantageous in these reactions (eq 38).56

The regioselective ring opening reactions of epoxides (eq 39),57,58 oxetanes,58 and tetrahydrofurans (eq 40)59 has been promoted by ZnCl2 to afford adducts with suitable nucleophiles.

Activation by ZnCl2 of allylic (eq 41)60 and propargylic chlorides (eq 42),61 as well as a-chloroenamines (eq 43),62 in the presence of simple alkenes has been shown to yield four-membered and five-membered cycloadducts.

Chlorination of alcohols by Thionyl Chloride,63 the preparation of acyl chlorides from lactones and anhydrides,64 and the bromination and iodination of aromatic rings by Benzyltrimethylammonium Tribromide and Benzyltrimethylammonium Dichloroiodate, respectively,65 are all effectively catalyzed by the presence of ZnCl2. In addition, ZnCl2 acts as a source of chloride for the halogenation of primary, secondary, and allylic alcohols using Triphenylphosphine-Diethyl Azodicarboxylate.66

Reduction.

The very useful reducing agent Zinc Borohydride is prepared by exposure of NaBH4 to ZnCl2 in ether solvents.67 Its use in selective reductions is described elsewhere.6a A complex reducing agent resulting from the mixture of NaH/t-pentyl-OH/ZnCl2, given the acronym ZnCRA (Zinc Complex Reducing Agents), is found to open epoxides in a highly regioselective fashion, favoring hydride delivery at the least hindered position.68 A related reagent, ZnCRASi, which includes Me3SiCl in the mixture, selectively reduces ketones in high yield, though the levels of selectivity do not compete with other selective reagents.69

The reduction of ketones and aldehydes by silicon and tin hydrides in the presence of ZnCl2 has been documented.70 In the presence of Pd0 catalysts and ZnCl2, these hydrides selectively reduce a,b-unsaturated aldehydes and ketones to the corresponding saturated products (eq 44).71 The presence of ZnCl2 has been shown to modify the reactivity of several common reducing agents. For example, the mixture of Sodium Cyanoborohydride and ZnCl2 selectively reduces tertiary, allylic, and benzylic halides (eq 45),72 Sodium Borohydride, in the presence of ZnCl2 and PhNMe2 will reduce aryl esters to primary alcohols,73 and Lithium Aluminum Hydride with ZnCl2/CuCl2 desulfurizes dithianes (eq 46).74

Stereoselectivity is also modified by the presence of ZnCl2 (eq 47).75 Enantioselective reduction of aryl ketones has been observed with Diisobutylaluminum Hydride (DIBAL) modified by ZnCl2 and chiral diamine ligands (eq 48).76

Protection/Deprotection.

The acetylation of carbohydrates and other alcohols has been realized using Acetic Anhydride/ZnCl2 (eq 49).77 It is found that ZnCl2 imparts selectivity to both acetylation78 and acetonide formation79 of polyols, which is useful in the synthetic manipulation of carbohydrates. Synthetically useful selective deprotection of acetates (eq 50)80 and dimethyl acetals (eq 51)81 has been reported to be mediated by ZnCl2.

Acylation.

Unsaturated esters are obtained through acylation of alkenes by anhydrides using activation by ZnCl2 (eq 52).82 The mixture of RCOCl/ZnCl2 is effective in the acylation of silyl enol ethers to afford b-dicarbonyl products (eq 53).83 Friedel-Crafts acylation is catalyzed by ZnCl2, using anhydrides or acyl halides as the electrophiles (eqs 54 and 55).84,85

Aromatic Substitution.

Several important classes of aromatic substitutions are mediated by ZnCl2, including the Hoesch reaction (eq 56)86 and the Fischer indole synthesis (eq 57).87 Haloalkylation of aromatic rings using Formaldehyde or Chloromethyl Methyl Ether is readily accomplished through the agency of ZnCl2 and warming (eq 58).88

Related Reagents.

Aluminum Chloride; Diphenylsilane-Tetrakis(triphenylphosphine)palladium(0)-Zinc Chloride; Phosphorus(III) Chloride-Zinc(II) Chloride; Phosphorus Oxychloride-Zinc(II) Chloride; Tin(IV) Chloride; Tin(IV) Chloride-Zinc Chloride; Titanium(IV) Chloride.


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83. Tirpak, R. E.; Rathke, M. W. JOC 1982, 47, 5099. See also: Reetz, M. T.; Kyung, S.-H. TL 1985, 26, 6333.
84. Cooper, S. R. OSC 1955, 3, 761. See also: Baddeley, G.; Williamson, R. JCS 1956, 4647. See also: Zani, C. L.; de Oliveira, A. B.; Snieckus, V. TL 1987, 28, 6561.
85. Dike, S. Y.; Merchant, J. R.; Sapre, N. Y. T 1991, 47, 4775. See also: (a) Shah, V. R.; Bose, J. L.; Shah, R. C. JOC 1960, 25, 677. (b) Dallacker, F.; Kratzer, P.; Lipp, M. LA 1961, 643, 97.
86. Ref. 5a and Ruske, W. In Friedel-Crafts and Related Reactions; Olah, G. A., Ed.; Interscience: New York, 1964, Vol. 3, p 383.
87. Ref. 5c and (a) Shriner, R. L.; Ashley, W. C.; Welch, E. OSC 1955, 3, 725. (b) Prochazki, M. P.; Cartson, R. ACS 1989, 43, 651.
88. Ref. 5b and Olah, G. A.; Tolgyesi, W. S. In Friedel-Crafts and Related Reactions; Olah, G. A., Ed.; Interscience: New York, 1964, Vol. 2, p 659.

Glenn J. McGarvey

University of Virginia, Charlottesville, VA, USA



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