The document discusses using natural abundance of isotopes and kinetic isotope effect (KIE) measurements to investigate chemical reaction mechanisms. It provides examples of using these techniques to determine reaction mechanisms for Diels-Alder reactions, osmium-catalyzed dihydroxylation of olefins, and dirhodium-catalyzed cyclopropanation reactions. For the last example, Singleton's KIE data supported a conventional tetrabridged carbenoid mechanism over Corey's proposed tribridged intermediate mechanism.

1. Organic Pedagogical Electronic
Network
Using Natural Abundance of
Isotopes to Investigate Chemical
Reaction Mechanisms
John Gipson & Victoria Russell
University of Utah

2. Determination of Kinetic Isotope Effects at Natural Abundance
Overview: The natural abundance of isotopes of a chemical element can
provide detailed information about the mechanism of a large range of
chemical reactions. Small heavy-atom and secondary hydrogen kinetic
isotope effects (KIEs) can be measured with high-precision, simultaneously
determining multiple small KIEs at natural abundance using NMR techniques.

3. Early Examples
Wiki Pages: http://en.wikipedia.org/wiki/Natural_abundance; http://en.wikipedia.org/wiki/Abundance_of_the_chemical_elements
Other References: Martin, G. J.; Martin, M. L. Tetrahedron Lett. 1981, 22, 3525-3528; Pascal, R. A., Jr.; Baum, M. W.; Wagner, C. K.; Rodgers, L.
R.; Huang, D.-S. J. Am. Chem. Soc. 1986, 108, 6477-6482; Singleton, D. A.; Thomas, A. A. J. Am. Chem. Soc. 1995, 117, 9357-9358.
𝑘 𝐻
𝑘 𝐷
=
𝑅 𝑌𝐻 𝑛−1
𝑅 𝑍𝐻
𝑛 − 1
=
11.0 0.46
12 − 1
= 2.2
𝑅 𝑌𝐻 𝑛−1
= 𝐷 𝑟𝑒𝑡𝑎𝑖𝑛𝑒𝑑
𝑅 𝑍𝐻 = 𝐷 𝑡𝑟𝑎𝑛𝑠𝑓𝑒𝑟𝑟𝑒𝑑
Primary Deuterium KIE – Insertion Reaction
𝐾𝐼𝐸𝑐𝑎𝑙𝑐𝑑 =
l n( 1 − 𝐹
l n[ 1 − 𝐹 𝑅 𝑅0
Natural Abundance – Diels-Alder Reaction
KIE = 1.05 – 25% enrichment of slower reacting isotopic
component at 99% converstion (F = fractional conv.).

4. Probing Mechanism With Singleton Experiment
Gonzalez-James, O. M.; Kwan, E. E.; Singleton, D. A. J. Am. Chem. Soc. 2012, 134, 1914-1917.
Unexpected secondary KIEs give insight into multiple transition states on a
bifurcated potential energy surface:

5. Probing Mechanism With Singleton Experiment
A qualitative depiction of the energy surface (M06, MPW1K, or MP2) for the [2 + 2]
cycloaddition of alkene 1 with ketene 2 (see previous slide for reaction):
Gonzalez-James, O. M.; Kwan, E. E.; Singleton, D. A. J. Am. Chem. Soc. 2012, 134, 1914-1917.

6. Problem 1
References: Corey, E. J.; Noe, M. C.; Grogan, M. J. Tetrahedron Lett. 1996, 37, 4899-4902; Delmonte, A. J.; Haller, J.; Houk, K.
N.; Sharpless, K. B.; Singleton, D. A.; Strassner, T.; Thomas, A. A. J. Am. Chem. Soc. 1997, 119, 9907-9908
1. The OsO4 catalyzed dihydroxylation of olefins was thought to occur by one of the two distinct
mechanisms: The 3+2 Corey-Criegee mechanism is concerted, while the 2+2 Sharpless mechanism has
a rate determining ring expansion.
a) How would you expect secondary 13C KIEs to be different for each mechanism?
b) Singleton’s method yields the following results: Which pathway is more likely?

7. Problem 2
References: Lou, Y.; Horikawa, M.; Kloster, R. A.; Hawryluk, N. A.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 8916-
8918.
2. In 2004, Corey proposed that dirhodium(II) catalysts 1, which are generally thought to be tetrabridged,
may react through a tribridged intermediate 2 based on ligand studies.
a. What is the proposed reaction mechanism for this cycloaddition process?
b. Based on your understanding of KIEs, what would you predict to observe in KIE studies of the alkyne if
this proposed mechanism were correct?
1 2

8. Problem 2 Continued
References: Lou, Y.; Horikawa, M.; Kloster, R. A.; Hawryluk, N. A.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 8916-
8918; Nowlan, D. T., III; Singleton, D. A. J. Am. Chem. Soc. 2005, 127, 6190-6191.
2c. Using natural abundance to determine KIEs, Singleton reported the following results, where an early
asynchronous transition state 3 and 4 is proposed. Are these KIE results consistent with Corey’s mechanism
above? Do tetrabridged or tribridged rhodium carbenoids account for the observed isotope effects and
selectivity?
3 4

9. Solution 1
References: Corey, E. J.; Noe, M. C.; Grogan, M. J. Tetrahedron Lett. 1996, 37, 4899-4902; Delmonte, A. J.; Haller, J.; Houk,
K. N.; Sharpless, K. B.; Singleton, D. A.; Strassner, T.; Thomas, A. A. J. Am. Chem. Soc. 1997, 119, 9907-9908
1. a) For a concerted mechanism, we would expect the secondary KIEs on each carbon to be normal,
large, and nearly equivalent. For a rate determining ring expansion, only one carbon on the olefin should show
a significant secondary KIE, not both carbons.
b) The Singleton method yields large, normal secondary 13C KIEs on both carbons- this is consistent
with the concerted 3+2 Corey-Criegee Mechanism.

10. Solution 2
References: Lou, Y.; Horikawa, M.; Kloster, R. A.; Hawryluk, N. A.; Corey, E. J. J. Am. Chem. Soc. 2004, 126,
8916-8918; Nowlan, D. T., III; Singleton, D. A. J. Am. Chem. Soc. 2005, 127, 6190-6191.
2a. The mechanism proposed to account for the proposed tribridged intermediate 2 proceeds through a
[2+2] cycloaddition followed by reductive elimination.
2b. If the proposed [2+2] cycloaddition was the prevailing mechanism for this transformation, one would
expect to observe a large and comparable KIE for both carbons of the alkyne.
2c. Based on Singletons KIE results, the proposed mechanism in Corey’s report is not consistent with the
observed data. The results support a conventional tetrabridged carbenoid mechanism which also suggest an
explanation for the selectivity observed, and it does not support a [2+2] cycloaddition of intermidiate 2
proposed by Corey. It was further shown that 2 is 21.5 kcal/mol uphill in energy from the tetrabridged
alternative 1. In additional simulations, the tribridged intermediates appeared to be resistant to effecting
cyclopropenation.
Although Singleton was able to identify a viable mechanism for cyclopropenation via the tribridged structures,
only the tetrabridged rhodium carbenoids can account for the isotope effects and eneantioselectivity of the
Rh2(O2CR)n(DPTI)4-n reactions. The tetrabridged mechanism is the more optimal starting point for ligand
design.

11. This work is licensed under a
Creative Commons Attribution-
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License.
Contributed by:
John Gipson and Victoria Russell (Undergraduate students)
University of Utah
2014