Frustrated Lewis Pair Catalyzed C–H Activation of Heteroarenes: A

Letter Cite This: Org. Lett. 2018, 20, 1102−1105

pubs.acs.org/OrgLett

Frustrated Lewis Pair Catalyzed C−H Activation of Heteroarenes: A Stepwise Carbene Mechanism Due to Distance Effect Youxiang Shao,† Jianyu Zhang,†,‡ Yinwu Li,† Yan Liu,*,‡ and Zhuofeng Ke*,† †

School of Materials Science and Engineering, PCFM Lab, Sun Yat-sen University, Guangzhou 510275, China School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, China

‡

S Supporting Information *

ABSTRACT: This study presents new mechanistic insights into the frustrated Lewis pairs (FLPs) catalyzed C−H activation of heteroarenes. Besides the generally accepted concerted C−H activation, a novel stepwise carbene type pathway is proposed as an alternative mechanism. The reaction mechanisms can be varied by tuning the distance between Lewis acid and Lewis base due to catalyst−substrate match. These results should expand the understanding of the structure and function of FLPs for catalyzed C−H activation.

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etal-free catalysts that can imitate a metallic system, including unsaturated heavier main group compounds,1 the carbenes,2 and the frustrated Lewis pairs (FLPs),3 have been developed during the past decades. In particular, the FLPs have attracted remarkable attention owing to the ability of the Lewis acid (LA) and the Lewis base (LB) in FLPs to act as an electron acceptor and an electron donor, respectively (Figure 1a), resulting in versatile FLPs cooperative reactivity. This characteristic offers FLPs unprecedented possibilities for the activation of small molecules similar to transition-metal catalysts.4 Since Stephan and co-workers discovered that the FLP, p(Mes2P)C6F4[B(C6F5)2] (Mes = mesityl), cleaved H2 under ambient conditions,5 the applications of FLPs have been extended from the activation of small molecules to organometallic chemistry.6 However, until very recently, the FLPs were successfully applied in catalytic activation of the unreactive C−H bond.7,8 Fontaine and co-workers beautifully employed a FLP named ansa-aminoborane (1-TMP-2-BH2-C6H4; TMP = 2,2,6,6-tetramethylpiperid-1-yl) to catalyze the C−H activation of heteroarenes, including furans, pyrroles, and electron-rich thiophenes.8a A concerted C−H activation mechanism was proposed8a in which the C−H bond was broken by LA and LB

Figure 2. (a) Borane-induced 1,2-H migration to CAAC−borane; (b) hypothesis of the stepwise carbene mechanism.

Figure 3. Structures of selected FLPs with varied B···P distances (in Å).

in a concerted manner (Figure 1b), similar to the mechanism of FLPs catalyzed H2 activation.9 Interestingly, the C−H activation is more preferred for the electron-rich heteroarenes over the electron-deficient heteroarenes or arenes.7b These clues imply another possibility that the C−H activation might also occur via an electrophilic Figure 1. (a) Structure of FLPs; (b) general concerted C−H activation of heteroarenes catalyzed by FLPs. © 2018 American Chemical Society

Received: January 3, 2018 Published: February 5, 2018 1102

DOI: 10.1021/acs.orglett.8b00024 Org. Lett. 2018, 20, 1102−1105

Letter

Organic Letters

Figure 4. Free energy profiles for the C−H activation of 1-methylpyrrole catalyzed by FLPs 1−4..

possible for the FLP-promoted C−H activation of heteroarenes depending on the distance effect. This stepwise mechanism, together with the general concerted C−H activation mechanism, will expand the understanding of FLP-catalyzed C−H activation. In order to address the distance effect on the mechanism, a series of intramolecular FLPs with different LA−LB distances were selected to study the catalyzed C−H bond activation of heteroarenes. Due to the diversity and wide use of phosphorus in the chemistry of FLPs,12 four kinds of phosphorus- and boron-based FLPs (see Figure 3) were taken into consideration as catalysts.13 1-Methylpyrrole was selected as the model substrate.8a The results obtained at the M062X/6-311+ +G(d,p)/SMD(toluene)//M062X/6-31G(d,p)/SMD(toluene) level of theory were employed in the discussions. All calculations were performed using the Gaussian 09 program.14 FLP1 with a linker identical to that of Fontaine’s system was evaluated first. The calculated free energy profiles of the concerted and the stepwise mechanisms are depicted in Figure 4a. The corresponding transition state of the concerted mechanism is TS1 with a six-membered ring geometry. The activation free energy of TS1 is 21.7 kcal/mol, which is in good accordance with Fontaine’s results.8a The cooperative cleavage of the C−H bond leads to the formation of PC1, which is 8.0 kcal/mol above the reactants. As a result, the overall reaction of C−H bond activation is thermodynamically feasible for further C−C coupling reaction. On the other hand, the stepwise mechanism for FLP1 is infeasible as the free energy barriers of the 1,2-H migration and the deprotonation steps are 32.4 and 23.4 kcal/mol, respectively, which are much higher than that of the concerted mechanism. It is worth noting that the free energy barrier of the 1,2-H migration has decreased by 23.7 kcal/mol owing to the promotion of FLP1 (see Figure S2).15 As shown in Figure 3, the distance between the phosphorus

substitution process in other situations. Recently, electrophilic C−H borylation of heteroarenes were also proposed in other systems.8e−g The electrophilic adduct of arene tends to undergo a rearrangement from a cation intermediate to an abnormal Nheterocyclic carbene (NHC) type intermediate. For example, the borane-induced 1,2-H migration pathway to generate CAAC−borane adducts from alkenes/arenes has been experimentally demonstrated by Kinjo (Figure 2a).10 Furthermore, many studies have also demonstrated the accessibility of CAAC−borane by X-ray structures (see Figure S1 in the Supporting Information),11 which are similar to our assumed NHC−borane intermediate (Figure 2b). It can be anticipated that the stepwise carbene mechanism (Figure 2b) cannot be totally excluded, especially when the cooperation of LA and LB for concerted C−H cleavage is difficult due to the long LA···LB distance in FLPs. Different from the concerted C−H activation mechanism, the proposed stepwise carbene mechanism involves (1) the 1,2-H migration step to form an NHC− borane intermediate and (2) the deprotonation step, in which the proton transfers from β-C to LB producing a zwitterionic heteroaryl-FLP species. It is worth noting that the transition state of the concerted mechanism only involves α-C−H, while the proton transfer in the stepwise mechanism involves both α-C and β-C−H groups. As a result, the geometric recognition between the catalyst and the substrate in the transition state is distinct between the concerted and the stepwise carbene mechanisms. In order to take advantage of the cooperative effect of the LA and the LB, the distance between LA and LB should be suitable to reduce the distortion energy of the substrate in the transition state. This implies that the distance between the LA and the LB in FLPs should influence the catalyst−substrate geometric match, thus tuning the reaction mechanism. In the present study, we will show that a stepwise carbene mechanism may also be 1103

DOI: 10.1021/acs.orglett.8b00024 Org. Lett. 2018, 20, 1102−1105

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Organic Letters

mechanism and the stepwise mechanism are decreased as compared to those of the FLP2-catalyzed reaction. Moreover, the rate-determining step of the stepwise mechanism is the 1,2H migration (TS3a) with a free energy barrier of 21.3 kcal/mol, which is 1.6 kcal/mol lower than that of the concerted transition state TS3. It is worth noting that the free energy barrier of the β-C−H process (TS3b) is 6.4 kcal/mol lower than that of the concerted mechanism (TS3). These results suggest that the stepwise carbene mechanism becomes slightly more favored than the concerted mechanism. Inspired by the results of FLP2 and FLP3 discussed above, we continue to consider the dibenzofuran based FLP4, in which the B···P distance is 5.55 Å. FLP4 was suggested to be inert for the hydrogen activation because the B···P distance is too long to cooperatively cleave the H−H bond.13c To our delight, calculations indicate that FLP4 is able to catalyze the C−H bond activation of 1-methylpyrrole via the stepwise carbene mechanism, as shown in Figure 4d. The free energy barrier of the 1,2-H transfer (TS4a) is only 17.4 kcal/mol, while that of the deprotonation (TS4b) is 18.3 kcal/mol, indicating the stepwise mechanism is accessible kinetically. It can be expected that the concerted mechanism could not be operated as the extremely long B···P distance prevents the cooperative cleavage of the C−H bond. It is similar to the results of H2 activation.13c These results further confirm that the distance between the LA and the LB centers can affect the catalytic reactivity of FLPs and tune the mechanism binary. According to the discussions above, the distance effect is of crucial importance in FLP-catalyzed C−H activation. In order to understand the intrinsic relationship between the LA−LB distance and the C−H activation mechanism, the structures and activation distortion−interaction energy decomposition analysis17 of the corresponding transition states are collected in Figure 5 (see Figures S4 and S5 for details). In the case of FLP1, the deformation energies of catalysts (Edef(cat.)) in the concerted mechanism and the stepwise mechanism are similar. However, the deformation energies of the substrate (Edef(sub)) are distinct as the length of the stretched C−H bond is different. For example, the broken α-C−H bond in TS1 is 1.32 Å, while the broken β-C−H in TS1b is 1.37 Å, indicating a lager Edef(sub) (66.3 kcal/mol) in TS1b. Fortunately, owing to the mediation of β-C in TS1b, the interaction energy (Eint) of TS1b is large, which could counterbalance the influence of Edef(sub). Therefore, the activation energy of TS1b is only 2.8 kcal/mol higher than that of TS1. On the other hand, the Eint of TS1a is similar to that of TS1, leading to a high activation energy of TS1a (32.4 kcal/mol). As a result, the stepwise mechanism is infeasible. With the B···P distance increasing, catalysts FLP2, FLP3, and FLP4 need less stretching in the B··· P distance, leading to a significant decrease of Edef(cat.) in both the concerted and the stepwise mechanisms. On the contrary, the Edef(sub) are distinct. Thus, the mechanism binary can be varied with the changes of the B···P distance. For the concerted mechanism, the longer B···P distance requires the C−H bond to stretch more severely, resulting in the increase of Edef(sub), which cancels out the Edef(cat.) and the Eint to some extent. As a result, the free energy barriers of the concerted mechanism are 26.8 and 22.0 kcal/mol for TS2 and TS3, respectively. However, the concerted mechanism does not operate in FLP4 due to the too long B···P distance (5.40 Å). With regard to the stepwise carbene mechanism, the Edef(sub) for the 1,2-H migration are remarkably insensitive to the changes of B···P distance (see Figure S5). The free energy barriers of the 1,2-H

Figure 5. Structures and activation distortion−interaction energy decomposition analysis of transition states corresponding for the concerted and stepwise mechanisms. The energies are in kcal/mol and the bond lengths are in Å.

atom and the boron atom in FLP1 is only 2.27 Å, indicating the interaction between P and B is strong, which will weaken the electrophilicity of the LA. The decreased Lewis acidity is disadvantageous for the formation of the NHC−borane intermediate. Thus, 1,2-H migration is required to overcome high activation free energy. These results further support that the concerted C−H activation mechanism should operate in Fontaine’s system.8a It is well-known that the catalytic reactivity of intramolecular FLPs is highly sensitive to the linker moiety.16 Thus, FLP2 with a B···P distance of 2.81 Å was further considered to evaluate the distance effect on the mechanism. As can be seen in Figure 4b, the free energy barrier of the concerted mechanism (TS2) has increased to 26.8 kcal/mol. It is intriguing that the free energy barrier of the 1,2-H migration (TS2a) and the deprotonation (TS2b) steps have decreased to 26.3 and 20.3 kcal/mol, respectively. It is obvious that the stepwise carbene mechanism are comparable to the concerted C−H activation mechanism in FLP2 catalyzed reaction. However, the free energy barriers of both the concerted and the stepwise mechanism are slightly higher than that of FLP1 catalyzed reaction. It indicates that the change of B···P distance affects not only the mechanism but also the catalytic reactivity. The dimethylxanthene system FLP3 with longer B···P distance (3.88 Å) was taken into account further. As exhibited in Figure 4c, the free energy barriers of both the concerted 1104

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migration are mainly influenced by Edef(cat.) and Eint. Therefore, the longer B···P distance significantly decreases the free energy barriers of 1,2-H migration in TS3a and TS4a (21.3 and 17.4 kcal/mol, respectively) due to the lower Edef(cat.) and the stronger Eint. Furthermore, as shown in Figure 5, owing to the mediation of β-C, the CC−H moiety of the substrate well matches the long B···P distance in TS3b and TS4b. A significant increase in the Eint (−122.1 and −124.2 kcal/mol) can well reflect the better catalyst−substrate match. As a result, the stepwise carbene mechanism can be competitive or even predominant in FLP3- and FLP4-catalyzed C−H bond activation. In summary, a novel stepwise carbene mechanism is proposed for FLP-catalyzed C−H activation of heteroarenes. Both the generally accepted concerted C−H activation mechanism and the stepwise carbene type mechanism can be possible. Moreover, the mechanisms can be varied by tuning the distance of LA and LB sites due to catalyst−substrate geometric match. The concerted mechanism is dominant in the case of FLP1-catalyzed reaction. However, the stepwise carbene mechanism can be competitive or even predominant as the LA−LB distance become longer. This alternative stepwise carbene mechanism, together with the general concerted C−H activation mechanism, will provide new mechanistic insights and expand the scenario to understand and design FLPs for C− H bond activation.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00024. Detailed computational methods, additional figures, and Cartesian coordinates (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Yan Liu: 0000-0002-3864-1992 Zhuofeng Ke: 0000-0001-9064-8051 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the NSFC (21473261, 21673301, 21502023) and the Guangdong Natural Science Funds for Distinguished Young Scholar (No. 2015A030306027). Computing facilities were supported in part by the Guangdong Province Key Laboratory of Computational Science and the National Supercomputing Center in Guangzhou.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b00024 Org. Lett. 2018, 20, 1102−1105