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• The C_sp3–H bond activation is a key foundation for the synthesis of complex molecules [1-4]. However, unactivated C_sp3–H bonds, characterized by a high bond dissociation energy (BDE > 100 kcal/mol) and weak acidity (pKa ≥ 35) [5, 6], present significant challenges for activation. Important strategies for C–H bond activation primarily involve direct deprotonation by very strong Brønsted bases [7, 8], oxidative addition via transition metals [9-11], and hydrogen atom abstraction by radical mechanisms [12, 13]. As Brønsted bases, alkali metal reagents are quite useful in C_sp3–H bond functionalization due to their high efficiency and atom economy. The mechanism of C_sp3–H activation by these reagents varies depending on their basicity (Scheme 1a): Under strong base conditions, direct activation and functionalization of C_sp3–H bonds occur via a thermodynamically stable carbanion intermediate [14-16] Under relatively weaker base conditions, an unstable carbanion intermediate is generated, necessitating subsequent kinetic transformations to overcome the inherent acid-base equilibrium and achieve functionalization [17-19]. Notably, alkali metal reagents exhibit not only anionic basicity but also cationic influences, as studies suggest that the coordination and aggregation states of cations may significantly influence reactivity [20-24]. However, the mechanistic understanding of these roles in synthetic transformations remains underexplored.

  Scheme 1

  

  Scheme 1.  The mechanistic study of C_sp3–H acylations of toluene or thioanisole with inert amide by LDA.

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  The C_sp3–H bond acylation reaction with inert amides has broad application prospects in fields such as drug synthesis, materials science, and natural product chemistry [25, 26]. However, the delocalization of the lone pair electrons of the nitrogen atom in the amide group leads to a decrease in the reactivity of the carbonyl group, resulting in poor reactivity and selectivity in the amide transformation [27, 28]. Therefore, achieving acylation of the unactivated C_sp3–H bond and inert amides under mild conditions poses a significant challenge. Charette and Huang developed a synthetic method using Triflic anhydride (Tf₂O) to pre-activate amides [29, 30], which can react with aromatic hydrocarbons and 1, 1-diborane hydrocarbons to produce ketone products [31, 32]. Guan utilized common lithium diisopropyl-amide (LDA) with insufficient basicity (conjugate acid diisopropylamine: pK_a = 35.7) [33, 34] to successfully achieve high-yield C_sp3–H bond acylation reactions with toluene (pK_a = 43) [35, 36], thioanisole (pK_a = 38.3) [37], and their derivatives [38, 39] (Scheme 1b). Despite comprehensive reports by Collum on LDA aggregates and solvation for organolithium reagents [40, 41], the mechanistic investigations initiated by LDA remains unclear during the complex multi-step transformations of organic synthesis.

  Therefore, the acylation reaction of unactivated C_sp3–H bonds with inert amides was used as a case study of reaction mechanisms through theoretical calculations and experimental validation (Scheme 1c). It is crucial to investigate how the relatively weak basic reagents can activate the inert C_sp3–H bonds, generating strong basic carbanions, as well as the aggregation effects of alkali metal reagents. The main questions are: (1) How does the weakly basic LDA activate the C_sp3–H bonds of weakly acidic toluene/thioanisole? (2) How does LDA aggregation affect the reaction mechanism? Through DFT theoretical calculations and KIE experiments, we propose a LDA dimeric mechanism, revealing a new model of base intermediate for unactivated C_sp3–H activation, as well as the synergistic regulatory effect of inert C_sp3–H acidity and its conjugate base nucleophilicity. Finally, the anomalous kinetic KIE values for 2-(methylthio)naphthalene were predicted based on the rate limiting step (RLS), which can be validated experimentally.

  The initial mechanism by which LDA promotes the acylation reaction of C_sp3–H bonds is illustrated in Fig. 1a. First, based on the sequence of C–H bond activations for different substrates (N,N-diisopropylbenzamide 1a and alkyl substrates 2), two pathways by LDA can be proposed to generate the alkyl lithium intermediate IN4_M. In the pathway 1 (black), LDA reacts with 1a to activate C_sp2–H bond via the carbonyl-directing model, forming the basic phenyl lithium intermediate IN2_M, which subsequently undergoes a σ-metathesis with the methyl group of toluene. The pathway 2 (cyan) involves LDA directly activating the methyl group of toluene to generate the alkyl lithium intermediate IN2'_M, which then coordinates with 1a. Next, the resulting alkyl lithium intermediate IN4_M undergoes nucleophilic addition to the amide carbonyl group, yielding the intermediate IN5_M, which then occurs β-N elimination to form the enol intermediate IN6_M. Finally, under the hydrolysis, the enol is converted to the acylation product 3.

  Figure 1

  

  Figure 1.  (a) The initial acylation reaction mechanism of C_sp3–H bonds promoted by LDA. (b) The key transition states of the acylation reaction between toluene 2a and amide 1a promoted by LDA monomer 1Li. ΔG^‡: the activation Gibbs free energy. *Without considering the 24.9 kcal/mol of zero point corrections. DFT calculations were preformed at the M062X-D3/6–311+G(d, p)//M062X-D3/6–31G(d, p) level of theory.

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  Based on the proposed mechanism by literatures in Fig. 1a [38], key transition states in Fig. 1b were calculated for the acylation reaction via C_sp3–H toluene activation by the monomer of LDA (1Li), and the complete free energy profile is shown in Fig. S1 (Supporting information). Calculated results indicate that the pathway 1 seems to be more favorable with firstly activating the C_sp3–H of toluene (pathway 1, TS1_M-1, 20.1 kcal/mol) than the activation of the C_sp2–H of 1a (pathway 2, TS2_M, 21.2 kcal/mol). The subsequent mechanism shows that the rate limiting step (RLS) of the reaction is the β-N elimination of the intermediate IN5_M via four member rings TS4_M, with an overall energy barrier of 22.1 kcal/mol, indicating that there is no correlation of C–H bond activation in the RLS. However, this theoretical result contradicts the primary kinetic isotope effect observed in kinetic isotopic experiments (KIE_exp = 4.0), suggesting the cleavage of C_sp3–H bond in toluene should be highly related with the RLS. This led us to reconsider the possibility of the LDA monomer model and establish a new mechanistic model to describe the process. Literature research revealed that LDA exists predominantly as aggregates in THF solvent rather than as monomers [40, 41]. Inspired by this, the thermodynamic free energy of the several LDA aggregate states were calculated in Fig. 2, which indicate the dimer of LDA is thermodynamically more stable than the monomer by 24.9 kcal/mol in THF, further supporting the inadequacy of the LDA monomer model. And thus, all related energy barriers would have to add the corresponding 24.9 kcal/mol (e.g., 22.1 + 24.9 kcal/mol for the barrier of TS4_M), making the reaction kinetics infeasible. Additionally, models with one or two THF solvent molecules coordinated to the two LDA (2Li-1, 2Li-2) were found to be relatively stable with only 0.6 kcal/mol slightly difference, which could be a zero point for further mechanistic studies. Other aggregation models were less stable than the LDA dimer in Fig. 2.

  Figure 2

  

  Figure 2.  The Gibbs free energy (ΔG) and structures of different LDA aggregates.

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  In light of LDA aggregates, we recalculated the potential energy surface for the acylation reaction of toluene using the dimer 2Li-2 (Fig. 3a) [47-49]. Unlike the mechanism of LDA monomer, the 2Li-2 model would favor the pathway 2 that activate the C_sp2–H of the amide substrate to rapidly form the key basic intermediate IN2. And then a cooperative σ-metathesis via TS2 occurs to activate the C_sp3–H of toluene. Note that this C–H activation indirectly by LDA but through a basic intermediate IN2 give a favorable energy barrier of 26.6 kcal/mol, which is 2.7 kcal/mol lower than that in pathway 1. Additionally, the radical mechanism of the cleavage of the benzyl C–H bond is excluded due to the inaccessible high endothermic energy (Fig. S7 in Supporting information). The resulting alkyl lithium intermediate IN4 undergoes nucleophilic addition (TS3, 17.9 kcal/mol), β-N elimination (TS4, 21.3 kcal/mol), and enolization to yield the final acylation product. The overall rate-limiting step of this mechanism is the σ-metathesis process via the activation of the C_sp3–H bond in toluene, and the cooperative two Li model of the basic intermediate (IN2) enables to lower the activation energy barrier via TS2. Furthermore, based on the Bigeleisen-Mayer theory [42], our calculated KIE is 3.8 (at 298 K) close to the experimental KIE value of 4.0, supporting the validity of the LDA dimer model. The electron localization function (ELF) of the transition state TS2 in Fig. S3 (Supporting information) indicates that the interaction between Li and the nitrogen atom is primarily electrostatic. In the transition state structure, the independent gradient model based on hirshfeld partition (IGMH) analysis [43] shows that Li1 interacts electrostatically with the carbonyl oxygen of the substrate and engages in η²-Li1-π interactions of phenyl group (Fig. 3b), probably also directing the reaction site. The bridging nitrogen ligand effectively connects Li1 and Li2 to achieve the synergistic effect, where the Li2 cation provides the main reactive site to stabilize the developing C_sp3 anion for toluene activation. Therefore, the dual lithium species promote the reaction through Li2 cation stabilization with the assistance of Li1 like a "synergistic main and auxiliary" model [44-46].

  Figure 3

  

  Figure 3.  (a) Free energy profile of the acylation reaction of toluene(2a) with amide(1a) promoted by LDA dimer. The selected single point energy of TS1, TS2 and TS3 were further evaluated by BDF software [47-49] at B2PLYP-D3/6–311+G(d, p) level of theory shown in parentheses. (b) Energy and structures of key transition states in the acylation reaction. IGMH analysis for TS2.

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  To further validate the LDA dimer model, a relatively acidic thioanisole 2a' substrate (reaction Ⅱ [39]) was applied in the acylation reaction through aryl dilithium base IN2 in Fig. 4a (Fig. S4 in Supporting information for details). The calculated results indicate that the reaction mechanism involving 2a' is consistent with that of toluene (2a). The dual lithium species also promote the reaction through Li2 cation with thioether under the assistance of Li1 with directing carbonyl group. The σ-metathesis process remains the RLS in the C_sp3–H bond activations with 23.5 kcal/mol energy barrier via TS2'. The calculated reaction KIE 3.6 is close to the experimental observation (KIE_exp = 3.2). However, the energy barriers of reaction Ⅱ between the σ-metathesis (TS2', 23.5 kcal/mol) and the nucleophilic addition (TS3', 22.1 kcal/mol) become closer with an energy difference of only 1.4 kcal/mol by thioanisole 2a' substrate comparing with that in reaction Ⅰ by toluene 2a (ΔΔG^‡ = 8.7 kcal/mol). To explain this trend, we conducted an in-depth electronic structure analysis of these two elementary reactions (Figs. 4b and c). Based on the intermediates of σ-metathesis in C_sp3–H bond activation, thioanisole 2a' comparing to 2a has a lower pK_a and a higher electrostatic potential (ESP at H5, −29.73 eV), making the proton of 2a' easier be activated with a lower energy barrier. In the transition state of nucleophilic addition, the major population of the frontier molecular orbital is distributed over the sp³ carbanion portion of HOMO and the carbonyl carbon of LUMO [50], respectively. A larger energy gap (E_gap = 5.16 eV) by using 2a' indicates that the nucleophilicity of its carbanion is weaker than that of toluene, leading to a relatively higher reaction barrier. Therefore, in the acylation reaction of C_sp3–H bonds promoted by the LDA dimer, the Brønsted acidity of the C_sp3–H substrate increases, the nucleophilicity of its conjugate base decreases, leading the close energy barriers between the σ-metathesis and nucleophilic addition. It suggests that the switchable RLS of the acylation might be achieved by using other sulfur substrate with a stronger Brønsted acidity of C_sp3–H bond and weaker nucleophilicity of its conjugate base than that of thioanisole, thereby eliminating the primary kinetic isotope effect of deuteration.

  Figure 4

  

  Figure 4.  (a) Free energy profile of the σ-metathesis and nucleophilic addition processes in the acylation reactions of 2a and 2a' promoted by LDA dimer (2Li-2). (b) Structural and electrostatic potential comparisons of intermediate IN3 and IN3'. (c) Frontier molecular orbital analysis of TS3 and TS3'in the nucleophilic addition, E_gap = E_LUMO - E_HOMO. The percentages of orbital composition were calculated using the Mulliken method: deprotonated toluene/thioether of HOMO, Li⁺ activated amide of LUMO.

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  To validate our presumption, pK_a values of four additionally designed molecules were calculated in THF solvent containing C_sp3–H bonds of 2-(methylthio)naphthalene, 2-methyl-sulfanyl-propane, 1-(methylthio)propane, and anisole (Table S2 in Supporting information). Among these, 2-(methylthio)naphthalene (2a'') exhibited the lowest pK_a, prompting further investigations for its reaction mechanism. The higher ESP of the C_sp3–H in 2a'' (H5: −29.50 eV), along with a larger E_gap in the TS3'' (E_gap = 5.24 eV, Fig. S5 in Supporting information), indicates its stronger acidity and weaker nucleophilicity of the conjugate base, which respectively lowers and raises the corresponding reaction barriers. Under our expectation in Fig. 5a, the RLS involving 2a'' substrate shifts from the σ-metathesis of C_sp3–H bond activation (TS2'', 21.3 kcal/mol) to the nucleophilic addition process (TS3'', 23.0 kcal/mol) with a calculated KIE value of 1.23 (273 K). Further control experiments confirm that the RLS in the acylation reaction of 2a'' is not directly related to the C_sp3–H activation, with an experimentally measured KIE of 1.23 in Fig. 5b, consistent with the calculations. Our findings reflect a new dual Li cooperative model for C_sp3–H acylation, which not only enhances the mechanism understanding for activation and transformation of inert bonds to clarify the electronic structures of intermediates and transition states, but also accurately predicts the "anomalous" kinetic phenomena in newly designed substrates.

  Figure 5

  

  Figure 5.  Free energy profile of the σ-metathesis and nucleophilic addition processes in the acylation reaction of 2-(methylthio)naphthalene (2a'') together with the calculated and experimental KIEs under dual lithium species.

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  In summary, a dual lithium synergistic mechanism model was proposed for the acylation reaction of C_sp3–H bonds, supported by theoretical calculations and experimental kinetics validation (Fig. 6). The LDA dimer promote the acylation reaction through a "synergistic main and auxiliary" model of two Li⁺ cations involving Li2-C_sp2/C_sp3 and Li1-O=C interactions. Additionally, LDA dimer as a relatively weak base can firstly activate the C_sp2–H bond of the amide substrate to generate a highly reactive aryl dilithium intermediate base (base intermediate) with Li2-C_sp2 bond, which then further activates C_sp3–H bond of alkyl group with the extremely weak acidity forming Li2-C_sp3 bond. This LDA dimer model not only effectively unifies the reaction mechanisms of different C–H bond substrates, such as toluene and thioanisole, rationalizing the mechanistic scenario and observed kinetic effects, but also successfully predicts the switchable rate limiting step in the reaction of 2-(methylthio)-naphthalene, which is subsequently validated by KIE experiments. This mechanistic control is mainly influenced by the Brønsted acidity of C_sp3–H bond of the alkyl substrate and the nucleophilicity of its conjugate base. Overall, the discovered synergistic model of LDA dimer for C_sp3–H acylation not only rationalizes existing experimental observations and accurately assesses the energy profiles, but also enables precise predictions of kinetic effects. This study may provide a useful foundation for reaction mechanisms of unactivated C–H functionalizations and the rational design of new reactions.

  Figure 6

  

  Figure 6.  Summary diagram of LDA promoted the acylation reaction.

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  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Changming Li: Writing – review & editing, Writing – original draft, Resources, Formal analysis, Conceptualization. Hongdan Zhu: Writing – original draft. Can-Can Bao: Investigation. Yongjia Lin: Data curation, Conceptualization. Bing-Tao Guan: Investigation. Qian Peng: Writing – review & editing, Writing – original draft, Project administration, Conceptualization.

  Acknowledgments

  We gratefully acknowledge the National Key Research and Development Program of China (No. 2021YFA1500100), the National Natural Science Foundation of China (Nos. 92156017 and 21890722), "Frontiers Science Center for New Organic Matter", Nankai University (No. 63181206) and Haihe Laboratory of Sustainable Chemical Transformation of Tianjin (No. 24HHWCSS00019) for generous financial support, and we also gratefully acknowledge HZWTECH for providing computation facilities.

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2024.110809.

  
  
• 1. [1]

     M. Bandini, F. Piccinelli, A. Melloni, Handbook of C–H Transformations: Applications in Organic Synthesis, 2005.

  2. [2]

     J. Wencel-Delord, F. Glorius, Nat. Chem. 5 (2013) 369–375. doi: 10.1038/nchem.1607

  3. [3]

     D.J. Abrams, P.A. Provencher, E.J. Sorensen, Chem. Soc. Rev. 47 (2018) 8925–8967. doi: 10.1039/c8cs00716k

  4. [4]

     G. Prakash, N. Paul, G.A. Oliver, D.B. Werz, D. Maiti, Chem. Soc. Rev. 51 (2022) 3123–3163. doi: 10.1039/d0cs01496f

  5. [5]

     X.S. Xue, P. Ji, B. Zhou, J.P. Cheng, Chem. Rev. 117 (2017) 8622–8648. doi: 10.1021/acs.chemrev.6b00664

  6. [6]

     Y.R. Luo, Comprehensive Handbook of Chemical Bond Energies, CRC press, 2007.

  7. [7]

     G. Wu, M. Huang, Chem. Rev. 106 (2006) 2596–2616. doi: 10.1021/cr040694k

  8. [8]

     P. Knochel, G.A. Molander, Comprehensive Organic Synthesis. 2nd ed. Amsterdam: Elsevier, 2014.

  9. [9]

     N.J. Gunsalus, A. Koppaka, S.H. Park, et al., Chem. Rev. 117 (2017) 8521–8573. doi: 10.1021/acs.chemrev.6b00739

  10. [10]

      C. Shan, R. Bai, Y. Lan, Acta Phys. Chim. Sin. 35 (2019) 940–953. doi: 10.3866/pku.whxb201810052

  11. [11]

      J. Han, L.L. Zeng, Q.Y. Fei, et al., Chin. Chem. Lett. 35 (2024) 109647.

  12. [12]

      X. Wang, J. He, Y.N. Wang, et al., Chem. Rev. 124 (2024) 10192–10280. doi: 10.1021/acs.chemrev.4c00188

  13. [13]

      W. Cui, Y. Li, X. Li, et al., Chin. Chem. Lett. 34 (2023) 107477.

  14. [14]

      R. Vanjari, K.N. Singh, Chem. Soc. Rev. 44 (2015) 8062–8096.

  15. [15]

      Y. Yamashita, H. Suzuki, I. Sato, T. Hirata, S. Kobayashi, Angew. Chem. Int. Ed. 57 (2018) 6896–6900. doi: 10.1002/anie.201711291

  16. [16]

      G. Liu, P.J. Walsh, J. Mao, Org. Lett. 21 (2019) 8514–8518. doi: 10.1021/acs.orglett.9b02737

  17. [17]

      D.D. Zhai, X.Y. Zhang, Y.F. Liu, L. Zheng, B.T. Guan, Angew. Chem. Int. Ed. 57 (2018) 1650–1653. doi: 10.1002/anie.201710128

  18. [18]

      Y.F. Liu, L. Zheng, D.D. Zhai, X.Y. Zhang, B.T. Guan, Org. Lett. 21 (2019) 5351–5356. doi: 10.1021/acs.orglett.9b01994

  19. [19]

      B. Guan, Z. Shi, Sci. Sin. Chim. 51 (2021) 201–212. doi: 10.1360/ssc-2020-0180

  20. [20]

      X.Z. Ouyang Kunbing, Acta Chim. Sinica 71 (2013) 13–25.

  21. [21]

      S.D. Robertson, M. Uzelac, R.E. Mulvey, Chem. Rev. 119 (2019) 8332–8405. doi: 10.1021/acs.chemrev.9b00047

  22. [22]

      N. Davison, E. Lu, Dalton Trans. 52 (2023) 8172–8192. doi: 10.1039/d3dt00980g

  23. [23]

      S. Chen, Z. Wang, S. Geng, et al., CCS Chem. 5 (2023) 1674–1685. doi: 10.31635/ccschem.022.202202234

  24. [24]

      Y. Zhang, P. Du, Y. Ji, et al., Chem 9 (2023) 3623–3636.

  25. [25]

      A. Greenberg, C.M. Breneman, J.F. Liebman, The Amide Linkage: Structural Significance in Chemistry, Biochemistry, and Materials Science, Wiley-Interscience, New York, 2000.

  26. [26]

      D. Kaiser, A. Bauer, M. Lemmerer, N. Maulide, Chem. Soc. Rev. 47 (2018) 7899–7925. doi: 10.1039/c8cs00335a

  27. [27]

      G. Li, S. Ma, M. Szostak, Trends Chem. 2 (2020) 914–928.

  28. [28]

      S. Shi, S.P. Nolan, M. Szostak, Acc. Chem. Res. 51 (2018) 2589–2599. doi: 10.1021/acs.accounts.8b00410

  29. [29]

      W.S. Bechara, G. Pelletier, A.B. Charette, Nat. Chem. 4 (2012) 228–234. doi: 10.1038/nchem.1268

  30. [30]

      K.J. Xiao, A.E. Wang, Y.H. Huang, P.Q. Huang, Asian J. Org. Chem. 1 (2012) 130–132. doi: 10.1002/ajoc.201200066

  31. [31]

      D.P. Wu, Q. He, D.H. Chen, J.L. Ye, P.Q. Huang, Chin. J. Chem. 37 (2019) 315–322. doi: 10.1002/cjoc.201900035

  32. [32]

      W. Sun, L. Wang, Y. Hu, et al., Nat. Commun. 11 (2020) 3113.

  33. [33]

      R.R. Fraser, M. Bresse, T.S. Mansour, J. Am. Chem. Soc. 105 (1983) 7790–7791. doi: 10.1021/ja00364a078

  34. [34]

      J. Clayden, Organolithiums: Selectivity for Synthesis, Oxford, Elsevier, 2002, pp. pp9–109.

  35. [35]

      J.D. Yang, X.S. Xue, P. Ji, X. Li, J.P. Cheng, Internet Bond-energy Databank (pKa and BDE): iBonD Home Page. http://ibond.nankai.edu.cn.

  36. [36]

      F. Bordwell, D. Algrim, N.R. Vanier, J. Org. Chem. 42 (1977) 1817–1819. doi: 10.1021/jo00430a039

  37. [37]

      K.B. Wiberg, H. Castejon, J. Am. Chem. Soc. 116 (1994) 10489–10497. doi: 10.1021/ja00102a016

  38. [38]

      C.C. Bao, Y.L. Luo, H.Z. Du, B.T. Guan, Sci. China Chem. 64 (2021) 1349–1354. doi: 10.1007/s11426-021-1035-5

  39. [39]

      C.C. Bao, H.Z. Du, Y.L. Luo, B.T. Guan, Commun. Chem. 4 (2021) 138–145.

  40. [40]

      K.J. Singh, D.B. Collum, J. Am. Chem. Soc. 128 (2006) 13753–13760. doi: 10.1021/ja064655x

  41. [41]

      R.F. Algera, L. Gupta, A.C. Hoepker, et al., J. Org. Chem. 82 (2017) 4513–4532. doi: 10.1021/acs.joc.6b03083

  42. [42]

      J. Bigeleisen, M.G. Mayer, J. Chem. Phys. 15 (1947) 261–267. doi: 10.1063/1.1746492

  43. [43]

      T. Lu, Q. Chen, J. Comput. Chem. 43 (2022) 539–555. doi: 10.1002/jcc.26812

  44. [44]

      K. Chen, H. Zhu, Y. Li, et al., ACS Catal. 11 (2021) 13696–13705. doi: 10.1021/acscatal.1c04141

  45. [45]

      K. Chen, H. Zhu, S. Liu, et al., J. Am. Chem. Soc. 145 (2023) 24877–24888.

  46. [46]

      S. Zheng, H. Zhang, Q. Peng, Chin. Chem. Lett. 34 (2023) 108067.

  47. [47]

      W. Liu, G. Hong, D. Dai, L. Li, M. Dolg, Theor. Chem. Acc. 96 (1997) 75–83.

  48. [48]

      W. Liu, F. Wang, L. Li, J. Theor. Comput. Chem. 2 (2003) 257–272.

  49. [49]

      Y. Zhang, B. Suo, Z. Wang, et al., J. Chem. Phys. 152 (2020) 064113.

  50. [50]

      L.G. Zhuo, W. Liao, Z.X. Yu, Asian J. Org. Chem. 1 (2012) 336–345. doi: 10.1002/ajoc.201200103

• 

  Scheme 1  The mechanistic study of C_sp3–H acylations of toluene or thioanisole with inert amide by LDA.

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  Figure 1  (a) The initial acylation reaction mechanism of C_sp3–H bonds promoted by LDA. (b) The key transition states of the acylation reaction between toluene 2a and amide 1a promoted by LDA monomer 1Li. ΔG^‡: the activation Gibbs free energy. *Without considering the 24.9 kcal/mol of zero point corrections. DFT calculations were preformed at the M062X-D3/6–311+G(d, p)//M062X-D3/6–31G(d, p) level of theory.

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  Figure 2  The Gibbs free energy (ΔG) and structures of different LDA aggregates.

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  Figure 3  (a) Free energy profile of the acylation reaction of toluene(2a) with amide(1a) promoted by LDA dimer. The selected single point energy of TS1, TS2 and TS3 were further evaluated by BDF software [47-49] at B2PLYP-D3/6–311+G(d, p) level of theory shown in parentheses. (b) Energy and structures of key transition states in the acylation reaction. IGMH analysis for TS2.

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  Figure 4  (a) Free energy profile of the σ-metathesis and nucleophilic addition processes in the acylation reactions of 2a and 2a' promoted by LDA dimer (2Li-2). (b) Structural and electrostatic potential comparisons of intermediate IN3 and IN3'. (c) Frontier molecular orbital analysis of TS3 and TS3'in the nucleophilic addition, E_gap = E_LUMO - E_HOMO. The percentages of orbital composition were calculated using the Mulliken method: deprotonated toluene/thioether of HOMO, Li⁺ activated amide of LUMO.

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  Figure 5  Free energy profile of the σ-metathesis and nucleophilic addition processes in the acylation reaction of 2-(methylthio)naphthalene (2a'') together with the calculated and experimental KIEs under dual lithium species.

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  Figure 6  Summary diagram of LDA promoted the acylation reaction.

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•