Organocopper(ii) complexes: new catalysts for carbon–carbon bond formation via electrochemical atom transfer radical addition (eATRA)

Organocopper(ii) complexes are a rarity while organocopper(i) complexes are commonplace in chemical synthesis. In the course of building a strategy to generate organocopper(ii) species utilizing electrochemistry, a method to form compounds with CuII–C bonds was discovered, that demonstrated remarkably potent reactivity towards different functionalized alkenes under catalytic control. The role of the organocopper(ii) complex is to act as a source of masked radicals (in this case ˙CH2CN) that react with an alkene to generate the corresponding γ-halonitrile in good yields through atom transfer radical addition (ATRA) to various alkenes. The organocopper(ii) complexes can be continuously regenerated electrochemically for ATRA (eATRA), which proceeds at room temperature, under low Cu loadings (1–10 mol%) and with the possibility of Cu-catalyst recovery.


Introduction
Organocopper(I) compounds are among the most extensively used reagents in the functionalization of organic molecules, namely in the form of nucleophilic C-C bond and C-heteroatom bond formation as stoichiometric reagents or catalysts. [1][2][3][4] In stark contrast to the myriad of organocopper(I) complexes that have been prepared, organocopper(II) compounds are rare. Only a few organocopper(II) complexes have been structurally characterized by X-ray diffraction, specically, those containing ligands that exert sufficient electronic and steric effects to protect the Cu II -C bond from dissociation. Examples of these include N-heterocyclic carbene, 5-7 N-confused porphyrin, 8 macrocyclic aryl tripyridyl 9 and tripodal tris(2-pyridylthio)methyl 10 ligands. Two particularly important cases include monodentate C-bound -CH 2 CN to copper(II) from the Tolman 11 and Huang groups, 12 where pyridine-2,6-dicarboxamide co-ligands were utilized. Huang and co-workers showed that the Cu II -CH 2 CN moiety acted as a cyanide source (activating the C-C bond) for catalytic cyanation of iodobenzene, phenylboronic acid, and 2-phenylpyridine. However, beyond these examples, the reactivity of organocopper(II) complexes remains largely unexplored.
[Cu II LR] + / [Cu II L] 2+ + R À (heterolytic dissociation), (1) [Cu II LR] + / [Cu I L] + + Rc (homolytic dissociation), A key issue is the reactivity of the Cu II -C bond, in terms of both its lability and cleavage mode. As shown in eqn (1), heterolysis of the Cu II -C bond generates Cu II and a carbanion (R À ); a powerful base and nucleophile. 13 Alternatively, homolysis liberates a radical (Rc) and Cu I (eqn (2)). The latter transformation would render the organocopper(II) species an ideal candidate for radical addition reactions since a controlled radical release via Cu II -C bond homolysis minimizes radical termination.
The role of Cu complexes in atom transfer radical addition (ATRA) has been well established. 14 The redox activity of Cu is central to the mechanism of ATRA and the key step is initiation whereby a reactive radical is generated from a dormant alkyl halide. As an illustrative example of initiation (Scheme 1, highlighted box), the Cu(I) complex of the tetradentate ligand Me 6 tren (hereaer abbreviated as L) reacts with an organic halide (XCH 2 CN, X ¼ Cl (1a) or Br (1b)) yielding a halido-copper(II) complex ([Cu II LX] + ) and the radical cCH 2 CN (see Scheme 1 Cite this: Chem. Sci., 2022, 13, 10506 All publication charges for this article have been paid for by the Royal Society of Chemistry leads to an accumulation of [Cu I L] + and cCH 2 CN near the electrode, which rapidly combine to form the organocopper(II) complex [Cu II L(CH 2 CN)] + . [15][16][17] The reactivity of [Cu II L(CH 2 CN)] + is now explored in the context of developing and executing controlled carbon-carbon bond formation based on ATRA. One of the main deciencies of conventional copper-catalyzed ATRA, however, is the need for high Cu loadings relative to the substrate (up to 30%) and high temperatures (over 90 C) to achieve desired yields and selectivities. 14,18,19 Electrosynthesis is a promising and innovative synthetic methodological tool in organic synthesis that can accomplish challenging transformations under mild conditions. 20-23 Herein we report, for the rst time, electrochemical atom transfer radical addition (eATRA) with [Cu II L(CH 2 CN)] + as the radical source using mild reaction conditions, and with a protocol for catalyst recovery.

Electrochemical synthesis of [Cu II L(CH 2 CN)] +
In order to generate [Cu II L(CH 2 CN)] + in solution, a bulk electrolysis protocol, based on a previously described method, was routinely employed for this work. 15,17 The stable [Cu II L(NCCH 3 )] 2+ complex forms spontaneously when crystalline [Cu II L(OH 2 )](ClO 4 ) 2 (ref. 24) is dissolved in CH 3 CN, and electrochemical reduction to [Cu I L] + is accompanied by a change in coordination number (5 to 4), which is typical of copper coordination chemistry. 25 In the presence of 1a or 1b radical activation occurs generating [Cu II LX] + and cCH 2 CN     Fig. S3A †), but only at potentials well below those shown in Fig. 1 (<À1600 mV vs. Fc +/0 ). The complex [Cu I L] + is essential in achieving controlled radical activation. CV experiments carried out with Cu(ClO 4 ) 2 in CH 3 CN (giving the [Cu(NCCH 3 ) 4 ] 2+/+ couple at ca. +650 mV vs. Fc +/0 ) led to no catalytic reaction with either ClCH 2 CN or BrCH 2 CN upon electrochemical reduction (ESI Fig. S3B and C †). This is in line with the known dependence   Reaction at 82 C (reuxing acetonitrile) gave no product due to the thermal polymerisation of 2. 28 Importantly, no elimination occurred when 1a was used under the same conditions given the greater stability of the chlorinated product 2a.
Electrocatalytic ATRA (eATRA) Gratifyingly, the same reaction outcome could be achieved at room temperature under electrocatalytic conditions with substoichiometric amounts of copper complex in the presence of 2 and two equivalents of 1a or 1b. This led to the formation of the ATRA adducts (2a and 2b) in good yields at room temperature with a signicant decrease in reaction time.
The effect of pre-catalyst [Cu II L(NCCH 3 )] 2+ concentration was examined by investigating the room temperature electrochemical ATRA reaction of 1a and 2. High conversions and good yields were obtained when using 1-10 mol% of the pre-catalyst with reaction times under 12 h ( Table 2, entries 1-4). When catalyst loadings decreased to 0.4 mol% or less, longer reaction times were required and lower yields were obtained (Table 2, entries 5-6). Loadings over 10 mol% Cu did not shorten reaction times or improve yields so all subsequent experiments were carried out with 10 mol% Cu loading.

eATRA scope
With optimum conditions determined, the scope of the coppercatalyzed eATRA was investigated by employing various functionalized alkenes (2-16, Scheme 2) to react with organic halides 1a or 1b (Table 3). Para-substituted styrenes afforded the expected ATRA g-halonitrile products (i.e., 2-9a, 2-5b, 9b) in moderate to excellent yields (52-96%) with no alkene elimination by-products (e.g. 2c). However, p-isopropylstyrene (5), also gave a small amount of isomeric halonitrile by-product 5a 0 . This is potentially due to an intermolecular radical chain transfer mediated by the reactive Me 2 CH-substituent (Scheme 3a). Nonaromatic alkenes (13)(14)(15)(16), exhibit full conversion to the corresponding ATRA products by 1 H NMR analysis. Volatility of these aliphatic products is the origin of their lower isolated yields. Of the two organic halides surveyed, 1b required shorter reaction times compared with 1a, which was in accord with the expected relative C-Br and C-Cl bond reactivity (strength). Despite this, the yields were consistently higher when 1a was employed, so 1a became the focus for eATRA while 1b was limited to representative examples from Scheme 2. The results are summarized in Table 3.

Mechanism
Scheme 4 illustrates the roles of each Cu complex (A-D) in the eATRA mechanism. Electrochemical reduction of [Cu II LX] + (A) to [Cu I L] + (C) via the halido cuprous complex [Cu I LX] (B) initiates the cycle. The role of [Cu II L(CH 2 CN)] + (D) in eATRA is to stabilise cCH 2 CN and block self-termination (to 1d). The complex [Cu II L(CH 2 CN)] + has proven to be a reactive yet robust intermediate that we have been able to prepare in situ and characterise spectroscopically. 15,17 However, the halido complex [Cu II LX] + (X ¼ Cl, Br) (A) is an equally essential participant in eATRA as a halogen atom donor to form the nal product and close the catalytic cycle (Scheme 4, le hand side). Without [Cu II LX] + (generated by the second equivalent of XCH 2 CN), dimers (6d/6d 0 -8d/8d 0 ) or polymeric products ensue. As illustrated in Scheme 4, this reaction is genuinely catalytic as no Cu complex is consumed; only the rst electron to reduce the initial [CuL(NCCH 3 )] 2+ pre-catalyst is required.

Conclusions
Electrochemically mediated atom transfer radical addition (eATRA), is enabled by a rare but resilient organocopper(II) species [Cu II L(CH 2 CN)] + (L ¼ Me 6 tren), generating new carboncarbon bonds in good to excellent yields under mild reaction conditions. The complex [Cu II L(CH 2 CN)] + is a controlled source of cCH 2 CN radicals that add to aromatic and aliphatic alkenes (2-16) either stoichiometrically or catalytically (1-10% mol Cu), and importantly the pre-catalyst can be easily recovered aer work-up.

Data availability
All experimental data are provided in the ESI. † Author contributions M. A. Gonzálvez and C. Su carried out all experimental work and contributed equally. All authors analysed the data and contributed to writing the manuscript.

Conflicts of interest
There are no conicts to declare.