Copper(II) Chloride

CuCl2

[7447-39-4]  · Cl2Cu  · Copper(II) Chloride  · (MW 134.45) (.2H2O)

[10125-13-0]  · Cl2CuH4O2  · Copper(II) Chloride  · (MW 170.48)

(chlorinating agent; oxidizing agent; Lewis acid)

Physical Data: anhydrous: d 3.386 g cm-3; mp 620 °C (reported mp of 498 °C actually describes a mixture of CuCl2 and CuCl); partially decomposes above 300 °C to CuCl and Cl2; dihydrate d 2.51 g cm-3; mp 100 °C.

Solubility: anhydrous: sol water, alcohol, and acetone; dihydrate: sol water, methanol, ethanol; mod sol acetone, ethyl acetate; sl sol Et2O.

Form Supplied in: anhydrous: hygroscopic yellow to brown microcrystalline powder; dihydrate: green to blue powder or crystals; also supplied as reagent adsorbed on alumina (approx. 30 wt % CuCl2 on alumina).

Analysis of Reagent Purity: by iodometric titration.70

Purification: cryst from hot dil aq HCl (0.6 mL g-1) by cooling in a CaCl2-ice bath.71

Handling, Storage, and Precautions: the anhydrous solid should be stored in the absence of moisture, since the dihydrate is formed in moist air. Irritating to skin and mucous membranes.

Chlorination of Carbonyls.

Copper(II) chloride effects the a-chlorination of various carbonyl functional groups.1 The reaction is usually performed in hot, polar solvents containing Lithium Chloride, which enhances the reaction rate. For example, butyraldehyde is a-chlorinated in DMF (97% conversion, eq 1) while the same reaction in methanol leads to an 80% yield of the corresponding a-chloro dimethyl acetal (eq 2).2

The process has been extended to carboxylic acids, anhydrides, and acid chlorides by using an inert solvent such as sulfolane.3 4-Oxo-4,5,6,7-tetrahydroindoles are selectively a-chlorinated, allowing facile transformation to 4-hydroxyindoles (eq 3).4 The ability of the reaction to form a-chloro ketones selectively has been further improved by the use of trimethylsilyl enol ethers as substrates.5 Recently, phase-transfer conditions have been employed in a particularly difficult synthesis of RCH(Cl)C(O)Me selectively from the parent ketones (eq 4).6

Chlorination of Aromatics.

Aromatic systems may be chlorinated by the reagent. For example, 9-chloroanthracene is prepared in high yield by heating anthracene and CuCl2 in carbon tetrachloride (eq 5).7 When the 9-position is blocked by a halogen, alkyl, or aryl group, the corresponding 10-chloroanthracenes are formed by heating the reactants in chlorobenzene.8,9 Under similar conditions, 9-acylanthracenes give 9-acyl-10-chloroanthracenes as the predominant products.10 Polymethylbenzenes are efficiently and selectively converted to the nuclear chlorinated derivatives by CuCl2/Alumina (eq 6).11

Reactions with Alkoxy and Hydroxy Aromatics.

Hydroxy aromatics such as phenols and flavanones undergo aromatic nuclear chlorination with copper(II) chloride.12 Thus heating 3,5-xylenol with a slight excess of the reagent in toluene at 90 °C gave a 93% yield of 4-chloro-3,5-xylenol (eq 7).13 2-Alkoxynaphthalenes are similarly halogenated at the 1-position.14 Attempted reaction of CuCl2 with anisole at 100 °C for 5 h gave no products; in contrast, it was found that alkoxybenzenes were almost exclusively para-chlorinated (92-95% para:0.5-3% ortho) using CuCl2/Al2O3 (eq 8).15 Anisole reacts with benzyl sulfides in the presence of equimolar CuCl2 and Zinc Chloride to give anisyl(phenyl)methanes (para:ortho = 2:1, eq 9).16,17

Reactions with Active Methylene-Containing Compounds.

9-Alkoxy(or acyloxy)-10-methylanthracenes react with CuCl2 to give coupled products (eq 10), while the analogous 9-alkoxy(or acyloxy)-10-benzyl(or ethyl)anthracenes react at the alkoxy or acyloxy group to afford 10-benzylidene(or ethylidene)anthrones (eq 11).18 The reactions are believed to proceed via a radical mechanism.

Under similar conditions, 9-alkyl(and aryl)-10-halogenoanthracenes give products resulting from replacement of the halogen, alkyl, or aryl groups with halogen from the CuCl2.19 Boiling toluene reacts with CuCl2 to yield a mixture of phenyltolylmethanes.20

Lithium enolates of ketones21 and esters22 undergo a coupling reaction with copper(II) halides to afford the corresponding 1,4-dicarbonyl compounds. Thus treating a 3:1 mixture of t-butyl methyl ketone and acetophenone with Lithium Diisopropylamide and CuCl2 gives a 60% yield of the cross-coupled product (eq 12).

The intramolecular variant of this reaction producing carbocyclic derivatives has been reported.23 Copper(II) chloride catalyzes the Knoevenagel condensation of 2,4-pentanedione with aldehydes and tosylhydrazones (eq 13).24 The reagent also catalyzes the reaction of various 1,3-dicarbonyls with dithianes such as benzaldehyde diethyl dithioacetal to give the corresponding condensation products (eq 14).25

Catalyst for Conjugate Additions.

The catalytic effect of copper(II) chloride on the 1,4-addition of b-dicarbonyl compounds to (arylazo)alkenes26,27 and aminocarbonylazoalkenes28,29 has been studied in some detail. The reactions proceed at ambient temperature in THF and afford the corresponding pyrrole derivatives (eq 15). This mild method requires no other catalyst and succeeds with b-diketones, b-ketoesters, and b-ketoamides. Copper(II) chloride also catalyzes the addition of water, alcohols, phenol, and aromatic amines to arylazoalkenes (eq 16).30

Oxidation and Coupling of Phenolic Derivatives.

In the presence of oxygen, copper(II) chloride converts phenol derivatives to various oxidation products. Depending on the reaction conditions, quinones and/or coupled compounds are formed.31 Several groups have examined different sets of conditions employing CuCl2 to favor either of these products. Thus 2,3,6-trimethylphenol was selectively oxidized to trimethyl-p-benzoquinone with CuCl2/amine/O2 as the catalyst (eq 17),32 while 2,4,6-trimethylphenol was converted to 3,5-dimethyl-4-hydroxybenzaldehyde using a catalytic system employing either acetone oxime or amine (eq 18).33,34

The oxidation of alkoxyphenols to the corresponding quinones has been studied,35 and even benzoxazole derivatives are oxidized by a mixture of copper(II) chloride and Iron(III) Chloride (eq 19).36 A CuCl2/O2/alcohol catalytic system has been used for the oxidative coupling of monophenols.37

Copper(II) amine complexes are very effective catalysts for the oxidative coupling of 2-naphthols to give symmetrical 1,1-binaphthalene-2,2-diols.38 Recent work has extended this methodology to the cross-coupling of various substituted 2-naphthols.39,40 For example, 2-naphthol and 3-methoxycarbonyl-2-naphthol are coupled under strictly anaerobic conditions using CuCl2/t-Butylamine in methanol to give the unsymmetrical binaphthol in 86% yield (eq 20).

Other ligands such as methoxide are also effective; a mechanistic study indicates that the selectivity for cross- rather than homo-coupling is dependent upon the copper:ligand ratio.41 A 1:1 mixture of 2-naphthol and 2-naphthylamine is cross-coupled with CuCl2/benzylamine to give 2-amino-2-hydroxy-1,1-binaphthyl (68% yield, eq 21).42 The cross-coupled products from these reactions are important in view of their use as chiral ligands for asymmetric synthesis.

Dioxygenation of 1,2-Diones.

1,2-Cyclohexanedione derivatives have been converted to the corresponding 1,5-dicarbonyl compounds by oxidation with O2 employing copper(II) chloride as the catalyst.43 More recently, CuCl2-Hydrogen Peroxide has been used to prepare terminal dicarboxylic acids in high yield.44 While 1,2-cyclohexanedione afforded a-chloroadipic acid in 85% yield, 1,2-cyclododecanedione was converted to 1,12-dodecanedioic acid in 47% yield under identical conditions (eq 22).

Addition of Sulfonyl Chlorides to Unsaturated Bonds.

The addition of alkyl and aryl sulfonyl chlorides across double and triple bonds is catalyzed by copper(II) chloride.45-51 The reaction appears to be quite general and proceeds via a radical chain mechanism. The 2-chloroethyl sulfones produced in the reaction with alkenes undergo base-induced elimination to give vinyl sulfones (eq 23).45-48 1,3-Dienes similarly react, yielding 1,4-addition products (eq 24) which may be dehydrohalogenated to 1,3-unsaturated sulfones.45,49

The stereoselectivity of the addition to alkynes can be controlled by varying the solvent or additive, and thus favoring either the cis or trans b-chlorovinyl sulfone.50,51 For example (eq 25), when benzenesulfonyl chloride is reacted with phenylacetylene in acetonitrile with added triethylamine hydrochloride, the trans:cis ratio is 92:8, while the same reaction performed in CS2 without additive favors the cis isomer (16:84).

Acylation Catalyst.

N-Trimethylsilyl derivatives of (+)-bornane-2,10-sultam (Oppolzer's chiral sultam) and chiral 2-oxazolidinones (the Evans chiral auxiliaries) are N-acylated with a number of acyl chlorides including acryloyl chloride in refluxing benzene in the presence of CuCl2.52 The N-acylated products were prepared in high yields; the method does not require an aqueous workup, making it advantageous for large-scale preparations.

Racemization Suppression in Peptide Couplings.

A mixture of copper(II) chloride and Triethylamine catalyzes the formation of peptide bonds.53 Furthermore, when used as an additive, CuCl2 suppresses racemization in both the carbodiimide54 and mixed anhydride55 peptide coupling methods. Recently it was shown that a combination of 1-Hydroxybenzotriazole and CuCl2 gives improved yields of peptides while eliminating racemization.56,57

Reaction with Palladium Complexes.

p-Allylpalladium complexes undergo oxidative cleavage with copper(II) chloride to form allyl chlorides with the concomitant release of PdCl2 (eq 26).58

This methodology has been used in the dimerization of allenes to 2,3-bis(chloromethyl)butadienes.59 1,5-Bismethylenecyclooctane was transformed into the bridgehead-substituted bicyclo[3.3.1]nonane system using CuCl2/HOAc/NaOAc, while the same substrate produced bicyclo[4.3.1]decane derivatives (eq 27) with a Palladium(II) Chloride/CuCl2 catalytic system.60

While reaction of a steroidal p-allylpalladium complex with AcOK yields the allyl acetate arising from trans attack, treatment of a steroidal alkene with PdCl2/CuCl2/AcOK/AcOH gave the allyl acetate arising from cis attack.61

Reoxidant in Catalytic Palladium Reactions.

Copper(II) chloride has been used extensively in catalytic palladium chemistry for the regeneration of PdII in the catalytic cycle. In particular, the reagent has found widespread use in the carbonylation of alkenes,62-64 alkynes,65 and allenes66,67 to give carboxylic acids and esters using PdCl2/CuCl2/CO/HCl/ROH, and in the oxidation of alkenes to ketones with a catalytic PdCl2/CuCl2/O2 system (the Wacker reaction).68 The PdCl2/CuCl2/CO/NaOAc catalytic system has been used in a mild method for the carbonylation of b-aminoethanols, diols, and diol amines (eq 28).69

Cyclopropanation with CuCl2-Cu(OAc)2 Catalyst.

Ethyl Cyanoacetate reacts with alkenes under CuCl2-Copper(II) Acetate catalysis to give cyclopropanes.72 Thus heating cyclohexene in DMF (110 °C, 5 h) with this reagent combination gives a 53% yield of the isomeric cyclopropanes. The reaction also proceeds with styrene, 1-decene, and isobutene. Byproducts formed from the addition to the alkene are removed with Potassium Permanganate.

Related Reagents.

Chlorine; N-Chlorosuccinimide; Copper(I) Chloride; Copper(II) Chloride-Copper(II) Oxide; Iodine-Copper(II) Chloride; Copper(I) Chloride-Oxygen; copper(I) chloride-tetrabutylammonium chloride Copper(I) Chloride-Sulfur Dioxide; Iodine-Aluminum(III) Chloride-Copper(II) Chloride; Iodine-Copper(I) Chloride-Copper(II) Chloride; Methylmagnesium Iodide-Copper(I) Chloride; Palladium(II) Chloride-Copper(I) Chloride; Palladium(II) Chloride-Copper(II) Chloride; Phenyl Selenocyanate-Copper(II) Chloride; Vinylmagnesium Chloride-Copper(I) Chloride; Zinc-Copper(I) Chloride.


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Nicholas D. P. Cosford

SIBIA, La Jolla, CA, USA



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