Kinetic Isotope Effects in Transition Metal-catalyzed C-H Activation

1. Kinetic Isotope Effects in Transition Metal-catalyzed C-H Activation Speaker: CHENG Guijuan Apr. 17th, 2014

2. Preface Tools of physical organic chemistry crossover experiments kinetic studies isotope labeling linear free-energy relationships (LFER) kinetic isotope effect (KIE) computational chemistry … KIE provide important information about which bonds are broken or formed at different stages of a reaction. KIE experiment computation

3. Outline • Introduction • what’s KIE • origin of KIE • magnitude of the observed KIEs • KIE in transition metal-catalyzed C-H activation • measurement of KIE • interpretation of KIE • mechanistic study employing KIE • Summary

4. Introduction Kinetic isotope effect (KIE): the change in the rate of a chemical reaction upon substitution of an atom in the reactants with one of its isotopes. The ratio of rate constants for the reactions involving the light (kL) and the heavy (kH) isotopically substituted reactants. Deuterium KIE: kH/kD Primary KIE: deuterated C-H bond breaks in the RDS (rate-determing step) kH/kD =1, no isotope effect Secondary KIE: deuterated C-H bond does not break in RDS but changes in hybridization (sp3 to sp2, sp2 to sp, and the reverse). kH/kD >1, normal KIE kH/kD <1, inverse KIE Gómez-Gallego, M.; Sierra, M. A. Chem. Rev.2011, 111, 4857.

5. Introduction • Origin of isotope effect Morse potential Stretching vibration Zero-point energy The isotope effects origins from the difference in ZpEs between unlabeled (C-H) and labeled (C-D) bonds. Gómez-Gallego, M.; Sierra, M. A. Chem. Rev.2011, 111, 4857.

6. Introduction • Origin of kinetic isotope effect---primary KIE According to Eyring equation: the C−H activation energy (AEH) is smaller than the C−D activation energy (AED), leading to a faster reaction (kH/kD > 1). Isotopic ZpE difference remains in the transition state Gómez-Gallego, M.; Sierra, M. A. Chem. Rev.2011, 111, 4857.

7. Introduction • Magnitude of the observed KIEs---primary KIEs According to Eyring equation: the maximum kH/kD: 6.5~7 (at 298 K) experimental kH/kD values are affected by the geometry the degree of bond breaking−bond making in the TS the position of the transition state in the reaction coordinate (early TS, late TS or centered TS) Gómez-Gallego, M.; Sierra, M. A. Chem. Rev.2011, 111, 4857.

8. Introduction • Magnitude of the observed KIEs---secondary KIEs maximum theoretical value is 1.4 Typical experimental values: 1.1~1.2 Typical experimental values: 0.8~0.9 Gómez-Gallego, M.; Sierra, M. A. Chem. Rev.2011, 111, 4857.

9. KIE in Transition Metal-catalyzed C-H Activation C-H activation is the rate-determing step Observation of primary KIE

10. KIE in Transition Metal-catalyzed C-H Activation • Measurement of KIE---common KIE experiments A) KIE determined by two parallel reactions provides conclusive information on whether the C-H bond cleavage occurs during the RDS or not. Absolute rate measurements are rarely sufficiently precise. B) KIE determined from an intermolecular competition Simple to conduct, give precise date No isotope effect: C-H activation is not rate-determing step Primary KIE: cannot conclude C-H activation is rate-determing step

11. KIE in Transition Metal-catalyzed C-H Activation • Measurement of KIE---common KIE experiments C) KIE determined from an intramolecular competition Simple to conduct, give precise data No isotope effect: C-H activation is not rate-determing step Primary KIE: cannot conclude C-H activation is rate-determing step rate-determing step (RDS) an elementary reaction which determines the overall rate product-determing step (selectivity-determing step) an irreversible step that determines the product distribution Although the product-determining step can also be the rate-determining step, the product-determining step does not need to be the rate-determining step Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed.2012, 51, 3066.

12. KIE in Transition Metal-catalyzed C-H Activation • Case 1: the C-H bond cleavage step is irreversible and is the RDS of the overall process Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed.2012, 51, 3066.

13. KIE in Transition Metal-catalyzed C-H Activation • Case 2: the C-H bond cleavage step is irreversible but it occurs after the RDS C-H cleavage is the product-determing step for experiments B and C but is not rate-determing step. Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed.2012, 51, 3066.

14. KIE in Transition Metal-catalyzed C-H Activation • Case 2: General Mechanism for the Palladium-Catalyzed Direct Arylation of Simple Arenes RDS: ligand dissociation or reductive elimination from a metal complex, or oxidative addition of C-X Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed.2012, 51, 3066.

15. KIE in Transition Metal-catalyzed C-H Activation • Case 3: the C-H bond cleavage step is irreversible but it occurs after the RDS Substrate-binding is the product-determing step for experiment B. C-H cleavage is the product-determing step for experiment C. Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed.2012, 51, 3066.

16. KIE in Transition Metal-catalyzed C-H Activation • Case 3: the C-H bond cleavage step is irreversible but it occurs after the RDS formation of π complex C-H activation Bhalla, G.; Liu, X. Y.; Oxgaard, J.; Goddard, W. A., III; Periana, R. A. J. Am. Chem. Soc. 2005, 127, 11372.

17. KIE in Transition Metal-catalyzed C-H Activation • Case 4: the C-H bond cleavage step is reversible and occurs before the RDS of the overall process No large primary KIE will be observed for any of three experiments. Potential KIE could be observed for these three experiments. k1 an k-1 are affected by isotope substitution. Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed.2012, 51, 3066.

18. KIE in Transition Metal-catalyzed C-H Activation • Case 4: C-H activation oxidative addition reductive elimination Nicholas R. Deprez; Melanie S. Sanford; J. Am. Chem. Soc. 2009, 131, 11234.

19. KIE in Transition Metal-catalyzed C-H Activation • Case 4: KIE=2.5±0.2 kH/kD =1 C-H cleavage is not the rate-determining step. Nicholas R. Deprez; Melanie S. Sanford; J. Am. Chem. Soc. 2009, 131, 11234.

20. KIE in Transition Metal-catalyzed C-H Activation • Case 5: the C-H bond cleavage step is reversible and occurs after the RDS of the overall process No large primary KIE will be observed. A small isotope effect could be observed from experiments B and C. Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed.2012, 51, 3066.

21. KIE in Transition Metal-catalyzed C-H Activation • Mechanistic study employing KIE---example 1 C-H cleavage is the rate-determining step. Chen, X.; Goodhue, C. E.; Yu, J-Q.  J. Am. Chem. Soc.2006, 128, 12634.

22. KIE in Transition Metal-catalyzed C-H Activation • Mechanistic study employing KIE---example 1 the C-H bond cleavage step is irreversible and is the RDS of the overall process Chen, X.; Goodhue, C. E.; Yu, J-Q.  J. Am. Chem. Soc.2006, 128, 12634.

23. KIE in Transition Metal-catalyzed C-H Activation • Mechanistic study employing KIE---example 2 C-H cleavage is not the rate-determining step. Geary, L. M.; Hultin, P. G. Eur. J. Org. Chem. 2010, 2010, 5563.

24. KIE in Transition Metal-catalyzed C-H Activation the C-H bond cleavage step is irreversible but it occurs after the RDS Substrate-binding is the product-determing step for experiment B. C-H cleavage is the product-determing step for experiment C. Geary, L. M.; Hultin, P. G. Eur. J. Org. Chem. 2010, 2010, 5563.

25. Take-home Message • KIE is an import tool in physical organic chemistry. KIE experiment computation • KIE in Transition Metal-catalyzed C-H Activation B) Intermolecualr competition A) Parallel reactions C) Intramolecular competition The observation of a primary KIE in experiments B and C do not indicate that C-H activation must involves in rate-determing step.

26. Thanks for your attention!