Testing a Mechanism: Kinetic Isotope Effects

 Primary Isotope Effect - rate change due to isotopic substitution at a site of bond breaking or bond making in the rate determining step of a mechanism.  Secondary Isotope Effect - rate change due to isotopic substitution at other than a site of bond breaking or bond making in the rate determining step of a mechanism. Primary Kinetic Isotope Effect: Typical Values

o Nuclide klight k heavy (at 25 C)

C-H/C-D 6 - 8

C-H/C-T 15 - 16

12 13 C/ C 1.04

12 14 C/ C 1.07 14 15 N/ N 1.03 16 18 O/ O 1.02

32 34 S/ S 1.01

35 37 Cl/ Cl 1.01 EXAMPLES OF KINETIC ISOTOPE EFFECTS

Consider the following dehydrohalogenation reactions:

NaOC H H3C 2 5 C CH CH3CH2CH2Br 2 k / k C2H5OH H H D = 6.7 Case I: o NaOC H H3C 1 KIE for C-H/C-D 2 5 C CH CH3CD2CH2Br 2 C2H5OH D

CH3 H2O H3C CH3 CH3CH2 C Br C C H CH3 CH3 k / k Case II: H D = 1.4 o CH3 2 KIE for C-H/C-D H2O H3C CH3 CH3CD2 C Br C C D CH3 CH3 Rationale:

Transition State for Case I (E-2) Transition State for Case II (E-1) δ- C2H5O + H CH3 CH3 H(D) H H(D) δ H(D) C C CH3 C CH3 + C C rds C - - δ (D)H Br δ (D)H Br (D)H Br- H3C H3C H3C More Examples of Kinetic Isotope Effects

Consider the following decomposition of an azo compound:

k k R N N R R N N R 2 R + N2 14 15 = 1.02 N N

Rationale: Although the above rate enhancement is small in absolute terms, for the nitrogen nuclides indicated, the enhancement is indicative of a primary kinetic isotope effect.

Consider the nitration of benzene shown below:

HNO /H SO 3 2 4 rate C6H6 C6H5NO 2 H HNO /H SO 3 2 4 rate C6D6 C6D5NO 2 D

Observation: rate ~ rate H = D

Conclusion to be drawn: A C-H (C-D) bond is not being broken in the rate determining step of electrophilic aromatic nitration. Secondary Kinetic Isotope Effects

 Differences in steric demand!  Hyperconjugative effects!  Differences in inductive effect! Examples of Secondary Kinetic Isotope Effects Differences in Steric demand!

Example I: CH Cl + H O CH OH + HCl k 3 2 3 H

CD3 Cl + H2O CD3 OH + HCl kD

Observation: kH / kD = 0.97

H In order to initiate bond making, the incoming nucleophile must be able to Rationale: H2O C approach the substrate from the rear. H Cl H The shorter C-D bonds (relative to C-H bonds) permit a closer approach by H2O Example of an inverse and bond making can begin sooner. α-isotope effect

Example II: (CH ) CHOTs + H O (CH3)2CHOH + TsOH k 3 2 2 H (CH ) CDOH + TsOH (CH3)2CDOTs + H2O 3 2 kD

Observation: kH / kD = 1.13 H Rationale: C+ In the transition state leading to the H3C CH3 isopropyl carbocation, there is a greater relief of strain for C-H relative to C-D. Secondary Kinetic Isotope Effects

Example III: + CH3I N N+ I- CH3

Observations: Pyridine Substrate k D / kH

CD3

1.001 N

CD3 1.009 N

1.030

N CD3

1.095

D3C N CD3 Secondary Kinetic Isotope Effects Hyperconjugative effects!

Example: β -Isotope effect (CH ) C OH + HCl k (CH3)3C Cl + H2O 3 3 H

(CD3)3C Cl + H2O (CD3)3C OH + HCl k D

k = Observation: H / k D 1.21

CH + Rationale: 3 CH2 H C+ C H3C CH3 H3C CH3

Whereas a C-D bond is slightly stronger than a C-H bond, hyperconjugation as shown above is not quite as effective at stabilizing the carbocationic intermediate for the reaction using deuterated reactant relative to that using unlabeled reactant.

Another view: Whereas C-H bonds at a given temperature are slightly longer than corresponding C-D bonds, formation of a carbocationic intermediate provides more relief from steric strain for unlabeled reactant compared with that experienced by deuterated reactant. SECONDARY KINETIC ISOTOPE EFFECTS

Inductive effects!

- + Example: CH3COOH CH3COO + H KH - + H+ K CD3COOH CD3COO D K 1.06 Observation: H /KD =

Rationale: Hydrogen is slightly more electronegative than deuterium.

Related Question: Which one of the following is more basic?

CH2NH2 vs. CD2NH2