Page 352 - Advanced Organic Chemistry Part A - Structure and Mechanisms, 5th ed (2007) - Carey _ Sundberg

Just how large the rate difference is depends on the nature of the TSs. The 333
maximum effect occurs when the hydrogen being transferred is bound about equally
to two other atoms at the TS. The calculated maximum for the isotope effect k /k SECTION 3.5
H D
involving C−H bonds is about 7 at room temperature. 121 When bond breaking is more Kinetic Isotope Effects
or less than half complete at the TS, the isotope effect is smaller and can be close
to 1 if the TS is very reactant-like or very product-like. Primary isotope effects can
provide two very useful pieces of information about a reaction mechanism. First, the
existence of a substantial isotope effect, i.e., k /k > 2, is strong evidence that the
D
H
bond to that particular hydrogen is being broken in the rate-determining step. Second,
the magnitude of the isotope effect provides a qualitative indication of where the TS
lies with regard to product and reactant. A relatively low primary isotope effect implies
that the bond to hydrogen is either only slightly or nearly completely broken at the
TS. That is, the TS must occur quite close to reactant or to product. An isotope effect
near the theoretical maximum is good evidence that the TS involves strong bonding
of the hydrogen to both its new and old bonding partner.
Isotope effects may also be observed when the substituted hydrogen atom is not
directly involved in the reaction. Such effects, known as secondary kinetic isotope
effects, are smaller than primary effects and are usually in the range of k /k =
D
H
0 7 − 1 5. They may be normal (k /k > 1) or inverse (k /k < 1), and are also
D
H
H
D
classified as or , etc., depending on the location of the isotopic substitution relative
to the reaction site. Secondary isotope effects result from a tightening or loosening of a
C−H bond at the TS. The strength of the bond may change because of a hybridization
3
change or a change in the extent of hyperconjugation, for example. If an sp carbon is
2
converted to sp as reaction occurs, a hydrogen bound to the carbon will experience
decreased resistance to C−H bending. The freeing of the vibration for a C−H bond
is greater that that for a C−D bond because the former is slightly longer, and the
vibration has a larger amplitude. This will result in a normal isotope effect. Entry 5
in Scheme 3.4 is an example of such a reaction that proceeds through a carbocation
intermediate. An inverse isotope effect will occur if coordination at the reaction center
increases in the TS. The bending vibration will become more restricted. Entry 4 in
Scheme 3.4 exemplifies a case involving conversion of a tricoordinate carbonyl group
to a tetravalent cyanohydrin. In this case the secondary isotope effect is 0.73.
Secondary isotope effects at the -position have been especially thoroughly
studied in nucleophilic substitution reactions. When carbocations are involved as
intermediates, substantial -isotope effects are observed because the hyperconjugative
stabilization by the -hydrogens weakens the C−H bond. 122 The observed secondary
isotope effects are normal, as would be predicted since the bond is weakened.

H H +
H C C H C C
H H

Detailed analysis of isotope effects reveals that there are many other factors that
can contribute to the overall effect in addition to the dominant change in bond vibra-
tions. There is not a sharp numerical division between primary and secondary effects,

121 K. B. Wiberg, Chem. Rev., 55, 713 (1955); F. H. Westheimer, Chem. Rev., 61, 265 (1961).
122
V. J. Shiner, W. E. Buddenbaum, B. L. Murr, and G. Lamaty, J. Am. Chem. Soc., 90, 809 (1968);
A. J. Kresge and R. J. Preto, J. Am. Chem. Soc., 89, 5510 (1967); G. J. Karabatsos, G. C. Sonnichsen,
C. G. Papaioannou, S. E. Scheppele, and R. L. Shone, J. Am. Chem. Soc., 89, 463 (1967); D. D. Sunko
and W. J. Hehre, Prog. Phys. Org. Chem., 14, 205 (1983).