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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
ΔED ΔEH
R—H
R—D
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
E.M. Simmons, J.F. Hartwig, Angew. Chem. Int. Ed., 2011, 51, 3066
Kinetic Isotope Effect (KIE)
• Important Classifications:
– Primary 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
• Considering:
Primary Kinetic Isotope Effect
KH > HD
R—H
R—D
SM Product
PKIE - Example
• For a synchronous TS at room temperature where the C-H
bond is broken in the RLS
KH/KD = 7
R—H
R—D
SM Product
• Bending modes have relatively low energy, therefore smaller effect than
for primary kinetic isotope effect
KH/KD = 1.1-1.2
• 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