Understanding Rate Acceleration and Stereoinduction of an

Communication pubs.acs.org/JACS

Understanding Rate Acceleration and Stereoinduction of an Asymmetric Giese Reaction Mediated by a Chiral Rhodium Catalyst Brandon Tutkowski,† Eric Meggers,‡ and Olaf Wiest*,†,§ †

Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 4, 35043 Marburg, Germany § Laboratory of Computational Chemistry and Drug Design, School of Chemical Biology and Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055, China ‡

S Supporting Information *

result, the energetics of the reactions were typically not studied. Surprisingly, there are, to the best of our knowledge, few studies of such reactions or their contemporary variants using modern electronic structure methods. Such investigations would provide more quantitative descriptions of the reactions.8 Although modern variants of the classic, uncatalyzed reaction provide better control of reactivity and stereochemistry using various photoredox and Lewis acid catalysts,9 control of stereochemistry of intermolecular radical additions by chiral catalysts is still a significant challenge. This is presumably due to the fast, nonselective background reaction and the fact that most radical additions proceed through early transition states. Building on the pioneering work of Sibi regarding chiral Lewis acid catalyzed radical reactions10,11 and recent photoredox chemistry by Yoon,12 an efficient catalyst for the catalytic enantioselective addition of alkyl radicals to electron-deficient alkenes was recently published (Figure 1).13,14

ABSTRACT: The surprising acceleration of the addition of electron-rich radicals to α,β-unsaturated 2-acyl imidazoles by a chiral-at-metal rhodium catalyst is investigated. M06/Lanl2DZ (Rh),6-31G(d) calculations reproduce the observed rate acceleration and shed light on a catalyst design where a rigid chiral pocket with a steric interaction >5 Å from the chiral metal center leads to the observed high stereoinduction. Analysis of the molecular orbitals of two key addition transition states emphasize the role of the catalyst as a Lewis acid without significant charge transfer.

P

hotoredox chemistry is attracting significant interest for its ability to provide highly reactive radical intermediates in a controlled fashion under mild conditions, with applications in oxygenations, oxidations, aminations, (de)halogenations, and perhalomethylation processes, as well as C−C coupling reactions.1,2 Recent applications couple the photoredox step with other modes of catalysis to expand the synthetic utility and allow stereoselective reactions of the reactive radical intermediates, an area of current interest where significant improvement is needed.3 Surprisingly, there are few mechanistic and computational studies of photoredox catalysis and even fewer for coupling photoredox with asymmetric catalysis.4 This is unfortunate because the mechanisms and transition states involved are poorly understood, making the rational extension of this useful methodology into enantioselective synthesis more difficult. The addition of nucleophilic alkyl radicals to electrondeficient alkenes, known as the Giese reaction, is an important C−C bond forming reaction in organic synthesis.5 The classic work by Giese, Houk, and others showed that the alkyl radical approaches the less-hindered olefinic carbon of the electrondeficient alkenes with a Bürgi-Dunitz angle between 104° and 110°.6 In agreement with the exothermic nature of the reaction, the transition states are quite early and have radical-olefinic carbon distances between 2.23 and 2.38 Å, depending on the nature of the radical and olefin. The few computational studies of the addition of the more stable benzyl radical indicate slightly later transition states.7 Although these early studies were seminal for the understanding of these useful reactions, they were done at the UHF level of theory with, by modern standards, relatively small basis sets and in the gas phase. As a © 2017 American Chemical Society

Figure 1. Catalytic enantioselective radical addition to acceptorsubstituted alkenes. EWG = 2-acyl imidazole or N-acyl 3,5dimethylpyrazole; PC = photocatalyst (ref 13).

The bis-cyclometalated chiral-at-rhodium catalyst Λ-RhS15,16 accelerates the addition of alkyl radicals generated by photoredox catalysis from organotrifluoroborates to acceptorsubstituted alkenes with enantiomeric excess up to 99% with as little as 4 mol % catalyst loading. The exceptionally high activity of this catalyst for a radical addition reaction in the presence of a 25-fold excess of free substrate is a unique feature of the reaction. Indeed, competition kinetic experiments revealed the catalyst leads to an acceleration by at least 3 × 104 times for the addition of a benzyl radical to an α,β-unsaturated 2acylimidazole (Figure 2) relative to the uncatalyzed background reaction.13 The origin of the dramatic acceleration compared to Received: February 20, 2017 Published: May 31, 2017 8062

DOI: 10.1021/jacs.7b01786 J. Am. Chem. Soc. 2017, 139, 8062−8065

Communication

Journal of the American Chemical Society

nucleophilic attack and very similar to values obtained in the earlier studies.6b,c The calculated Gibbs free energies of activation for TS1 and TS2 are 16.7 and 16.9 kcal/mol, respectively, surprisingly high for a radical addition. However, this is in line with the observation that the addition of alkyl radicals to α,β-unsaturated N-enoyloxazolidinones is “extremely sluggish” when performed without the presence of a Lewis acid.21 This is, at least in part, due to the later character of the transition state for the benzyl radical addition, which leads to a larger deformation energy compared to the addition of an alkyl radical. Figure 4 shows the four possible transition structures TS1RhR, TS1RhS, TS2RhR, and TS2RhS for the same reaction

Figure 2. Model enantioselective Giese reaction investigated (ref 13).

the uncatalyzed reaction and the structural origin of the stereoselection are not clear. Given these unresolved questions, the lack of modern, quantitative studies of the addition of alkyl radicals to electron deficient alkenes, and the intense interest of the organic community in photoredox reactions, we decided to investigate this synthetically promising reaction. The reaction is initiated by photoinduced oxidative conversion of benzyl trifluoroborates to carbon-centered radicals.17,18 Control reactions show that the radical addition does not occur in the absence of light or photoredox catalyst. The reaction will, however, occur without the presence of the rhodium-based complex. This, along with the fact that the initiation is known to have a low barrier indicates that the radical formation is not rate-limiting. Instead, the radical addition is apparently the stereodetermining step of the reaction and the only step in which the Rh complex is likely to have significant influence. We therefore studied the addition step shown in Figure 2 at the M0619//Lanl2DZ (Rh), 631G(d) (all other atoms) level of theory, followed by M06// Lanl2DZ (Rh), 6-311+G(d,p) (all other atoms) single point calculations with the CPCM implicit solvent model using the parameters for acetone using Gaussian 09 (for details, see the Supporting Information).20 Figure 3 shows the transition structures TS1 and TS2 for the stereoselecting addition step of the benzyl radical to the olefins

Figure 4. Transition structures for alkyl radical addition catalyzed by Λ-RhS. Activation free energies shown in kcal/mol. Distances shown in Å. Hydrogens removed for clarity.

where the 2-acyl imidazole acts as a bidentate ligand of the Rh catalyst Λ-RhS, similar to the crystal structure of the starting material complexed to the catalyst.15 The forming carbon− carbon bond has distances between 2.29 and 2.31 Å, slightly longer than in TS1 and TS2. Interestingly, the calculated Rh− O and Rh−N distances are 2.34 and 2.25 Å, respectively, essentially identical between the starting complex and the transition structures. In a typical Lewis acid catalyzed reaction, stabilization of a developing charge would be expected to decrease the Rh−O bond length, raising the question of how complexation to Rh accelerates the reaction. The calculated Gibbs free energy of activation for TS2RhR is 11.3 kcal/mol. This 5.6 kcal/mol difference from TS2 is in excellent agreement with the experimentally observed acceleration of 3 × 104 for substrate 2. The difference in free energies of activation leading to the S product via TS2 and TS2RhS is 2.1 kcal/mol. The difference between TS2RhR and TS2RhS of 3.5 kcal/mol is again in excellent agreement with the high enantioselectivity, up to 99% ee, observed experimentally. Similarly, the difference in free energies of activation for the methyl analog via TS1 and TS1RhR was 4.0

Figure 3. Transition structures for uncatalyzed alkyl radical addition. Activation free energies shown in kcal/mol. Distances shown in Å.

1 and 2. The calculated bond lengths for the forming carbon− carbon bonds are 2.24 and 2.25 Å, substantially shorter than the 2.34 Å previously reported for the similar addition of methyl radical to acrylonitrile.6b This suggests a significantly later transition structure, presumably because of the lower overall exothermicity due to the higher stability of the benzyl radical. The calculated Bürgi-Dunitz attack angle of 102° is typical for a 8063

DOI: 10.1021/jacs.7b01786 J. Am. Chem. Soc. 2017, 139, 8062−8065

Communication

Journal of the American Chemical Society kcal/mol, and leading to the S product via TS1 and TS1RhS, was 3.0 kcal/mol. Again, these differences quantitatively agree with the experimental results, suggesting that the transition structures shown in Figures 3 and 4 are good models for the reaction. To probe the role of the catalyst, we analyzed the orbitals involved in the addition of benzyl radical to alkene 1 in free form and complexed to Λ-RhS (1Rh), Figure 5A. The

even for an early transition state. Although the incoming benzyl radical in the favored transition state TS2RhR is positioned over the benzothiazole moiety without any repulsive interactions, the distance between the hydrogens at the benzyl position and the tert-butyl group on the ligand in TS2RhS is only 2.13 Å, leading to substantial steric repulsion. This is an interesting example of a design where a rigid chiral pocket with a steric interaction far from the chiral metal center (more than 5 Å) leads to high stereoinduction in an early transition state. A second steric repulsion with a hydrogen−hydrogen distance of 2.42 Å between a tert-butyl group and the phenyl ring on the imidazole leads to a further increase of the stereoselectivity. In summary, the first computational study of the addition of a stabilized radical, photoinduced single electron oxidation of organotrifluoroborates, to an electron deficient alkene and its catalysis by the chiral-at-metal Rh complex Λ-RhS is presented. Using modern electronic structure methods, the transition structures for the catalyzed and uncatalyzed reaction provide a detailed view of the origin of the unusual rate acceleration of 3 × 104 as well as the high degree of stereoinduction in an intermolecular radical addition to an alkene. The computational results are in excellent quantitative agreement with the experimentally observed rate acceleration and enantioselectivities. The energies of the orbitals involved indicate that the origin of the substantial increase in observed reaction rate is a lowering of the SOMO−LUMO gap due to the Lewis acid character of Λ-RhS. Analysis of the transition structure geometries emphasize the importance of the rigid pocket created by the catalyst for stereoinduction far from the chiral center. Taken together, these results provide the basis for the design of more active and selective catalysts for the combined use of photoredox and Lewis acid catalysis.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b01786. Computational details; complete ref 20; results summary table; HOMO and LUMO orbitals for alkene 1 and 1Rh; Cartesian coordinates for complexes and transition states including alternative conformations considered (PDF)

Figure 5. (A) Molecular orbital diagram for substrates 1, Bn•, and 1Rh. HOMO and LUMO energies for alkenes 1 and 1Rh, SOMO energy for Bn•. Energy values in [eV]. (B) SOMO orbitals for TS1RhR and TS1.

■

participating orbitals of the reactants consist of the HOMO and LUMO of the electron deficient alkene substrate and the SOMO of the benzyl radical acting as a nucleophile, the energies of which are shown in Figure 5A. The full structures of these orbitals are shown in the Supporting Information, Figure S1. Because bond making and bond breaking are not far advanced in the early addition TSs, polar effects of the catalyst may be rationalized in terms of the frontier MOs of the optimized reactants.7a The SOMO of the benzyl radical will more strongly interact with the LUMO of the electron deficient alkene.7b The results show that the complexation to Λ-RhS lowers the SOMO−LUMO gap from 4.06 eV in the uncatalyzed reaction to 0.49 eV in the catalyzed reaction. This, together with the unchanged Rh−O bond length in the transition structure and the similarities observed between the TS SOMO orbitals, Figure 5B, emphasizes the role of the catalyst as a Lewis acid without significant charge transfer in an early transition state. Finally, the computed structures also provide insights into the origin of the experimentally observed high stereoselectivity,

AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Eric Meggers: 0000-0002-8851-7623 Olaf Wiest: 0000-0001-9316-7720 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We gratefully acknowledge support from the National Science Foundation (CHE-1361296 and CHE-1565669) and the Center for Research Computing at the University of Notre Dame. E.M. acknowledges funding from the Deutsche Forschungsgemeinschaft (ME 1805/13-1). This work is dedicated to Professor Yun-Dong Wu on the occasion of his 60th birthday. 8064

DOI: 10.1021/jacs.7b01786 J. Am. Chem. Soc. 2017, 139, 8062−8065

Communication

Journal of the American Chemical Society

■

(17) (a) Tellis, J. C.; Primer, D. N.; Molander, G. A. Science 2014, 345, 433. (b) Huang, H.; Zhang, G.; Gong, L.; Zhang, S.; Chen, Y. J. Am. Chem. Soc. 2014, 136, 2280. (18) See also: (a) Sorin, G.; Martinez Mallorquin, R.; Contie, Y.; Baralle, A.; Malacria, M.; Goddard, J.-P.; Fensterbank, L. Angew. Chem., Int. Ed. 2010, 49, 8721. (b) Yasu, Y.; Koike, T.; Akita, M. Adv. Synth. Catal. 2012, 354, 3414. (19) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215. (20) Frisch, M. J.; et al. Gaussian 09, Revision D.01; Gaussian, Inc.: Wallingford, CT, 2013. (21) Sibi, M. P.; Ji, J.; Sausker, J. B.; Jasperse, C. P. J. Am. Chem. Soc. 1999, 121, 7517.

REFERENCES

(1) Balzani, C., Campagna, S. Photochemistry and Photophysics of Coordination Compounds I, Vol. 280; Springer: New York, 2007. (2) For recent reviews on photoredox catalysis, see: (a) Yoon, T. P. Acc. Chem. Res. 2016, 49, 2307. (b) Schultz, D. M.; Yoon, T. K. Science 2014, 343, 985. (c) Ischay, M. A.; Yoon, T. P. Eur. J. Org. Chem. 2012, 2012, 3359. (d) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322. (e) Staveness, D.; Bosque, I.; Stephenson, C. R. J. Acc. Chem. Res. 2016, 49, 2295. (f) Tucker, J. W.; Stephenson, C. R. J. J. Org. Chem. 2012, 77, 1617. (g) Reckenthäler, M.; Griesbeck, A. G. Adv. Synth. Catal. 2013, 355, 2727. (h) Ravelli, D.; Protti, S.; Fagnoni, M. Chem. Rev. 2016, 116, 9850. (3) (a) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116, 10035. (b) Levin, M. D.; Kim, S.; Toste, F. D. ACS Cent. Sci. 2016, 2, 293. (c) Hopkinson, M. N.; Sahoo, B.; Li, J.-L.; Glorius, F. Chem. - Eur. J. 2014, 20, 3874. (4) For outlooks and perspectives, see: (a) Demissie, T. B.; Hansen, J. H. Dalton Trans. 2016, 45, 10878. For selected studies, see: (b) Heitz, D. R.; Tellis, J. C.; Molander, G. A. J. Am. Chem. Soc. 2016, 138, 12715. (c) Demissie, T. B.; Hansen, J. H. J. Org. Chem. 2016, 81, 7110. (d) Pan, X.; Fang, C.; Fantin, M.; Malhotra, N.; So, W. Y.; Peteanu, L. A.; Isse, A. A.; Gennaro, A.; Liu, P.; Matyjaszewski, K. J. Am. Chem. Soc. 2016, 138, 2411. (e) Gutierrez, O.; Tellis, J. C.; Primer, D. N.; Molander, G. A.; Kozlowski, M. C. J. Am. Chem. Soc. 2015, 137, 4896. (5) (a) Giese, B. Radicals in Organic Synthesis: Formation of CarbonCarbon Bonds; Pergamon: Oxford, 1986. (b) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237. (c) Porter, N. A.; Giese, B.; Curran, D. P. Acc. Chem. Res. 1991, 24, 296. (6) (a) Giese, B. Angew. Chem., Int. Ed. Engl. 1983, 22, 753. (b) Damm, W.; Giese, B.; Hartung, J.; Hasskerl, T.; Houk, K. N.; Hüter, O.; Zipse, H. J. Am. Chem. Soc. 1992, 114, 4067. (c) Zipse, H.; He, J.; Houk, K. N.; Giese, B. J. Am. Chem. Soc. 1991, 113, 4324. (d) Thoma, G.; Curran, D. P.; Geib, S. V.; Giese, B.; Damm, W.; Wetterich, F. J. Am. Chem. Soc. 1993, 115, 8585. (e) Dewar, M. J. S.; Olivella, S. J. Am. Chem. Soc. 1978, 100, 5290. (f) Canadell, E.; Poblet, J. M.; Olivella, S. J. Phys. Chem. 1983, 87, 424. (g) Arnaud, R.; Barone, V.; Olivella, S.; Sole, A. Chem. Phys. Lett. 1985, 118, 573. (h) Houk, K. N.; Paddon-Row, M. N.; Spellmeyer, D. C.; Rondan, N. G.; Nagase, S. J. Org. Chem. 1986, 51, 2874. (7) (a) Héberger, K.; Walbiner, M.; Fischer, H. Angew. Chem., Int. Ed. Engl. 1992, 31, 635. (b) Arnaud, R.; Postlethwaite, H.; Barone, V. J. Phys. Chem. 1994, 98, 5913. (8) (a) Jamison, C. R.; Overman, L. E. Acc. Chem. Res. 2016, 49, 1578. (b) De Vleeschouwer, F.; Jaque, P.; Geerlings, P.; Toro-Labbé, A.; De Proft, F. J. Org. Chem. 2010, 75, 4964. (c) Bernardi, F.; Bottoni, A.; Garavelli, M. Quant. Struct.-Act. Relat. 2002, 21, 128. (d) Arnaud, R.; Vetere, V.; Barone, V. Chem. Phys. Lett. 1998, 293, 295. (e) Bottoni, A. J. Chem. Soc., Perkin Trans. 2 1996, 2, 2041. (f) Barone, V.; Orlandini, L. Chem. Phys. Lett. 1995, 246, 45. (9) (a) Giese, B. Angew. Chem., Int. Ed. Engl. 1989, 28, 969. (b) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163. (10) (a) Sibi, M. P.; Ji, J. J. Org. Chem. 1997, 62, 3800. (b) Sibi, M. P.; Ji, J.; Wu, J. H.; Gürtler, S.; Porter, N. A. J. Am. Chem. Soc. 1996, 118, 9200. (11) For a review on enantioselective radical reactions, see: Zimmermann, J.; Sibi, M. P. Top. Curr. Chem. 2006, 263, 107. (12) Espelt, L. R.; McPherson, I. S.; Wiensch, E. M.; Yoon, T. P. J. Am. Chem. Soc. 2015, 137, 2452. (13) Huo, H.; Harms, K.; Meggers, E. J. Am. Chem. Soc. 2016, 138, 6936. (14) See also: Wang, C.; Harms, K.; Meggers, E. Angew. Chem., Int. Ed. 2016, 55, 13495. (15) Ma, J.; Shen, X.; Harms, K.; Meggers, E. Dalton Trans. 2016, 45, 8320. (16) See also: (a) Wang, C.; Chen, L.-A.; Huo, H.; Shen, X.; Harms, K.; Gong, L.; Meggers, E. Chem. Sci. 2015, 6, 1094. (b) Zhang, L.; Meggers, E. Acc. Chem. Res. 2017, 50, 320. 8065

DOI: 10.1021/jacs.7b01786 J. Am. Chem. Soc. 2017, 139, 8062−8065