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.

1. Introduction

Fundamental mechanistic understanding of Ullmann-type aryl-heteroatom cross-coupling chemistry is still scn class="Chemical">arce 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−CuI/CuIII 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 n class="Chemical">aryl-CuIII 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-CuIII 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 n class="Chemical">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 H2O2 (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 H2O [30,31] and (d) Cu-catalyzed cross coupling reactions using H2O [32,33], among many others [34,35,36].

In this work, we study the reactivity of well-defined triazamacrocyclic n class="Chemical">aryl-CuIII species with water to evaluate the possibility to synthesize phenol products and to understand the mechanistic details of this coupling. The triazamacrocyclic aryl-CuIII species can be obtained via two synthetic strategies: (1) quantitative formation via CuI oxidative addition with triazamacrocyclic aryl-X substrates (Figure 1a) [11,16,23], or (2) via C-H activation and metalation with CuII using triazamacrocyclic aryl-H substrates and further disproportionation to afford equimolar amounts of the desired aryl-CuIII, CuI salt and protonated substrate (Figure 1b) [16,37]. The unreported reactivity of the well-defined aryl-CuIII 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-CuII2 complexes nicely show the effectivity of the C-O reductive elimination at CuIII and the easy oxidation of the resulting CuI to bis-phenoxo-CuII2 complexes as thermodynamic sink.

Figure 1

Fundamental organometallic reaction features by triazamacrocyclic ligands (L3-X and L3-H shown). (a) Quantitative formation of aryl-CuIII complex through oxidative addition at CuI with L3-X (X = Cl, Br, I). (b) Equimolar formation of aryl-CuIII complex and CuI through CuII disproportionation upon aromatic C-H activation of L3-H at CuII. (c) C-Heteroatom bond formation through reductive elimination of HY-Nuc (Y N, O, S, Se, P) with the aryl-CuIII complex.

2. Results and Discussion

2.1. Aryl-CuIII Complexes and Their Reactivity with Basic Water

The well-defined macrocyclic aryl-CuIII complexes (1L1–1L3) used in this work were prepn class="Chemical">ared following our reported protocols [11,16,23,24,37].

Complexes [(Lx)CuIII](X)2 (x = 1–3; X = n class="Chemical">ClO4−, OTf−, PF6−) dissolved in CH3CN 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: [(L1-O)2CuII2](OTf)2 (3L1-(OTf)2) in 30% isolated yield, [(L2-O)2CuII2](X)2 (3L2-(X)2, X = OTf, ClO4) in 65% yield and [(L3-O)2CuII2](PF6)2 (3L3-(PF6)2) in 60% yield.

Figure 2

Reactivity of aryl-CuIII complexes with basic water (route a) through initial deprotonation, axial coordination of H2O, internal deprotonation of water to hydroxide and reductive elimination to form the aryl-OH products and CuI. Subsequent air oxidation of CuI to CuII causes the formation of the very stable bis-phenoxo-CuII2 final complexes. On the upper part of the figure (route b), the same colored deprotonated aryl-CuIII species can be obtained through CuI/air reaction via concomitant C-H activation and disproportionation at CuII. These reactions are featured with triaazamacrocyclic systems L1–L3.

The structures are all analogous and consist of a dimetallic CuII complex showing a N3O2 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.

2.2. X-ray Diffraction Analysis of the Bis-Phenoxo-CuII2 Complexes ()

Crystal structure for complex [(L1-O)2CuII2](OTf)2 (3L1-(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] of 0.56), and can be considered a mixture of both. Copper centers share coordinative sites with both ligands. Each copper atom is coordinated to a phenoxo O atom and an N atom from one of the macrocyclic ligands, and to the phenoxo O atom and two N atoms from the second macrocyclic ligand. The copper metal centers become doubly bridged by each macrocyclic ligand. The oxygen atoms of the phenoxo groups are bridging the copper metal centers so that the axial oxygen atom from one pyramid also occupies a position in the trigonal base of the other pyramid. The Cu2O2 core atoms lie in a plane forming a rhomboidal arrangement (Cu-O 1.930(2) Å, 2.174(2) Å), Cu···Cu 3.085 Å and O···O 2.718 Å).

Figure 3

ORTEP diagrams corresponding to the cationic fragments of complexes (a) [(L1-O)2CuII2](OTf)2 (3L1-(OTf)2), (b) [(L2-O)2CuII2](ClO4)2·CH3CN (3L2-(ClO4)2·CH3CN) and (c) [(L3-O)2CuII2](PF6)2 (3L3-(PF6)2) (only hydrogen atoms from NH moieties are shown and atoms coordinating to Cu are labelled for clarity).

Structures of complexes [(L2-O)2CuII2](n class="Chemical">ClO4)2·CH3CN (3L2-(ClO4)2·CH3CN) and [(L3-O)2CuII2](PF6)2 (3L3-(PF6)2) were also determined by X-ray diffraction (Figure 3b,c, respectively). Both dinuclear structures 3L2 and 3L3 bear the same ligand-donor set N3O2 per Cu atom and copper metal centers become doubly bridged by each macrocyclic ligand, as the previously described complex 3L1. Each copper metal atom in complexes 3L2 and 3L3 has a strongly distorted trigonal bipyramidal towards a square-planar pyramidal geometry (with a τ factor of 0.61 for 3L2 and 0.62 for 3L3), featuring the same macrocyclic ligand size (14-membered). The oxygen atoms of the phenoxo groups in complex 3L2 are bridging the copper metal centers so that the axial oxygen atom from one pyramid also occupies a position in the trigonal base of the other pyramid. The Cu2O2 core atoms lie in a plane forming a rhomboidal arrangement (Cu-O 1.925(1) Å, 2.128(2) Å, Cu···Cu 3.132 Å and O···O 2.581 Å). A rhomboidal arrangement of the Cu2O2 core is also found for complex 3L3 (Cu-O 1.930(3) Å, 2.122(3) Å, Cu···Cu 3.103 Å and O···O 2.613 Å).

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-CuII2 compound through route b (Figure 2), but no aryl-CuIII was detected, probably due to its small size and its inability to accommodate aryl-CuIII 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 class="Chemical">N3O2 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 L4, τ factor of 0.21) [39], whereas 13-membered L1 afforded a τ factor of 0.56, and 14-membered macrocyclic rings (L2–L3) showed τ values in the range of 0.60–0.67.

2.3. Mechanistic Investigation on the Aromatic Hydroxylation Reaction

In order to gain more mechanistic insight of the C-O coupling by reaction of aryl-CuIII with n class="Chemical">water under basic conditions, the synthetic conditions have been optimized for the synthesis [(L2-O)2CuII2](ClO4)2 (3L2-(ClO4)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 H2O2 are also able to perform the hydroxylation reaction. However, the addition of H2O2 3% in water did not cause any change to copper(III) until the base Et3N 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 H2O2 does not affect the stability of the aryl-CuIII, and only the presence of a base triggers the reaction to bis-phenoxo complex formation through a colored intermediate. The presence of O2 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 3L2 was obtained in substantially better yield (40%, entry 9) when 0.5 equivalents of the DABCO.2H2O2 adduct were used.

Table 1

Different reactivity behavior of [(L2)CuIII](OTf)2 (1L2) in front of different bases and water content to finally obtain 3L2. Typical experiment conditions: CH3CN, [CuIII] = 5–20 mM, N2 atmosphere (unless change specified), R.T. Traces of water are always present.

Entry	Reagents	Reaction Time (min)	Isolated Yield of 3L2 (%)
1	KOH (1 eq.), H2O (54 eq.)	60 min	65%
2	KOH (2 eq.), H2O (108 eq.)	25 min	8%
3	Proton Sponge (1 eq.), H2O (7 eq.)	180 min	53%
4	Proton Sponge (1 eq.)	60 min	0%
5	Proton Sponge (1 eq.), O2 (excess)	240 min	20%
6	H2O2 (3% in H2O) (1 eq.), H2O (52 eq.), Et3N (1 eq.)	10 min	31%
7	H2O2 (3% in H2O) (1 eq.), H2O (52 eq.)	60 min	0%
8	DABCO.2H2O2 (2 eq.)	45 min	15%
9	DABCO.2H2O2 (0.5 eq.)	40 min	40%

The colored intermediate was characterized by UV-vis and corresponded to the deprotonated n class="Chemical">aryl-CuIII species for L1–L3 systems (Figure 4), analogously to the reported case of deprotonated-1L2 complex (depro-1L2) [40]. In addition, weak axial coordination of a water molecule to the CuIII center is proposed as a necessary species towards C-O reductive elimination. The same reactivity behavior is found for complex [(L3)CuIII]2+, whereas significant differences are shown by complex [(L1)CuIII]2+. For the latter, stability of red-brown intermediate depro-1L1 is much higher than for depro-1L2, depro-1L3, 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 [(L1-O)2CuII2]2+ (3L1) was found.

Figure 4

Electronic spectra of deprotonated aryl-CuIII intermediates (depro-1L1, depro-1L2, depro-1L3) UV-Vis plots for aryl-CuIII complexes ([(Lx)CuIII]2+, x = 1–3) (1L1–1L3) are also shown in the plot.

2.4. Aromatic Hydroxylation via Arene C-H Activation with CuI/O2

The study of dioxygen activation by the n class="Chemical">CuI complexes synthesized with ligands L1–L3 demonstrated another mechanistic twist regarding formal aromatic C-H hydroxylations. Bubbling O2 to [(L1-H)CuI](OTf) (2L1-H), [(L2-H)CuI](OTf) (2L2-H), and [(L3-H)CuI](OTf) (2L3-H) at room temperature in CH3CN caused the formation of intense colored intermediates resembling intermediates depro-1L1, depro-1L2, and depro-1L3, respectively (Figure 2, route b). Besides, decomposition of colored intermediates gives the same bis-phenoxo copper(II) complexes [(L1-O)2CuII2]2+ (3L1), [(L2-O)2CuII2]2+ (3L2) and [(L3-O)2CuII2]2+ (3L3) as final products, although in significantly lower yields (25% isolated yield for 3L2). The UV-vis monitoring of these reactions confirmed that hydroxylation was occurring through the same aryl-CuIII intermediates, featuring the same LMCT bands in each case, albeit with lower intensities. In addition, 1H NMR monitoring of the O2 bubbling to [(L1-H)CuI](OTf) (2L1-H) in CD3CN clearly shows the formation of peaks corresponding to depro-1L1 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 [(L3-H)CuI]+ 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)CuI](OTf) (2L2-H) with n class="Chemical">O2 first undergoes an oxidation to CuII, which enables it to then undergo a C-H activation through a disproportionation reaction (50% aryl-CuIII and 50% CuI). 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.

3. Materials and Methods

All reagents and solvents were purchased from Sigma Aldrich (Saint Louis, MO, USA) and used without further purification. CuIII complexes [(Lx)n class="Chemical">CuIII](X)2 (x = 1–3; X = ClO4−, OTf−, PF6−) [16,23], and CuI complexes [(L1-H)CuI](OTf) (2L1-H), [(L2-H)CuI](OTf) (2L2-H) and [(L3-H)CuI](OTf) (2L3-H) were synthesized following reported procedures [41]. NMR data concerning product identity were collected with a Bruker 400 AVANCE (Billerica, MA, USA). Preparation and handling of air-sensitive CuI complexes were carried out in a N2 drybox. High resolution mass spectra (HRMS) were recorded on a Bruker MicrOTOF-Q IITM instrument (Billerica, MA, US) using ESI-MS at Serveis Tècnics University of Girona.

Warning: Although we have experienced no problems with the compounds reported herein, n class="Chemical">perchlorate salts are potentially explosive, and should only be handled in small quantities and never heated in a solid state.

[(L1-O)2CuII2](OTf)2 (3L1-(OTf)2): the synthesis was carried out under N2. Into a solution of complex 1L1-(OTf)2 (0.05 g, 8.7 × 10−5 mol) in CH3CN (1 mL) was injected a KOH(aq) 1M (87 μL, 8.7 × 10−5 mol). Reaction was stirred until the red-brown intermediate formed faded to green (48 h). Diffusion of diethyl ether and overnight storing at −25 °C allowed formation of green crystals in 30% isolated yield (0.012 g). ESI-MS (CH3CN): 3L1743 [-(OTf)]+, 297 [(L1-O)CuII]+; UV/Vis (CH3CN): λmax (ε)= 394 (760), 699 (615); IR (KBr pellet, cm−1): 3258 (m), 3121 (m), 2924 (w), 1591 (w), 1456 (m), 1285 (s), 1252 (s), 1165 (m), 1031 (m), 640 (m); elemental analysis calcd for C26H40N6O2Cu2(C2F6S2O6)·0.5CH3CN (%): C 38.1, H 4.60, N 10.00, S 7.00; found: C 37.95, H 4.82, N 10.22, S 6.75.

Complex 3L1-(OTf)2 can also be obtained by O2 bubbling of the n class="Chemical">CuI complex [(L1-H)CuI](OTf) (2L1-H) (see synthesis of complex 3L2).

[(L2-O)2CuII2](OTf)2 (3L2-(OTf)2): Synthesis was carried out under N2. Into a solution of complex 1L2-(OTf)2 (0.03 g, 4.9 × 10−5 mol) in CH3CN (2 mL) was injected a KOH(aq) 1M (50 μL, 5.0 × 10−5 mol). Reaction was stirred until the violet intermediate formed faded to green (2–3 h). Slow diffusion of diethyl ether allowed the formation of green crystals in 65% isolated yield (0.011 g). ESI-MS (CH3CN): 799 [3L2-(OTf)]+, 325 [(L2-O)CuII]+; UV/Vis (CH3CN): λmax (ε) = 411 nm (1000), 765 nm (610); IR (KBr pellet, cm−1): 3258 (m), 3210 (m), 2931 (m), 2869 (m), 1592 (m), 1463 (s), 1282 (s), 1236 (s), 1162 (s), 1022 (s), 636 (s); elemental analysis calcd for C30H48N6O2Cu2(C2F6S2O6) (%): C 40.50, H 5.10, N 8.80, S 6.70; found: C 40.10, H 5.40, N 8.40, S 6.40.

Perchlorate complex n class="Chemical">3L2-(ClO4)2 is synthesized in a similar manner, and X-ray quality crystals of 3L2-(ClO4)2·CH3CN were obtained by recrystallization in CH3CN/ether.

Complex 3L2-(OTf)2 can also be obtained by O2 bubbling of the n class="Chemical">CuI complex [(L2-H)CuI](OTf) (2L2-H). Colorless complex [(L2-H)CuI](OTf) (0.025 g, 5.4 × 10−5 mol) in 2 mL CH3CN/CH2Cl2 1/3 under N2 is treated with 1.75 mL of dioxygen O2 (8.4 × 10−5 mol). Solution changes to violet slowly and after 3 h stirring fades to green. Slow diffusion of diethyl ether allowed isolation of bis-phenoxo complex 3L2-(OTf)2 in 25% isolated yield.

[(L3-O)2CuII2](OTf)2 (3L3-(OTf)2): synthesis was carried out under N2. Into a solution of complex 1L3-(OTf)2 (0.03 g, 5.05 × 10−5 mol) in CH3CN (2 mL) was injected a KOH(aq) 1M (50 μL, 5.0 × 10−5 mol). Reaction was stirred until the violet intermediate formed faded to green (1–2 h). Slow diffusion of diethyl ether allowed the formation of green crystals in 60% isolated yield (0.014 g). ESI-MS (CH3CN): 771 [3L3-(OTf)]+, 311 [(L3-O)CuII]+; UV/Vis (CH3CN): λmax (ε) = 436 nm (830), 756 nm (485); IR (KBr pellet, cm−1): 3336 (m), 3294 (m), 1591 (m), 1465 (m), 1280 (s), 636 (s).

Complex 3L3 can also be obtained from oxygenation of the corresponding n class="Chemical">CuI complex: colorless solution of complex [(L3-H)CuI](PF6) (2L1-H) (0.025 g, 5.57 × 10−5 mol) in 2 mL CH3CN/CH2Cl2 1/3 under Ar is treated with excess O2 at room temperature. Solution changes to violet and slowly and after 3 h stirring fades to green. Slow diffusion of diethyl ether allowed isolation of bis-phenoxo complex 3L3-(PF6)2 in 20% isolated yield. ESI-MS (CH3CN): 767 [3L3-(PF6)]+, 311 [(L3-O)CuII]+. Elemental analysis calcd for C28H44N6O2Cu2P2F6 (%): C 36.80, H 4.90, N 9.20; found: C 37.09, H 5.11, N 9.10.

X-ray diffraction analysis. The measurement was carried out on a n class="Chemical">BRUKER SMART APEX CCD diffractometer (Billerica, MA, US) using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). CCDC 2027155 (3L1-(OTf)2), 2027156 (3L2-(ClO4)2·CH3CN), 2027157 (3L3-(PF6)2) contain the supplementary crystallographic data for this paper.

4. Conclusions

In summary, seven well-defined n class="Chemical">aryl-CuIII complexes featuring different ring sizes and different electronic properties have been reacted with water in basic conditions to produce intriguing bis-phenoxo-CuII2 complexes (3L1–3L6), 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 (L4) favors square-pyramidal geometry, whereas 13-membered (L1) and 14-membered macrocyclic rings (L2–L3) favored trigonal bipyramidal geometries [39]. 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 [(Lx-H)CuI](OTf) (2Lx-H) complexes react with O2 to undergo 1e− oxidation to CuII and subsequent C-H activation via disproportionation to form aryl-CuIII species, which then undergo the same reaction path towards bis-phenoxo-CuII2 complexes. Facile formation of bis-phenoxo-CuII2 complexes through aryl-CuIII reductive elimination with basic water is shown, and also the formal aromatic hydroxylation of arene substrates (Lx-H) via aryl-CuIII is mechanistically unraveled.