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...
• H2 activation
𝐶𝑢2+ + 𝐻2 → [𝐶𝑢𝐻]+ +𝐻 +
• Later found to apply to Hg2+ and Ag+
• Oxidative addition pathway identified in 1962 by
Vaska for iridium complexes
ACS Symposium Series 885, Activation and Functionalization of C-H Bonds,
Karen I. Goldberg and Alan S. Goldman, eds. 2004.
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, 558-560.
Löffler, K.; Freytag, C. Berichte. 1909, 43, 3727.
Barton, D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1961, 83, 4083-4089.
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, 1353.
Green, M. L. H.; Knowles, P. J. J. Chem. Soc., Chem. Comm. 1970, 1677.
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, 67-72.
Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169.
Carbenoids and Nitrenoids
Godula, K.; Sames, D. Science 2006, 312, 67-72.
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, 7247-7249.
Teleocidin B4
Electrophilic C-H Activation
B. D. Dangel, K. Godula, S. W. Youn, B. Sezen, D. Sames, J. Am. Chem. Soc. 124, 11856 (2002).
(+)-Lithospermic Acid
Oxidative Addition
C-H Activation
S. J. OMalley, K. L. Tan, A. Watzke, R. G. Bergman, J. A. Ellman,
J. Am. Chem. Soc. 2005, 127, 13496 –13497.
(-)-Rhazinilam
Oxidative Addition/
Dehydrogenation
J. A. Johnson, D. Sames, J. Am. Chem. Soc. 2000, 122, 6321–6322
(-)-Tetrodotoxin
Carbene & Nitrene Activation
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510–11511.
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.