Group Meeting Special Topic:C-H Activation

John Hayes1/6/15

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

• 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

O

ONO

h

O

OHN

OH

R1 NR2

Cl 1. H+,

2. -OH NR1

R2

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 – MuraiGol'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

B. D. Dangel, K. Godula, S. W. Youn, B. Sezen, D. Sames, J. Am. Chem. Soc. 124, 11856 (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, 13496 –13497.

Oxidative AdditionC-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, 11510–11511.

Carbene & Nitrene Activation

Dictyodendrin AConsecutive 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.