Group Meeting Special Topic: C-H Activation John Hayes 1/6/15

C-H Activation and Significance Active functionalization of inert C-H bonds – Does not include nucleophilic arene substitution Typified by reaction of alkanes to induce functionalization at “inactive” positions – Can include alkenes/arenes for instances such as terminal olefins and cross coupling Potential to produce a wide variety of complex materials from simple starting materials

Types of C-H Activation Electrophilic – Coordination to C-H bond followed by alkyl transfer and loss of proton Nucleophilic/Oxidative Addition – Metal insertion into coordinated C-H bond Carbenoid/Nitrenoid – Metal bonding to formal carbene/nitrene

Humble Beginnings... ACS Symposium Series 885, Activation and Functionalization of C-H Bonds, Karen I. Goldberg and Alan S. Goldman, eds Halpern, J.; Peters, E. J. Chem. Phys. 1955, 23, 605. Webster, A. H.; Halpern, J. J. Phys. Chem. 1956, 60, 280. Vaska, L. Acc. Chem. Res. 1968, 1, 335.

… and Radical Beginnings Hoffman-Löffler-Freytag Reaction Barton Nitrite Photolysis Hofmann, A. W. Berichte. 1883, 16, Löffler, K.; Freytag, C. Berichte. 1909, 43, Barton, D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1961, 83,

Organometallic C-H Activation 1965: Oxidative addition activation process discovered by Chatt 1969: Electrophilic activation discovered by Shilov Chatt, J.; Davidson, J. M. J. Chem. Soc. 1965, 843. Gol'dshleger, N. F.; Tyabin, M. B.; Shilov, A. E.; Shteinman, A. A. Zhurnal Fizicheskoi Khimii 1969, 43, 2174.

Other Notable Historic Records 1972 – Shilov 1970 – Green 1993 – Murai Gol'dshleger, N. F.; Es'kova, V. V.; Shilov, A. E.; Shteinman, A. A. Zhurnal Fizicheskoi Khimii 1972, 46, Green, M. L. H.; Knowles, P. J. J. Chem. Soc., Chem. Comm. 1970, Murai,S.; Kakiuchi, S.; Sekine, S.; Tanaka, A.; Kamatani, M.; Chatani, N. Nature, 1993, 366, 529.

Selectivity and Guiding Effects Selectivity largely determined by electron density – Other factors include sterics and strain Coordination-directed metallation can direct towards more electron deficient C-H bonds BrÜckl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem. Res. 2012, 45, 826–839.

Coordination-directed Metallation Godula, K.; Sames, D. Science 2006, 312, Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169.

Carbenoids and Nitrenoids Godula, K.; Sames, D. Science 2006, 312,

Borylation via C-H Activation Steric control provides borylation at least hindered site J.-Y. Cho, M. K. Tse, D. Holmes, R. E. Maleczka, M. R. Smith III, Science 295, 305 (2002). T. Ishiyama et al., J. Am. Chem. Soc. 124, 390 (2002).

4 Natural Products Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130,

Teleocidin B4 B. D. Dangel, K. Godula, S. W. Youn, B. Sezen, D. Sames, J. Am. Chem. Soc. 124, (2002). Electrophilic C-H Activation

(+)-Lithospermic Acid S. J. OMalley, K. L. Tan, A. Watzke, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2005, 127, – Oxidative Addition C-H Activation

(-)-Rhazinilam J. A. Johnson, D. Sames, J. Am. Chem. Soc. 2000, 122, 6321–6322 Oxidative Addition/ Dehydrogenation

(-)-Tetrodotoxin Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510– Carbene & Nitrene Activation

Dictyodendrin A Consecutive C-H Activation Sequence Yamaguchi, A. D.; Chepiga, K. M.; Yamaguchi, J.; Itami, K.; Davies, H. M. L. J. Am. Chem. Soc. 2015, ASAP.

L-glycosides Frihed, T. G.; Pedersen, C. M.; Bols, M. Angew. Chem. Int. Ed. 2014, 53, 13889–13893.

Regioselective C-H Activation Curto, J. M.; Kozlowski, M. C. J. Am. Chem. Soc. 2014, ASAP.

Regiodivergent Cyclization Donets, P. A.; Cramer, N. Angew. Chem. Int. Ed. 2014, 633 – 637.