Kinetic Isotope Effect

Rachel Nicholls

30/04/14

Overview

• Determining Reaction Mechanisms

• Isotope Substitution Effects

• Kinetic Isotope Effect – Primary Kinetic Isotope Effect

– Secondary Kinetic Isotope Effect

– Heavy Atom Isotope Effects

– Solvent Kinetic Isotope Effects

• Further Resources

Determining Reaction Mechanisms

• Why? – Optimisation – Prediction and design of new reactions – Safety – Curiosity

• How? – Kinetic Studies – Isotope Effects – Substituent effects – Linear Free Energy Relationships – Solvent Effects – Transition states / Isolating intermediates

Isotope Effects • Isotope substitution:

– Change in vibrational frequency – No chemical difference

• Consider substitution of a hydrogen (1H) for a deuterium (2H) atom

Increased Reduced mass

Lower Vibrational freqn

Lower Zero point energy

Larger Bond dissociation

energy

Isotope Effects

R—D R—H

ΔEH ΔED

Increased Reduced mass

Lower Vibrational freqn

Lower Zero point energy

Larger Bond dissociation

energy

Kinetic Isotope Effect (KIE)

• Study the change of rate associated with substitution of an isotope

• Expressed as ratio of rates, e.g. KH/KD etc.

• Clearest isotope effect with H and D

– Largest mass difference, largest observed effect

• Assume no effect on:

– electronic structure of the molecule

– potential energy surface of the reactions

E.M. Simmons, J.F. Hartwig, Angew. Chem. Int. Ed., 2011, 51, 3066

Kinetic Isotope Effect (KIE) • Three general experiments to determine KIE:

1. Two parallel experiments

2. Intermolecular competition experiment

3. Intramolecular competition experiment

E.M. Simmons, J.F. Hartwig, Angew. Chem. Int. Ed., 2011, 51, 3066

Kinetic Isotope Effect (KIE)

• Important Classifications: – Primary Kinetic Isotope Effect

– Secondary Kinetic Isotope Effect

– Normal KIE • KH/KD ≥ 1

– Inverse KIE • KH/KD ≤ 1

Primary Kinetic Isotope Effect

• Bond to isotope is broken in the reaction

• H/D has a large effect and easy to measure

• Considering:

Primary Kinetic Isotope Effect

SM Product

R—H R—D

ΔGH‡ < ΔGD

‡

KH > HD

PKIE - Example

• For a synchronous TS at room temperature where the C-H bond is broken in the RLS

KH/KD = 7

• I.e. Can investigate if bond is broken in the rate limiting step (RLS):

• If KH/KD = 1 then Step A is the RLS

7 then Step B is the RLS

Secondary Kinetic Isotope Effect

• The isotope bond is not broken however is near to the reaction centre

• Alpha-KIE and beta-KIE can be observed

• Alpha: change in hybridisation

• Beta: stabilisation of carbocation by hyperconjugation

Secondary Kinetic Isotope Effect

Smaller KH/KD due to smaller energy difference

SM Product

R—H R—D

α – SKIE

• Predominantly a result of in-plane and out-of-plane bending vibrations

• Bending modes have relatively low energy, therefore smaller effect than for primary kinetic isotope effect

• For sp3 to sp2: KH/KD ≥ 1 (i.e. decrease in p character)

• For sp2 to sp3: KH/KD ≤ 1 (i.e. increase in p character)

β - SKIE

• Small SKIE effect dependent on extent of hyperconjugation

KH/KD = 1.1-1.2

• Dependent on ability to stabilise an adjacent carbocation

• CH stabilises C+ more by hyperconjugation

• Therefore C—H lowers in vibrational frequency to a larger extent than C—D

Other Kinetic Isotope Effect

Heavy Atom Isotope Effects: • Smaller effect as less mass difference between isotopes • 12C/13C • 14N/15N • 16O/18O • 35Cl/37Cl Solvent Kinetic Isotope Effect: • PKIE where solvent acts as the reactant • Protic solvents: H and D exchange between molecules and the

solvent • Solvent and solute interactions may affect transition state

Summary

• Study the change of rate associated with substitution of an isotope

• Used to develop an understanding of the reaction mechanism • Primary kinetic isotope effect involves breaking of the isotope

bond • Secondary isotope effect arises from changes in hybridisation

and hyperconjugation

• Limitations – Isotopic labelling can be challenging, time-consuming and costly – Requires high experimental accuracy – High yield required, reproducible, few or no side reactions

Further Resources

General Guides:

• E.V. Anslyn, D.A. Dougherty, Modern Physical Organic Chemistry, University Science Books, Sausalito, 2006, p 421-441

• H. Maskill, The Physical Basis of Organic Chemistry, Oxford University Press, Oxford, 1985, p367-404

• N.S. Isaacs, Physical Organic Chemistry, Prentice Hall, Harlow, 2005

Literature Examples:

• E.M. Simmons, J.F. Hartwig, Angew. Chem. Int. Ed., 2011, 51, 3066

• J.E. Baldwin et al., J. Org. Chem., 2004, 69, 7212

• K.B. Wiberg, L.H. Slaugh, J. Am. Chem. Soc., 1958, 80, 3033