Introduction

Copper(II) chloride (copper chloride,CuCl?,Figure 1), a common inorganic copper salt with stable chemical activity, exists mainly in two prevalent crystalline states in practical applications: anhydrous copper(II) chloride with a yellowish-brown powdery appearance and blue-green crystalline copper(II) chloride dihydrate (CuCl?·2H?O). This compound features excellent water solubility and moderate solubility in common organic solvents, endowing it with convenient processing conditions for solution-based material synthesis and chemical reactions. Different from toxic heavy metal salts such as mercury and lead derivatives, copper(II) chloride possesses relatively low biological toxicity, stable redox characteristics, and outstanding environmental adaptability, which enables it to serve as a reliable functional reagent in diverse chemical and material research fields.

In recent years, copper(II) chloride has emerged as a reagent of choice for various synthetically useful transformations replacing successfully the mercury (II), thallium (III) and lead (IV)compounds, due to its similarity in oxidation reactions, low toxicity,ready availability, ease of handling and inexpensiveness. In this regard, some recent applications include: copper(II) chloride catalyzed intramolecular C-H oxidation/acylation of formyl-N-arylformamides to indoline-2,3-diones via O₂ as terminal oxidant, copper(II) chloride-mediated oxidative cyclization of heterocyclically substituted aldimines and regioselective C-allylation of enaminones.[1] Several relevant research cases are presented below.

Copper(II) Chloride-Mediated Synthesis and DNA Photocleavage of 1,2,4-Triazolo[4,3-a]quinoxaline Derivatives

A new class of photonucleases, 1-aryl/heteroaryl-4-substituted-1,2,4-triazolo[4,3-a]quinoxalines  was synthesized in a facile and efficient manner via copper(II) chloride mediated oxidative intramolecular cyclization of 2-(arylidenehydrazino)-3-substituted-quinoxalines. DNA cleavage potency of compounds 4a-d (bearing 2’-chlorophenyl, 2’-nitrophenyl, 2’-thienyl and 2’-furyl at position-1,40μg each) was quantitatively evaluated on supercoiled plasmid ΦX174 under UV irradiation (312nm, 15 W) without any additive. Compound 4c[4-methyl-1-(thiophen-2-yl)-[1,2,4]triazolo[4,3-a]quinoxaline] was found to be the most efficient DNA photocleaver which had converted supercoiled DNA (form I) into the relaxed DNA (form II) at 30 μg and the DNA photocleavage activity increases with increase in concentration of 4c.[1]

Oxidative C–H Coupling to Access (Aza)oxindole Mediated by Copper(II) Chloride

Oxindoles are interesting synthetic targets for organic chemists owing to the presence of this heterocyclic motif in many natural products and pharmaceutically active compounds. The copper(II) chloride-mediated oxidative coupling protocol was extended to the synthesis of 3,3-disubstituted aza-oxindoles.The key step of this transformation is a Minisci reaction, the intramolecular radical cyclization on a pyridine ring. This method was applied to a range of o-, m-, and p-pyridyl amides to obtain aza-oxindoles in good to excellent yields. Motivated by this finding, the present research was carried out. A copper(II) chloride mediated direct intramolecular oxidative coupling of C_sp2-H and C_sp3-H centers gives access to 3,3-disubstituted oxindoles containing aromatic, heteroaromatic and alkyl substituents as well as a heteroatom at the quaternary center in good to excellent yields. The reaction is carried out in the presence of NaOtBu and copper(II) chloride in DMF at 110°C. The key step of this reaction is the formation of an amidyl radical by one electron oxidation of amide enolate followed by an intramolecular radical cyclization reaction (homolytic aromatic substitution reaction). A detailed DFT study shows that the cyclization of the amidyl radical is the rate-limiting step in the oxindole synthesis, whereas the second single electron transfer (SET) becomes the rate-determining step in the aza-oxindole formation. Computational data are in agreement with the experimentally observed relative reactivity and regioselectivity.[2]

Copper(II) Chloride suppresses racemization in peptide synthesis via mixed anhydride methods

In the carbodiimide mediated segment condensation copper(II) chloride is exceptionally effective as a racemization-suppressing additive compared with other hitherto known compounds. This remarkable effect of racemization suppression by copper(II) chloride can be related mechanistically to its strong ability to suppress the racemization of the 5(4H)-oxazolone which may be formed from an activated carboxyl component during the coupling. This suggests that copper(II) chloride may be effective also in couplings by the other methods where 5(4H)-oxazolones are primarily responsible for the observed racemization.In segment couplings by the mixed anhydride method using isobutyloxycarbonyl chloride, the use of copper(II) chloride as an additive suppressed racemization completely in the same manner as in the carbodiimide method. This was confirmed by employing a number of couplings between Z-dipeptides and amino acid esters. The racemization-suppressing effect of other compounds were also evaluated by employing one of these model couplings to be at best only limitedly effective. Copper(II) chloride was effective also in the related method using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. Thus, in the couplings where a low level of racemization was observed without an additive, the addition of copper(II) chloride eliminated racemization even at ambient temperature where N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline is usually used. The effectiveness of copper(II) chloride was confirmed also in the  bis(2-oxo-3-oxazolidinyl)-phosphinic chloride method. In the presence of 1-hydroxybenzotriazole racemization was reduced to a low but still detectable level, while it was suppressed completely by the addition of copper(II) chloride.[3]

References

[1] Aggarwal R, Sumran G, Kumar V, Mittal A. Copper(II) chloride mediated synthesis and DNA photocleavage activity of 1-aryl/heteroaryl-4-substituted-1,2,4-triazolo[4,3-a]quinoxalines. Eur J Med Chem. 2011;46(12):6083-6088. doi:10.1016/j.ejmech.2011.10.032

[2] Dey C, Larionov E, Kündig EP. Copper(ii) chloride mediated (aza)oxindole synthesis by oxidative coupling of Csp(2)-H and Csp(3)-H centers: substrate scope and DFT study. Org Biomol Chem. 2013;11(39):6734-6743. doi:10.1039/c3ob41254g

[3] Miyazawa T, Donkai T, Yamada T, Kuwata S. Effect of copper(II) chloride on suppression of racemization in peptide synthesis by the mixed anhydride and related methods. Int J Pept Protein Res. 1992;40(1):49-53. doi:10.1111/j.1399-3011.1992.tb00103.x