Cobalt-Catalyzed Borylation of Fluorinated Arenes: Thermodynamic Control of C(sp²)-H Oxidative Addition Results in ortho-to-Fluorine Selectivity

Abstract

The mechanism of C(sp²)–H borylation of fluorinated arenes with B₂Pin₂ (Pin = pinacolato) catalyzed by bis(phosphino)pyridine (^iPrPNP) cobalt complexes was studied to understand the origins of the uniquely high ortho-to-fluorine regioselectivity observed in these reactions. Variable time normalization analysis (VTNA) of reaction time courses and deuterium kinetic isotope effect measurements established a kinetic regime wherein C(sp²)–H oxidative addition is fast and reversible. Monitoring the reaction by in situ NMR spectroscopy revealed the intermediacy of a cobalt(I)–aryl complex that was generated with the same high ortho-to-fluorine regioselectivity associated with the overall catalytic transformation. Deuterium labeling experiments and stoichiometric studies established C(sp²)-H oxidative addition of the fluorinated arene as the selectivity-determining step of the reaction. This step favors the formation of ortho-fluoroaryl cobalt intermediates due to the ortho fluorine effect, a phenomenon whereby ortho fluorine substituents stabilize transition metal-carbon bonds. Computational studies provided evidence that the cobalt-carbon bonds of the relevant intermediates in (^iPrPNP)Co-catalyzed borylation are strengthened with increasing ortho fluorine substitution. The atypical kinetic regime involving fast and reversible C(sp²)-H oxidative addition in combination with the thermodynamic preference for forming cobalt-aryl bonds adjacent to fluorinated sites are the origin of the high regioselectivity in the catalytic borylation reaction.

Graphical Abstract

INTRODUCTION

The transition metal-catalyzed borylation of C(sp²)-H bonds has emerged as a widely utilized and impactful application of C-H functionalization^1–4 owing in part to the utility and versatility of the resulting aryl boronate ester products.^5,6 Combination of the iridium(I) precursor, [Ir(COD)OMe]₂ (COD = 1,5-cyclooctadiene) with a substituted bipyridine ligand, most typically dtbpy (4,4’-di-tert-butyl-2,2’-bipyridine), and either B₂Pin₂ or HBPin (Pin = pinacolato) as the boron source constitutes the most commonly used method. The high activity, predictable sterically driven site selectivity, and complementarity to traditional aromatic substitution methods are responsible for the widespread application of the iridium catalysts. Both experimental⁷ and computational⁸ studies support a pathway involving rate-determining oxidative addition of a C(sp²)-H bond to an iridium(III) tris(boryl) intermediate followed by reductive elimination to form the arylboronate ester.^7,8 Computational studies support late transition states with fully formed iridium-carbon bonds with regioselectivity determined by the difference in the interaction energies between the iridium and arene carbon at each possible site.⁹

Controlling the regioselectivity of C-H functionalization is of practical importance given the abundance of carbon-hydrogen bonds in organic molecules.¹⁰ In iridium-catalyzed C(sp²)-H borylation, the regioselectivity of the reaction is predominantly steric in origin, as the standard iridium catalysts do not readily activate aryl C-H bonds ortho to large substituents (methyl and larger).^11–13 In cases where there are multiple sterically accessible C(sp²)-H bonds, statistical selectivity is typically observed; for example, the bipyridine-iridium catalyst was shown to borylate both toluene and trifluorotoluene with approximately 2:1 selectivity favoring the meta over the para product.¹² Strategies to overcome this inherent selectivity typically rely on directing groups - functionality designed to coordinate to the metal and activate a specific C(sp²)-H toward oxidative addition and ultimately borylation (Scheme 1).¹⁰ Introduction of hydridosilyl¹⁴ or benzylic tertiary amine¹⁵ groups on the arene substrate has been employed to promote ortho-directed borylation. Recent variants of this approach including hydrogen bonding interactions between the substrate and modified bipyridine ligands,^16–18 ion pairing,^19–21 electrostatic interactions,^22,23 and others^24,25 have been used to bias iridium- catalyzed reactions away from statistical selectivity.

Scheme 1.

Directing group strategies for ortho-to-functional group C(sp²)-H borylation with bipyridine iridium catalysts (top) and origins of selectivity in (^iPrPNP) cobalt-catalyzed C(sp²)-H borylation (bottom).

The regioselective C(sp²)-H borylation of fluorinated arenes is of practical interest as an enabling approach for the construction of fluorine-containing small molecules, a substructure prevalent in pharmaceuticals and agrochemicals.²⁶ The energetics of C(sp²)-H activation and competing C(sp²)-F activation of fluorinated arenes have been analyzed by Eisenstein and Perutz in a comprehensive review.²⁷ Braun and coworkers have also reported that a rhodium(I)-boryl (PEt₃)₃Rh(BPin) promoted the selective activation of C(sp²)-H bonds in fluorinated benzene and pyridine derivatives, and C(sp²)-F activation was only observed in the presence of perfluorinated substrates.²⁸ From a fundamental perspective, the selective borylation of electronically distinct C(sp²)-H bonds without exploiting steric effects is an unmet challenge in C-H functionalization catalysis.¹⁰ Despite the ubiquity of fluorinated arenes, few methods for their selective C(sp²)-H borylation have been reported. With state-of-the-art iridium catalysts,¹² borylation of various 3-substituted fluoroarenes resulted in little deviation from statistical selectivity for the ortho and meta-borylated products (Table 1a).²⁹ Platinum catalysts supported by N-heterocyclic carbene ligands³⁰ or a [PSiN]-pincer³¹ exhibited higher ortho-to-fluorine selectivity (Table 1b) although elevated temperatures (typically between 80 and 150 °C) were required, and the origin of the improved selectivity remains unknown.

Table 1.

Selectivity^a in the C(sp²)-H Borylation of Fluorinated Arenes with (a) State-of-the-art Iridium Catalysts, (b) Platinum Catalysts, (c) (^iPrPNP) Cobalt Catalysts, and (d) SiNSi Cobalt Catalysts.

^aThe numbers in the table are the reported ratios of arylboronate product isomers resulting from the borylation of the substrate drawn.

Our laboratory has reported that cobalt complexes bearing bis(phosphino)pyridine (^iPrPNP) pincers are active for the C(sp²)-H borylation of arenes and heteroarenes.³² With fluorinated arenes, synthetically useful ortho-to-fluorine selectivity was observed (Table 1c), and this selectivity was maintained even in the presence of functional groups that typically serve as directing groups in iridium-catalyzed reactions; initially, the observed regioselectivity was attributed to the increased acidity of C(sp²)-H bonds ortho to fluorine substituents.²⁹ Subsequent to these findings, Driess, Cui and coworkers reported that in situ activation of a bis(silylene) pyridine (SiNSi) cobalt(II) dibromide with NaBEt₃H in the presence of cyclohexene afforded meta-to-fluorine selectivity in C(sp²)-H borylation of fluorinated arenes (Table 1d).³³ Importantly, these findings demonstrate that first-row transition metals not only offer improved selectivity over precious metals but also the opportunity for inversion of selectivity with appropriate choice of pincer ligand. An understanding of the origins of these selectivities would inform the rational design of catalysts for a desired regioselectivity, perhaps extending to transformations beyond C(sp²)-H borylation.

Our previous studies on C(sp²)-H borylation catalyzed by cobalt complexes of ^iPrPNP have shown that mechanism and kinetic regime may vary with the identity of the substrate class examined. Mechanistic investigations into the borylation of 2,6-lutidine with B₂Pin₂ and [(^iPrPNP)Co] precatalysts established a Co(I)-Co(III) redox cycle with oxidative addition of the C(sp²)-H to a cobalt(I)- boryl as the turnover limiting step (Scheme 2a). ³⁴ This pathway is similar to the bipyridine-iridium catalysts that operate through an Ir(III)-Ir(V) cycle with rate-determining oxidative addition to a iridium(III) tris(boryl).⁷ For the borylation of heteroarenes with activated C(sp²)-H bonds such as benzofuran with HBPin, a different kinetic regime was observed whereby reductive elimination from (^iPrPNP)Co(H)₂BPin (1-(H)₂BPin) to generate the cobalt(I)-boryl is slow and oxidative addition is fast (Scheme 2b).³⁵ Computational studies on the borylation of benzene with B₂Pin₂ and [(^iPrPNP)Co] established that pathways involving phosphine dissociation, σ-bond metathesis and ligand dearomatization were not kinetically competent, supporting the proposed Co(I)-Co(III) pathway.³⁶ The flexibility and dynamics of the methylene linkers of the PNP pincer were found to be important as oxidative addition, isomerization, and reductive elimination steps occurred with concomitant interconversion between cisoid and transoid conformations of the ligand.

Scheme 2.

Experimental Results of Previous Mechanistic Studies on (^iPrPNP)Co-Catalyzed Borylation of (a) 2,6-lutidine with B₂Pin₂ and (b) Benzofuran with HPBin

This mechanistic information combined with the enhanced regioselectivity observed in the [(PNP)Co]-catalyzed borylation of fluoroarenes with B₂Pin₂ raised questions pertaining to the origin of the unique selectivity as well as the kinetic regime operative. Here we describe a comprehensive study on the mechanism of these reactions, establish the reversibility of C(sp²)-H oxidative addition and demonstrate the role of cobalt-C(sp²) bond thermodynamics as the origin of selectivity.

RESULTS AND DISCUSSION

Rate Law for the [(^iPrPNP)Co]-Catalyzed Borylation of Fluorinated Arenes.

Our studies commenced with determination of the experimental rate law for the borylation of fluorinated aryl sulfonamide 2a with B₂Pin₂ using 1-(H)₂BPin as the cobalt precatalyst. A 3-substituted fluoroarene was selected for these investigations in order to limit the number of possible borylation products; only two sterically accessible C(sp²)-H bonds are present in substrate 2a. Variable time normalization analysis (VTNA) of reaction time courses as described by Burés was applied³⁷ where the initial concentrations of 1-(H)₂BPin, 2a, B₂Pin₂ and HBPin, the stoichiometric boron-containing byproduct, were systematically varied. Analysis of the resulting overlay plots (Figure l) established the rate law in eq. 1.

Figure 1.

Overlay plots obtained from VTNA for the determination of the rate law for the borylation of 2a with B₂Pin₂ with 1-(H)₂BPin as the precatalyst.

$$\text{Rate}=k{\left[1-{(H)}_{2}BPin\right]}^1{\left[2a\right]}^0{\left[B_{2}Pi{n}_2\right]}^0{\left[HBPin\right]}^{0.5}$$ (1)

For the majority of the reaction’s time course, the reaction was found to be zeroth order in 2a, a result distinct from previous reports involving the borylation of 2,6-lutidine with B₂Pin₂ by [(^iPrPNP)Co] precursors³⁴ and the borylation of benzene or 1,2-dichlorobenzene by bipyridine iridium precatalysts.⁷ In these previous studies, a first-order dependence on arene was observed, and mechanisms involving turnover-limiting C(sp²)-H oxidative addition to metal-boryl were proposed. In contrast to these established pathways, the zeroth order (or saturation³⁸) behavior of the present reaction implies reversible C-H activation of 2a prior to the turnover limiting step. Another striking feature of the rate law in equation 1 is the half-order dependence on HBPin, the stoichiometric boron-containing byproduct from the C(sp²)-H functionalization. While half-order behavior is often attributed to monomer-dimer speciation, HBPin is monomeric in solution as are the cobalt pincer complexes. The origin of this fractional order will be discussed in a later section (see “Proposed Mechanism”).

Deuterium Kinetic Isotope Effects.

To further assay the possibility of C(sp²)-H oxidative addition as the turnover limiting step, deuterium kinetic isotope effect (KIE) measurements were conducted in two separate vessels at 50 °C with identical concentrations of 2a and 2a-d₂ in the presence of 10 mol% of 1-(H)₂BPin and superstoichiometric B₂Pin₂ (Scheme 3). KIE values of 1.1(1) and 0.9(1) were determined for borylation of the ortho and meta sites arising from formation of the major and minor isomers, respectively. The absence of a significant deuterium KIE supports a pathway wherein C(sp²)-H bond activation does not occur in the turnover-limiting step. These observations in combination with the rate law for the catalytic reaction demonstrate that the cobalt- catalyzed borylation of fluorinated arenes operates in a distinct kinetic regime from the borylation of 2,6-lutidine using (^iPrPNP)CoCH₂SiMe₃, where C(sp²)-H oxidative addition to cobalt(I) is turnover limiting.

Scheme 3.

Determination of Deuterium Kinetic Isotope Effects (KIE) for the Borylation of 2a and 2a-d₂ with 1-(H)₂BPin in Two Separate Vessels.

Determination of the Catalyst Resting State as a Function of Time.

The borylation of 3-fluoro-α,α,α-trifluorotoluene (2b) promoted by 1-(H)₂BPin was monitored by ¹H, ¹⁹F and ³¹P NMR spectroscopies in an attempt to gain insight into the resting state(s) of the cobalt catalyst. A higher precatalyst loading of 20 mol% was used to facilitate observation of metal-containing products. Substrate 2b was selected over 2a due to its slower turnover. We previously reported that 2b undergoes borylation with 95:5 selectivity favoring the ortho-to-fluorine isomer and this ratio was unperturbed with variations in temperature, catalyst loading or reaction time.²⁹

The ³¹P NMR spectra recorded over time for the borylation of 2b at 23 °C are depicted in Figure 2. At the earliest time point (5 min, 48% conversion), two major ³¹P signals were observed at 103.9 ppm and 53.2 ppm, corresponding to 1-(H)₂BPin and a new, unidentified cobalt species, respectively. The observed ³¹P NMR shift of the new cobalt species is similar to those of previously reported cobalt(I) methyl (50.6 ppm)³⁴ and benzofuranyl (54.7 ppm)³⁹ compounds supported by the PNP pincer. Over the course of 60 minutes at which point the reaction reached 89% conversion, the ³¹P NMR signal corresponding to the unidentified species gradually diminished. The ¹⁹F NMR spectra collected during this time period exhibit two signals (in addition to those of 2b and its borylation products) at −60.4 ppm and −82.1 ppm that integrate in a 3:1 ratio. Based on these NMR data and independent syntheses (vide infra), the new cobalt species was identified as cobalt(I) aryl complex ortho-4b (Scheme 4). The ³¹P and ¹⁹F NMR spectra were also collected throughout the time course for the borylation of 2a catalyzed by 1-(H)₂BPin at 50 °C in THF-d₈. While the reaction reached complete conversion in 15 minutes, cobalt species with similar spectroscopic features were observed (see the Supporting Information for additional details and spectroscopic data).

Figure 2.

The benzene-d₆ ³¹P NMR spectra of the borylation of 2b with 20 mol % 1-(H)₂BPin and B₂Pin₂ at 23 °C over time.

Scheme 4:

Mechanism of (^iPrPNP) Cobalt Aryl Complex Formation Supported by Previous Computational Study³⁴ and the Experimental Observation of ortho-4b During Catalysis

The intermediacy of cobalt(I) aryl complexes is consistent with recently reported computational results on the borylation of benzene with 1-(H)₂BPin.³⁶ The density functional theory (DFT) results support oxidative addition of benzene to (^iPrPNP)CoBPin to generate a Co(III) boryl-hydride-aryl complex with mutually trans boryl and aryl ligands as the most favorable pathway (Scheme 4). Reductive elimination of HBPin then generates (^iPrPNP)CoPh, which can then react with HBPin or B₂Pin₂ to produce the aryl-boronate product. The observation of cobalt(I) aryl resting states by ³¹P and ¹⁹F NMR spectroscopy provide evidence that these events occur in the borylation of fluoroarenes 2a and 2b. As we reported in our previous investigation of cobalt-catalyzed borylation of 2,6-lutidine, dihydride boryl 1-(H)₂BPin is also observed spectroscopically throughout the course of the reaction, and at later conversion it becomes the predominant cobalt species in solution by ³¹P NMR. This suggests that as the concentration of HBPin increases, it reacts with cobalt hydride intermediates to regenerate the precatalyst, an off-cycle resting state.

Independent Syntheses of Cobalt Aryl Complexes.

To establish the identity of the cobalt(I) aryl intermediates unequivocally, diamagnetic ortho-4b and meta-4b were synthesized independently. An initial attempt to prepare ortho-4b by reaction of 1-CH₃³⁴ with excess 2b in THF-d₈ at room temperature was unsuccessful, as the cobalt methyl complex failed to promote C(sp²)-H oxidative addition under these conditions. Subsequently, an experiment designed to generate 1-H in the presence of 2b was attempted. Exposure of a benzene-d₆ solution containing 1-CH₃ and 20 equivalents of 2b to 1 atm H₂ for one hour at 23 °C resulted in quantitative conversion to cobalt trihydride 1-H₃ as judged by ¹H NMR spectroscopy. Conducting repeated freeze-pump-thaw cycles on this mixture resulted in complete conversion to a product with spectroscopic features identical to those observed when the borylation of 2b catalyzed by 1-(H)₂BPin was monitored in situ. This species, assigned as ortho-4b, likely arises from in situ generation of cobalt(I) hydride 1-H, which undergoes C(sp²)-H oxidative addition of 2a followed by loss of H₂ (Scheme 5). Notably, only the ortho fluorinated isomer of this compound was observed by ¹⁹F and ³¹P NMR spectroscopies. Single crystals suitable for X-ray diffraction were obtained from slow evaporation of a pentane solution of the compound over the course of one week and the solid-state structure confirmed the identity of ortho-4b (Scheme 6). The selective formation of the ortho isomer of the cobalt(I) aryl complex demonstrates that C(sp²)-H oxidative addition maintains high ortho site selectivity in the absence of carbon-boron bond-forming processes.

Scheme 5:

Proposed Mechanism for the Formation of ortho-4b from 1-CH₃ and Excess 2a Following Exposure to 1 atm H₂

Scheme 6.

Synthesis and selected spectroscopic data for ortho-4b and meta-4b, as well as solid-state molecular structures of ortho-4b and meta-4b at 30% probability ellipsoids. Hydrogen atoms, except for those on the methylene units, are omitted for clarity.

The meta isomer of 4b was also synthesized to evaluate its competency and propensity for isomerization in cobalt-catalyzed borylation. This complex was successfully prepared from straightforward transmetallation of the cobalt(I) bromide, 1-Br with the appropriate aryl Grignard reagent. The desired cobalt aryl complex, meta-4b was obtained in 95% yield and exhibited a broad ³¹P NMR signal at 49.2 ppm, similar to but distinct from the value of 53.2 ppm for ortho-4b. While the ¹⁹F NMR resonance corresponding to the aryl fluoride substituent of ortho-4b appears at −82.1 ppm, the corresponding ¹⁹F NMR shift in the meta isomer appears at −118.1 ppm.

The independent synthesis and characterization of the cobalt aryl compounds confirmed the identity of ortho-4b as one of the resting states observed during the catalytic borylation of 2b. Observation of ortho-4b by in situ ³¹P and ¹⁹F NMR spectroscopy provides additional support for rapid C(sp²)-H oxidative addition, as observation of this intermediate would be unlikely if this step was turnover-limiting. Furthermore, meta-4b was not present in detectable quantities during catalysis, suggesting that the formation of the cobalt aryl intermediate or a prior step is selectivity determining.

Stoichiometric Reactivity Studies.

The intermediacy of ortho-4b in catalysis prompted study of its reactivity with both B₂Pin₂ and HBPin. Addition of one equivalent of B₂Pin₂ to a benzene-d₆ solution of ortho-4b resulted in immediate formation of 1-(N₂)BPin and ortho-borylated fluoroarene ortho-3b by ¹⁹F NMR (Scheme 7a). The meta-borylated product meta-3b was not detected by ¹⁹F NMR. This result is consistent with a possible pathway involving oxidative addition of B₂Pin₂ to the cobalt(I)-aryl followed by C-B reductive elimination of the aryl boronate product.

Scheme 7.

Reactivity of Cobalt(I) Aryl Complexes Towards Boron Reagents

An analogous single turnover experiment was also conducted with HBPin (Scheme 7b). Addition of 4 equivalents of HBPin to ortho-4b produced ortho-3b in 91% yield along with 9% of 2b. Regeneration of the arene, 2b provides insight into the course of B-H oxidative addition to the cobalt(I) aryl complex where the arrangement of the ligands in the Co(III) product determines reaction outcome. To further explore this hypothesis, an analogous experiment was conducted using DBPin in place of HBPin (Scheme 7c). In this case, the recovered fluoroarene was deuterated in the position ortho to fluorine, confirming that C(sp²)-H oxidative addition occurred to generate mutually cis deuteride and aryl ligands resulting in deuterium incorporation, albeit to a minor extent. Addition of four equivalents of HBPin to meta-4b yielded meta-3b exclusively, with no 2b observed by ¹⁹F NMR spectroscopy (Scheme 7d).

The selectivity of the oxidative addition of fluorinated arene 2b was explored with other (^iPrPNP)Co(I)-X derivatives (Scheme 8). Because in a previous report³⁴ the isolation of cobalt(I)-boryl complex 1-(N₂)BPin proved to be recalcitrant, the more easily isolated pyrrolidinyl-substituted pincer complex 5-(N₂)BPin was chosen to examine the reactivity of a well-defined cobalt(I)-boryl towards 2b. Importantly, the analogous dihyride boryl complex 5-(H)₂BPin exhibited similar activity and regioselectivity to 1-(H)₂BPin in the catalytic borylation of 2b (see the Supporting Information). Addition of 2.1 equivalents of 2b to a benzene-d₆ solution of 5-(N₂)BPin at 23 °C rapidly produced a mixture of the cobalt(I)-aryl complex ortho-6b and 5-(H)₂BPin (Scheme 8a). This result demonstrates that cobalt(I)-aryl species can be generated by oxidative addition of a fluoroarene to a cobalt(I)-boryl followed by reductive elimination of HBPin. Moreover, observation of the 5-(H)₂BPin demonstrates that HBPin can react with cobalt(I) intermediates to generate the dihydride boryl resting state. Analysis of the organic products 24 hours after the addition of 2b revealed that the ortho- and meta-borylated products were produced in a 9:1 ratio, consistent with the regioselectivity of the catalytic reaction. The reactivity of 2b towards a cobalt alkyl complex supported by the pincer was also investigated. When five equivalents of 2b were added to a benzene-d₆ solution of 1-CH₃, ortho- and meta-4b were produced in a 94:6 ratio upon heating to 60 C for one hour.

Scheme 8.

Formation of Cobalt(I) Aryl Complexes from C(sp²)–H Oxidative Addition.

Deuterium Labeling Experiments.

The observation and isolation of cobalt(I) aryl complexes, the rate law for the catalytic borylation reaction and the absence of significant deuterium kinetic isotope effects support a pathway involving facile oxidative addition of the C(sp²)-H bond to the cobalt(I)-boryl. To gain insight into the origins of ortho-to-fluorine selectivity, deuterium labeling experiments were conducted. The catalytic borylation of 2-fluoro-α,α,α-trifluorotoluene (2c) with 5 mol% of 1-CH₃ was performed with DBPin rather than B₂Pin₂ as the boron source. It should be noted that the rate of the reaction was much slower when HBPin was used in place of B₂Pin₂ (see SI for additional details). Substrate 2c was chosen due to its inferior ortho-to-fluorine selectivity compared to 2a and 2b - 80:18:2 o/m/p versus 95:5 o/m.²⁹ A less selective reaction was studied to enable the reliable detection of minor deuteration and borylation products by NMR spectroscopy. In addition, the volatility of 2c allowed for facile separation of the borylated products from natural abundance and deuterated arenes enabling deconvolution of NMR spectra for definitive characterization.

The borylation of 2c in the presence of two equivalents of DBPin and 5 mol% of 1-CH₃ produced the arylboronate ester in 22% yield after 24 hours with an 82:18 ratio of ortho to meta products (Scheme 9a). Conversion and product ratios were determined by ¹⁹F NMR spectroscopy, and deuterium incorporation was quantified using ¹H, ²H and ¹⁹F NMR spectroscopies.⁴⁰ Analysis of the meta-borylated product revealed 42% deuterium incorporation at the site ortho to fluorine. No deuterated isotopologue of the ortho aryl boronate ester was detected, but this may be a result of low concentrations below the detection limits of the NMR experiment. Analysis of the recovered arene, 2c established deuterium incorporation at both the ortho (62% incorporation) and meta (13%) sites, an 82:18 ratio. No evidence for deuteration or borylation of the position para to the fluorine substituent was observed. That the observed selectivity for both borylation and deuteration are identical supports the hypothesis that C(sp²)-H oxidative addition is the selectivity-determining step.

Scheme 9.

(a) Catalytic Borylation of 2c with DBPin Catalyzed by 5 mol % of 1-CH₃, (b) Mechanistic Explanation of the Observed Hydrogen Isotope Exchange, and (c) Catalytic Borylation of 2c in the Presence of Both DBPin and B₂Pin₂. (n. d.: none detected)

A proposed pathway for the observed hydrogen isotope exchange reaction with 2c is illustrated in Scheme 9b. Oxidative addition of DBPin to the cobalt(I) aryl intermediate (4b) generates two isomers of the cobalt(III) product depending on the approach of the borane. In one isomer, the deuteride and aryl groups are cis, and are capable of undergoing productive C-D reductive elimination to generate ortho-d₁-2c. In the second isomer, the boryl and deuteride ligands are inverted such that the deuteride and aryl groups are trans, and this isomer can undergo C-B reductive elimination to generate the aryl boronate ester. It is by the latter pathway that hydrogen isotope exchange occurs when DBPin is used as the boron source.

To determine whether hydrogen isotope exchange occurs under conditions more similar to those of the catalytic reaction, an additional labeling experiment was conducted in which both B₂Pin₂ (one equivalent to 2c) and DBPin (two equivalents) were present (Scheme 9c). The reaction was quenched with air at 40% conversion to arylboronate products and the volatiles were then separated by vacuum distillation. Analysis of the aryl boronate esters (82:18 ortho:meta) by ¹⁹F and ¹³C NMR spectroscopies established no detectable deuterium incorporation while the volatile component, containing the fluorinated arene, exhibited only trace (<5%) deuterium incorporation, which was observed exclusively at the site ortho to fluorine by ¹⁹F NMR spectroscopy. This result demonstrates that, while DBPin may react with the cobalt(I) aryl intermediates to affect either borylation or hydrogen isotope exchange, the borylation reaction is faster than the deuteration reaction under catalytically relevant conditions. This is consistent with the stoichiometric experiments in which HBPin was added to ortho- and meta-4b and the aryl boronate product was produced in greater quantities than the fluoroarene 2b.

Proposed Mechanism.

Based on the experimental results described in this work and previously reported computational results³⁶, a proposed mechanism for the cobalt-catalyzed borylation of fluorinated arenes is presented in Scheme 10. The cobalt(III) precatalyst, 1-(H)₂BPin undergoes isomerization and reductive elimination of H2 to generate the cobalt(I)-boryl.³⁶ This compound promotes fast and reversible C(sp²)-H oxidative addition of the fluorinated arene to generate a cobalt(III) boryl-hydride-aryl intermediate. The kinetically favored stereochemistry for this intermediate is the isomer with mutually trans aryl and boryl substituents; DFT calculations established that C-H oxidative addition of the arene to generate this intermediate occurs with a lower activation barrier than the corresponding reaction to produce the stereoisomer containing cis aryl and boryl substituents.³⁶ Because the aryl and boryl groups are trans, direct reductive elimination to aryl boronate ester product is not possible. Instead, B-H reductive elimination occurs to generate HBPin and the experimentally observed cobalt(I)-aryl product. Oxidative addition of HBPin generates the corresponding cobalt(III)-aryl-hydride-boryl. If the cobalt(III) product has the aryl and boryl groups cis, it is poised to undergo B-C reductive elimination and form aryl-boronate product. If the opposite isomer is formed, arene reductive elimination would generate a catalytically competent cobalt(I)- boryl. In the productive pathway, reductive elimination of the product yields the cobalt(I)-hydride, 1-H which can be trapped by HBPin to form 1-(H)₂BPin accounting for the observation of this compound as the cobalt resting state at higher conversion where the concentration of HBPin is also high.

Scheme 10.

Proposed Mechanism of Fluoroarene Borylation Catalyzed by 1-(H)₂BPin

The observed fractional order in HBPin may be rationalized by multiple equilibria involving oxidative addition of HBPin to catalytically competent cobalt intermediates. Oxidative addition of HBPin to the cobalt(I) aryl (e.g. 4) is one such process and is driven forward and productively as the borane accumulates and gives rise to net acceleration. However, as HBPin forms, an equilibrium between the cobalt(I) hydride 1-H and off-cycle 1-(H)₂BPin reduces the concentration of active cobalt in solution. The product of these two equilibria is net-positive and results in the observed fractional order in HBPin.

Origin of Ortho Selectivity: The Ortho-Fluorine Effect.

With a firm understanding of the mechanism of fluoroarene borylation in hand, the origin of the high ortho site selectivity may be rationalized. All the experimental data are consistent with selectivity-determining C(sp²)-H oxidative addition. That each of the stoichiometric reactions between 1-(N₂)BPin, 1-(H)₂BPin, 1-H and 1-CH₃ and 3-fluorobenzotrifluoride (2b) resulted in the same ortho:meta site selectivity support that subsequent steps in the catalytic cycle such as C-B bond formation have no significant influence on the selectivity of the reaction. In addition, observation of the ortho isomer of the cobalt(I) fluoroaryl complex as a catalyst resting state supports that the ortho-to-fluorine selectivity is established prior to the formation of this resting state. Lastly, both the ortho and meta isomers of the cobalt(I) fluoroaryl intermediates react with HBPin to generate the ortho and meta arylboronate products, respectively, ruling out any isomerization processes after C(sp²)-H oxidative addition and influence of C-B bond formation events on the regioselectivity of borylation. Taken together with the deuterium labeling studies, which demonstrate the reversibility of oxidative addition, these results support an initial C(sp²)-H activation step that is fast and reversible and which favors ortho fluoroaryl intermediates resulting in the high ortho fluorine selectivity in (PNP)Co-catalyzed borylation.

The thermodynamic preference for oxidative addition of C-H bonds ortho to fluorine arises from a previously studied phenomenon whereby ortho fluorine substituents in transition metal aryl complexes result in stabilization of the metal-carbon bond.^27,41–48 In seminal studies establishing the ortho fluorine effect, Jones, Perutz and coworkers demonstrated that addition of 1,3-difluorobenzene to (η⁵-C₅Me₅)Rh(PMe₃)(Ph)(H) resulted in initial formation of the 3,5- and 2,4-isomers of the rhodium difluoroaryl complexes (Scheme 11). Continued heating of the mixture to higher temperatures for an extended time resulted in conversion of this mixture exclusively to the 2,6-isomer of the rhodium difluoroaryl product. The same product mixture was obtained from photolysis demonstrating that the 3,5- and 2,4-isomers are kinetic products of oxidative addition and the 2,6-isomer is thermodynamic establishing preference for coordination of the rhodium to the carbon ortho to two fluorine substituents.⁴³ Subsequent computational investigations by Eisenstein, Perutz and coworkers demonstrated that for a variety of transition metal aryl complexes, the carbon-metal bond strength increases with increased ortho fluorine substitution. While the origins of this effect are not completely understood, it has been suggested that ortho-to-fluorine substitution imparts additional stabilization through inductive effects due to the ionic character of the metal-carbon bond.

Scheme 11.

Early Experimental Observation of the ortho Fluorine Effect by Jones and Perutz (ref. 43). The thermodynamic product of C-H oxidative addition is the product with the maximum number of fluorine substituents ortho to the transition metal.

Applying this effect to cobalt-catalyzed C(sp²)-H borylation explains the observed regioselectivity of the reaction. Thermodynamic control of oxidative addition produces the cobalt aryl complex with the strongest metal-carbon bond - the one stabilized by ortho to fluorine substituents. This proposal is consistent with our previous observations that the selectivity of the borylation reaction for a given fluoroarene substrate does not change with temperature, catalyst loading, or reaction progress. Consistent with these observations, the cobalt-catalyzed borylation of 1,3-difluorobenzene with 1-H₂(BPin) proceeded with exclusively selectivity for the 2-position. A qualitative reaction coordinate diagram accounting for the proposed origins of selectivity in cobalt-catalyzed C(sp²)-H borylation is depicted in Figure 3. The cobalt boryl species can oxidatively add a fluoroarene substrate to generate either the ortho or meta isomer of the cobalt(III) aryl-hydride-boryl intermediate, an equilibrium process which favors the thermodynamic ortho isomer. Because the concentration of the ortho fluoroaryl intermediate is greater than that of the meta, reductive elimination of HBPin generates predominantly the ortho fluoroaryl cobalt(I) species. The irreversibility of this step under catalytic conditions was established in deuterium labeling experiments, where no significant deuterium incorporation was observed in the borylation of 2c in the presence of both DBPin and B₂Pin₂.

Figure 3.

Qualitative reaction coordinate diagram accounting for the selective formation of ortho-fluoroaryl intermediates in cobalt-catalyzed C(sp²) H borylation.

Ostensibly, reductive elimination of HBPin should occur from the ortho and meta fluoroaryl cobalt(III) species with comparable kinetic barriers; as such, the kinetic contributions to the regioselectivity of the catalytic reaction are expected to be insignificant. Unfortunately the kinetics of the catalytic borylation reaction have prohibited experimental verification of this assumption. Either cobalt(I) fluoroaryl intermediate then reacts with HBPin (or B₂Pin₂) to generate the arylboronate ester product. As observed in stoichiometric reactions of ortho- and meta-4b with HBPin, DBPin, and B₂Pin₂, the regioselectivity of the cobalt(I) aryl intermediate is conserved in the arylboronate product upon reaction with any of the boron reagents present during catalysis. Therefore, the ortho-selective borylation of fluorinated arenes is attributed to the selective formation of the ortho-fluoroaryl cobalt(I) intermediate that is a result of the stabilization imparted by ortho fluorine substituents on the cobalt (III) aryl-hydride-boryl intermediate.

Computational Studies.

To evaluate our conclusion that the ortho fluorine selectivity in cobalt-catalyzed borylation is thermodynamic in origin, DFT calculations were performed to assess the different metal-carbon bond strengths of catalytically relevant intermediates. These studies followed the approach employed by Eisenstein and Perutz, who calculated the metal-carbon bond energies of various C(sp²)-H oxidative addition products to assess the effects of various aryl substituents on the strength of the M-C bond.⁴⁷ For a given transition metal-aryl complex, the metal-carbon bond strength increases linearly as a function of the number of ortho fluorine substituents and that meta and para fluorine substituents have minimal influence on stabilization of the M-C bond. It should also be noted that this effect is also observed with carbon-hydrogen bonds, albeit to a lesser extent than with metal-carbon bonds. Ei-senstein and Perutz quantified the magnitude of the ortho fluorine effect for various transition metal complexes by plotting the change in metal-carbon bond strength with increasing ortho fluorine substitution against the change in C-H bond strength for the corresponding free arenes. The slope of the R^MC/HC correlation provided values in the range of 1.93 to 3.05, with higher values indicating more pronounced M-C bond stabilization as a function of increased ortho fluorine substitution.

The ωB97XD functional, a hybrid functional with empirical long-range dispersion corrections was selected for the present study due to its superior performance as compared to other dispersion-corrected hybrid functionals such as B3LYP-D as well as for its computational expedience.⁴⁹ Cobalt-carbon bond dissociation free energies (BDFEs) were calculated for the series of compounds 1-(Ar)(H)(BPin), where Ar = phenyl, para-tolyl, and para-trifluoromethylphenyl. For each of these compounds, the cobalt-carbon BDFE was also calculated for the derivatives with one and two ortho fluorine substituents, for a total of nine aryl complexes. The carbon-hydrogen BDFEs were also calculated for the corresponding fluorinated arenes. From the computational data, an MC/HC BDFE correlation plot was constructed with a slope of 2.87, confirming that the Co(III) ortho fluoroaryl complexes invoked in cobalt-catalyzed C-H borylation are stabilized as a result of the ortho fluorine effect (Figure 4). Notably, this value of R^MC/HC is near the upper bound of values obtained by Eistenstein and Perutz, indicating that cobalt-carbon bonds in (PNP)Co complexes are particularly responsive to ortho fluorine substitution.

Figure 4.

Correlation between the Co-C bond dissociation free energies (BDFEs) of 1-(Ar)(H)(BPin) and the C-H BDFEs of the corresponding arenes. The zero points for the x and y axes correspond to the values for the C-H BDFE in benzene and the Co-C BDFE in 1-(Ph)(H)(BPin), respectively.

With an understanding of the effect of fluorine substitution on the BDFEs of (^iPrPNP)Co-Ar complexes in hand, the observed ortho selectivity arises from the relative stability of the ortho and meta isomers of the putative Co(III) aryl hydride boryl intermediate. The selectivity of the reaction reflects the energy difference between the two oxidative addition products, a reversible process under thermodynamic control (Scheme 12). The ground state energies of the optimized structures of both compounds were calculated, and the ortho isomer was calculated to be more stable than the meta isomer by 2.6 kcal/mol. Based upon the proposed mechanism and the associated origins of regioselectivity, this value projects to a borylation selectivity of 99:1 in favor of the ortho product. This computational result is in excellent agreement with the experimental selectivity of 95:5 (o:m) observed for the catalytic borylation of 2b. These results support the role of the ortho fluorine effect in stabilizing ortho fluoroaryl intermediates in cobalt-catalyzed C-H borylation, which results in the high selectivity observed for borylation ortho to fluorine substituents. The key to this effect is the interplay of kinetics and thermodynamics; because oxidative addition is kinetically facile and therefore under thermodynamic control, the difference in Co-C BDFEs dictates the selectivity of the reaction.

Scheme 12.

Proposed Origins of ortho-to-Fluorine Selectivity in Cobalt-catalyzed C-H Borylation: Thermodynamic Control of C-H Oxidative Addition.

CONCLUDING REMARKS

Studies into the origin of the high ortho-to-fluorine site selectivity in the cobalt-catalyzed borylation of fluorinated arenes revealed a kinetic pathway where oxidative addition of the C(sp²)-H bond is fast and reversible. In previous studies with iridium and cobalt catalysts with benzene and N-heteroarenes, C(sp²)-H bond activation of the substrate by a metal-boryl was turnover limiting and hence slow and irreversible. In the present cases, fluorination of the substrate activates the C(sp²)-H bonds such that the barrier for oxidative addition is decreased and the turnover limiting step of the catalyst cycle shifts to product-forming C-B reductive elimination.

Identification of a cobalt(I)-aryl resting state, in combination with deuterium labeling studies, further support selectivity- determining C(sp²)-H oxidative addition to the cobalt-boryl and demonstrated that this process in under thermodynamic control. Computational studies demonstrated fluorination of the aryl ring stabilizes the adjacent cobalt-aryl bond and this effect is magnified for the transition metal as compared to the free arene. The combination of this thermodynamic preference with fast and reversible C(sp²)-H oxidative addition are the origin of the high regioselectivity in the catalytic borylation reaction, rather than relative C(sp²)-H acidities. These principles, along with insights for kinetic preferences for oxidative addition, may allow rational design of next generation catalysts with distinct regioselectivity for C-H function- alization that are based on inherent electronic differences in C-H bonds rather than exogenous directing group strategies.