Kinetic Isotope Effect-Primary,Secondary.Normal,Inverse.pdf

Kinetic Isotope Effect-Primary,Secondary.Normal,Inverse

1. Kinetic Isotope effect
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2. Sources
Fiat justitiaruatcaelum
Kinetic Isotope Effects in Organic Chemistry
Rob Knowles
https://macmillan.princeton.edu/wp-content/uploads/RRK-
KIE.pdf
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3. Origin of Primary Kinetic Isotope Effects
Fiat justitiaruatcaelum
➢Isotopesmaydifferchemically,becausesomechemicalpropertiesdodependonatomicmass.However,thisdifferenceis
onlysignificantforhydrogen—nootherelementhasoneisotopetwiceasmassiveasanother!
➢Toagoodapproximation,substitutionofoneisotopeforanotherdoesnotalterthepotentialenergysurface.
➢ReactionsinwhichC–HbondsbreakgofasterthanreactionsinwhichC–Dbondsbreak,providingthebondtoH(orD)is
involvedintherate-determiningstep.
Why ZPE?
Eveninitslowestenergystateacovalentbondneverstops
vibrating.IfitdiditwouldviolateHeisenberg’suncertainty
principle,whichstatesthatpositionandmomentumcannot
beknownexactlyatthesametime:anon-vibratingpairof
atomshavepreciselyzeromomentumandpreciselyfixed
locations.
Origin
Difference in frequencies of various vibrational
modes, which is in turn dependent inversely on
square root of reduced mass (μ).
Greater the mass, the lower will be the ZPE
Unimolecular reactions
but most org rxnnot
unimolecular
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4. Magnitude of Primary Kinetic Isotope Effects
Fiat justitiaruatcaelum
➢Tounderstandanykineticphenomenon,onealwayscomparesreactantwithtransitionstate.Forisotopeeffectswecompare
theZPEsofthevariousvibrationsofthereactantandtheactivatedcomplex
➢ΔZPE'sintheGS&TSdeterminethemagnitudeofthekineticisotopeeffect.
➢ZPEchangesbetweenGS&TS:Forceconstantofthebondchanges(kislowerforTSsodiffb/wZPEforH&Disless)
H(D) substitution is most widely studied
H(D)(2 vs 1 in mass-100%),
13C/12C (13 vs 12 in mass-8%)
value of 7 determined assumed that the
bond was freely dissociated thus went
from a bond to no bond
➢VariationinKIE:Neglectbending,Tunneling
➢MagnitudeoftheobservedKIE:
I.MaxatsymmetricTS
II.GeometryoftheTS:IngeneralprimaryKIE'sfornonlinearTSarelowerthanthoseformorelinearTS
III.HighertemperaturesproducesmallerKIE
IV.StericisotopeeffectisthereforeanidealwayofestimatingthestericcrowdingoftheTSrelativetotheGS
V.Hybridizationchanges
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5. Hammond Postulate and Isotope Effects
Fiat justitiaruatcaelum
❖Hammond Postulate states that TS structure most resembles the molecule that it is closest in energy
If the transition state occurs
early, the C—H or C—D bond will
be broken only slightly in the
transition structure. The
stretching vibration in the
transition state will be affected
by the mass of the hydrogen (or
deuterium) atom in much the
same way as in the reactant.
Therefore, the difference in
transition state energy for the
C—H or C—D species will be
nearly the same in the transition
structure as in the reactant.
10
20
C-D
C-H
C-D
C-D
C-D
C-H
C-H
C-H
70
68
40
50
62
70
Reaction Ground State Transition
State
Δ ΔΔ
Exothermic C-D 40u 62u 22u 2u
C-H 50u 70u 20u
Thermoneutral C-D 10u 68u 58u 8u
C-H 20u 70u 50u
* Values just for understanding
Hydrogen atom does not move in the vibrational
mode so the frequency of the vibration does not
depend on its mass.
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6. Symmetrical & Non-linear Transition states
Fiat justitiaruatcaelum
❖IngeneralprimaryKIE'sfornonlinearTS'sarelowerthanthoseformorelinearTS’s
❖Reason:TSwithbentbonds,thebendingvibrationalmodesbecomemoreimportant.bendingmodesaremuchlower
energythanstretchingmodesinlinearTS's.
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7. Secondary Kinetic Isotope effects
Fiat justitiaruatcaelum
➢Deuterium labelled molecule has a stronger bond to carbon, participates in hyperconjugation to a lesser extent
➢β-secondary isotope effect is strongly dependent on geometric factors (not always
Ideally oriented)
➢secondary kinetic isotope effect arises from differences in bending vibrations.
Reaction Ground StateTransition StateΔ
Sp
3
to sp
2
C-D 10u 40u 30u C-H > C-D
Normal
KIE
C-H 20u 48u 28u
sp
2
to Sp
3
C-D 15u 40u 25u C-D > C-H
Inverse KIE
C-H 20u 48u 28u
10u
20u
40u
48u
48u
40u
15u
20u
C-D
C-D
C-D
C-DC-H
C-H
C-H
C-H
The biggest (energy)
change occurs in the out-
of-plane bending motion
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8. Steric Isotope Effect
Fiat justitiaruatcaelum
➢StericIsotopeEffect:C-DbondisslightlyshorterthantheC-Hbond,deuteriumatomfeelsmore'comfortable'ina
stericallycongestedenvironmentthanahydrogen
➢IftheGSmorecrowdedthantheTS,KIEwillbenormal
➢TSismorecrowded,adeuteriumcanbeaccommodatedmoreeasilyinitsoobservedKIEwillthenbeinverse
➢IntheplanartransitionstructurethesmallerspacerequirementofDatomsinthedeuteratedcompoundsneedsalower
energyofactivation,andthereforeaninversekineticisotopeeffectisobserved.
The steric isotope effect is therefore an ideal way of estimating the steric crowding of the transition state relative to the
ground state.
Drawbacks to using KIE's
➢difficulty in synthesizing isotopically labelled compounds
➢Getting accurate kinetic data
Solution: As the reaction progresses, the starting material
becomes enriched in the slower reacting component
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Hydrogen-containing molecule
undergoesconformationalchange
slowerthanthedeuterium-substituted
molecule

9. Fiat justitiaruatcaelum
Kinetic Isotope Effect
(rate of a reaction changes with an isotopic substitution)
Primary Kinetic Isotope
Effect (1°KIE)
Secondary Kinetic Isotope
Effect (2°KIE)
K
H/K
DValue
Normal (K
H/K
D>1)
Sp
3
sp
2
orsp
2
sp
Inverse(K
H/K
D<1)
Sp sp
2
orsp
2
sp
3
Different isotopic positions
α(atom undergoing
reaction has the associated
isotope)
β(neighboring atom has
the isotope)
PKIE: labelled bond is made or
broken in the RDS, arise mainly
from differences in ZPE
SKIE: labelled bond notmade or
broken in the RDS, labelled atoms are
proximal to the reaction center, arise
mainly from changes in hybridization
and hyperconjugation, generally
smaller than PKIE
What is primary & secondary Kinetic Isotope effects? Ifos2013
Protonation of alkene
Ionization of an alkyl halide
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