Transmetalation of Ar¹ZnX with [Ar²–Pd–X] is the rate-limiting step: kinetic insights from a live Pd-catalyzed Negishi coupling

Abstract

Transmetalation is the rate-limiting step in Negishi coupling: in a live “Pd-catalyzed Negishi coupling of ArI with Ar′ZnX”, the transmetalation was assigned as the rate-limiting step through kinetic investigation. Quantitative measurements of the transmetalation of ArZnX with [Ar–Pd–X] from this live Pd-catalyzed coupling reaction were obtained and the activation enthalpy is 11.3 kcal mol⁻¹.

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Negishi coupling, as one of the most powerful synthetic tools for C–C bond construction, has been widely applied in chemical synthesis.^1–6 However, the mechanistic proposals on Negishi coupling are relatively speculative and the kinetic aspects remain obscure.⁷

The Pd-catalyzed Negishi coupling is generally believed to follow three fundamental steps: oxidative addition, transmetalation and reductive elimination.⁸ Among these three steps, the transmetalation occurs between an organozinc reagent and [RPdX] species, which is one of the most important ways to introduce σ-bonded carbon atoms into the coordination sphere of palladium and furnish the [R–Pd–R′] species.^2,9 Obviously, revealing mechanistic insights into the transmetalation step of Negishi coupling is significant and urgent for better conducting these transformations in chemical synthesis.^10–13

However, mechanistic studies on the transmetalation of Negishi coupling are relatively less reported compared with Suzuki coupling and Stille coupling,^14–30 especially the transmetalation of the Ar¹ZnX reagent with Ar²PdX species from “live” Pd-catalyzed biaryl-syntheses (Ar¹–Ar²). In recent years, mechanistic studies on transmetalation of organozinc reagents have drawn more and more attention. For example, Espinet and coworkers continually reported their understanding of the transmetalation step of [R_alkyl–Pd–X] with MeZnX/Me₂Zn through stoichiometric experiments under low temperature with special ligands and substrates.^7,31,32 However, the stoichiometric experiments would become problematic as the transmetalation of [R–Pd–X] with an organozinc reagent is too rapid to be probed under “live” Negishi coupling reaction conditions. Therefore, the challenge remains in gaining mechanistic insights into the transmetalation of Negishi coupling under live catalytic reaction conditions. Herein, we document our recent results in quantitative measurements of the transmetalation of Ar¹ZnX with [Ar²–Pd–X] through kinetic investigations from a live Pd-catalyzed Negishi coupling.

Our initial studies commenced from the curiosity about the real catalytic capability of Pd(OAc)₂ in Negishi coupling. The Pd-catalyzed cross-coupling between ethyl 4-iodobenzoate (1) and p-MeC₆H₄ZnCl (2) using Pd(OAc)₂ as the catalyst precursor was investigated. The reactions could proceed smoothly in quantitative yields with both 5 mol% and 1 mol% catalyst loadings. The TONs were 20 and 100, respectively. We also found that these reactions were very rapid (within 60 seconds) and clearly there was Pd-black formation shown in Fig. 1A when 5 mol% or 1 mol% Pd(OAc)₂ was employed. However, when 0.1 mol% Pd(OAc)₂ was employed, the reaction could proceed smoothly and no Pd-black was observed. It is very interesting that the TONs could reach up to 290 000 at 10 °C when the concentration of Pd was decreased (Fig. 1A). The continuous increase of TONs indicated the powerful catalytic potential.

Fig. 1 Pd-catalyzed cross-coupling between ethyl 4-iodobenzoate 1 and p-MeC₆H₄ZnCl 2. Reaction conditions: (A) 1 (0.25 M in THF), 2 (0.4 M in THF, 4 mL), Pd(OAc)₂ (8.2 × 10⁻⁷–1.3 × 10⁻⁵ M in THF), 10 °C; (B) 1 (0.12 M in THF), 2 (0.28 M in THF, 4 mL), Pd(OAc)₂ (8.2 × 10⁻⁷–1.1 × 10⁻⁵ M in THF), −10 °C.

To our great surprise, when kinetic studies were performed using in situ IR, a strange [catalysts]-kinetic dependence was observed. As shown in Fig. 1B, when the reaction was performed using a lower concentration of the Pd catalyst (<8.0 × 10⁻⁶ M), the initial rates exhibited a positive dependence on the concentration of the catalyst. However, when the reaction was performed using a higher concentration of the Pd catalyst (≥8.0 × 10⁻⁶ M), a negative dependence on the concentration of the catalyst was determined. The impressive efficiency and unpredictable kinetic behavior in this Pd-catalyzed Negishi coupling inspired us to further probe the transformation in detail.

With this Pd-catalyzed cross-coupling between 1 and 2 as a model, further kinetic investigations were carried out. As mentioned above, when [Pd] ≥ 8.0 × 10⁻⁶ M, increasing the concentration of Pd would result in lower reaction rates, revealing that some Pd species might be out of the catalytic cycle and decompose under these conditions. Thus, the reaction performed at high concentration of Pd could not be employed for kinetic studies. Subsequently, reactions with different concentrations of Pd at 10 °C ([Pd] < 8.0 × 10⁻⁶ M) were carried out. As shown in Fig. 2, when plotting the initial rates vs. [Pd], a linear relationship could be determined, suggesting that the reaction exhibits first-order kinetic behavior on the concentration of Pd under those conditions. In this regard, the following kinetic experiments were performed under the obtained Pd concentration range ([Pd] ≤ 7.0 × 10⁻⁶ M).

Fig. 2 Plotting initial rates vs. [Pd]. Reaction conditions: 1 (0.25 M in THF), 2 (0.34 M in THF, 4.0 mL), Pd(OAc)₂ (8.2 × 10⁻⁷–7.2 × 10⁻⁶ M in THF), 10 °C.

The subsequent reactions with different concentrations of ArI were performed and monitored by in situ IR. As shown in Fig. 3, the reactions show similar reaction rates, suggesting that the reactions exhibited zero order dependence on [ArI]. Meanwhile, the kinetic behavior of ArZnCl was examined. It was observed that plotting initial rates vs. [ArZnCl] yielded a line, revealing that the reaction exhibited a first-order dependence on [ArZnCl] (Fig. 4).

Fig. 3 Plotting initial rates vs. [ArI]. Reaction conditions: 1 (0.073–0.26 M in THF), 2 (0.33 M in THF, 4.0 mL), Pd(OAc)₂ (5.2 × 10⁻⁶ M in THF), −10 °C.

Fig. 4 Plotting initial rates vs. [ArZnCl]. Reaction conditions: 1 (0.082 M in THF), 2 (0.17–0.35 M in THF, 6.0 mL), Pd(OAc)₂ (6.6 × 10⁻⁶ M in THF), −10 °C.

On the basis of the kinetic results above, the rate law of this Pd-catalyzed cross-coupling between ethyl 4-iodobenzoate and p-Me C₆H₄ZnCl could be derived as: rate = k × [Pd] × [ArZnCl]. Zero-order kinetic dependence on [1] and first-order dependence on [2] suggest that transmetalation might be the rate-limiting step.

Subsequently, the rates of this Negishi coupling using different para-substituted (R = MeO, Me, H, Cl) arylzinc reagents were measured. Arylzinc reagents with electron-donating substituents reacted faster than electron-deficient arylzinc reagents. As shown in Fig. 5, a linear free energy relationship was observed with a calculated ρ-value of −1.07. The negative ρ-value signified that in the rate limiting step, arylzinc should be involved in the transition state and a positive charge buildup exists in the phenyl ring of arylzinc, further supporting that the transmetalation is the rate-limiting step.

Fig. 5 Hammett plot of Pd-catalyzed Negishi coupling between 1 and ArZnX. Reaction conditions: 1 (0.12 M in THF), ArZnX (0.31 M in THF, 4.0 mL), Pd(OAc)₂ (5.2 × 10⁻⁶ M in THF), −10 °C.

Having confirmed that transmetalation was the rate-limiting step, we were allowed to gain further understanding of the transmetalation of arylzinc. Then the activation parameters were determined through Eyring analysis by measuring the reaction rates from −20 to 30 °C. As shown in Fig. 6, the activation enthalpy ΔH^≠ was measured to be 11.3 kcal mol⁻¹.

Fig. 6 Eyring plots of Pd-catalyzed Negishi coupling between 1 and 2. Reaction conditions: 1 (0.12 M in THF), 2 (0.25 M in THF, 4.0 mL), Pd(OAc)₂ (5.2 × 10⁻⁶ M in THF), −20–30 °C.

Conclusions

In summary, using a Pd-catalyzed Negishi coupling between ethyl 4-iodobenzoate and p-MeC₆H₄ZnCl as the model, transmetalation has been identified as the rate-limiting step through kinetic investigations. Quantitative measurements have been obtained with the activation energy at a value of 11.3 kcal mol⁻¹. This rate-limiting transmetalation could rationalize the high efficiency of this transformation, which will provide an implication for further development in increasing TONs and TOFs.

Acknowledgements

This work was supported by the 973 Program (2012CB725302), the National Natural Science Foundation of China (21025206 and 21272180), and the Program for Changjiang Scholars and Innovative Research Team in University (IRT1030) and the Research Fund for the Doctoral Program of Higher Education of China (20120141130002).

Notes and references

1. Organozinc Reagents: A Practical Approach, ed. P. Knochel and P. Joned, 1999.
2. E.-i. Negishi and A. d. Meijere, Handbook of organopalladium chemistry for organic synthesis, Wiley-Interscience, New York, 2002.
3. X.-F. Wu, P. Anbarasan, H. Neumann and M. Beller, Angew. Chem., Int. Ed., 2010, 49, 9047–9050.
4. P. Knochel and R. D. Singer, Chem. Rev., 1993, 93, 2117–2188.
5. R. Jana, T. P. Pathak and M. S. Sigman, Chem. Rev., 2011, 111, 1417–1492.
6. V. B. Phapale and D. J. Cardenas, Chem. Soc. Rev., 2009, 38, 1598–1607.
7. J. A. Casares, P. Espinet, B. Fuentes and G. Salas, J. Am. Chem. Soc., 2007, 129, 3508–3509.
8. A. d. Meijere and F. Diederich, Metal-catalyzed cross-coupling reactions, Wiley-VCH, Weinheim, 2nd, completely rev. and enlarged edn, 2004.
9. O. F. Wendt, Curr. Org. Chem., 2007, 11, 1417–1433.
10. Q. Liu, Y. Lan, J. Liu, G. Li, Y.-D. Wu and A. Lei, J. Am. Chem. Soc., 2009, 131, 10201–10210.
11. P. Ribagnac, M. Blug, J. Villa-Uribe, G. X.-F. Le, C. Gosmini and N. Mezailles, Chem.–Eur. J., 2011, 17, 14389–14393.
12. L. Jin and A. Lei, Org. Biomol. Chem., 2012, 10, 6817–6825.
13. A. B. Gonzalez-Perez, R. Alvarez, O. N. Faza, L. A. R. de and J. M. Aurrecoechea, Organometallics, 2012, 31, 2053–2058.
14. P. Espinet and A. M. Echavarren, Angew. Chem., Int. Ed., 2004, 43, 4704–4734.
15. A. L. Casado and P. Espinet, J. Am. Chem. Soc., 1998, 120, 8978–8985.
16. A. L. Casado, P. Espinet and A. M. Gallego, J. Am. Chem. Soc., 2000, 122, 11771–11782.
17. A. Ricci, F. Angelucci, M. Bassetti and S. C. Lo, J. Am. Chem. Soc., 2002, 124, 1060–1071.
18. D. Canseco-Gonzalez, V. Gomez-Benitez, S. Hernandez-Ortega, R. A. Toscano and D. Morales-Morales, J. Organomet. Chem., 2003, 679, 101–109.
19. J. Louie and J. F. Hartwig, J. Am. Chem. Soc., 1995, 117, 11598–11599.
20. A. Nova, G. Ujaque, F. Maseras, A. Lledos and P. Espinet, J. Am. Chem. Soc., 2006, 128, 14571–14578.
21. M. H. Perez-Temprano, A. Nova, J. A. Casares and P. Espinet, J. Am. Chem. Soc., 2008, 130, 10518–10520.
22. A. Ariafard, Z. Y. Lin and I. J. S. Fairlamb, Organometallics, 2006, 25, 5788–5794.
23. Y. Nishihara, H. Onodera and K. Osakada, Chem. Commun., 2004, 192–193.
24. B. Crociani, S. Antonaroli, A. Marini, U. Matteoli and A. Scrivanti, Dalton Trans., 2006, 2698–2705.
25. C. Adamo, C. Amatore, I. Ciofini, A. Jutand and H. Lakmini, J. Am. Chem. Soc., 2006, 128, 6829–6836.
26. B. P. Carrow and J. F. Hartwig, J. Am. Chem. Soc., 2011, 133, 2116–2119.
27. N. Miyaura, J. Organomet. Chem., 2002, 653, 54–57.
28. K. Osakada, H. Onodera and Y. Nishihara, Organometallics, 2005, 24, 190–192.
29. C. Amatore, A. Jutand and D. G. Le, Chem.–Eur. J., 2011, 17, 2492–2503.
30. X. He, S. Zhang, Y. Guo, H. Wang and G. Lin, Organometallics, 2012, 31, 2945–2948.
31. B. Fuentes, M. Garcia-Melchor, A. Lledos, F. Maseras, J. A. Casares, G. Ujaque and P. Espinet, Chem.–Eur. J., 2010, 16, 8596–8599.
32. M. Garcia-Melchor, B. Fuentes, A. Lledos, J. A. Casares, G. Ujaque and P. Espinet, J. Am. Chem. Soc., 2011, 133, 13519–13526.

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures and kinetic parameters detected by a Mettler Toledo ReactIR™ 15 spectrometer. See DOI: 10.1039/c3qo00021d

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