Anaerobic photoinduced Cu(0/I)-mediated Glaser coupling in a radical pathway

The reaction mechanism of the historic copper-catalyzed Glaser coupling has been debated to be based on redox cycles of Cu ions in specific oxidation states or on a radical mechanism based on Cu(0)/Cu(I). Here, the authors demonstrate two coexisting Glaser coupling pathways which can be differentiated by anaerobic/irradiation or aerobic reaction conditions. Without O2, copper(I) acetylides undergo a photo-excited pathway to generate highly reactive alkynyl radicals, which combine together to form a homo-coupling product or individually react with diverse X-H (X = C, N, O, S and P) substrates via hydrogen atom transfer. With O2, copper(I) acetylides are oxidized to become a Cu-acetylide/Cu-O merged Cu(I/II) intermediate for further oxidative coupling. This work not only complements the radical mechanism for Glaser coupling, but also provides a mild way to access highly energetic alkynyl radicals for efficient organic transformations.

Siqi Zhang 1,2 & Liang Zhao 1 The reaction mechanism of the historic copper-catalyzed Glaser coupling has been debated to be based on redox cycles of Cu ions in specific oxidation states or on a radical mechanism based on Cu(0)/Cu(I).Here, the authors demonstrate two coexisting Glaser coupling pathways which can be differentiated by anaerobic/irradiation or aerobic reaction conditions.Without O 2 , copper(I) acetylides undergo a photo-excited pathway to generate highly reactive alkynyl radicals, which combine together to form a homo-coupling product or individually react with diverse X-H (X = C, N, O, S and P) substrates via hydrogen atom transfer.With O 2 , copper(I) acetylides are oxidized to become a Cu-acetylide/Cu-O merged Cu(I/II) intermediate for further oxidative coupling.This work not only complements the radical mechanism for Glaser coupling, but also provides a mild way to access highly energetic alkynyl radicals for efficient organic transformations.
Glaser coupling reaction of terminal alkynes is a classical textbook reaction with over 150-year history 1 .It provides an indispensable and easily accessible synthetic approach to efficiently construct 1,3-diynes as an important building block in polymers [2][3][4] , macrocycles [5][6][7] and rigid supramolecular architectures [8][9][10] .Starting from the initial catalyst version in 1869 by using CuCl and NH 4 OH under O 2 atmosphere 11 , it has evolved from the combination of Cu(II)-acetate and pyridine to the most popular CuCl-TMEDA(N,N,N',N'-tetramethylethylenediamine) adduct established by Hay and co-workers 12 .Continuous mechanistic studies have revealed that Cu(I) acetylides as a key intermediate probably experience oxidation by O 2 to generate a dimeric Cu(II) acetylide species [13][14][15] towards the final oxidative coupling step (Fig. 1a).Nevertheless, the composition and structure of catalytically active Cu(I)-acetylide intermediates remains elusive because synthetic Cu(I) acetylides are easily aggregated into insoluble polymers with low kinetic activity in chemical reactions.Lately, a Cu(I)-Cu(II) synergistic model was proposed as an alternative intermediate based on X-ray absorption spectroscopy investigations 16 .In addition, Cu(II)-alkynyl species [17][18][19][20] are also considered as key intermediates in both Glaser coupling and other copper-catalyzed organic transformations [21][22][23] , which readily disproportionate by other Cu(II) complexes to generate high valence Cu(III) species for the completion of the oxidative coupling as a result of the Cu(I)-Cu(II)-Cu(III) redox cycle (Fig. 1b).On the other hand, a radical-involved mechanism in terms of the oxidation of acetylide by Cu(II) has been proposed at the very early stage of Glaser coupling in 1936 24,25 .However, it was subsequently repudiated in view of harsh conditions for the generation of alkynyl radicals (C(sp)-H bond dissociation energy ≈ 130 kcal mol −1 ) and their short life time [26][27][28][29] .To date, the detailed mechanism of the Glaser coupling is still a largely unsolved problem, primarily owing to the complexity of variable copper oxidation states and a diverse range of possible copper-oxygen intermediates.
In this work, we demonstrate two different Glaser coupling pathways under anaerobic and aerobic conditions by means of a macrocycleencircled octanuclear Cu(I)-acetylide cluster [(PhC≡C) 4 Cu I 8 (MeCN) 4 ] @Py [8] (1) (Py [8] = azacalix [8]pyridine).In the absence of O 2 and under the irradiation of visible light, 1 undergoes a homo-coupling pathway as similar as the common Cu(I)/O 2 -based Glaser reaction.The radical trapping and EPR monitoring experiments validate the in situ generation of highly reactive alkynyl radicals upon photoexcitation (Fig. 1c).Moreover, the energetic Ph-C ≡ C • exhibits high hydrogen atom transfer (HAT) reactivity towards diverse X-H (X = C, N, O, S, and P) substrates.In the presence of O 2 , 1 could be oxidized to form a Cu-acetylide/Cu-O merged Cu(I/II) cluster [(PhC≡CCu II Cu I )-(μ 2 -O)-Cu II ]@Py [8] (2) as the first isolated mixed-valence bicopper acetylide intermediate.The release of the merged Cu(I/II) cluster core out from the macrocycle leads to the homo-coupling product as well (Fig. 1d).Thus, the anaerobic/photoexcitation and aerobic conditions distinguish two feasible coupling pathways of the historic Glaser reaction.The unprecedented radical mechanism via a O 2 -free photo-induced Cu(0/I)-mediated process not only provides a mild way to access highly energetic alkynyl radicals for efficient organic transformations, but also exemplifies a new mechanistic perspective for copper-catalyzed alkynylation and photo-induced transformations 29,30 .

Results
Macrocycle-encircled Cu(I)-acetylide cluster 1 Cu(I) acetylides are supposed as key intermediates in many Cu/O 2 catalyzed coupling reactions.However, their structures vary with the substituted groups on terminal alkynes from polymeric, oligomeric to discrete clusters 31,32 .Therein, the polymeric (e.g., [(PhC≡CCu I ) ∞ ] as a chain polymer) or oligomeric (e.g., the interlocking ring-like [( t BuC≡CCu I ) 20 ]) copper acetylides show almost no kinetic activity due to its extremely poor solubility.In a practical reaction system, it is expected that low nuclearity soluble Cu(I)acetylide clusters derived from insoluble crude copper acetylides actually act as true catalytically active species, while their composition and dynamic structural variation remain elusive.We herein attempt to destruct the polymeric copper acetylides and stabilize active Cu(I)-acetylide cluster segments by coordinative and protective macrocyclic ligands.The anaerobic treatment of Ph-C ≡ C-TMS with [Cu(CH 3 CN) 4 ](BF 4 ) in the presence of the macrocyclic ligand azacalix [8]pyridine (Py [8]), which is composed of eight 2,6-pyridine rings annularly bridged by eight NCH 3 groups, led to a yellow crystalline compound.Its chemical formula was characterized by X-ray crystallographic analysis as [Cu 8 (μ 3 -PhC≡C) 4 (CH 3 CN) 4 (Py [8])](BF 4 ) 4 •3(CH 3 OH)•(H 2 O) (1).Therein, the cluster moiety within Py [8] is properly described as four identical [PhC≡CCu I 3 ] units fused by sharing four central Cu(I) atoms (Fig. 2a).The phenylacetylide group in each [PhC≡CCu I 3 ] unit adopt a mixed σ/π μ 3 -η 1 ,η 1 ,η 2 mode to interact with three Cu(I) atoms.This rhombus-like Cu 4 plane in 1 shows high geometric and dimensional similarity with the repeating unit of the previously reported polymeric [(PhC≡CCu I ) ∞ ] determined by X-ray powder diffraction 32,33 .
Further structural characterizations by electron-spray ionization mass spectroscopy (ESI-MS), X-ray photoelectron spectroscopy (XPS), and electron paramagnetic resonance (EPR) spectra identified the composition and oxidation states of copper ions in 1.The XPS measurement (Supplementary Fig. 1) shows only one intensive peak at 932.8 eV for Cu 2p under X-ray irradiation of 1486.6 eV.In combination with the Cu LMM Auger spectrum at 571.2 eV, the corresponding Auger parameter is deduced to be 1848.0eV, which is close to the standard Cu(I) sample CuCl (1847.6 eV) 34 .Therefore, the copper ions in 1 are assigned as 1+ oxidation state, which is also verified by the EPR silent feature (Supplementary Fig. 2) and a high-resolution ESI-MS peak at m/ z = 2021.0278corresponding to ([Cu I 8 (PhC≡C) 4 (Py [8])(BF 4 ) 3 ] + , Supplementary Fig. 3).

Anaerobic photoinduced Glaser coupling of 1 in a radical pathway
Under the irradiation of visible light at 432 nm, the solid of 1 exhibited an intensive green emission at λ em = 530 nm (Supplementary Fig. 4).However, the photo-excitation of 1 in solution resulted in quick quenched luminescence even under N 2 atmosphere (Fig. 2b), which was accompanied with the solution color change from yellow to dark orange.TEM monitoring revealed an irradiation-caused stepwise aggregation from nanoclusters (d ≈ 5 nm) to large nanoparticles (d ≈ 150 nm, Fig. 2c and Supplementary Fig. 5).This process was also validated by a series of mass spectra peaks with escalating molecular weights (Supplementary Fig. 6).Furthermore, GC-MS monitoring on the photo-irradiated solution identified the formation of the homocoupling PhC≡C-C≡CPh as a major organic product (Supplementary Fig. 7).In order to make clear the possible redox cycle in the photoirradiated transformation, we conducted XPS measurement on the isolated product, which showed no characteristic shake-up peak of Cu(II) (Supplementary Fig. 8).Further peak fitting illustrated two intensive peaks at 932.3 and 932.8 eV for Cu 2p in a ratio of 2:1 under X-ray irradiation of 1486.6 eV.In combination with the Cu LMM peaks at 570.6 and 568.1 eV respectively, the corresponding Auger parameters were deduced as 1848.3 and 1851.3 eV, which are in good consistence with the standard 1+ sample CuCl (1848.0eV) and metallic Cu(0) (1851.3eV).In addition, the EPR silence result also confirmed no Cu(II) formed during this photo-induced coupling reaction (Supplementary Fig. 9).We next tried to gain detailed mechanistic insights into this Cu(0/I)-mediated Glaser type coupling under the anaerobic/photoinduced condition.Firstly, a cross reaction of 1 and its F-substituted analogue 1-F ([(4-F-C 6 H 4 -C≡C) 4 Cu I 8 (MeCN) 4 ]@Py [8]) under irradiation was applied to make sure that the coupling reaction is intra-or inter-molecular.The identification of both homo-and hetero-coupling products substantiates its inter-molecular pathway (Supplementary Fig. 10).In combination with the vide supra Cu(0)/ Cu(I) redox cycle and a considerable yield of 25% for the heterocoupling product 4-F-C 6 H 4 -C≡C-C≡C-Ph, we postulate a possible radical-based reaction pathway that includes the homolysis split of RC ≡ C-Cu(I) to generate RC≡C • and the further combination of two alkynyl radicals outside the Py [8] macrocycle to form either homoor hetero-coupling products (Fig. 3a).This radical-based Glaser type coupling pathway has been rarely paid attention due to the difficult generation of alkynyl radicals (C(sp)-H bond strength ≈ 130 kcal mol −1 ), which generally requires a very high reaction temperature.
The generation of highly energetic phenylethynyl radicals in the photo-induced Glaser type coupling of 1 was confirmed by radical trapping experiments.The employment of TEMPO 28 or 1,1diphenylethylene 35,36 yielded the radical trapping adducts 3 and 4 as evidenced by HR-MS (Fig. 3b and Supplementary Fig. 12).A similar radical trapping experiment of 1-F also resulted in two corresponding radical trapping adducts 3-F and 4-F (Supplementary Fig. 13).Moreover, EPR spin-trapping experiments with DMPO (5,5-dimethyl-1-pyrroline N-oxide) offer a more direct approach to identify the phenylethynyl radical 28 .The irradiation on the mixed sample [1 + DMPO] showed intensive EPR signals that can be assigned as a carbon species-based radical 5 (A Hβ = 22 G; A N = 15 G) based on simulation (Fig. 3c).In the control experiments of [1 + DMPO] in the dark (Fig. 3c) or just the DMPO under irradiation, no EPR signals were detected (Supplementary Fig. 14).
The energetic alkynyl radicals in situ generated by the photoinduced transformation of 1 showed high reactivity with diverse X-H substrates including alkynes, amines, alcohols, thiols, and phosphines.As a result of hydrogen atom transfer (HAT) between the active Ph-C ≡ C • and the X-H substrates, a series of desired radicals (MeO   15), which is generally formed by exciting the ammonia gas at a high temperature.Furthermore, we also applied diyne substrates to verify the feasibility of radical transfer.As evidenced by HR-MS, a diversity of oligomer products via multi-step coupling were identified (Fig. 4 and Supplementary Fig. 16).The homocoupling product of the diyne substrate itself provides further evidence for the photo-induced radical transfer mechanism.
Furthermore, we found that the O 2 -free photo-induced Cu(0/I)mediated Glaser coupling pathway is also applicable to the polymeric [(PhC≡CCu) ∞ ] (6).Despite of the poor solubility of 6, the corresponding radical trapping adduct 5 was also generated either in [6 + DMPO] (Fig. 3c) or [6 + DMPO] with Py [8] or the commonly used auxiliary ligands such as TMEDA and 1,10-phenanthroline (Supplementary Fig. 17).Moreover, the radical transfer of the newly generated Ph-C ≡ C • towards X-H (X = N, O, S, and P) substrates via HAT also worked very well (Supplementary Fig. 18).These results collectively substantiate that this novel alkynyl radical pathway under anaerobic and photo-induced condition is universal in the common Glaser coupling reaction.
The release of the merged [(PhC≡CCu II Cu I )-(μ 2 -O)-Cu II ] core from Py [8] by heating or adding coordinative solvents (e.g., CH 3 CN) led to the homo-coupling diyne product as well (Supplementary Fig. 23).Meanwhile, along with the addition of CH 3 CN, the EPR signature for Cu(II) in 2 disappeared immediately (Fig. 5c), which should be attributed to the Cu(II)-mediated reductive elimination of phenylacetylides in the merged [(PhC≡CCu II Cu I )-(μ 2 -O)-Cu II ] core.In contrast, no coupling reactions took place if irradiating 2 by visible light (Supplementary Fig. 24).Clearly, two different pathways including the photoinduced Cu(0/I)-mediated radical coupling of 1 and the synergistic Cu(I/II)-mediated oxidative coupling of 2 co-exist in the macrocyclebased copper acetylide system, and they are differentiated by anaerobic/photo-excitation or aerobic conditions.

Discussion
Cu/O 2 -catalyzed C-C and C-heteroatom coupling reactions have been a continuance attention hotspot ever 39 .To date, a number of important copper-oxygen or organo-copper complexes with high absorption of visible light have been identified as active intermediates 39,40 , which

General Information
All commercially available chemicals were used without further purification.The solvents used in this study were processed by standard procedures.Mass spectra were obtained using a Thermo Scientific Exactive Orbitrap instrument.UV-vis measurements were performed using Agilent Cary 7000 UV-Vis-NIR spectrophotometer.EPR experiments were carried out using JEOL JES-FA200 ESR Spectrometer and CIQTEK EPR100.Transmission electron microscopy (TEM) measurements were performed on Hitachi H-7650 microscope.Luminescent spectra were recorded on an Edinburgh spectrofluorimeter (FLS980).Luminescent decay experiments were measured on an Edinburgh FLS980 spectrometer using time-correlated single photon counting (TCSPC).The details of X-ray crystallographic measurements are summarized in X-ray Crystallographic Analysis.Octamethylazacalix [8]  pyridine (Py [8]) macrocycle was synthesized according to the reported synthetic protocol 41 by Pd-catalyed [3 + 5] fragment coupling reactions between a terminal dibrominated linear pentamer and a terminal diaminated linear trimer.(Py [8])](BF 4 ) 4 ) The synthetic procedure for 1-F was similar to that of 1 but using 4-F-

Computational details
Theoretical calculations of 2 were performed using the Gaussian 09 program 42 .Initial structures for natural bond orbital (NBO) analysis of 2 for calculations were built up on the basis of single-crystal structure.
Becke three parameter hybrid functional accompanied by Lee-Yang-Parr correlation functional (B3LYP) 43,44 was employed in DFT calculation without any symmetry constraints on molecular structures.Dunning correlation-consistent basis set ccpVTZ-pp (a triple-ζ basis set) 45,46 was applied for copper atoms and 6-311 G** basis set 47 for other atoms in NBO calculation.The Hay and Wadt effective core potentials with a double-ζ basis set (LanL2DZ) [48][49][50][51] were applied for copper atoms and 6-31 G basis set 47 for other atoms in optimization for molecular orbitals.The root is set as 1 in all of the DFT calculations.

Fig. 1 |
Fig. 1 | Distinct proposed mechanisms for the Glaser coupling.a Dimeric Cu(II) acetylides as key intermediates.b Disproportionation of Cu(II)-alkynyl species.c Anaerobic photoinduced coupling mediated by Cu(0/I) in a radical pathway.d Aerobic oxidative coupling mediated by a merged Cu(II) acetylide and Cu-O species.

Fig. 2 |
Fig. 2 | Structural characterization of 1. a Crystal structure and the cluster core of 1 with partial atom labeling (50% thermal ellipsoid probability level).Hydrogen atoms, BF 4 ˉanions and solvent molecules are omitted for clarity.b Absorption and emission spectra of 1 in dichloroethane (DCE) with different scan times.c TEM images of 1 under the irradiation of λ ex = 420 nm at different intervals.

Fig. 3 |
Fig. 3 | Photo-induced radical mechanism and radical transfer from Ph-C≡C • in 1. a Cross experiment of 1 and 1-F in propylene carbonate (PC) under the irradiation at 420 nm in N 2 atmosphere for 30 min.b Radical trapping experiments for 1 in PC under irradiation with different radical capture agents (left: TEMPO; right: 1,1-diphenylethylene) for 10 min.c Experimental and simulated EPR spectra of 1 and 6 with DMPO under in situ irradiation with Xenon lamp (filter >360 nm) in N 2 atmosphere.EPR signals with triangle are assigned as the oxidized product of DMPO.Simulations are listed in Supplementary Fig.11.

Fig. 4 |
Fig. 4 | Radical transfer between Ph-C ≡ C • and various X-H substrates.Experimental and simulated EPR spectra of 1 plus X-H substrates with DMPO in PC under in situ irradiation (Xenon lamp, filter >360 nm) in N 2 atmosphere.BDE is the abbreviation of bond dissociation energy.EPR simulations are listed in Supplementary Fig. 15.HR-MS spectra for the oligomerized products in PC under the irradiation at 420 nm in N 2 atmosphere for 30 min are shown in Supplementary Fig. 16.