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. 2026 May 22;65(29):e6050863. doi: 10.1002/anie.6050863

Spin‐State Dichotomy of On‐Cycle Cobalt(II) Organometallics Informs Polar Cobalt(0/II) Versus Radical Cobalt(I/II/III) Cross‐Coupling Mechanisms

Kavita Choudhary 1, Bhaswati Paul 1, L Reginald Mills 1,✉
PMCID: PMC13360549  PMID: 42169555

ABSTRACT

A well‐defined, single‐component precatalyst N,N,N′,N′‐tetramethylethylenediamine (TMEDA)cobalt(II) dibromide catalyzed Negishi arylation reactions of alkyl bromide, N‐hydroxyphthalimide ester, and (hetero)aryl halide electrophiles, exhibiting both C(sp2)─C(sp2) and C(sp2)─C(sp3) bond‐formation. Organometallic reactions of relevant weak field ligand cobalt(II) dihalide complexes with arylzinc reagents demonstrated monoarylation, yielding a series of isolable high spin (S = 3/2) cobalt(II)–monoaryl bromide compounds supported by TMEDA, 3,5‐lutidine, or bis(oxazoline) (BOX) ligands. Relevant to C(sp2)–C(sp2) cross‐coupling, cobalt(II)–monoaryl bromide complexes reacted with arylzinc nucleophiles to yield TMEDA‐supported and bpy‐supported low‐spin (S = 1/2) cobalt(II)–diaryl complexes, which underwent reductive elimination in acetonitrile to provide direct evidence for cobalt(0/II) cycles. In C(sp2)─C(sp3) Negishi cross‐coupling reactions, the isolated TMEDA‐supported and BOX‐supported cobalt(II)–monoaryl complexes were determined to be catalyst resting states by 1H and 19F NMR spectroscopies in acetonitrile‐d3 . Stoichiometric reactions demonstrated high spin (TMEDA)cobalt(II)–monoaryl to be competent for alkyl bromine atom abstraction and for alkyl radical capture, yielding C(sp2)─C(sp3) product by reductive elimination at (TMEDA)cobalt(III). These data demonstrated the versatile reactivity of high‐spin (S = 3/2) cobalt(II)–monoaryl and low‐spin cobalt(II)–diaryl (S = 1/2) complexes, engaging productive closed‐shell cobalt(0/II) or open‐shell cobalt(I/III) cross‐coupling mechanisms depending on the aryl or alkyl electrophile substrate.

Keywords: catalysis, cobalt, cross‐coupling, mechanism, organometallics

While metal–aryl intermediates are central to all cross‐coupling reactions, for state‐of‐the‐art cobalt‐catalyzed C(sp2)─C(sp2) and C(sp2)─C(sp3) cross‐coupling reactions, the identities of key organocobalt intermediates have been elusive. This work describes the synthesis, isolation, and reactivity of paramagnetic cobalt(II)–aryl compounds, which proved to be on‐cycle catalytic intermediates for Negishi arylation of a variety of (hetero)aryl and alkyl substrates.

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1. Introduction

For the implementation of new methods in pharmaceutical synthesis, well‐established reactivity principles are necessary for effective, robust reaction processes [1]. Indeed, some of organic chemistry's premier achievements have entailed theories of reactivity that enable both chemical understanding and rational reaction design [2]. In carbon–carbon bond‐forming reactions catalyzed by transition metals, organometallics are central intermediates [3], such that organometallic study precedes the catalytic mechanistic understanding needed to develop reproducible and efficient catalysts [4]. As catalysis by Earth‐abundant transition metals becomes more common in pharmaceutical reactions [5], the development of reactivity principles employing these catalysts is essential for optimizing methodologies and designing new strategies for synthetic disconnections [1, 6].

Among Earth‐abundant transition metal catalysts, those based on cobalt exhibit synthetic versatility, long‐established for enabling both C(sp2)─C(sp2) and C(sp2)–C(sp3) bond‐forming reactions [7, 8, 9, 10]. While other metals such as nickel or copper catalyze broadly similar reactions [5], cobalt(II) may be especially poised for the cross‐coupling of alkyl partners, due to its inherent open‐shell character that enables the generation and capture of alkyl radical intermediates [11] and lower propensity for β‐hydride elimination in high‐spin configurations [12]. Indeed, early work from Knochel and coworkers demonstrated cobalt‐catalyzed alkyl–alkyl Negishi cross‐coupling [13, 14], with many other cobalt‐catalyzed Negishi reactions developed since then, including C(sp2)–C(sp2) and C(sp2)–C(sp3) Negishi couplings (Figure 1a) [15, 16, 17, 18, 19], especially demonstrating wider C(sp2)–C(sp3) development compared to nickel‐ [20] or iron‐catalyzed [21] Negishi reactions [22]. These reports established some optimal precatalyst systems, with versatile supporting ligands for cobalt being of type N,N, including N,N,N’,N’‐tetramethylethane‐1,2‐diamine (TMEDA) [23, 24], neocuproine [25], and 2,2’‐bipyridyl (bpy) [25, 26, 27, 28], implying the persistence of weak ligand fields and productive, high‐spin catalytic intermediates (Figure 1a) [29].

FIGURE 1.

FIGURE 1

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Cobalt‐catalyzed Negishi cross‐coupling of C(sp2) and C(sp3) electrophiles.

While the Negishi methodology development with cobalt has been fruitful, the direct characterization of cobalt cross‐coupling catalysts has been less well developed, especially compared to that of other first‐row cross‐coupling catalysts of nickel [30] or of copper [31]. Indeed, after decades of work on cobalt‐catalyzed carbon–carbon bond‐forming reactions, limited organocobalt cross‐coupling catalysts have been identified. For the common cases of C(sp2)–C(sp2) and C(sp2)–C(sp3) Negishi cross‐coupling, there is yet no general consensus on relevant geometries, coordination numbers, oxidation states, or pathways of catalyst initiation when cobalt(II) precatalysts are employed [32, 33, 34]. Partly, this may be attributed to limited organometallic precedent of catalytic intermediates. For instance, while metal–aryl intermediates are central to all catalytic arylation reactions, few arylcobalt(II) compounds exist bearing ligands relevant to cross‐coupling (Figure 1b). Most of these arylcobalt(II) examples include bulky di(2‐mesityl)cobalt(II) complexes [35, 36, 37, 38] or aryl complexes with bulky ancillary ligands (Figure 1b) [39]. Notably, to date all isolated cobalt–aryl complexes demonstrate steric protection of the metal center and exhibit strong ligand fields (Figure 1b), limiting the organometallic relevance toward generally observed (N,N)cobalt‐catalyzed cross‐coupling reactions in presumed weak ligand fields with sterically accessible catalyst centers. The lack of well‐defined weak‐field cobalt(II)–aryls anecdotally corroborates the proposed instability of cobalt(II)–aryl halide complexes drawn by Kharasch and coworkers in 1941 (Figure 1c) [40]. Therefore, when employing cobalt(II) dihalide precatalysts, it is ambiguous if on‐cycle arylcobalt complexes are cobalt(II)–monoaryls, with the vast majority of proposed mechanisms drawing initial rapid reduction of the starting cobalt(II) dihalide to the proposed on‐cycle cobalt(I) [41].

The limited examples of arylcobalt compounds anecdotally demonstrate the challenge in isolation and/or characterization of such paramagnetic complexes; however, catalytic intermediates such as cobalt(II)–aryls in principle should be thermodynamically accessible, and therefore assignable, which is necessary for developing productive catalyst design principles. To tackle this need for organocobalt catalytic principles, herein are investigated the synthesis and isolation of (N,N)cobalt–aryl complexes supported by catalytically relevant ligands (Figure 1d). In particular, major unknown questions involved the identities of organocobalt intermediates during cross‐coupling reactions that employ cobalt(II) precatalysts, including oxidation state, coordination number, and spin state. These studies were thus conducted with the goal of elucidating productive synthetic and characterization strategies for these catalytic intermediates.

2. Results and Discussion

With an interest in understanding cobalt cross‐coupling catalysts supported by weak ligand fields, initial reactions evaluated Negishi arylation catalyzed by a prototypical well‐defined, single‐component precatalyst (TMEDA)cobalt(II) dibromide (Figure 2) [23, 42]. Negishi cross‐coupling reactions of interest included the arylation of C(sp3) electrophiles, such as secondary alkyl halide (1a‐1b) [43, 44], redox‐active ester (2a–2b) [45], and (hetero)aryl halide (3a–3b) [16]. Employing one equivalent of the desired electrophile (1–3), a diarylzinc reagent as a nucleophile, and catalytic 10 mol% of the (TMEDA)cobalt(II) dibromide in an appropriate solvent (MeCN/THF or DMA/THF), the generality of (TMEDA)cobalt(II) dibromide catalyst toward cross‐coupling was measured in the yield of the C–C bond‐formed cross‐coupled product (Figure 2). In C(sp2)–C(sp3) cross‐coupling reactions, arylation was achieved of N‐Boc‐4‐bromopiperidine (4a, 96%), ethyl 2‐bromopropanoate (4b, 68%), N‐hydroxphthalimide esters of L‐proline (4c, 56%), and oxaprozin (4d, 52%) (Figure 2). Precatalyst (TMEDA)cobalt(II) dibromide also proved viable for cross‐coupling of heteroaryl electrophile 2‐chloro‐6‐fluorobenzothiazole (3a) [46] and of aryl halide 4‐bromobenzonitrile (3b), yielding the C(sp2)–C(sp2) products in 63%–65% yield (4e–4f). The reactivity observed with TMEDA was also observed with comparable weak‐field ligands, for instance, bis(benzyloxazoline) R,R‐Bn‐BOX in α‐arylation (4b, 78%) [44] and 2,2’‐bipyridyl (bpy) in biaryl coupling (4g, 50%) [28]. These data implicated the (N,N)‐supported compound (TMEDA)cobalt(II) dibromide as a generally catalytically relevant complex for cobalt‐catalyzed Negishi cross‐coupling, and implied that its reactivity might be comparable to and/or instructive toward other cobalt‐catalyzed cross‐couplings with weak‐field N,N ligands.

FIGURE 2.

FIGURE 2

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Representative Negishi arylation reactions catalyzed by (TMEDA)cobalt(II) dibromide. Reactions performed on 0.20–0.30 mmol scale. aEmploying (4‐F‐C6H4)2 Zn instead of (4‐F‐C6H4)2Zn•TMEDA. bEmploying 10 mol% (R,R)‐Bn‐BOX ligand + 10 mol% CoBr2 instead of (TMEDA)CoBr2. cEmploying 10 mol% CoBr2 instead of (TMEDA)CoBr2. dReaction performed at 50°C. eEmploying 10 mol% (bpy)CoBr2 instead of (TMEDA)CoBr2.

While TMEDA is commonly used as an additive in cobalt‐catalyzed cross‐coupling [23, 25, 47, 48, 49, 50], the data herein demonstrated that TMEDA acts as an L2‐type ancillary ligand for the high‐spin (S = 3/2) cobalt(II) dibromide precatalyst. However, imperfect selectivity for the formation of the desired cross‐coupled products left important unanswered questions about the nature of cobalt‐catalyzed carbon–carbon bond‐formation and side‐reaction pathways. While organometallic intermediates were proposed as essential for bond‐forming steps, limited established examples of cross‐coupling‐relevant TMEDA‐supported organometallics restricted the insight that could be gained a priori. Therefore, initial experiments targeted the synthesis of catalytically relevant (TMEDA)cobalt organometallics to inform thermodynamically preferred oxidation and spin states.

The initial target complexes entailed (TMEDA)cobalt(II)–aryls, which derive from the transmetalation of the diarylzinc nucleophile with the (TMEDA)cobalt(II) dibromide catalyst. Particularly, phenylcobalt(II) chloride was proposed as early as 1941 by Kharash [40], and elsewhere, metal–aryls are common intermediates in nearly all C(sp2) cross‐coupling reactions. However, examples of cobalt–aryls supported by weak ligand fields are rare, leaving significant unknowns about favored coordination chemistry, oxidation state, and electronic structure. A related compound, high‐spin (TMEDA)cobalt(II) bis(neosilyl) reported by Wilkinson, Hursthouse, and coworkers [51, 52], suggested that analogous (TMEDA)cobalt(II)–aryls might be isolable. Thus, an initial transmetalation reaction was performed between (TMEDA)cobalt(II) bis(acetylacetonate) [53] and solid arylating reagent (TMEDA)magnesium(II) bis(4‐fluorophenyl) (Scheme 1). In PhMe solution, stirring one equivalent of pink‐red (TMEDA)Co(acac)2 with one equivalent of (TMEDA)Mg(4‐F‐C6H4)2 resulted in an immediate solution color change to blue, followed by subsequent precipitation of Co0‐black nanoparticles within 5 min at ambient temperature (21°C), with aryl homodimer 4,4′‐difluorobiphenyl (5a) detected as the only fluorine‐containing product by 19F NMR spectroscopy (Scheme 1). These data indicated a reaction of the diarylmagnesium reagent with (TMEDA)Co(acac)2, which resulted in facile reductive aryl homodimerization, evidencing the instability of putative (TMEDA)cobalt(II)–diaryl and of cobalt(0) under reaction conditions.

SCHEME 1.

SCHEME 1

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Diaryl reductive coupling mediated by cobalt(II).

Due to excess aryl nucleophile leading to diaryl reductive elimination at cobalt(II), modification of the stoichiometry of the diarylmagnesium reagent led to the formation of isolable compounds (6a–6c) when 0.30 equivalents of the diarylmagnesium reagent were stirred with (TMEDA)Co(acac)2 (Table 1). The procedure was performed using the series of diarylmagnesium reagents di(4‐fluorophenyl), di(2‐methyl‐4‐fluorophenyl), and di(2‐tolyl), with substoichiometric magnesium(II) bromide (0.5 equiv) added to ensure complete acac‐to‐bromide substitution. In acetonitrile‐d3 solution at 25°C, the 1H NMR spectra of compounds 6a–6c exhibited broad, paramagnetically shifted signals between 292.1 and 13.1 ppm, evidencing formation of compounds of general structure (TMEDA)cobalt(II)–monoaryl bromide (6a–c), which were isolable as a 1:1 mixture with (TMEDA)CoBr2 apparent by 1H NMR spectroscopy in all cases (Table 1). At 77 K, samples of 6a–6c in glassy PhMe exhibited broad, high‐spin signals by X‐band EPR spectroscopy, which was consistent with the 25°C solution‐state magnetic moments of 3.6(3)–3.8(3) μ B and assignment as high‐spin (S = 3/2) cobalt(II) centers. These conditions were generalized to other catalytically relevant weak field ligands, including monodentate 3,5‐lutidine (6d) and R,R‐Bn‐BOX (6e), additionally informing their coordination chemistry. Identification of the series of fluoroaryl compounds was apparent by 19F NMR spectroscopy in acetonitrile‐d3 or benzene‐d6 solution, exhibiting paramagnetically shifted signals at 72.2–77.4 ppm (6a–6b, 6d–6e). The successful isolation of cobalt(II)–monoaryl halide compounds (6a–6e) was also noted to be sensitive to the substoichiometry (0.3 equiv) of diarylmagnesium reagent employed, proposed due to even small amounts of cobalt(0) formation by diaryl reductive elimination resulting in autocatalytic decomposition of the rest of the cobalt(II)–aryl material via comproportionation (Figure S19).

TABLE 1.

Synthesis of high‐spin (S = 3/2) (TMEDA)cobalt(II) monoaryl bromide compounds a .

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a

Due to instability, compounds 6a–6d were isolated as 1:1 mixture of (L2)CoX(Aryl) (6a–6d) and (L2)CoX2; the yield represents the combined yield of the 1:1 mixture (see Supporting Information for details).

b

Determined at 25°C in benzene‐d6 .

c

Employing (3,5‐lut)2CoCl2 and 0 equiv of MgBr2 instead of Co(acac)2.

Although all experiments indicated putative diaryl (TMEDA)cobalt(II) di(fluorophenyl) to be unstable toward isolation, understanding the structure of cobalt(II)–diaryls was still of interest, particularly for informing the mechanism of C(sp2)–C(sp2) bond‐formation that was apparent when reductive aryl homodimerization occurred (Scheme 1). To target cobalt(II)–diaryl formation, transmetalation of 2,6‐ and 2‐substituted diarylmagnesium reagents was performed for TMEDA and bpy complexes, forming compounds of identity (TMEDA)Co(2,6‐Me‐4‐F‐C6H2)2 (7a) and (bpy)Co(2‐Me‐4‐F‐C6H3)2 (7b) (Scheme 2). By 1H NMR spectroscopy, both (TMEDA)Co(2,6‐Me‐4‐F‐C6H2)2 (7a) and (bpy)Co(2‐Me‐4‐F‐C6H3)2 (7b) exhibited paramagnetically broadened signals between 135.3 and −33.0 ppm, and by 19F NMR spectroscopy, displayed paramagnetically shifted signals at −153.1 ppm (7a) and −145.5 ppm (7b). In frozen THF at 77 K, the X‐band EPR spectrum of (TMEDA)Co(2,6‐Me‐4‐F‐C6H2)2 (7a) displayed a pseudoaxial signal (g = 3.01, 3.02, 1.85) with large eight‐line hyperfine coupling of 950, 953, and 450 MHz to a single cobalt nucleus (I = 7/2) in the respective g‐tensors (Figure 3), all data together consistent with square‐planar, low‐spin (S = 1/2) cobalt(II) centers in both cases (7a–7b).

SCHEME 2.

SCHEME 2

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Synthesis of low‐spin (S = 1/2) complexes (TMEDA)cobalt(II)–diaryl (7a) and (bpy)cobalt(II)–diaryl (7b). aDetermined in the solid state at 21°C. bDetermined by benzene‐d6 at 25°C.

FIGURE 3.

FIGURE 3

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CW X‐band EPR spectrum of compound 7a in frozen THF at 77 K. Experimental parameters: frequency = 9.662 GHz, power = 0.316 mW, and modAmp = 1 G. Simulation parameters: g 1 = 3.01, g 2 = 3.02, g 3 = 1.85; g strain = (0.50, 0.20, 0.10); A Co = 950, 953, 450 MHz; A strain = (77, 62, 0).

The electronic structures of (TMEDA)cobalt(II)–aryls (6a–e, 7a–b) were further informed by their solid‐state structures determined by X‐ray diffraction (Figure 4). The structures of cobalt(II)–monoaryl halides (TMEDA)CoBr(4‐F‐C6H4) (6a), (TMEDA)CoBr(2‐Me‐4‐F‐C6H3) (6b), and (3,5‐lut)2CoCl(2‐Me‐4‐F‐C6H3) (6d) exhibited idealized tetrahedral geometry, expected for high‐spin (S = 3/2) cobalt(II). These data demonstrate rare examples of tetrahedral, high‐spin (S = 3/2) cobalt(II)–aryl compounds obtained by transmetalation at a cross‐coupling catalyst, evidencing that it is the stable initial product of transmetalation; and, with the appropriate supporting ligand, the cobalt(II)–monoaryl halide does immediately undergo reductive homodimerization as proposed by Kharasch [40]. The diaryl compounds (TMEDA)Co(2,6‐Me‐4‐F‐C6H2)2 (7a) and (bpy)Co(2‐Me‐4‐F‐C6H3)2 (7b) exhibited idealized square‐planar geometry expected for the low‐spin (S = 1/2) cobalt(II) centers. While both high‐spin and low‐spin cobalt(II) organometallics are well established, the compounds herein represent a rare example in which both high‐spin and low‐spin configurations are observed with the otherwise same supporting ligand, TMEDA, indicating the effect of two aryl groups enforcing a strong ligand field. Importantly, the propensity of TMEDA‐supported cobalt(II) to cross between spin states according to organometallic substituents is also proposed to be relevant to understanding cross‐coupling mechanisms that involve both mono‐arylcobalt and diarylcobalt intermediates.

FIGURE 4.

FIGURE 4

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Solid‐state molecular structures of (TMEDA)CoBr(4‐F‐C6H4) (6a), (TMEDA)CoBr(2‐Me‐4‐F‐C6H3) (6b), (3,5‐lut)2CoCl(2‐Me‐4‐F‐C6H3) (6d), (TMEDA)Co(2,6‐Me‐4‐F‐C6H2)2 (7a), and (bpy)Co(2‐Me‐4‐F‐C6H3)2 (7b) determined by x‐ray diffraction (30% probability ellipsoids). Hydrogen atoms, solvent molecules, and disorder were omitted for clarity.

With the electronic structures of (TMEDA)cobalt(II)–diaryl (7a) and (bpy)cobalt(II)–diaryl (7b) determined, additional insight into the thermodynamics of catalytically relevant C(sp2)–C(sp2) diaryl reductive elimination was obtained by DFT calculation (Figure 5). Beginning with structures corresponding to (N,N)cobalt(II)(phenyl)(4‐fluorophenyl) (Int1), the barrier for C(sp2)–C(sp2) reductive elimination in MeCN was evaluated according to N,N ligand identity (Figure 5). From low‐spin (S = 1/2) (N,N)cobalt(II)–diaryl (Int1), coordination of MeCN forms five‐coordinate pre‐reductive elimination intermediate (Int2), which is thermodynamically favored for both bpy and TMEDA (Figure 5). From the five‐coordinate (N,N)cobalt(II)–diaryl (Int2), C─C reductive elimination was located with a barrier of +18.0 kcal/mol for the TMEDA‐supported complex (t 1/2 ∼ 1 s at 25°C), and +12.8 kcal/mol for the bpy‐supported complex (t 1/2 ∼ 100 µs at 25°C), indicating rapid rates of reductive diaryl coupling in acetonitrile solvent at ambient temperature with TMEDA and bpy ligands (Figure 5). These data may provide evidence of more facile C(sp2)–C(sp2) cross‐coupling by (bpy)cobalt catalysts compared to (TMEDA)cobalt catalysts, the former of which are generally efficient for biaryl coupling [28]. Further, for TMEDA–cobalt(II), the barrier for reductive elimination from four‐coordinate cobalt(II)–diaryl was significantly higher +23.9 kcal/mol (Figure S78), indicating that coordinating solvent acetonitrile acts as ligand in diaryl coupling, and may additionally play a role in stabilizing cobalt(0) intermediates [54, 55], although the precise identity of the short‐lived cobalt(0) formed in a cross‐coupling reaction was not apparent. The axial coordination of the donor ligand prior to reductive elimination helps to inform the apparent stability of 2,6‐disubstituted arylcobalt(II) complexes (bpy)Co(Mes)2 [36] and (TMEDA)Co(2,6‐Me‐4‐F‐C6H2)2 (7a), in which the 2,6‐disubstitution blocks ancillary ligand coordination from the axial face, preventing the formation of the five‐coordinate complex necessary for reductive coupling. Indeed, incubation of (bpy)Co(2‐Me‐4‐F‐C6H3)2 in acetonitrile‐d3 at 50°C for 15 min resulted in full conversion, with biaryl 4,4′‐difluoro‐2,2′‐dimethyl‐1,1′‐biphenyl detected as the major product in 42% yield (theoretical max. yield = 50%) (Figure S77). In reactions that observed reductive elimination from (TMEDA)cobalt(II) without a coordinating solvent (Scheme 1), it is proposed that an exogenous ancillary ligand can bind to form a five‐coordinate metal center, such as free TMEDA coordinating in a monodentate fashion.

FIGURE 5.

FIGURE 5

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DFT‐calculated gas‐phase energies for reductive elimination of (N,N)cobalt(II)–diaryl on the S = 1/2 surface. Level of theory = TPSS/def2‐SVP.

For C(sp2)–C(sp2) Negishi cross‐coupling, well‐defined reactions with (TMEDA)cobalt(II/0) compounds informed a reasonable catalytic cycle. While oxidation states including cobalt(I) and cobalt(III) have sometimes been proposed in cobalt‐catalyzed C(sp2)–C(sp2) cross‐coupling reactions [56, 57], herein the reaction employing precatalyst (TMEDA)cobalt(II) dibromide was observed to form well‐defined (TMEDA)arylcobalt(II) complexes by transmetalation. Namely, in the cross‐coupling reaction of 4‐bromobenzonitrile (3b) with 2‐tolylzinc nucleophile (Scheme 3), the catalyst resting state detected by freeze‐quench X‐band EPR spectroscopy at t = 5 min and t = 20 min (9%–59% conversion) was (TMEDA)cobalt(II)–diaryl, indicating that catalyst turnover begins with a (TMEDA)cobalt(II) intermediate. The catalytic mechanism thus involves initial double transmetalation of the tolylzinc nucleophile to (TMEDA)CoBr2, yielding planar, low‐spin (S = 1/2) (TMEDA)cobalt(II)–diaryl (7c). After C(sp2)–C(sp2) reductive homocoupling, ligand exchange with excess aryl halide electrophile (3b) results in rapid oxidative addition, yielding high‐spin, tetrahedral (TMEDA)cobalt(II)–monoaryl bromide (6f). Then, transmetalation of arylzinc nucleophile yields productive (TMEDA)cobalt(II)–diaryl (7d), undergoing subsequent C(sp2)–C(sp2) reductive cross‐coupling to yield product (4f), turning over the cycle. An organic side‐product, homobiaryl bis(2‐tolyl) resulting from catalyst (re)initiation via reductive elimination was observed as the major side‐product in 28% GC‐MS yield after 16 h. The other side‐product was benzonitrile, resulting from the apparent reduction of 4‐bromobenzonitrile (3b). Benzonitrile was detected in 1% yield by GC‐MS, which is proposed to form by slow, unproductive Co‐to‐Zn transmetalation from catalytic intermediate (TMEDA)CoBr(4‐CN‐Ph) (6f) [58], yielding (TMEDA)CoBr2 and the corresponding 4‐cyanophenylzinc reagent, which is protonated at the end of the reaction by aqueous workup.

SCHEME 3.

SCHEME 3

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Cobalt(0/II) catalytic cycle for C(sp2)–C(sp2) cross‐coupling.

After investigating the role of cobalt(II)–aryls in C(sp2)–C(sp2) bond‐formation, subsequent experiments studied the role of cobalt(II)–aryls in C(sp2)–C(sp3) bond‐formation. Namely, (TMEDA)cobalt(II)–fluorophenyl bromide (6a) was additionally proposed to be a catalytic intermediate in the cross‐coupling of arylzinc reagents with alkyl electrophiles catalyzed by (TMEDA)cobalt(II) dibromide, since initial arylzinc transmetalation to the (TMEDA)cobalt(II) dibromide precatalyst yields (TMEDA)cobalt(II)–fluorophenyl bromide (6a). To probe the reactivity of (TMEDA)cobalt(II)–fluorophenyl bromide (6a), one equivalent was stirred with one equivalent of a suitable alkyl electrophile at ambient temperature, N‐Boc‐4‐bromopiperidine (1a). Additionally, it was not clear if high‐spin (S = 3/2) (TMEDA)CoBr(4‐F‐C6H4) (6a) would be sufficiently competent for alkyl electrophile activation, or if an exogenous low‐valent cobalt intermediate would play the role of alkyl electrophile activation, as often proposed in alkyl radical chain reactions [59]; therefore, additional (PMe3)3CoICl was added as sacrificial activating reagent, to model the role of an on‐cycle, ancillary reductant for alkyl electrophile activation via bromine atom abstraction or inner‐sphere electron transfer (Table 2) [60].

TABLE 2.

Stoichiometric reactions of (TMEDA)cobalt(II)–Aryl compounds (6a/7a) with N‐Boc‐4‐bromopiperidine a .

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Entry Equiv (PMe3)3CoCl Yield 4a Yield 5a
1 0 66% 10%
2 0.1 90% 3%
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Entry Equiv (PMe3)3CoCl Yield 4h Yield 5b
3 0 13% 2%
4 0.2 152% 1%
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a

Yields determined after aqueous workup (aq. NH4Cl/CDCl3) by 19F NMR spectroscopy using 2‐fluorobiphenyl as an internal standard. In all cases, the remaining mass balance was detected as protonated aryl (fluorobenzene or 3,5‐dimethylfluorobenzene).

When (TMEDA)CoBr(4‐F‐C6H4) (6a) was stirred with alkyl bromide (1a) in THF at ambient temperature (21°C) for 10 min, full conversion of (TMEDA)cobalt(II)–aryl (6a) was achieved, with the C(sp2)–C(sp3) cross‐coupled product (4a) being detected in 66% yield (Table 2, Entry 1). The major side‐product was biaryl homodimer (5a), formed in 10% yield, and the major detectable cobalt product by 1H NMR spectroscopy was (TMEDA)CoBr2. These data demonstrated that (TMEDA)CoBr(4‐F‐C6H4) (6a) alone was kinetically competent for alkyl bromide activation and product‐formation, implicating (TMEDA)cobalt(II)–monoaryl as catalytically relevant in C(sp2)–C(sp3) cross‐coupling. Next, the same reaction between (TMEDA)CoBr(4‐F‐C6H4) (6a) and alkyl bromide (1a) was performed, however with additional (PMe3)3CoICl (0.1 equiv) as sacrificial alkyl bromide activating reagent. In this case, the yield of C(sp2)–C(sp3) product (4a) was increased to 91%, with improved selectivity over biaryl side‐product (5a, 3%) (Entry 2). These data additionally corroborate the role of (TMEDA)CoBr(4‐F‐C6H4) (6a) in bond‐formation, which is the productive intermediate responsible for alkyl radical capture and C(sp2)–C(sp3) reductive elimination [59]. However, the reaction observed in the absence of (PMe3)3CoICl (Entry 1) demonstrated a second role of (TMEDA)CoBr(4‐F‐C6H4) (6a), namely its ability to also perform alkyl bromide activation, likely via bromine atom abstraction, concomitant with an increased 10% yield of unproductive homodimer side‐product (Entry 1). Therefore, when an exogenous catalytic intermediate serves to activate the alkyl bromide and generate alkyl radical, the on‐cycle (TMEDA)cobalt(II)–monoaryl only engages the fast, productive role of alkyl radical capture, leading to good selectivity for C(sp2)–C(sp3) cross‐coupling. However, when exogenous alkyl bromide activator is not present, some (TMEDA)CoBr(4‐F‐C6H4) (6a) is competent to initiate alkyl bromide activation at the cost of aryl fragment sacrifice, yielding both alkyl radical and (TMEDA)CoIIIBr2(4‐F‐C6H4), which is proposed to decompose in a bimolecular fashion to form biaryl (4‐F‐C6H4)2 (5a) [61]. These data also challenge a commonly proposed notion that low‐valent cobalt is necessary for alkyl electrophile activation in cross‐coupling reactions, rather demonstrating that high‐spin (S = 3/2) cobalt(II)–monoaryl alone is competent for alkyl radical initiation, which is proposed to occur by bromide atom abstraction since outer‐sphere electron transfer to alkyl bromide 1a (1a/1a •– ≪ −2.5 V vs. Fc/Fc+) [62, 63] was not thermodynamically possible from (TMEDA)CoBr(Aryl) (CoII/III ∼ +0.20 V vs. Fc/Fc+) (Figure S31).

To compare with the reactivity of high‐spin (TMEDA)cobalt(II)–monoaryl bromide intermediate (6a), the incubation of low‐spin (S = 1/2) diaryl (TMEDA)Co(2,6‐Me‐4‐F‐C6H2)2 (7a) with alkyl bromide (1a) resulted in minimal conversion to C(sp2)–C(sp3) cross‐coupled product (4h, 13%), indicating negligible reaction (Entry 3). Addition of 0.2 equiv alkyl bromide activator (PMe3)3CoCl resulted in significantly increased conversion (152% yield 4h) (Entry 4). These data implied that putative cobalt(II)–2,6‐dimethyl‐4‐fluorophenyl intermediates were competent for C(sp2)–C(sp3) bond formation, however (TMEDA)Co(2,6‐Me‐4‐F‐C6H2)2 (7a) alone was not competent for bromine atom abstraction, likely due to steric blocking of the metal center. Together, these data demonstrate the uniquely productive reactivity of (TMEDA)cobalt(II)–monoaryl bromide (6a) complexes, which are productive in alkyl radical capture, and alone are also capable of alkyl bromide activation by virtue of their high spin nature.

With well‐defined (TMEDA)CoBr(4‐F‐C6H4) (6a) invoked as a catalytic intermediate in C(sp2)–C(sp3) cross‐coupling, the thermodynamics of (TMEDA)cobalt(II)‐mediated alkyl radical generation, capture, and reductive elimination were studied by DFT calculation, to obtain insight into the comparative reactivity of high‐spin cobalt(II)–monoaryl and low‐spin cobalt(II)–diaryl complexes (Figure 6). Beginning with either (TMEDA)cobalt(II)–fluorophenyl bromide (6a) or (TMEDA)Co(4‐F‐C6H4)2 (7e), the transition state for bromine atom abstraction (S = 3/2) was located with a barrier of +24.6 kcal/mol for the diaryl structure (TS2b), compared to the barrier of +19.6 kcal/mol for the monoaryl bromide structure (TS2a). The bromine abstraction transition states (S = 3/2) implied the (TMEDA)CoBr(4‐F‐C6H4) (6a) ground state to exhibit the correct electronic structure for alkyl radical generation, whereas the diaryl (TMEDA)Co(4‐F‐C6H4)2 (S = 1/2) was required to undergo spin crossover to the +7.3 kcal/mol S = 3/2 electronic isomer prior to bromine atom abstraction. These data also corroborate the stoichiometric reactivity that the direct bromine atom abstraction from (TMEDA)CoBr(4‐F‐C6H4) (6a) was thermodynamically accessible at reaction temperature (+19.6 kcal/mol) and significantly faster than bromine atom abstraction from an analogous low‐spin (TMEDA)cobalt(II)–diaryl (+24.6 kcal/mol).

FIGURE 6.

FIGURE 6

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DFT‐calculated gas‐phase energies for alkyl radical formation and capture. Level of theory = TPSS/def2‐SVP.

After alkyl radical formation, the alkyl radical capture to form (TMEDA)CoBr(Alk)(4‐F‐C6H4) (Int4) was thermodynamically favored by a modest 8.7 kcal/mol. From the five‐coordinate pre‐reductive elimination cobalt(III) intermediate (Int4), C(sp2)–C(sp3) reductive coupling on the S = 1 surface was calculated to have a barrier of +12.2 kcal/mol (TS3), estimating reductive elimination to be rapid at ambient temperature (t 1/2 ∼ 100 µs at 25°C) [64, 65]. These data demonstrated feasible alkyl radical capture and bond‐formation at (TMEDA)CoBr(4‐F‐C6H4) (6a), consistent with the observed reactivity. These data also implicate alkyl radical capture/homolysis as reversible, indicating that productive C(sp2)–C(sp3) cross‐coupling is promoted with relatively higher concentration of (TMEDA)CoBr(4‐F‐C6H4) and low concentration of alkyl radical, since high concentration of alkyl radical would favor C(sp3)–C(sp3) homodimerization. Therefore, alkyl radicals are generated at low concentration and are rapidly captured to form the cross‐coupled product in a productive cross‐coupling reaction. Altogether, these data implicate the alkyl radical generation and capture initiated at high‐spin (S = 3/2) (TMEDA)cobalt(II)–monoaryl bromide, positioning open‐shell cobalt(II) as a uniquely effective catalyst for alkyl bromide cross‐coupling reactions.

To further understand alkyl radical capture during (TMEDA)cobalt(II)‐catalyzed cross‐coupling, an alkyl radical clock experiment was performed employing 6‐bromohex‐1‐ene (1c) (Figure 7). Using the substrates alkyl bromide (1c) and 4‐fluorophenylzinc nucleophile, a series of reactions were performed in which the concentration of precatalyst (TMEDA)CoBr2 was varied between 1–25 mol%. After 18 h at 21°C, the yields of cross‐coupled products were determined, namely the linear product (4i) resulting from direct alkyl bromide arylation, and cyclized product (4j), which resulted from arylation following 5‐exo‐trig cyclization (k = 105 s−1 at 25°C) [66] of the primary alkyl radical (Figure 7). Evaluation of product selectivity at different concentrations of (TMEDA)cobalt(II) dibromide indicated a dependence of linear/cyclization product ratio according to catalyst concentration, in which the linear product was favored at higher loadings of (TMEDA)CoBr2, and the cyclized product was favored at lower loadings of (TMEDA)CoBr2. These data indicate a change in the lifetime of the free alkyl radical depending on the concentration of cobalt catalyst. At lower catalyst loading, the alkyl radical exhibits a longer lifetime before finding productive cobalt catalyst, which is apparent as the higher proportion of cyclized product formed (4j). At higher catalyst loading, the alkyl radical exhibits a proportionally shorter lifetime, apparent as higher proportion of linear product formed (4i), due to more rapid rate of alkyl radical capture by the higher concentration of cobalt catalyst. These data are consistent with the catalytic cross‐coupling reaction involving the formation of a cage‐escaped alkyl radical, which is captured by a persistent (TMEDA)cobalt intermediate to result in product formation, namely, (TMEDA)cobalt(II)–monoaryl bromide (6a) that engages productive alkyl radical capture. By 1H and 19F NMR spectroscopies in acetonitrile‐d3 /THF, the only apparent resting state at t = 30 min (∼10% conversion) during a catalytic C(sp2)–C(sp3) cross‐coupling reaction was (TMEDA)CoBr(4‐F‐C6H4) (6a) (Figure S57), consistent with (TMEDA)CoBr(4‐F‐C6H4) (6a) being the productive intermediate involved in catalytic alkyl radical capture and product formation. These data reinforce that efficient alkyl radical capture occurs at persistent, long‐lived, stable catalytic intermediates so that the alkyl radical may engage productive chemistry rapidly after its formation.

FIGURE 7.

FIGURE 7

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5‐exo‐trig cyclization of radical clock 6‐bromo‐1‐hexene (1c) according to (TMEDA)cobalt(II) dibromide loading.

In the (TMEDA)cobalt(II)‐catalyzed cross‐coupling of N‐Boc‐4‐bromopiperidine (1a) to yield C(sp2)–C(sp3) product (4a), the proposed mechanism involves an alkyl radical chain cycle propagated by (TMEDA)cobalt(II)–monoaryl bromide (6a) (Figure 8). Starting with (TMEDA)cobalt(II) dibromide, arylzinc transmetalation yields catalyst resting state (TMEDA)CoBr(4‐F‐C6H4) (6a). Cobalt(II)–aryl complex (TMEDA)CoBr(4‐F‐C6H4) (6a) was observed to have two roles in cross‐coupling, namely alkyl radical initiation and alkyl radical capture, the latter of which directly leads to cross‐coupled product. To begin the alkyl radical chain (initiation), initial reaction of (TMEDA)CoBr(4‐F‐C6H4) (6a) with alkyl bromide (1a) yields secondary alkyl radical (8) and putative intermediate (TMEDA)CoIIIBr2(4‐F‐C6H4) (9) (Figure 8). While well‐defined cross‐coupling‐relevant cobalt(III)–monoaryl compounds and studies of their reactivity are rare, five‐coordinate intermediate (TMEDA)CoIIIBr2(4‐F‐C6H4) (9) is proposed to be unstable, undergoing bimolecular homodimerization to yield (TMEDA)CoBr2 and half an equivalent of aryl homodimer (4‐F‐C6H4)2 (5) [67], which was the major organic side‐product in the stoichiometric reaction of (TMEDA)CoBr(4‐F‐C6H4) (6a) with alkyl bromide (1a). Thus, alkyl radical (8) is formed, initiating the radical chain cycle.

FIGURE 8.

FIGURE 8

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Proposed catalytic cycle for (TMEDA)cobalt(II)‐catalyzed C(sp2)–C(sp3) cross‐coupling.

Once cage‐escaped alkyl radical (8) is generated, interception by resting‐state (TMEDA)cobalt(II)–monoaryl (6a) results in rapid alkyl radical capture (10), followed by C(sp2)–C(sp3) reductive elimination (4a), yielding a putative cobalt(I) product (11). The alkyl radical capture by (TMEDA)CoBr(4‐F‐C6H4) (6a) is evidenced to be rapid during a catalytic reaction, since free alkyl radical was not detected by freeze‐quench EPR spectroscopy, and the organic product of alkyl radical accumulation, an alkyl–alkyl homodimer, was never detected by GC‐MS at the end of a cross‐coupling reaction. Therefore, the success of the alkyl radical chain requires maintenance of active concentration of (TMEDA)cobalt(II)–monoaryl (6a) as a catalyst resting state, which captures the alkyl radical. After C(sp2)–C(sp3) reductive elimination, the putative low‐valent (TMEDA)cobalt(I) intermediate (11) rapidly reacts with additional alkyl bromide (1a), generating additional alkyl radical (8) to propagate the radical chain, concomitant with (TMEDA)CoBr2 formation. Subsequently, arylzinc transmetalation to (TMEDA)CoBr2 regenerates the (TMEDA)cobalt(II)–monoaryl (6a), necessary for continued alkyl radical chain propagation. Thus, with (TMEDA)cobalt(II)–monoaryl (6a) in solution, alkyl radical capture continues to propagate the alkyl radical chain, until either alkyl bromide (1a) is depleted or (TMEDA)cobalt(II)–monoaryl (6a) cannot be regenerated, due to depletion of the arylzinc nucleophile. Altogether, these data demonstrated that high‐spin (TMEDA)cobalt(II)–monoaryl catalysts are stable intermediates during cross‐coupling, providing general insight into oxidation and spin states of cobalt catalysts in weak ligand fields. As case in point, the C(sp2)–C(sp3) cross‐coupling reactivity of the (TMEDA)cobalt(II) catalyst was mimicked in the Negishi arylation of secondary α‐bromoester (1b) catalyzed by weak‐field complex (R,R‐Bn‐BOX)cobalt(II) dibromide, in which high‐spin (S = 3/2) (R,R‐Bn‐BOX)cobalt(II)–fluorophenyl bromide (6e) was detected as catalyst resting state (Figure S61). Therefore, these catalytic reactivities are proposed to extrapolate to other cobalt‐catalyzed cross‐coupling reactions (Figure S62).

The productive reactions of (TMEDA)cobalt(II)–monoaryl catalysts thus demonstrate selectivity in cross‐coupling of aryl and alkyl electrophiles with arylzinc nucleophiles (Figure 9). A central productive intermediate is well‐defined, isolable, high‐spin (S = 3/2) (TMEDA)cobalt(II)–aryl monobromide, which led to C(sp2)–C(sp2) and C(sp2)–C(sp3) cross‐coupled products, according to presence of aryl or alkyl electrophile (Figure 9). In C(sp2)–C(sp2) cross‐coupling reactions, formation of (TMEDA)cobalt(II)–monoaryl by oxidative addition to cobalt(0) was followed by slow arylzinc transmetalation of the second aryl group, yielding low‐spin (TMEDA)cobalt(II)–diaryl that forms C(sp2)–C(sp2) product by subsequent rapid reductive elimination (Figure 9, left arrow). Alternatively, for alkyl–aryl cross‐coupling in the presence of alkyl electrophile, the low‐spin (TMEDA)cobalt(II)–diaryl was not competent for alkyl bromide activation (Table 2, entries 3–4). Rather, the alkyl radical chain is more rapidly initiated by the high‐spin (TMEDA)cobalt(II)–monoaryl bromide, yielding cage‐escaped alkyl radical (Figure 9, middle arrow). The (TMEDA)cobalt(II)–monoaryl persists as resting state during the cross‐coupling reaction, which captures the alkyl radical to form the C(sp2)–C(sp3) cross‐coupled product (Figure 9, right arrow). These fast reactions with alkyl bromide electrophile, compared to slower double transmetalation with arylzinc nucleophile, enable the same intermediate (TMEDA)cobalt(II)–monoaryl to engage cross‐coupling partners selectively, yielding C(sp2)–C(sp3) or C(sp2)–C(sp2) products by open‐ or closed‐shell catalytic cycles depending on the presence of the appropriate electrophile.

FIGURE 9.

FIGURE 9

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Summary of well‐defined, productive organometallic reactions of (TMEDA)Co(II)–monoaryl bromide in C(sp2)–C(sp2) and C(sp2)–C(sp3) cross‐coupling.

3. Concluding Remarks

The synthesis, isolation, and characterization of monoaryl (TMEDA)cobalt(II) compounds enabled identification of catalytic intermediates in C(sp2)–C(sp2) and C(sp2)–C(sp3) Negishi cross‐coupling. In C(sp2)–C(sp2) cross‐coupling, well‐defined reactions demonstrated facile reductive elimination at on‐cycle (TMEDA)diarylcobalt(II), supporting an uncommonly proposed cobalt(0/II) catalytic cycle for biaryl formation. In C(sp2)–C(sp3) cross‐coupling, reaction of catalyst resting state (TMEDA)cobalt(II)–monoaryl with alkyl bromide demonstrated kinetically relevant alkyl radical initiation and rapid alkyl radical capture, highlighting the propensity of open‐shell, high‐spin (TMEDA)cobalt(II) to engage radical reactivity. Compared to diamagnetic nickel(II) or copper(I) catalysts, cobalt(II) is therefore especially suited for radical cross‐coupling reactions, demonstrating inherent radical reactivity from cobalt(II), whereas nickel(II) or copper(I) often necessitates precatalyst activation steps to access open‐shell intermediates. Together, the reactions studied herein also highlight the divergent reactivities that transition metal catalysts are generally known to engage in, herein accessing either cobalt(0/II) or cobalt(I/II/III) cycles according to substrate.

These results also highlight the importance of well‐defined complexes for understanding organometallic intermediates, especially in discovering and characterizing thermodynamically favored oxidation states, spin states, and coordination chemistries. While assignment of paramagnetic complexes may not always be trivial by standard techniques such as 1H NMR spectroscopy, this work shows that a range of techniques enable unambiguous characterization of paramagnetic complexes, even catalytically relevant ones, such that synthetic practitioners need not be blind to the mechanisms of first‐row transition metal–catalyzed reactions.

Author Contributions

Kavita Choudhary: methodology, investigation, conceptualization, writing – original draft, writing – review and editing. Bhaswati Paul: methodology, writing – original draft, writing – review and editing. L. Reginald Mills: conceptualization, investigation, methodology, funding acquisition, writing – original draft, writing – review and editing, project administration, supervision.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Full experimental details, characterization data, and XYZ coordinates of DFT‐optimized structures are available in the Supporting Information of this article. CCDC deposition numbers 2498957–2498962 and 2547396–2547397 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.ac.uk, or by contacting the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Supporting File 1: anie72807‐sup‐0001‐SuppMat.pdf.

ANIE-65-e6050863-s003.pdf (35.8MB, pdf)

Supporting File 2: anie72807‐sup‐0002‐cif.zip.

ANIE-65-e6050863-s001.zip (1.2MB, zip)

Supporting File 3: anie72807‐sup‐0003‐XYZ‐Coordinates.xyz.

ANIE-65-e6050863-s002.xyz (73.6KB, xyz)

Acknowledgments

This work was supported by University of Houston startup funding via the Texas University Fund. The Robert A. Welch Foundation (#H‐E‐0041) is thanked for providing funds to obtain an EPR spectrometer through the Center of Excellence in Polymer Chemistry. DFT calculations were enabled by the Research Computing Data Core at the University of Houston.

Data Availability Statement

The data that supports the findings of this study are available in the supplementary material of this article.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Full experimental details, characterization data, and XYZ coordinates of DFT‐optimized structures are available in the Supporting Information of this article. CCDC deposition numbers 2498957–2498962 and 2547396–2547397 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.ac.uk, or by contacting the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Supporting File 1: anie72807‐sup‐0001‐SuppMat.pdf.

ANIE-65-e6050863-s003.pdf (35.8MB, pdf)

Supporting File 2: anie72807‐sup‐0002‐cif.zip.

ANIE-65-e6050863-s001.zip (1.2MB, zip)

Supporting File 3: anie72807‐sup‐0003‐XYZ‐Coordinates.xyz.

ANIE-65-e6050863-s002.xyz (73.6KB, xyz)

Data Availability Statement

The data that supports the findings of this study are available in the supplementary material of this article.

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