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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