Mechanism and Origins of Regio- and Stereoselectivities in Iridium

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Mechanism and Origins of Regio- and Stereoselectivities in IridiumCatalyzed Isomerization of 1‑Alkenes to trans-2-Alkenes Lingfei Hu, Zhenzhen Wu, and Genping Huang* Department of Chemistry, School of Science and Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Tianjin University, Tianjin 300072, P. R. China

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S Supporting Information *

ABSTRACT: Density functional theory calculations were performed to investigate the iridium-catalyzed isomerization of 1-alkenes to trans2-alkenes. The computations show that the originally proposed π-allyl mechanism is kinetically unfeasible. A metal−ligand cooperative mechanism was suggested to account for the experimental results. The reaction was found to begin with the C(sp2)−H oxidative addition of the pyridine ligand to give the Ir(III) hydride intermediate, from which the isomerization further takes place via the insertion/ elimination pathway.

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Given the importance of the olefin isomerization, the detailed reaction mechanism has been the subject of intensive experimental and computational studies.6 Generally, depending on the metal catalyst employed in the reaction, two possible reaction mechanisms have been proposed for transition-metalcatalyzed olefin isomerization (Scheme 2). The π-allyl

he development of an efficient method for the synthesis of alkenes is of key importance since C−C double bonds are frequently used as key intermediates in various important chemical processes.1 In this regard, transition-metal-catalyzed olefin isomerization has attracted tremendous research interest, which provides one of the most efficient and atom-economical protocols for the synthesis of the internal alkenes from the widely accessible terminal alkenes.2 A broad range of transitionmetal catalysts, including those containing Co, Pd, Cr, Ni, Ru, Fe, and Ir, have been developed to facilitate this type of transformation.3,4 However, a major drawback is that the process is often under thermodynamic control, which consequently results in moderate or low regio- and stereoselectivities.4 Notwithstanding the significant progress in this field, the development of highly efficient and selective olefin isomerization remains a key challenge. In this context, Huang and coworkers recently developed a pyridine−phosphine Ir complex A, which showed great potential for the olefin isomerization under very mild reaction conditions (Scheme 1).5 It was found that with Ir complex A, the 1-alkenes 1 undergo isomerization to the trans-2-alkenes E-2 with excellent stereoselectivity (E/Z ≥ 20:1). Moreover, the regioselectivity of the reaction is also notable. The overisomerization products were observed to be ≤2% yield in all cases.

Scheme 2. Possible Reaction Mechanisms for TransitionMetal-Catalyzed Olefin Isomerization

mechanism involves the oxidative addition of the allylic C−H bond to form the key η3-allyl metal hydride complex, from which the C−H reductive elimination then delivers the final isomerization product. Alternatively, when the metal hydride was used as the catalyst, the insertion/elimination pathway turns out to be the preferred mechanism for the olefin isomerization. Such pathway is initiated by the migratory insertion of the C−C double bond into the M−H bond to give the alkyl−metal intermediate, which undergoes the β-hydride elimination step to afford the isomerization product. Considering that the detailed reaction mechanism and the origins of the regio- and stereoselectivities remain unclear, we therefore decided to investigate the title reaction by means of density functional theory (DFT) calculations. The results show that the reaction does not proceed through the originally proposed π-allyl mechanism. Instead, a metal−ligand cooperative mechanism was proposed to account for the experimental outcomes. The reaction was found to begin with the C(sp2)−H

Scheme 1. Ir-Catalyzed Isomerization of 1-Alkenes to trans-2Alkenes

Received: July 23, 2018

© XXXX American Chemical Society

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DOI: 10.1021/acs.orglett.8b02319 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Figure 1. Calculated energy profile of the Ir-catalyzed isomerization of 1a via π-allyl mechanism. The blue and red pathways lead to the isomerization products E-2a and Z-2a, respectively.

INT2′ and Z-INT2′ by the re-coordination of the pyridine ligand to the Ir center. Then, the η3-η1 isomerization takes place via transition states E-TS2 and Z-TS2, leading to η1-allyl Ir hydride intermediates E-INT3 and Z-INT3, respectively. The ensuing rotation of the Ir−C1 bond gives intermediates E-INT3′ and Z-INT3′, followed by the η1−η3 isomerization via transition states E-TS3 and Z-TS3 to finish the η3-allyl rearrangement and generate the η3-allyl Ir hydride complexes E-INT4 and Z-INT4, where the C1 atom is trans to the H. Finally, the C1−H reductive elimination via transition states E-TS4 and Z-TS4 delivers the product coordinated intermediates E-INT5 and Z-INT5, which then undergo a ligand dissociation step to release final olefin isomerization products E-2a and Z-2a, respectively.9 The results show that via the π-allyl mechanism, the energy barrier of the isomerization of 1a to Z-2a is 4.6 kcal/mol higher in energy than that to E-2a (32.4 kcal/mol of Z-TS4 versus 27.8 kcal/mol of E-TS2),10 which indicates that E-2a should be formed exclusively in the reaction, being rather overestimated compared with the experimentally observed E/Z ratio of about 96:4.5 Moreover, the energy barrier of the isomerization of 1a to E-2a was calculated to be 27.8 kcal/mol (E-TS2 relative to A + 1a), being relatively high compared with the reaction condition (room temperature). These results indicate that the reaction most likely does not proceed through the originally proposed πallyl mechanism. Indeed, our calculations reveal a new kinetically more favorable metal−ligand cooperative mechanism, where the olefin isomerization could take place via the alternative insertion/elimination pathway. For the insertion/elimination pathway, a metal hydride species is required, which could be generated by the C(sp2)− H oxidative addition of the pyridine ligand. As shown in Scheme 3, π complex INT1 first undergoes an isomerization to intermediate INT6, which was calculated to be 4.8 kcal/mol more stable than INT1. The subsequent C(sp2)−H oxidative addition of the pyridine ligand via transition state TS5 was found

oxidative addition of the pyridine ligand to give the key Ir(III) hydride intermediate, from which the final isomerization product can be generated through the insertion/elimination pathway.7 At the outset, the originally proposed π-allyl mechanism was investigated. The experimentally used substrate 1-hexene (1a) was chosen as the model substrate under the current calculations. As shown in Figure 1, the reaction starts with the coordination of the C−C double bond of 1a to the Ir center of catalyst A to form π complex INT1, which was calculated to be endergonic by 15.2 kcal/mol. From INT1, the subsequent allylic C3−H oxidative addition can take place through two possible modes via transition states E-TS1 and Z-TS1, resulting in the formation of the η3-allyl Ir hydride complexes E-INT2 and ZINT2, respectively. The optimized geometric structures show that during this process, the Ir−N interaction is broken in order to avoid the steric repulsion between the η3-allyl moiety and the pyridine ligand (see the Supporting Information (SI) for the optimized geometric structures). It should be pointed out here that the C3−H oxidative addition can also occur without the coordination of the C1−C2 bond to the Ir center, which was, however, calculated to be much higher in energy than E-TS1 and Z-TS1, thus ruling out this possibility (see the SI for details). Upon formation of η3-allyl Ir hydride complexes E-INT2 and Z-INT2, the next step is the C1−H reductive elimination to give the final isomerization products E-2a and Z-2a, respectively. However, the C1−H reductive elimination cannot take place directly from E-INT2 and Z-INT2, since the C1 atom is cis to the H. Therefore, an η3-allyl rearrangement has to occur first to place the C1 atom trans to the H. Previous studies have shown that such rearrangement could be realized through an η3−η1−η3 pathway.8 The η3−η1 isomerization directly from E-INT2 and ZINT2 were first tried. However, all attempts failed and always converged back to E-INT2 and Z-INT2. Instead, E-INT2 and ZINT2 were found to isomerize to less stable intermediates EB

DOI: 10.1021/acs.orglett.8b02319 Org. Lett. XXXX, XXX, XXX−XXX

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to be relatively feasible, with an energy barrier of only 19.3 kcal/ mol relative to A + 1a.11 The C(sp2)−H oxidative addition was calculated to be exergonic, and the resulting Ir(III) hydride intermediate INT7 is 4.5 kcal/mol more stable than INT1. Once Ir(III) hydride intermediate INT7 is generated, the isomerization of 1a could be realized through the insertion/ elimination pathway (Figure 2). The 2,1-insertion of the C−C

Figure 3. Optimized geometric structures of E-TS7 and Z-TS7. Bond distances are given in angstroms.

methyl group were observed (H−H interactions = 1.89 and 2.19 Å), while in E-TS7, the steric repulsions between the nPr group with the phosphine ligand and the methyl group are smaller (H− H interaction = 2.15 and 2.52 Å), thus resulting in E-TS7 being more favored than Z-TS7. Finally, the regioselectivity of the reaction was considered (Scheme 4). The computations show that the 3,2-insertion of Scheme 4. Energetics for Overisomerization

C−C double bond of E-2a into the Ir−H bond occurs via transition state TS8, which leads to alkyl Ir intermediate INT10. The β-hydride elimination from INT10 would generate the possible overisomerization products. The 3,2-insertion requires an energy barrier of 28.8 kcal/mol relative to A + E-2a, which is 5.0 kcal/mol higher in energy than that of the 2,1-insertion of C−C double bond of 1a into the Ir−H bond (28.8 kcal/mol of TS8 versus 23.8 kcal/mol of TS6), being in accordance with the experimental results that the overisomerization products were observed to be ≤2% yield. The origins of the regioselectivity are mainly due to that E-2a is more stable than 1a by 3.4 kcal/mol, which consequently makes E-2a much less reactive than 1a. In addition, the steric repulsion in the insertion of the internal C−C double bond into the Ir−H bond should be greater than that in the insertion of the terminal C−C double bond into the Ir−H bond, which also contributes somewhat to the experimentally observed regioselectivity. To summarize, we have presented a mechanistic study on the iridium-catalyzed isomerization of 1-alkenes to trans-2-alkenes by means of DFT calculations. The computations show that the originally proposed π-allyl mechanism is kinetically unfeasible. Instead, the calculations reveal a new metal−ligand cooperative mechanism to account for the experimental results. The reaction was found to begin with the C(sp2)−H oxidative addition of the pyridine ligand to give the Ir(III) hydride intermediate, from which the isomerization can take place via the insertion/ elimination pathway. The experimentally observed regio- and stereoselectivities were reproduced quite well with this mechanistic scenario. The origins of the excellent stereoselectivity could be explained by the steric repulsions in the Z-β-

Figure 2. Calculated energy profile of the Ir-catalyzed isomerization of 1a via insertion/elimination mechanism. The blue and red pathways lead to the isomerization products E-2a and Z-2a, respectively.

double bond of 1a into the Ir−H bond was found to take place via transition state TS6, which leads to alkyl Ir intermediate INT8. The catalytic cycle is then closed by β-hydride elimination via transition states E-TS7 and Z-TS7 to afford product-coordinated intermediates E-INT9 and Z-INT9, which was followed by a ligand-exchange step with 1a to regenerate intermediate INT7 and release final olefin isomerization products E-2a and Z-2a, respectively. The calculations show that the energy barriers of the isomerization of 1a via our proposed metal−ligand cooperative mechanism are much lower than that through the π-allyl mechanism by at least 4 kcal/mol (Figure 2 versus Figure 1), indicating that the reaction should take place through our proposed mechanistic scenario. The β-hydride elimination is the stereoselectivity-determining step of the overall reaction. The calculated energy difference between E-TS7 and Z-TS7 is 1.8 kcal/mol, which corresponds to a calculated ratio of 95:5 at room temperature, being in good agreement with an experimentally observed ratio of 96:4. The optimized geometric structures of E-TS7 and Z-TS7 show that the stereoselectivity is mainly caused by the steric repulsions in Z-TS7 being larger than in E-TS7 (Figure 3).12 In particular, in Z-TS7, the strong steric repulsions between the nPr group with the pyridine ligand and C

DOI: 10.1021/acs.orglett.8b02319 Org. Lett. XXXX, XXX, XXX−XXX

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Zhang, Z.-X.; Jiao, L.; Liu, Q. J. Am. Chem. Soc. 2018, 140, 6873−6882. (c) Trost, B. M.; Cregg, J. J.; Quach, N. J. Am. Chem. Soc. 2017, 139, 5133−5139. (d) Mayer, M.; Welther, A.; Jacobi von Wangelin, A. ChemCatChem 2011, 3, 1567−1571. (e) Zhuo, L.-G.; Yao, Z.-K.; Yu, Z.-X. Org. Lett. 2013, 15, 4634−4637. (f) Kocen, A. L.; Brookhart, M.; Daugulis, O. Chem. Commun. 2017, 53, 10010−10013. (g) Vasseur, A.; Bruffaerts, J.; Marek, I. Nat. Chem. 2016, 8, 209−219. (h) Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S. Science 2012, 338, 1455− 1458. (4) For selected examples, see: (a) Li, H.; Mazet, C. Org. Lett. 2013, 15, 6170−6173. (b) Lim, H. J.; Smith, C. R.; RajanBabu, T. V. J. Org. Chem. 2009, 74, 4565−4572. (c) Gauthier, D.; Lindhardt, A. T.; Olsen, E. P. K.; Overgaard, J.; Skrydstrup, T. J. Am. Chem. Soc. 2010, 132, 7998−8009. (d) Larsen, C. R.; Grotjahn, D. B. J. Am. Chem. Soc. 2012, 134, 10357−10360. (e) Schmidt, A.; Nödling, A. R.; Hilt, G. Angew. Chem., Int. Ed. 2015, 54, 801−804. (f) Jia, X.; Zhang, L.; Qin, C.; Leng, X.; Huang, Z. Chem. Commun. 2014, 50, 11056−11059. (5) Wang, Y.; Qin, C.; Jia, X.; Leng, X.; Huang, Z. Angew. Chem., Int. Ed. 2017, 56, 1614−1618. (6) For selected reviews, see: (a) Biswas, S. Comments Inorg. Chem. 2015, 35, 300−330. (b) Sommer, H.; Juliá-Hernández, F.; Martin, R.; Marek, I. ACS Cent. Sci. 2018, 4, 153−165. (7) For selected DFT calculations on olefin isomerization via the insertion/elimination pathway, see: (a) Dang, Y.; Qu, S.; Wang, Z.-X.; Wang, X. J. Am. Chem. Soc. 2014, 136, 986−998. (b) Chen, Y.; Wang, M.-y.; Fang, S.; Wang, T.; Liu, J.-y. Organometallics 2015, 34, 4864− 4870. (c) Henriksen, S. T.; Tanner, D.; Cacchi, S.; Norrby, P.-O. Organometallics 2009, 28, 6201−6205. (d) Xu, L.; Hilton, M. J.; Zhang, X.; Norrby, P.-O.; Wu, Y.-D.; Sigman, M. S.; Wiest, O. J. Am. Chem. Soc. 2014, 136, 1960−1967. (e) Zhang, M.; Hu, L.; Lang, Y.; Huang, G. J. Org. Chem. 2018, 83, 2937−2947. (8) (a) Ariafard, A.; Bi, S. W.; Lin, Z. Y. Organometallics 2005, 24, 2241−2244. (b) Fish, R. W.; Giering, W. P.; Marten, D.; Rosenblum, M. J. Organomet. Chem. 1976, 105, 101−118. (c) Gibson, D. H.; Hsu, W.-L.; Steinmetz, A. L.; Johnson, B. V. J. Organomet. Chem. 1981, 208, 89−102. (9) The C1−H reductive elimination directly from η1-allyl Ir hydride intermediates was also considered, which was calculated to be higher in energy than that from η3-allyl Ir hydride complexes. See the SI for details. (10) The stereoselectivity with this mechanistic scenario is mainly due to steric repulsion between the pyridine−phosphine ligand and nPr group in the Z-pathway. See the SI for the optimized geometries. (11) The C(sp2)−H oxidative addition of the pyridine ligand without the coordination of 1a was calculated to be much higher in energy than TS5. See the SI for details. (12) The reduced density gradient analyses of E-TS7 and Z-TS7 were conducted, which showed that the steric repulsions between the alkene moiety and the pyridine ligand in Z-TS7 are stronger than in E-TS7. See the SI for details. (13) Frisch, M. J.; et al. Gaussian 09, revision E.01; Gaussian, Inc.: Wallingford, CT, 2013. See the SI for the full reference. (14) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378−6396. (15) (a) Lee, C. T.; Yang, W. T.; Parr, R. G. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785−789. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648−5652. (c) Grimme, S.; Ehrlich, S.; Goerigk, L. J. Comput. Chem. 2011, 32, 1456−1465. (16) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270−283. (17) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215−241.

hydride elimination being greater than the E-β-hydride elimination. The regioselectivity is mainly thermodynamically controlled, which makes the relatively more stable 2-alkenes being much less reactive compared with the 1-alkenes. Computational details. All of the calculations were performed with the Gaussian 09 package. 13 Geometry optimizations were performed in solution with the SMD14 model (solvent = benzene, ε = 2.2706) and were carried out using B3LYP-D3(BJ)15 functional with a mixed basis set of LANL2DZ16 for Ir and 6-31G(d) for other atoms. Vibrational frequencies were computed analytically at the same level of theory to confirm whether the structures are minima (no imaginary frequencies) or transition states (only one imaginary frequency). To obtain better accuracy, energies of the optimized geometries were calculated using M0617 solution-phase singlepoint calculations with a larger basis set, which is SDD for Ir and 6-311+G(d,p) for other atoms. The final free energies (ΔGsol) discussed in the article are the large basis set single-point energies with Gibbs free energy correction (at 298.15 K). The enthalpies (ΔHsol) obtained by the large basis set single-point energies with enthalpy correction (at 298.15 K) were provided for reference. Additionally, the B3LYP-D3(BJ) solution-phase single-point calculations were also conducted, which lead to the same conclusions as those from M06 functional (see the SI for details).

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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.8b02319. Complete ref 13, additional computational results, computed energies and energy corrections, and Cartesian coordinates of all optimized structures (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Web: http://genpinghuang. weebly.com. ORCID

Genping Huang: 0000-0002-2249-1248 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is supported by the National Natural Science Foundation of China (No. 21503143) and the Natural Science Foundation of Tianjin (No. 16JCQNJC05600).

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REFERENCES

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DOI: 10.1021/acs.orglett.8b02319 Org. Lett. XXXX, XXX, XXX−XXX