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.