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

2. Preface 2 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. computation experiment KIE

3. Outline 3  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 4 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 (k L ) and the heavy (k H ) isotopically substituted reactants. Deuterium KIE: k H /k D k H /k D =1, no isotope effect k H /k D >1, normal KIE Primary KIE: deuterated C-H bond breaks in the RDS (rate-determing step) k H /k D <1, inverse KIE Secondary KIE: deuterated C-H bond does not break in RDS but changes in hybridization (sp 3 to sp 2, sp 2 to sp, and the reverse). Gómez-Gallego, M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857.

5. Introduction 5 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 6 Origin of kinetic isotope effect---primary KIE According to Eyring equation: Isotopic ZpE difference remains in the transition state the C−H activation energy (AE H ) is smaller than the C−D activation energy (AE D ), leading to a faster reaction (k H /k D > 1). Gómez-Gallego, M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857.

7. Introduction 7 Magnitude of the observed KIEs---primary KIEs According to Eyring equation: the maximum k H /k D : 6.5~7 (at 298 K) experimental k H /k D 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 8 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 9 Observation of primary KIE Observation of primary KIE C-H activation is the rate-determing step C-H activation is the rate-determing step

10. KIE in Transition Metal-catalyzed C-H Activation 10 Measurement of KIE---common KIE experiments provides conclusive information on whether the C-H bond cleavage occurs during the RDS or not. Absolute rate measurements are rarely sufficiently precise. 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 A) KIE determined by two parallel reactions B) KIE determined from an intermolecular competition

11. KIE in Transition Metal-catalyzed C-H Activation 11 Measurement of KIE---common KIE experiments 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) product-determing step (selectivity-determing step) an elementary reaction which determines the overall rate 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 C) KIE determined from an intramolecular competition Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066.

12. KIE in Transition Metal-catalyzed C-H Activation 12 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 13 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 14 Case 2: Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066. 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

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

16. KIE in Transition Metal-catalyzed C-H Activation 16 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 17 Case 4: the C-H bond cleavage step is reversible and occurs before the RDS of the overall process Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066. No large primary KIE will be observed for any of three experiments. k 1 an k -1 are affected by isotope substitution. Potential KIE could be observed for these three experiments.

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

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

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

21. KIE in Transition Metal-catalyzed C-H Activation 21 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 22 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 23 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 24 the C-H bond cleavage step is irreversible but it occurs after the RDS Geary, L. M.; Hultin, P. G. Eur. J. Org. Chem. 2010, 2010, 5563. C-H cleavage is the product-determing step for experiment C. Substrate-binding is the product-determing step for experiment B.

25. 25 Take-home Message KIE is an import tool in physical organic chemistry. KIE in Transition Metal-catalyzed C-H Activation computation experiment KIE A) Parallel reactions B) Intermolecualr competition 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.

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