Insight into the mechanism of the arylation of arenes via norbornene relay palladation through meta- to para-selectivity

Abstract

A novel mechanism of the arylation of arenes via norbornene (NBE) relay palladation through meta- to para-selectivity was revealed via density functional theory (DFT) calculations. Our calculated results revealed that the reaction was initiated by a [mono-N-protected amino acid ligand (MPAA)–Pd] complex to activate at first the meta-C–H guided by the directing group (DG), and para-arylation was subsequently achieved by NBE relay palladation from meta- to para-position. Significantly, the palladium/norbornene (Pd/NBE) cooperative catalysis was catalyzed by a Pd–Ag bimetallic complex, which accounted for the experimental fact that no yield detected without Ag. The reaction pathway through para- to meta-selectivity was also investigated, while this pathway was kinetically unfavorable. The results revealed that the initial DG guided C–H site activation was the rate-determining step and played an important role in determining site-selectivity. The primary meta-activation was favorable in energy due to the less ring strain in the cyclic nitrile-coordinated C–H transition states in the meta position. Moreover, the perfect cooperation of a remote directing template and a transient mediator NBE through the alternating association with the Pd center achieved the relay through meta- to para-position. The present results provide a reasonable insight into the para-C–H arylation by the Pd/MPAA/NBE cooperative catalysis in conjunction with a precise DG and Ag(I) additive.

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1. Introduction

Undoubtedly, practical and site-selective arene functionalization plays an important role in pharmaceutical, agrichemical and materials research.¹ However, the precise site-selective C–H functionalization of aromatic compounds is a fundamental challenge because of the inherently similar electronic and steric properties of the C–H bonds. To achieve the C–H bond functionalization of aromatic compounds at a desired position, directing group (DG) assistance has become an effective strategy.² This strategy is widely employed for proximal ortho-C–H activation (Scheme 1a),³ but the selective functionalization of remote meta- and para-position is still underdeveloped. Although a few elegant approaches were reported to expand the scope of arene meta-C–H functionalizations (Scheme 1b),⁴ in contrast, studies of para-selective C–H functionalization⁵ are significantly limited. Recently, several protocols of para-selective C–H functionalizations were developed by the groups of Itami,⁶ Chattopadhyay,⁷ Hiyama⁸ and others,⁹ but these protocols were successful only for borylation, olefination,¹⁰ alkylation,¹¹ acetoxylation,¹² ketonisation¹³ and cyanation¹⁴ reactions. It is urgently needed to develop an alternate method to diversify the scope of para-functionalizations, particularly arylation, because biaryls are basic building blocks of pharmaceuticals and agricultural chemicals.¹⁵ Therefore, it is important to selectively introduce an aromatic ring at the para position, which will promote the development of the diaryl synthesis.

Scheme 1 Site-selective C–H functionalization.

In 2020, Maiti et al. developed a para-selective C–H arylation method by a unique combination of a meta-DG and NBE as a transient mediator (Scheme 1c).¹⁶ This strategy first implements meta-C–H activation via DG guidance; subsequently, the transient mediator NBE relays Pd to the para-position to achieve precise site-selectivity. The effective ligand was N-acetylglycine (Ac-Gly-OH), which is a mono-N-protected amino acid (MPAA).¹⁷ However, the mechanism of how to utilize a transient mediator to combine the remote directing effect with a ligand and palladium relay is still ambiguous. Moreover, the experimental observations showed that Ag(I) was a crucial additive, and the reaction could not proceed without Ag(I).¹⁶ How does Ag(I) play an important role in certain Pd-catalyzed C–H functionalization reactions? Investigation into this subject has been scarce and limited to only a few theoretical studies that proposed heterodimeric transition states of C–H activation.¹⁸ The mechanism of this novel strategy achieving precise para-C–H arylation and the role of additive, such as AgOAc, are still unknown. Herein, we reported density functional theory (DFT) calculations to explore the mechanism of NBE relay palladation and origins of the site selectivity.

2. Computational methods

All geometry optimizations and single point energy calculations were performed using Gaussian 09.¹⁹ The intermediates and transition states were optimized at the B3LYP level²⁰ of DFT. The basis set of SDD²¹ was employed for Pd, Ag, I and the 6-31G (d,p)²² for other atoms. Vibrational frequencies were calculated to confirm if each optimized structure is a local minimum or a transition state structure. All optimized structures were calculated for single point energy using M06 functional²³ and mixed basis set of [6-311++G(d,p)+SDD] at the hexafluoro-2-propanol solvent with parameters “solvent = generic, eps = 16.7, epsinf = 1.63” to simulate by the SMD solvation model.²⁴ In a previous study of Pd-catalyzed C–H activation, the similar level of method was reported to have demonstrated satisfactory performance.^18,25

The NBO 6.0²⁶ program was used to perform the Natural Bond Orbital analysis using the wavefunction obtained from the B3LYP level. The 3D structures were prepared using CYLView.²⁷

3. Results and discussion

We selected the arylation of arene reaction as a representative system to explore the mechanism of the site-selective C–H activation under Pd/MPAA/NBE cooperative catalysis, as shown in Scheme 1c. Based on our calculations and the experimental results, we designed two reaction pathway scheme (Scheme 2) of NBE relay palladation through meta- to para-position and para- to meta-position, respectively. For the pathway of the para-C–H-arylated product p^p (left cycle),¹⁶ the overall catalytic cycle mainly included the primary meta-C–H activation, NBE insertion, secondary para-C–H activation, oxidative addition and reductive elimination, and then, NBE extrusion and protodemetallation. NBE as a transient mediator achieves the expected palladium relay via migratory insertion. The pathway of meta-arylation p^m was derived from the primary para-C–H activation and secondary meta-C–H arylation (right cycle). We also explored the possible side reactions that the active aryl-palladium intermediates are direct meta-functionalized (A to F) and reductive eliminated (cyclobutane G formation from C and D).²⁸

Scheme 2 Proposed mechanism for para-C–H arylation (left cycle) and meta-C–H arylation (right cycle) catalyzed by the Pd/MPAA.

3.1 Energy profiles for the NBE relay palladation through meta- to para-position

3.1.1 Primary meta-C–H activation. Pd catalysts can be effective in various forms depending on the ligand, temperature, solvent, and other reaction conditions.^17,29 Palladium acetate was used as the pre-catalyst in this experiment,¹⁶ which maintains the most stable form of the trimeric structure in the absence of coordinating ligands (Fig. S1†). Experimentally, the introduction of the MPAA ligand may dissociate the trimeric species Pd₃(OAc)₆ to form active monomeric Pd(II) complexes.³⁰ MPAAs as bidentate ligands for Pd-catalyzed C–H functionalizations were first introduced by Yu's laboratory in 2008.¹⁷ Sunoj et al. revealed that in the presence of silver additives, the Pd–Ag dinuclear pathway was favored in the C–H activation.³¹ So, we optimized several C–H activation pathways involving monomeric Pd, dimeric Pd and Pd–Ag dinuclear complexes by employing either acetate or MPAA (Scheme S1 and Tables S1, S2†). The calculation results show that the monomeric Pd catalyst with MPAA as a bidentate ligand was the most effective. MPAA not only stabilized the monomeric Pd and acted as the internal base for proton abstraction. This result is also consistent with the previous report by Houk, Yu, and Wu.³⁰ Moreover, the energy unfavorable Pd–Ag dimeric catalyzed pathway could be basically ruled out. This means that Ag does not participate in the primary C–H activation step. In addition, Houk and Ehara et al.^18a,32 reported several possible pathways for the C–H activation of arenes, and they found that the concerted metalation/deprotonation (CMD)³³ pathway is favorable. We also explored these four pathways (Fig. S2†) including CMD, σ-bond metathesis, oxidative addition of the C–H bond and AcOH-assisted CMD mechanism. The present calculated results showed that among these, the CMD pathway is also found to be the most favorable one.³⁴

Fig. 1 depicts the formation of the active catalyst and the CMD pathway of primary C–H activation. Mono-deprotonation of MPAA by one of the acetates leads to monodentate Pd–MPAA complex int0, and then further deprotonation of the MPAA N–H bond by another acetate is highly favored,³⁰ forming a bidentate Pd–MPAA complex int1 coordinated with two neutral acetic acid molecules. Para-Arylation and meta-arylation products are derived from the primary meta-C–H activation and primary para-C–H activation, respectively. We next investigated ortho-, meta- and para-C–H activation steps. The calculation results indicated that the energy barrier for the meta-C–H activation of TS1^m was lower than that of the ortho-TS1^o and para-TS1^p.

Fig. 1 Free energy profiles for the primary C–H activation steps. The selected NPA atomic charges are given in numbers in substrate 1.

The MPAA ligand promoted the primary C–H activation step, and then provided a vacant coordination site for subsequent NBE insertion.³⁵ As shown in Fig. 2, int3 isomerizes to the more stable int4, allowing the competitive direct meta-arylation and NBE insertion. The energy barrier of the direct oxidation addition (TS2) is higher than that of NBE insertion (TS3 and TS4), so the direct meta-functionalization is overridden by the faster NBE coordination to allow the expected Pd relay. Moreover, the MPAA ligand is more beneficial to the stability of the transition state (TS3) than acetate (TS4). In addition, other three kinetically unfavorable pathways of the NBE insertion are given in Fig. S3.†

Fig. 2 Free energy profiles for the NBE insertion.

3.1.2 NBE relay monomeric Pd from meta- to para-C–H activation. We next investigated the subsequent steps, para-C–H activation, oxidative addition and reductive elimination, NBE extrusion and protodemetallation, based on the Catellani-Type reaction mechanism.³⁶ The calculated results for these processes are summarized in Fig. 3. First, NBE transfers Pd near the para-C–H bond by single bond rotation. Moreover, DG has come off the metal Pd, which requires endothermic 13.1 kcal mol⁻¹. The para-C–H activation from int11 takes place via the transition state TS5 (28.1 kcal mol⁻¹), leading to a unique aryl-norbornyl-palladacycle int12.³⁷ Both experiment and theory show that the Pd/NBE-catalyzed selective arylation follows the Pd(II)/Pd(IV) catalytic cycle.^25b,38Int12 undergoes a ligand exchange to generate Pd(II)-IAr int13, and then, the ArI oxidation of Pd(II) to Pd(IV) viaTS6 (16.0 kcal mol⁻¹) happens to generate the four-coordinate Pd(IV) complex int14. It is generally accepted that an Ag(I) additive helps to remove the Pd-coordinated halide ion from a product of oxidative addition of an alkyl/aryl halide.³⁹ Subsequently, the C–C reductive coupling starts from the iodide abstraction of int14 by Ag(I), and acetate is bound to the Pd center to provide the int15. Para-Arylation is achieved through TS7 (14.9 kcal mol⁻¹) to form int16, and the metal center is reduced to Pd(II). Another competitive pathway is that reduction coupling occurs first in int14viaTS8, and then Ag(I) can extract iodine from int17 to form int16. Finally, the catalytic cycle is completed through NBE extrusion and protodemetallation. The NBE extrusion is from int16 to int18viaTS9, and the DG nitrile group coordinates with metal Pd. Int18 undergoes a ligand exchange with HOAc to release NBE, and the para-arylation product p^p can be obtained according to a protodemetallation viaTS11. We also considered three possible reductive elimination steps (viaTS12, TS13, and TS14) to form the byproduct benzocyclobutane, and these competitive reactions are energetically unfavourable. In summary, the energy of NBE relay monomeric Pd from meta- to para-C–H activation appeared to be too high, reaching 28.1 kcal mol⁻¹, which has prompted us to search for alternative, low-energy para-C–H activation pathways.

Fig. 3 Free energy profiles for the para-C–H arylation catalyzed by the monomeric Pd complex.

3.1.3 NBE relay Pd–Ag from meta- to para-C–H activation. The experimental observation found that AgOAc is a crucial additive for the Pd(II)-catalyzed arylation of arene derivatives with a nitrile-containing template, and replacing Ag with other oxidants leads to very low or no yield,¹⁶ which prompted us to further explore the role of the Ag(I) additive. Based on Houk and Dang's previous studies on the PdAg(OAc)₃ heterodimeric mechanism,^18a,31b we explored the Ag assisted C–H arylation pathway (Fig. 4). First, int10 reacts with Ag(I) to afford the Pd–Ag heterodimeric complex int20 with an endothermicity of 0.7 kcal mol⁻¹. Ag(I) coordinates with Pd/MPAA to separate DG from Pd. The Ag(I)-coordinated acetate acts as an internal base to activate the para-C–H bond and the energy barrier is lowered to 23.7 kcal mol⁻¹. The aryl iodide coordinates with sliver, and then, oxidative addition happens through a cyclic transition state TS16. Silver iodide extrusion offers the Pd(IV) intermediate int24. If aryl iodide directly adds to the Pd(II) center through a LAg-HOAc substitution from int21, it is energetically unfavorable (Fig. S4†). Finally, the catalytic cycle is completed via similar reductive elimination, NBE extrusion and protodemetallation (viaTS17, TS18 and TS19) to produce the para-arylation product.

Fig. 4 Free energy profiles for the para-C–H arylation catalyzed by the Pd–Ag bimetallic complex.

The calculated free energy barrier of the Pd–Ag bimetallic complex catalyzed para-C–H activation (TS15) is lower than that of the aforementioned monomeric Pd mechanisms (TS5) by 4.4 kcal mol⁻¹ (Fig. 5). It suggested that the Pd–Ag bimetallic complex played a significant role in stabilizing TS15 in a secondary para-C–H activation. We also explored the effect of the tether length on regioselectivity differences. We used an acetic acid to replace silver acetate to calculate the energy barrier of the para-C–H activation step. The result showed that the energy barrier is 31.3 kcal mol⁻¹ (TS15′), which is 10.0 kcal mol⁻¹ higher than that of bimetallic Pd–Ag (TS15), and 5.6 kcal mol⁻¹ higher than monomeric Pd–MPAA (TS5). This suggested that the regioselectivity difference in this reaction did not depend on the tether length. We also calculated the para-C–H activation step with two silver acetates to increase the tether length (Fig. S7†), and it needed to overcome a higher energy barrier (33.4 kcal mol⁻¹). It followed that the bimetallic Pd–Ag played a significant stabilization role in the secondary para-C–H activation.

Fig. 5 Free energy profiles for the para-C–H activation catalyzed by monomeric Pd and heterodimeric Pd–Ag.

3.2 Origin of site-selectivity for NBE relay Pd through meta- to para-position

The calculated energy profiles of the NBE relay Pd through meta- to para-position to produce para-arylated product are summarized in Fig. 6a. The calculated studies revealed that the reaction was initiated by a monomeric Pd/MPAA complex to achieve a primary meta-C–H activation and a subsequent secondary para-C–H activation catalyzed by a Pd–Ag bimetallic complex (black pathway). In 2019, Yu et al.⁴⁰ found that the meta-arylated product originates from the initial para- and ortho-C–H activation, followed by subsequent meta-C–H activation in the arylation of the electron-rich arene reaction. Inspired by Yu's report, we further optimized the energy profiles of NBE relay palladation through para- to meta-position (blue pathway). The mechanistic details can be seen in the ESI.† We analyzed free energy pathways for two different meta- and para-arylations based on the Curtin-Hammett scenario⁴¹ (Fig. 6b). The results indicated that the competition between the primary C–H activation transition states TS1^m and TS1^p controlled the site selectivity. The calculated selectivity was ΔΔG^‡ = 2.3 kcal mol⁻¹, and the ratio of p^p and p^m was calculated to be 20 : 1. It is in good agreement with the experimental observation of ratio 20 : 1.¹⁶ The present result shows that the site selectivity of the reaction was controlled by kinetics.

Fig. 6 (a) Free energy profiles of the full catalytic cycle of the two pathways. (b) Free energy profiles for the major and minor pathway based on the Curtin-Hammett scenario. (c) Structure conversion of NBE relay Pd from meta- to para-position.

In order to understand the origins of the cooperative mechanism of the transient mediator and remote directing group to achieve palladium relay, we further investigated the structure conversion of the NBE relay Pd from meta- to para-position (Fig. 6c). After Pd accesses meta-position, the norbornene attacks the meta-Pd–C_sp² bond from below the substrate benzene ring (int9). With the rotation of the C_NBE–Csp² bond from 80.5° (int10) to 62.3° (int20), Ag(I) coordinates with Pd/MPAA to get rid of the binding of the directing group, and then, Pd is relayed to the para-position. The Ag(I)-coordinated acetate acts as an internal base to abstract proton (int21). To quantitatively illustrate the NBE relay palladation, we further analyzed the thermodynamics and kinetics for the process of conversion based on the Curtin-Hammett scenario, as illustrated by the Gibbs energy profile in Fig. 6b. Here, as for the single intermediate, ratio [int4]/[int10] was determined by their relative stabilities.⁴² This means that NBE insertion as the key step can take place spontaneously with exothermic of 7.1 kcal mol⁻¹via a low barrier (7.4 kcal mol⁻¹). The energy released in this step basically compensates for that needed to cross the barrier. It follows that the Pd relay process is driven thermodynamically to achieve the activation from meta- to para-position.

The discussion above shows that the DG-directed Pd activates favorably the meta-position (TS1^m) compared to the para-position (TS1^p). To further understand how these different factors control the site selectivity, we performed the distortion/interaction analysis⁴³ on these competitively transition states (Fig. 7). The distortion energies of the substrate in TS1^p were 3.4 kcal mol⁻¹ higher than that in TS1^m, and demonstrated that the distortion of substrate in the C–H activation transition states was a dominant factor (38.5 and 41.9 kcal mol⁻¹ for TS1^m and TS1^p, respectively). The greater strain in TS1^p was due to the significant distortion of the C–S bond from −70.4° to −50.2° compared to substrate 1. However, TS1^m barely changed (ψ2 = −69.3°).

Fig. 7 (a) Optimized geometry of the toluene derivative substrate with the nitrile-containing template. (b) Optimized geometries of the meta- and para-C–H activation transition states of Pd/MPAA catalysis.

4. Conclusions

A novel mechanism of the site selective arylation of arenes via Pd/MPAA/NBE cooperative catalysis in conjunction with a precise DG and silver(I) additive was explored using DFT calculations. The results revealed that the reaction was initiated by a Pd/MPAA complex to activate at first the meta-C–H guided by the directing group, and the para-arylation was achieved by the NBE relay palladation from meta- to para-position. The secondary para-C–H activation was catalyzed by a Pd–Ag bimetallic complex, which unraveled the crucial role of the silver additive. We also explored energy pathways through para- to meta-selectivity. The calculation results showed that the DG-assisted primary C–H activation was the rate-determining step for the overall catalytic cycle, and also the key step of determining the site selectivity. The meta-C–H activation was favorable in energy due to the less ring strain in the cyclic nitrile-coordinated C–H activation transition states in meta-position.

Notably, we explored in detail the origin of the cooperative mechanism of the transient mediator and remote directing group to achieve the palladium relay. The directing group guided the active monomeric Pd/MPAA catalyst to achieve primary meta-C–H activation. Then, it had to cooperate with a transient mediate NBE to alternate association with the Pd center driven by thermodynamics for the catalytic cycle to proceed. The NBE insertion, as the key step to achieve the expected Pd relay, can take place spontaneously with exothermic of 7.1 kcal mol⁻¹, which can compensate for the energy needed to cross the barrier. The palladium relay process was driven thermodynamically to achieve the activation from meta- to para-position. We expect that this study would have implications for the understanding of C–H functionalization chemistry by norbornene relay palladation and would be helpful to design new reaction systems to access more accurate site selectivity in syntheses.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the Natural Science Foundation of Shandong Province (ZR2019YQ11).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1qo01500a

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