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Toolkit for the study of catalytic reaction mechanisms.A. Reaction kinetics
Kinetics tells us about the reaction order - the change in molecularitybetween the resting state and rate-limiting transition state
Potential information obtained:
What is the response of the reacting system to changes in the concentrationof each component? I.e. contribution to terms in the rate equation.
How does the reactivity change in response to changes (electronic or steric)in the structure of reactants?
Is there evidence of an induction period? Loss of reactivity through catalystdegradation? Acceleration by additives?
1
Toolkit for the study of catalytic reaction mechanismsB. Spectroscopy and structure
NMR Permits detailed analysis of the structure (and dynamics) of stable states-resting state, reactive intermediates - accurate concentrations. Proton NMR shows full complexity of the system, heteronuclear NMR gives selective information (controlled). Phosphorus and carbon NMR very useful.
X-ray structureProvides detailed understanding of ground states and reactive intermediates
Electrospray Mass SpectrometrySamples the solution, and reveals ions or easily ionised components. Defines molecular weights with high precision but is insensitive to concentration.
Infra-red (React-IR) Rapid in situ measurements provide an easy way to follow the course of a reaction
Circular DichroismUseful for following chiroptical changes in asymmetric catalysis.
Challenges; ground (resting) state; transition state(turnover-limiting); true intermediates
If we need to understand a reaction mechanism, here is the ground to cover:
Full kinetic model, identification of reactive intermediates.
Tracking atoms between reactant and product.
Variation of reactivity with structure
The extent of charge separation as the reaction proceeds
Whether the reaction is concerted or stepwise.
We can employ experimental techniques that probe transition states indirectly, but increasingly their analysis is illuminated by Quantum Chemistry.
The combination of DFT and fast computers makes this accessible to all.
The Hammond postulate informs us about the likelystructure of transition states
If two states, for example, a transition state and an unstable intermediate, occur consecutivelyduring a reaction process and have nearly the same energy content, their interconversion willinvolve only a small reorganization of the molecular structures.
In plain English that means - transition-states for quenching of highly reactive speciesare close to them in structure and energy
The Curtin-Hammett Principle applies to all equilibratingsystems
Where fast equilibria exist in a reacting system theproportions of products formed are independent ofthe equilibrium ratio.
B is more stable than Ain their fast equilibrium.In contrast the formationof C is faster than the formation of D. The ratio is onlydependent on DDG‡.
The historical basis for analysis of catalytic kinetics lies in theanalysis of enzymes by Michaelis and Menten; simplified case
presented here
BindingTurnover
Fuller derivation at the end of this lecture.
Typical low pressureconstant volumehydrogenation kit
During the reaction thepressure changes and sothe data needs to beanalysed by computersimulation
Starting pressure ca. 2 atm.
7
Two step mechanism - substrate binds strongly to the catalyst.Measure [H2] uptake = [Substrate] depletion
Two step mechanism; substrate binds weakly to the catalyst
Real life data for a hydrogenation reaction in two differentsolvents
The mechanism of hydrogenation with Wilkinson’s catalyst31P NMR evidence
Reactive intermediates observed by spin excitation transfer; both thediphosphine A and the diphosphine dihydride B are accessible
Cl
PPh3
PPh3
Rh
H
H
Cl
Ph3P Rh
PPh3Rh
Ph3P
Cl
PPh3
PPh3
Cl
Rh
Ph3PH
H
-PPh3
PPh3
-PPh3
PPh3
fast
4 secs
PPh3
RhPh3P Cl
PPh3H
H
Ph3P
Ph3P
PPh3
-PPh3
Ph3P Rh Cl
PPh3
PPh3
PPh3
-PPh3
0.3 secs
separate experiments
A
B
The mechanism of hydrogenation with Wilkinson’s catalyst -kinetic evidence
P2Rh
H H
Cl
P2Rh
H
H
Cl
Ph3P Rh
PPh3
RhPh3P
Cl
PPh3
PPh3
Cl
P2RhCl
H2 fast
Ph3PH
H
H2 slow
2%
98%
products
fast
rate-determining
Kinetics: inverse dependence on [PPh3]; dependence on [alkene]
Resting state
The accepted mechanism for hydrogenation with Wilkinson’s catalyst;dihydride under reaction conditions
Migration
Association
Typically 10 turnovers per minute
P2Rh
H
H
Cl
Ph3P Rh
PPh3Rh
Ph3P
Cl
PPh3
PPh3
Cl
P2Rh
H H
Cl
Addition
P2RhH
Cl
H
Elimination
(i)
(ii)
(iii)
(iv)
H
HP2RhCl
H2
Ph3PH
H
H2
resting state
2%
98%
13
Now take the case of a chelating diphosphine under conditions thatare relevant to asymmetric catalysis; typical pre-catalyst shown
PPh2
PPh2Me
Me(S,S)-CHIRAPHOS
bis-(C7H8)-Rh BF4
H2, MeOH RhPh2P PPh2
+
BF4–
The 31P NMR of diphosphine dialkene complexes CHIRAPHOS isdistinctive,and changes cleanly under H2 (proton-decoupled)
Rh-coupled doublet, JPRh 150 Hz
Rh-coupleddoublet,JPRh 200 Hz
No hydrides! What would happen with PPh3 as ligand under these conditions?
A
B1H,31P,103RhAll spin 1/2 nuclei
Adding dehydroamino ester (B->C) gives a new spectrumshowing strong binding of the alkene to Rh
Enamide complex; Rh-coupled AB quartet meansinequivalent P environments
Why are there not two enamide complexes one for Re- and one for Si-bound alkene? Why 8 lines??
B
C
The 8-line 31P NMR species (C) observable in the absence ofhydrogen, now with DIPAMP (Monsanto)
OCH3Rh
OCH3
H
H
P
P
Ph
Ph
MeO
MeO
+
NH
CO2Me
OMe
CH3O
CO2CH3
NH
Ar
H
Rh
P
P
Ph
Ph
MeO
MeO
+
Rh
P
P
Ph
Ph
MeO
MeO
+ Ar
Hfast equilibria (seconds); all species characterised by 31P and13C NMR.
10%
90%
Solvate
Enamide complexes
Re-face bound
Si-face bound
Here both diastereomers are detectable by 31P NMR!
The 31P NMR species observable in the presence ofhydrogen only at low temperature
NH
CO2Me
OMe
CH3O
CO2CH3
NH
Ar
H
Rh
P
P
Ph
Ph
MeO
MeO
+
Rh
P
P
Ph
Ph
MeO
MeO
+ Ar
H
10%
90%
Enamide complexes
Re-face bound
Si-face bound
H2
MeOH, 223KNH
CO2Me
OMe
ArH
Rh
P
P
Ph
Ph
MeO+
H
irreversiblesteps
(S)-product
OMe
H
Alkene dihydrides have been elusive in Rh asymmetrichydrogenation
NEVEROBSERVED !!NH
CO2Me
OMe
P2RhHH +
19
When intermediate C is prepared in the DIPAMP Rh case then twosets of 8-line signals can be seen
NH
CO2Me
OMe
CH3O
CO2CH3
NH
Ar
H
RhP
P
Ph
Ph
MeO
MeO
+
RhP
P
Ph
Ph
MeO
MeO
+ Ar
H
Re
Si
or
In a different Rh enamide case two sets of 8-line signals are seen in a ratio of 92:8
A transient alkylhydride is seen at -50 ˚C from the minor enamide- stable at this temperature
H2
By making the enamide complex at lowtemperatures a mixture rich in the less-favoured form can be formed. This iscaptured selectively by H2, still at lowtemperatures
PRh
PPh
OMe
H O
NH
MeO2C
PhH2C
+
Me
Ph OMe
Which hand of product is formed from this intermediate?
Rhodium asymmetric hydrogenation has been a rich source ofreactive intermediates; all cations here:
MeO2C NHCOMe
CH3
HProduct
CH2
MeO2C NHCOMe
SM
H2, catalyst
HP2Rh
OMe
CO2CH3
CH2
NH
NH
CH2MeO2C
OMe
CH3
H2C
O
CO2CH3
NH
P2Rh
P2Rh
NH
CH2MeO2C
OMe
P2H2Rh
minorenamide
majorenamide
H
SMMonohydrideobservable at -500C
H2
Reactant manifold
solvate
Product
P2Rh
O
Me
CO2CH3
CH2
NH
H
H
SM
RhP2(MeOH)2
SM
DihydrideNot normally observed
Transient product complex
Computational chemistry indicates a further intermediate between the minor enamide and the dihydride at *. Suggest what this might be.
*
Kinetic analysis of asymmetric hydrogenation is broadly inagreement with NMR observations
Major contributor Jack Halpern - Chicago
Difference from Wilkinson’s catalyst - several NMR characterisable intermediates in the true catalytic cycle
Combination of kinetics of H2 addition (vary pressure, temperature, concentrations of substrate and catalyst).
Coupled with NMR, UV, fast reaction kinetics - stopped flow.
Aim is to build a complete picture of the catalytic cycle
Principles of stopped flow kinetics; useful e.g for measuring therate of substrate binding to catalyst
Reactants
catalyst and substrate
Observation cell
Fast mixing chamber
Stop
The full consequences of the kinetic analysis are shown here. Strongbinding, cf Micaelis-Menten treatment - watch out for saturation!
P2Rh(MeOH)2
P2Rh(enamide) majorminor P2Rh(enamide)
(S)-product (R)-product
d[R-product]/dt = k2(maj)K1(maj)[H2][ Rh]tot/(K1(maj) + K1(min))
k1(min)
k2(min)
k–1(min)k–1(maj)
k1(maj)
k2(maj)
K1(min) K1(maj)
Binding
Turnover
d[S-product]/dt = k2(min)K1(min)[H2][ Rh]tot/(K1(maj) + K1(min))
From steady state:
25
k2 (min) ca. 700 times k2 (maj) - minor enamide pathway dominates
Here’s the complete set of experiments; NB all the reactiveintermediates are characterised by NMR
P2Rh(MeOH)2
P2Rh(enamide) majorminor P2Rh(enamide)
UV, stopped flowUV, stopped flow
(NMR)(NMR) (NMR)
H2 rate
(S)-product (R)-productvary conditions
The transient alkylhydride is not “seen” in the kinetics - What’s the reason?
Related topic; asymmetric synthesis by alkeneisomerisation.
Principle:
Y
H
R
XH
The two CH2 H's are enantiotopic and will respond distinctly in an asymmetric environment
MLn
Y R
X H
MLnHY
H
RX H
Allyl formation by alkenecoordination followed by C-H abstraction
Face-selective new C-Hformation and metaldecoordination
– MLn
H-Migration on the front side of the allyl shown; how would you carry out the reaction by reversible M-H addition to the alkene?
The synthesis of menthol has an alkene isomerisation as thekey enantioselective step
NEt2
condensation of 2 x isoprene and HNEt2Nickel - catalysed
RhP
P
+
X–PP =
PPh2PPh2
(S)-BINAP
catalyst
NEt2
H H
enamine, >95% e.e.
H
H
OH
several steps
(begin with hydrolysis of enamine)
solvent = THF oracetone
Find conditions for the remaining steps in menthol synthesis?
Appendix: A more detailed exposition of the Michaelis-Mentenmethods for analysing catalytic kinetic data
The historical basis for analysis of catalytic kinetics lies in theanalysis of enzymes by Michaelis and Menten; simplified case
presented here
BindingTurnover
Enzymologists have developed simple treatments for plotting andanalysing kinetic data
Michaelis-Menten Lineweaver-Burk
KMM is the Michaelis(Menten) constant
ν is the reaction rate(velocity).
Derivation of these equations is based on the steady-stateapproximation
Hypotheses:1. The concentration of [E.S] changes much more slowly that that of either [S] or [P]2. At a set concentration [S]0 initial rate of product formation varies linearly with
[E]0
3. At a set concentration [E]0 and low [S]0 product formation varies linearly with [S]0
4. At a set concentration [E]0 and high [S]0 a maximum rate νmax is attained
!max
Rate
[s]
E + S E.S P + E
Michaelis-Menten converts the data into somethingmanageable
Steady State Approximation:
Rate of product formation ν = k2[ES]Rate of reactant loss ν = k1[E][S] - k–1[ES] d[ES]/dt = k1[E][S] – k–1[ES] – k2[ES] = 0
From this: [ES] = k1k-1 + k2
[E][S]
Define KMM = k-1 + k2k1
units of Molarity
If the catalyst is in excess then: [ES] = [E]01 + KMM/[S]0
[E][S][ES]
Substituting into our definition of the rate:
! = k2[E]01 + KMM/[S]0
This is the Michaelis-Menten equation
Reorganising:
Lineweaver-Burk type plots are easier to use in practice
! = k2[E]01 + KMM/[S]0
Michaelis-Menten !max
1 + KMM/[S]0
Rearrange this:
1!
1!max
+!max
KMM 1[S]0
Lineweaver-Burk
0 1/[S]0
1/!
Y Intercept1/!max
SlopeKMM/!max
X Intercept–1/KMM
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