Bis-Phenoxo-CuII2 Complexes: Formal Aromatic Hydroxylation via Aryl-CuIII Intermediate Species

Ullmann-type copper-mediated arylC-O bond formation has attracted the attention of the catalysis and organometallic communities, although the mechanism of these copper-catalyzed coupling reactions remains a subject of debate. We have designed well-defined triazamacrocyclic-based aryl-CuIII complexes as an ideal platform to study the C-heteroatom reductive elimination step with all kinds of nucleophiles, and in this work we focus our efforts on the straightforward synthesis of phenols by using H2O as nucleophile. Seven well-defined aryl-CuIII complexes featuring different ring size and different electronic properties have been reacted with water in basic conditions to produce final bis-phenoxo-CuII2 complexes, all of which are characterized by XRD. Mechanistic investigations indicate that the reaction takes place by an initial deprotonation of the NH group coordinated to CuIII center, subsequent reductive elimination with H2O as nucleophile to form phenoxo products, and finally air oxidation of the CuI produced to form the final bis-phenoxo-CuII2 complexes, whose enhanced stability acts as a thermodynamic sink and pushes the reaction forward. Furthermore, the corresponding triazamacrocyclic-CuI complexes react with O2 to undergo 1e− oxidation to CuII and subsequent C-H activation to form aryl-CuIII species, which follow the same fate towards bis-phenoxo-CuII2 complexes. This work further highlights the ability of the triazamacrocyclic-CuIII platform to undergo aryl-OH formation by reductive elimination with basic water, and also shows the facile formation of rare bis-phenoxo-CuII2 complexes.


Introduction
Fundamental mechanistic understanding of Ullmann-type aryl-heteroatom cross-coupling chemistry is still scarce and difficult to obtain in actual catalytic systems, due to the elusive formation of very reactive intermediate species [1][2][3][4][5][6][7]. Methodological approaches consist of extensive optimization protocols to finally reach an effective method to obtain the desired reaction and performance [8][9][10], at the expense of intrinsic mechanistic understanding. Indeed, spectroscopic monitoring of the reactions is precluded by the use of high concentrated solutions and heterogeneous bases. It is proposed that complex mixtures of copper-complexes are involved, and that several mechanisms can be active in parallel. Nevertheless, one of the most accepted mechanisms involves a 2e−Cu I /Cu III catalytic cycle via the classical oxidative addition/reductive elimination steps [7,11].
A successful strategy to overcome the problem of mechanistic understanding is the design of macrocyclic substrate scaffolds to tame the reactivity of the intermediate copper species [7,10,12]. In this manner, well-defined aryl-Cu III key intermediate species have been isolated and crystallized, and their reactivity in reductive elimination processes with heteroatom nucleophiles (O, N, S, Se, P) has been widely studied [11][12][13][14][15][16][17][18][19][20][21][22][23]. In addition, upgrading to catalytic C-Heteroatom cross couplings has been proved in some of them [7,11,21]. A particularly interesting type of nucleophiles are those bearing O-heteroatoms, which streamline the synthesis of biaryl ethers and aryl-alkyl ethers [24][25][26], and this copper-catalyzed reactivity has proved to be very effective [8,27]. In this regard, we reported a detailed mechanistic investigation on the reactivity of well-defined triazamacrocyclic aryl-Cu III species with HO-nucleophiles (HONuc = carboxylic acids, phenols and aliphatic alcohols) [26]. These reactions afforded the corresponding aryl-O-Nuc products under mild conditions, via a reductive elimination path.
A remarkable case of C-O coupling is the synthesis of phenol (aryl-OH), since this would imply the use of water as a nucleophile. Actually, the current synthetic methods of phenol include the classical non-metal-catalyzed transformations, such as (a) the oxidation of aryl aldehydes or aryl ketones with H 2 O 2 (Dakin reaction) [28] and (b) the reaction of water with diazo-aryl compounds (Sandmeyer reaction) [29], and the transition metal-catalyzed transformations, such as (c) Pd-catalyzed cross coupling reactions using H 2 O [30,31] and (d) Cu-catalyzed cross coupling reactions using H 2 O [32,33], among many others [34][35][36].
In this work, we study the reactivity of well-defined triazamacrocyclic aryl-Cu III species with water to evaluate the possibility to synthesize phenol products and to understand the mechanistic details of this coupling. The triazamacrocyclic aryl-Cu III species can be obtained via two synthetic strategies: (1) quantitative formation via Cu I oxidative addition with triazamacrocyclic aryl-X substrates ( Figure 1a) [11,16,23], or (2) via C-H activation and metalation with Cu II using triazamacrocyclic aryl-H substrates and further disproportionation to afford equimolar amounts of the desired aryl-Cu III , Cu I salt and protonated substrate ( Figure 1b) [16,37]. The unreported reactivity of the well-defined aryl-Cu III complexes with water in basic conditions is presented in this work, leading to aryl-OH coupling species, a formal aromatic hydroxylation of arenes. The crystal structures of the final bis-phenoxo-Cu II 2 complexes nicely show the effectivity of the C-O reductive elimination at Cu III and the easy oxidation of the resulting Cu I to bis-phenoxo-Cu II 2 complexes as thermodynamic sink.
In this work, we study the reactivity of well-defined triazamacrocyclic aryl-Cu III species with water to evaluate the possibility to synthesize phenol products and to understand the mechanistic details of this coupling. The triazamacrocyclic aryl-Cu III species can be obtained via two synthetic strategies: (1) quantitative formation via Cu I oxidative addition with triazamacrocyclic aryl-X substrates ( Figure 1a) [11,16,23], or (2) via C-H activation and metalation with Cu II using triazamacrocyclic aryl-H substrates and further disproportionation to afford equimolar amounts of the desired aryl-Cu III , Cu I salt and protonated substrate ( Figure 1b) [16,37]. The unreported reactivity of the well-defined aryl-Cu III complexes with water in basic conditions is presented in this work, leading to aryl-OH coupling species, a formal aromatic hydroxylation of arenes. The crystal structures of the final bis-phenoxo-Cu II 2 complexes nicely show the effectivity of the C-O reductive elimination at Cu III and the easy oxidation of the resulting Cu I to bis-phenoxo-Cu II 2 complexes as thermodynamic sink.
one equivalent of aqueous KOH 1M at room temperature to give colored intermediates ( Figure 2, route a). Solution acquires a red-brown (when L 1 is used) or deep-violet (when L 2 -L 3 is used) color, which fade to obtain final green solutions. Colored intermediates take 2-3 h to totally fade to green products. Slow diethyl ether diffusion leads to the final bis-phenoxo complexes as green crystals: Molecules 2020, 25, x FOR PEER REVIEW 3 of 11
react with one equivalent of aqueous KOH 1M at room temperature to give colored intermediates ( Figure 2, route a). Solution acquires a red-brown (when L1 is used) or deep-violet (when L2-L3 is used) color, which fade to obtain final green solutions. Colored intermediates take 2-3 h to totally fade to green products. Slow diethyl ether diffusion leads to the final bis-phenoxo complexes as green crystals: The structures are all analogous and consist of a dimetallic Cu II complex showing a N 3 O 2 distorted trigonal bipyramidal geometry for each metal, where the two phenoxo groups are bridging and the three amine moieties belong to the two ligands featured in the structure.

X-ray Diffraction Analysis of the Bis
Crystal structure for complex [(L 1 -O) 2 Cu II 2 ](OTf) 2 (3 L1 -(OTf) 2 ) was obtained, and its ORTEP diagram is shown in Figure 3a. The molecule sits on a symmetrical center that transforms one macrocyclic ligand into the other. Each copper metal atom has a strongly distorted trigonal bipyramidal towards a square-planar pyramidal geometry (with a τ factor [38]  These structures are very rare, and to our knowledge there is only one precedent in the literature, reported in 2002 [39], where a small (12-membered) triazamacrocycle (L 4 -H, m = 2, n = 2, R 1 = H) already showed the ability to form a bis-phenoxo-Cu II 2 compound through route b (Figure 2), but no aryl-Cu III was detected, probably due to its small size and its inability to accommodate aryl-Cu III intermediate species. Contrary to the structures reported in this work, the smaller macrocycle favored a more square-planar geometry for each copper center (with a τ factor of 0.21).
The comparison of crystal structures of these complexes shows the same type of N 3 O 2 coordination sphere for each Cu atom, although geometry environment for copper is directly related to conformational constraints imposed by ligand backbone. Thus, the trend found shows that the smaller size of the macrocycle favors square-pyramidal geometry (12-membered L 4 , τ factor of 0.21) [39], whereas 13-membered L 1 afforded a τ factor of 0.56, and 14-membered macrocyclic rings (L 2 -L 3 ) showed τ values in the range of 0.60-0.67. These structures are very rare, and to our knowledge there is only one precedent in the literature, reported in 2002 [39], where a small (12-membered) triazamacrocycle (L4-H, m = 2, n = 2, R1 = H) already showed the ability to form a bis-phenoxo-Cu II 2 compound through route b (Figure 2), but no aryl-Cu III was detected, probably due to its small size and its inability to accommodate aryl-Cu III

Mechanistic Investigation on the Aromatic Hydroxylation Reaction
In order to gain more mechanistic insight of the C-O coupling by reaction of aryl-Cu III with water under basic conditions, the synthetic conditions have been optimized for the synthesis [(L 2 -O) 2 Cu II 2 ](ClO 4 ) 2 (3 L2 -(ClO 4 ) 2 . In principle, any aqueous base reagent instead of KOH 1 M can be used to achieve the final product, as shown in Table 1. Interestingly, other O-containing reagents such as H 2 O 2 are also able to perform the hydroxylation reaction. However, the addition of H 2 O 2 3% in water did not cause any change to copper(III) until the base Et 3 N was injected into the solution (see entries 6-7 in Table 1). From these series of reactions, it may be concluded that the addition of water or H 2 O 2 does not affect the stability of the aryl-Cu III , and only the presence of a base triggers the reaction to bis-phenoxo complex formation through a colored intermediate. The presence of O 2 in the solution in entry 5 was tested to check if it had any influence in reaction time-scale or final yield. No quenching of violet intermediate was found but differences in final yield were noticeable: 20% yield for reaction (entry 5) and 53% for entry 3. When using the hydrogen peroxide activated with DABCO (entries 8-9), we noticed that product 3 L2 was obtained in substantially better yield (40%, entry 9) when 0.5 equivalents of the DABCO.2H 2 O 2 adduct were used. The colored intermediate was characterized by UV-vis and corresponded to the deprotonated aryl-Cu III species for L 1 -L 3 systems (Figure 4), analogously to the reported case of deprotonated-1 L2 complex (depro-1 L2 ) [40]. In addition, weak axial coordination of a water molecule to the Cu III center is proposed as a necessary species towards C-O reductive elimination. The same reactivity behavior is found for complex [(L 3 )Cu III ] 2+ , whereas significant differences are shown by complex [(L 1 )Cu III ] 2+ . For the latter, stability of red-brown intermediate depro-1 L1 is much higher than for depro-1 L2 , depro-1 L3 , and reaction is not finished in less than 24 h upon KOH addition. In line with the enhanced stability, a significantly lower yield (30%) for the corresponding bis-phenoxo complex [(L 1 -O) 2 Cu II 2 ] 2+ (3 L1 ) was found.

Aromatic Hydroxylation via Arene C-H Activation with Cu I /O 2
The study of dioxygen activation by the Cu I complexes synthesized with ligands L 1 -L 3 demonstrated another mechanistic twist regarding formal aromatic C-H hydroxylations. Bubbling  (3 L3 ) as final products, although in significantly lower yields (25% isolated yield for 3 L2 ). The UV-vis monitoring of these reactions confirmed that hydroxylation was occurring through the same aryl-Cu III intermediates, featuring the same LMCT bands in each case, albeit with lower intensities. In addition, 1 H NMR monitoring of the O 2 bubbling to [(L 1 -H)Cu I ](OTf) (2 L1-H ) in CD 3 CN clearly shows the formation of peaks corresponding to depro-1 L1 after 30 min (see Figure S1 in the Supplementary Materials), reaching full formation above 10 h [11,40]. The ESI-MS spectrum for violet intermediate obtained by reacting [(L 3 -H)Cu I ] + with O 2 shows a characteristic peak at m/z = 294 corresponding to the fragment depro-1 L3 (see Figure S2). Under these conditions, decomposition of the intermediate towards 3 L2 formation was slow and was detected after 40 h.

Aromatic Hydroxylation via Arene C-H Activation with Cu I /O2
The  Figure S1 in the Supplementary Materials), reaching full formation above 10 h [11,40]. The ESI-MS spectrum for violet intermediate obtained by reacting [(L3-H)Cu I ] + with O2 shows a characteristic peak at m/z = 294 corresponding to the fragment depro-1L3 (see Figure S2). Under these conditions, decomposition of the intermediate towards 3L2 formation was slow and was detected after 40 h.
The lower yield obtained is related to the fact that the reaction of [(L2-H)Cu I ](OTf) (2L2-H) with O2 first undergoes an oxidation to Cu II , which enables it to then undergo a C-H activation through a disproportionation reaction (50% aryl-Cu III and 50% Cu I ). Therefore, route b converges with route a (Figure 2) and the obtaining of the low 25% yield for 3L2 through route b, compared to the 65% obtained through route a (Figure 2), mainly stems from the disproportionation pathway.

Materials and Methods
All reagents and solvents were purchased from Sigma Aldrich ( The lower yield obtained is related to the fact that the reaction of [(L 2 -H)Cu I ](OTf) (2 L2-H ) with O 2 first undergoes an oxidation to Cu II , which enables it to then undergo a C-H activation through a disproportionation reaction (50% aryl-Cu III and 50% Cu I ). Therefore, route b converges with route a (Figure 2) and the obtaining of the low 25% yield for 3 L2 through route b, compared to the 65% obtained through route a (Figure 2), mainly stems from the disproportionation pathway.

Materials and Methods
All reagents and solvents were purchased from Sigma Aldrich (Saint Louis, MO, USA) and used without further purification. Cu III complexes [(L x )Cu III ](X) 2

Conclusions
In summary, seven well-defined aryl-Cu III complexes featuring different ring sizes and different electronic properties have been reacted with water in basic conditions to produce intriguing bis-phenoxo-Cu II 2 complexes (3 L1 -3 L6 ), all of which are characterized by XRD. A structural trend correlating the size of the macrocycle and the geometry of each metal center is found, where the smaller 12-membered macrocycle ring (L 4 ) favors square-pyramidal geometry, whereas 13-membered (L 1 ) and 14-membered macrocyclic rings (L 2 -L 3 ) favored trigonal bipyramidal geometries [39]. Mechanistic investigations indicate that the reaction takes place by an initial deprotonation of the NH group coordinated to Cu III center, subsequent reductive elimination with H 2 O as nucleophile to form phenoxo products, and finally air oxidation of the Cu I produced to form the final bis-phenoxo-Cu II 2 complexes, whose enhanced stability acts as a thermodynamic sink and pushes the reaction forward. Furthermore, the corresponding [(L x -H)Cu I ](OTf) (2 Lx-H ) complexes react with O 2 to undergo 1e − oxidation to Cu II and subsequent C-H activation via disproportionation to form aryl-Cu III species, which then undergo the same reaction path towards bis-phenoxo-Cu II 2 complexes. Facile formation of bis-phenoxo-Cu II complexes through aryl-Cu III reductive elimination with basic water is shown, and also the formal aromatic hydroxylation of arene substrates (L x -H) via aryl-Cu III is mechanistically unraveled.
Author Contributions: Conceptualization, X.R.; methodology and formal analysis, R.X., X.F. and X.R.; writing-original draft preparation and editing, X.R.; funding acquisition, X.R. All authors have read and agreed to the published version of the manuscript.