CH538: Molecular Catalysis
Dr M.D. Spicer
Contents
1. Introduction
1.1 What is a catalyst
1.2 Homogeneous vs Heterogeneous Catalysts
2. The Fundamentals of Catalytic Reactions
2.1 Tolman’s Rules
2.2 Organometallic Reactions
2.3 Construction of Catalytic Cycles
3. Case Studies
3.1 Catalytic Hydroformylation
3.1.1 Cobalt Catalysed Hydroformylation
3.1.2 Phosphine modified Hydroformylation
3.1.3 Rhodium Catalysed Hydroformylation
3.1.4 Comparisons
3.2 Wacker-Schmidt Aldehyde Synthesis
3.3 Olefin Hydrogenation by Wilkinson’s Catalyst
4. Immobilisation of Homogeneous Catalysts
5.1 Polymer Bound catalysts
5.2 Functionalised Inorganic supports
5. Biphasic Catalysis
5.1 Aqueous Biphasic Catalysts
5.2 Fluorous Biphasic Catalysts
6. Organocatalysis
7. Enzyme catalysts
Assumed Background Knowledge: 3rd Year Inorganic Chemistry (Organometallics)
Recommended Books:
“Organometallic Chemistry”, G.O. Spessard and G.L. Miessler, Prentice Hall, 1997.
“Applied Homogeneous Catalysis with Organometallic Compounds” Eds Cornils and
Herrmann, VCH,
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1. Introduction
1.1 What is a Catalyst?
There are many reactions in chemistry which are favourable thermodynamically, but
which for various reasons occur at very slow rates. Consider the three very important
reactions below:
The Water Gas Shift Reaction
H2O (g) + CO (g)

H2 (g) + CO2 (g)
ΔH = - 6.9 kcal mol-1
Alkene Hydrogenation

CH3CH=CH2 (g) + H2 (g)
CH3CH2CH3 (g)
ΔH = -20.6 Kcal mol-1
Glucose Metabolism
C6H12O6 + 6 O2 (g)

6 H2O (g) + 6 CO2 (g) ΔH = -688 Kcal mol-1
Potentially all these reactions should proceed, since the products are more stable than
the starting materials. However, in practice none of the take place under ambient
conditions. Each requires a catalyst because there is a kinetic barrier to the reaction
taking place.
The phenomenon of catalysis was first recognised over 150 years ago by Berzelius, who
referred to the “catalytic power of substances” which were able to “awake affinities
which are asleep at this temperature by their mere presence and not their own affinity”.
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CH538: Molecular Catalysis
Dr M.D. Spicer
With our modern understanding of thermodynamics and equilibria, we now know that
a catalyst is a substance which alters the rate at which a reaction reaches equilibrium,
without altering the equilibrium distribution of reactants and products. For many years
the action of catalysts was something of a mystery. Now, however we know that
catalysts interact with the reactants to provide a reaction pathway with a significantly
lower free energy of activation than the corresponding uncatalysed pathway. Consider
the following diagram:
The solid trace represents the un-catalysed reaction. It has a large activation energy,
ΔG‡ which makes the reaction unlikely to occur. So although the products have lower
free energy than the starting materials, there is no way of getting from one to the other.
The dotted trace show the effect of adding a catalyst. A substrate-catalyst complex is
formed, which then provides a much lower energy route (ΔGc‡ << ΔG‡) to the products
of the reaction. This can pass through a number of intermediates and transition states.
We will see examples of this phenomenon in action as we consider some catalytic
reactions later in the course.
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Catalysis is of great importance to the chemical industry – more than 60% of chemical
products, and greater than 90% of chemical processes are based on catalytic reactions.
In turn, the development of organometallic chemistry has been a key to the rapid
growth of catalysis, and the award of Nobel Prizes to Ziegler and Natta (Olefin
Polymerisation), Wilkinson and Fischer (Organometallic Chemistry) and most recently
Grubbs, Schrock and Chauvin (Olefin Metathesis) are recognition of this fact.
Consider the timeline below, which shows in parallel the development of organometallic
chemistry and of the development and industrial use of homogeneous catalysis.
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CH538: Molecular Catalysis
Dr M.D. Spicer
It can be seen that the discovery of ferrocene and the ensuing explosion of organoelement chemistry led to a huge expansion of catalytic chemistry in industrial
processes.
1.2 Homogeneous vs Heterogeneous Catalysis.
It was Sabatier who, in 1927, published the first classification of catalysts and used the
terms homogeneous and heterogeneous.
A heterogeneous catalyst exists in a separate phase to the reaction medium (most
commonly as a solid in either a liquid or gaseous reaction medium).
A homogeneous catalyst is miscible with (or dissolves in) the reaction medium, along
with the reactants.
In the early 20th Century catalysis was inextricably linked with large volume industrial
processes, such as ammonia synthesis via the Haber process, coal hydrogenation, fat
hardening, Fischer-Tropsch synthesis and mineral oil processing. These were all
heterogeneous processes, and with the exception of the occasional use of Grignard and
organozinc reagents and in the Mond process (extraction of Nickel via the carbonyl,
[Ni(CO)4]), organometallics were almost unheard of in industrial processes.
Furthermore, heterogeneous processes were also rare, partly for chemical and partly
for engineering reasons. However, with the rapid development of organometallic
chemistry in the latter part of the 20th century, homogeneous catalysis became far more
important.
Heterogeneous catalysts typically comprise of metals, metal oxides or metals finely
dispersed on a supporting material to increase the surface area (e.g. rhodium on silica;
palladium on charcoal). These are generally robust materials and so can be used at high
temperature with either gaseous or liquid reaction media.
By contrast, homogeneous catalysts are generally used in the liquid (solution) phase at
much lower temperatures, since the catalysts tend to be sensitive, to some degree, to
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heat. Reactions are often carried out at elevated pressure to a) increase the
concentration of gaseous components in the reaction medium and b) to maintain highly
volatile species in the liquid phase, thus rendering the process engineering more
straightforward.
The two classes of catalyst have both advantages and disadvantages and these are
summarised in the table below:
Homogeneous
Heterogeneous
Activity (vs metal content)
High
Variable
Selectivity
High
Variable
Mild (< 250 °C)
Harsh (250 – 500 °C)
Variable
Long
Sensitivity to poisoning
Low
High
Diffusion Problems
None
May be important
Catalyst recycling
Expensive
Not necessary
Catalyst “Tuning”
Possible
Rarely Possible
Mechanistic Understanding
Possible
Rarely Possible
Reaction Conditions
Catalyst Lifetime
Let us consider these advantages and disadvantages in a little more detail.
Activity and Selectivity: these often have an inverse relation in both homogeneous and
heterogeneous catalysis. i.e. faster reactions are often less selective. So, although
homogeneous catalysis has a major advantage in the high selectivities which can be
achieved, this is sometimes at the expense of lower reaction rates. Selectivity normally
arises in homogenous catalysis because a single molecular species is in present in
solution and so there is only one type of reaction site for the substrate. This results in
fewer side products from the reaction. On the other hand, reactions in heterogeneous
catalysts occur at the non-ideal catalyst surface and so there can be many different
reaction sites, leading to a decrease in selectivity.
Produt Separation: This is the main disadvantage of homogeneous catalysis. Since the
catalyst is in the same phase as the substrates and products, simple mechanical
separation is not possible. Occasionally, if the product has a low molecular weight and
boiling point then distillation of the product may be possible (e.g. CH3CHO from Pd
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CH538: Molecular Catalysis
Dr M.D. Spicer
catalysed ethane oxidation). Even more rarely, if the product precipitates from solution
(e.g. a polymer) then again separation is more practical.
Catalyst Tuning: Homogeneous catalysts are much more readily modified in a controlled
manner to give well defined variations in properties. This can be done in a number of
ways:

Change the metal type (e.g. Co to Rh)

Change co-ligands (steric and electronic properties affect
regioselectivity, and kinetics)

Cation or anion additives

Change solvent
Such changes can greatly improve (or worsen) the performance of a catalyst system and
is the focus of an enormous amount of academic and industrial research.
Mechanistic Understanding: Homogeneous catalysts are far easier to study
mechanistically for a number of reasons:

Single active site

Single reaction pathway

Can be studied spectroscopically (in solution).
Since the catalyst is uniformly dispersed in the medium, at a measurable concentration,
it is usually possible to apply standard spectroscopic procedures to investigate these
catalytic reactions. By contrast, the active sites of heterogeneous catalysts are on the
surface of the catalyst, with the bulk of the material being inactive. Consequently, the
active sites are at a low concentration. Furthermore, the characterisation of chemical
species on a surface, except in very ideal circumstances, is extremely difficult. Thus,
heterogeneous catalysts remain rather poorly understood.
Other courses will cover the study and application of heterogeneous catalysts, while this
course will focus on the understanding of molecular (homogeneous) catalysts.
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2. Fundamentals of Catalytic Reactions
We will look at three systems as case studies showing how catalysts are developed, how
mechanisms can be probed and the origin of selectivity. In order to make sense of
catalytic reactions we need a basis on which to approach them. A set of rules have been
developed, which when coupled with a knowledge of organometallic reactions can give
us a great deal of insight into these processes.
2.1 Tolman’s Rules
Tolman’s rules were developed in the early 1970s, based on the observation that the
majority of well characterised transition metal organometallic complexes have either 16
or 18 valence electrons (although there are now plenty of exceptions, especially in the
early transition elements) and this observation can be used in a predictive capacity.
Rule 1: Diamagnetic organometallic complexes of the transition metals may exist
in significant concentrations at moderate temperatures only if the valence shell
contains 16 or 18 electrons. (N.B. significant concentration is defined as one
which can be detected either spectroscopically or inferred from kinetics).
Rule 2: Organometallic reactions proceed by a series of elementary steps
involving only intermediates with 16 or 18 electrons.
These rules, together with some basic organometallic reactions (summarised in the
following section) allow us to propose mechanistic pathways which can be investigated
and confirmed or ruled out experimentally.
2.2 Reactions of Organometallic Compounds
Let us then consider the main classes of reactions undergone by organometallic
compounds. You will have covered most of these in detail in the 3rd year Inorganic
Chemistry course with Dr O’Hara, and you should consult his notes or an organometallic
textbook if you need to refresh your memory. The table below shows the reaction types
as pairs (which are essentially the reverse of each other) and highlights the changes in
the number of valences electrons, the formal oxidation state of the metal and the
coordination number of the metal which accompany the reaction.
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CH538: Molecular Catalysis
Reaction Type
Dr M.D. Spicer
Example
NVE OS CN
Lewis Acid dissociation
0
-2
-1
Lewis acid association
0
+2
+1
Lewis base dissociation
-2
0
-1
Lewis Base association
+2
0
+1
Reductive elimination
-2
-2
-2
Oxidative addition
+2
+2
+2
Insertion
-2
0
-1
Elimination
+2
0
+1
[HCoI(CO)4] 
[Rh(L)3(H)2Cl] 
H+ + [Co-I(CO)4][Rh(L)2(H)2Cl + L
[Ir(H)2(L)2(CO)Cl]  [Ir(L)2(CO)Cl] + H2
[Pt(L)2(H)Cl(C2H4)]  [Pt(L)2(Et)Cl]
As can be seen, these reactions all result in changes of -2, 0 or +2 valence electrons,
supporting the assertion in Tolman’s rules that the component steps in catalytic
reactions should proceed via intermediates with either 16 or 18 valence electrons.
When we consider catalytic reactions, they can be split down into three main phases:
Catalyst Activation: catalysts are required to be coordinatively unsaturated (i.e. have
less than 18 valence electrons to allow a low energy path for the substrate to bind to the
metal centre prior to reaction taking place. Other reagents may also require activation
at the catalyst centre (e.g. H2, RX), usually by oxidative addition.
Reaction at the Metal Centre: Various types of reaction, such as alkyl migration or
migratory insertion, metallacycle formation, nucleophilic or electrophilic addition and
halide or hydrogen abstraction are all common. These allow the activated substrate to
be transformed at the metal centre.
Release of Product from the Metal Centre: this most commonly occurs by either reductive
elimination or by -, β-, or γ- hydride elimination.
2.3 Construction of Catalytic Cycles
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By combining Tolman’s rules with our knowledge of organometallic reactions, we can
propose a series of reactions which describe the action of the catalyst and other
reagents on the substrate in order to generate the product. Such a series of recations is
known asa catalytic cycle and should return to the starting catalyst or activated catalyst.
Consider the example below which shows a simplified cycle for alkene hydrogenation
using Wilkinson’s catalyst, [Rh(PPh3)3Cl] which illustrates the points above:
Step 1:
oxidative addition of H2 to the 16e- RhI complex.
Step 2:
coordination of alkene
Step 3:
migratory insertion of the alkene into the Rh – H bond
Step 4:
Reductive elimination of product with catalyst regeneration
So a catalytic cycle can be regarded as a series of reaction steps such that during one
cycle around the loop the substrate (reactant) is converted into the product. There is no
net change in the catalyst itself (i.e. it is regenerated in the cycle).
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Dr M.D. Spicer
3. Case Studies
3.1 Catalytic Hydroformylation
Catalytic hydroformylation (sometimes referred to as the oxo-reaction in older
literature) was first discovered in 1938 by Otto Roelen (Ruhrchemie) and is one of the
oldest processes still in use. It was used extensively during the second World War to
generate aldehydes from alkenes, H2 and CO. The reaction may be summarised as
follows:
The catalysed reaction is the formation of butenal. Both the linear and branched
isomers are formed. Subsequently, these can react further, depending on the precise
conditions. The hydrogenation of butenal results in reduction to the corresponding
alcohol, while aldol condensation, followed by reduction, results in formation of 2-ethylhexan-1-ol.
The overall hydroformylation reaction (the first step above) is exothermic, with ΔH =
-125 KJ mol-1 for propene and in the range -115 to -145 KJmol-1 for other alkenes.
Despite being thermodynamically favourable under ambient conditions, it took a long
time to realise this reaction experimentally, and eventually it was the use of metal
carbonyl catalysts which yielded success.
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CH538: Molecular Catalysis
Dr M.D. Spicer
Cobalt Catalysed Reaction.
Although the process apparently uses a heterogeneous catalyst, a mixture of
Co/SiO2/ThO2/MgO in a 30:66:2:2 ratio, it is almost certain that it is homogeneously
catalysed. Under the reaction conditions cobalt carbonyl complexes are formed which
are readily displaced from the silica-based support and which can catalyse the process.
The mechanism of the homogeneous process has been extensively studied and a
catalytic cycle has been proposed. We will look at this cycle in some detail, as this can
help us to understand how the intricacies of such reactions can be unravelled.
The Heck-Breslow Mechanism
This is the accepted general mechanism for this process:
So, let us dissect the reaction, step by step – this will give us an insight into each of the
steps and how we assess whether a particular pathway is likely or not.
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Step 1. The pre-catalyst, HCo(CO)4 is readily formed from Co, CO and H2 under the
reaction conditions (>100ºC, 300 bar pressure). It is an 18 electron complex and
reasonably stable. This dissociates to give the 16 electron complex, HCo(CO)3 which is
most probably the active catalyst:
The concentration of HCo(CO)3 will be low, because the high pressure of CO will force
the equilibrium to the left hand side. However, enough is present for catalysis to occur
at a reasonable rate because of the high temperature at which the reaction is carried out
– this overcomes the activation energy of the dissociation process. There are two
possible structures of HCo(CO)3:
From computational methods it is found that the structure on the left is most stable and
thus more likely to occur.
Step 2. Once the active catalyst is formed the next step is alkene binding to the metal
centre to form an 18 electron complex once more. The bound alkene can have two
possible orientations:
The double bond can either lie in the equatorial plane (left) or perpendicular to the
equatorial plane (right). While the structure on the left is slightly more stable (again
from calculations) the one on the right has the correct orientation for the next step. Both
will exist and will be able to interconvert with one another.
Step 3. Alkene insertion – this takes place by a concerted process with a cyclic transition
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Dr M.D. Spicer
state to give a 16 electron species which very rapidly picks up CO to form an 18 electron
alkyl species:
The “addition” of Co – H to the alkene is in an anti-Markovnikov sense (the cobalt is
attached to the least substituted carbon), which will give rise to the linear aldehyde. The
alternative Markovnikov addition is possible, but is more sterically hindered and so
occurs to a lesser degree. β-hydride elimination is possible from the “untrapped” 16
electron intermediate, but the high partial pressure of CO drives the formation and
stabilisation of the 18 electron RCo(CO)4 species, and so the elimination does not occur
to any significant extent.
Step 4. CO insertion – which in all likelihood is in fact alkyl migration.
Calculations show that the rearrangement has a low activation energy and is slightly
endothermic.
The RC(O)Co(CO)4 species is the only intermediate which has been detected when the
reaction is followed by infra-red spectroscopy.
Step 5. This step is probably the rate limiting step. Three different possible processes by
which hydrogen is activated and transferred to the acyl group have been suggested:
a) Oxidative addition of H2 followed by reductive elimination of the aldehyde.
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b) A bimolecular reaction involving HCo(CO)4 and the acyl tricarbonyl intermediate
followed by hydrogenation.
c) Side on-bonding of H2 followed by a concerted elimination of the product and
catalyst.
It is not certain which process occurs. While the bimolecular process (b) has been
observed to occur under normal conditions, the concentrations of the proposed reacting
species under the catalytic conditions are so low that the reaction is unlikely to occur at
a significant rate. Process (a) is probably most intuitive, but the oxidative addition of H2
to the metal centre has a high activation energy. Process (c), the formation of an η2dihydrogen complex followed a a four-centred rearrangement is a much lower energy
process, and seems more likely that the other alternatives.
This process is still used in industry, despite some fairly major drawbacks, namely
Linear to branched ratio is never better than 4:1
The active catalyst is both unstable and hard to separate
High pressure of CO (200-300 atm) make the plant expensive
Phosphine Modified Cobalt Catalysed Hydroformylation
In 1968 it was discovered (Shell) that addition of phosphine (and in particular P nBu3) to
the reaction resulted in hydroformylation at a much lower pressure (ca 100 atm). The
ratio of linear to branched isomers also improved to 9:1 and, as the modified catalyst,
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Dr M.D. Spicer
HCo(PnBu3)(CO)3, was more stable, it was more easily separated from the reaction
products.
However, despite the advantages there were also drawbacks to this process. While the
lower pressure is useful, the payback was that higher temperatures were required
(160-200ºC). Furthermore, the alkene can also be hydrogenated under these conditions
with about a 15% conversion by a process thought to proceed as shown below:
The origin of the improved selectivity is most likely steric, the bulky phosphine
(compared to CO) can influence the orientation of the alkene in the complex prior to the
insertion into the Co-H bond. The different orientations lead to different transition
states and thus to either linear or branched products.
There is more steric repulsion in the transition state shown on the right hand side
(indicated by the arrow) due to the bulk of the coordinated phosphine.
Studies have shown that changing the phosphine influences both the rate and selectivity
of the hydroformylation. There are two sources of influence, which may be summarised
by saying that steric effects alter the selectivity, while electronic effects alter the
reaction rates. Thus, the presence of more electron donating phosphines results in
greater electron density at the metal, which in turn results in stronger M-CO bonds. This
means that the intermediates are more stable, and alkyl migration/CO insertion step is
less favourable and hence slower.
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When studying this reaction spectroscopically only phosphine substituted cobalt
carbonyl complexes are observed (in contrast to the phosphine free reaction, no alkyl or
acyl species are seen). It is thought that the reaction proceeds via a very similar
mechanism to the phosphine free reaction, but this is by no means certain.
Rhodium Catalysed Hydroformylation
Naturally, since rhodium is in the same group as cobalt, chemists soon attempted the
use of rhodium based catalysts in hydroformylation reactions. Under the conditions
used for cobalt catalysed reactions (i.e. H2 + CO at high temperature and under high
pressure) HRh(CO)4 forms rhodium carbonyl cluster compounds such as Rh4(CO)12.
Under milder conditions it does catalyse hydroformylation (although the linear to
branched ratio is low), but it is also a good hydrogenation catalyst which makes it
unviable as a commercial catalyst.
The addition of phosphines, however allows hydroformylation at close to atmospheric
pressure and at moderate temperature. Use of the appropriate phosphine allows good
linear to branched product ratios to be attained.
There are a number of advantages of the rhodium/phosphine hydroformylation
catalysts..
-
Activity: the rhodium catalysts are 102 – 103 times more active than their
cobalt counterparts. This means that less catalyst is required, thus
outweighing the high cost of rhodium.
-
Conditions: the low pressures and temperatures required mean that the cost
of the plant for production will be much lower
-
Selectivity: linear to branched ratios of 14:1 can be attained if a pure 1-alkene
feed stock is used.
-
Hydrogenation: the rate of hydrogenation is low under these conditions, so
good if the aldehyde is required.
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Dr M.D. Spicer
Let us consider the mechanism of the reaction, which may be represented by the
scheme below:
The catalyst precursor can be either HRh(CO)(PPh3)3 or HRh(CO)2(PPh3)2, depending
on the concentrations of CO and PPh3 in the reaction mixture, both of which give the
same active catalyst, HRh(CO)(PPh3)2. In contrast to the cobalt catalysed process, the
use of alkyl phoshines (such as PnBu3) renders the catalysts too inactive. The donation
of electron density presumably stabilses the catalytic intermediates too much,
preventing the reactions from proceeding. The ideal ligand appears to be
triphenylphosphine (PPh3) which has a combination of appropriate electron donating
ability and reasonable steric bulk, which gives an acceptable rate and leads to high
selectivity for the linear aldehyde product.
The various processes are compared in the table below.
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Phosphine
Process
Cobalt catalyst
modified cobalt
catalyst
Rhodium
phosphine catalyst
Catalyst Precursor
HCo(CO)4
HCo(CO)4 + PnBu3
HRh(CO)(PPh3)3
PR3 : Metal ratio
-
2:1
50 : 1 to 100 : 1
Pressure (bar)
200 – 300
50 – 100
15 – 25
Temperature (ºC)
110 – 160
160 – 200
80 – 120
0.1 – 1.0
0.6
4:1
7:1
8 : 1 – 16 : 1
<2
15
5
5
5
2
Difficult
Simple
Catalyst
Concentration
0.01 – 0.05
(% metal/olefin)
Linear : branched
ratio
Alkene
Hydrogenation (%)
Higher B.Pt. Products
(%)
Catalyst Recovery
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Simple (for C3 and
C4 alkenes)
CH538: Molecular Catalysis
Dr M.D. Spicer
3.2: Wacker-Smidt Aldehyde Synthesis
Background
Ethanal (acetaldehyde) is another commercially important precursor. It was originally
prepared by the following method:
This can be thought of as the hydration of ethyne (acetylene). It is a facile and high
yielding reaction, but one which is fraught with difficulties. Acetylene is prepared by
heating a hydrocarbon gas stream to high temperature (often in the presence of an
electric discharge). This is an energy intensive process which is inefficient.
Furthermore, acetylene is thermodynamically unstable and is an explosive hazard! So,
there was a strong incentive to develop a more energy efficient and less hazardous
process.
The following stoichiometric reaction was known:
In the 1950s, Smidt at Wacker Chemie developed a commercially viable process which
is a modification of the above reaction, using a catalytic amount of palladium chloride
(PdCl2) in the presence of CuCl2, HCl and O2 (which help to maintain the palladium in the
correct oxidation state) as follows:
Combining the three equations, the overall reaction can be considered to be:
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So, the stoichiometric process is rendered catalytic. This is an extremely atom-efficient
reaction – the oxidation of ethane by oxygen! The acetaldehyde produced is converted
to acetic acid or acetic anhydride.
If the reaction is run in the presence of copper(II) acetate and KCl/KOAc then the
resulting product is vinyl acetate, which is important as the precursor to polyvinyl
acetate (PVA).
For many years this was a highly important source of acetic acid, although latterly a
rhodium catalysed synthesis from synthesis gas has become prevalent. One problem
with the reaction was maintaining the plant, as the reaction mixture is extremely
corrosive.
The overall reaction may be summarised as shown below…..
Under the reaction conditions (high concentration of Cl-), PdCl2 is converted to [PdCl4]2-.
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Dr M.D. Spicer
Step (a) – involves the displacement of 2 chloride ligands by alkene and water.
Step (b) is a nucleophlic attack of water on the alkene. The mechanism of this step is by
no means certain, although it appears that there are two main options:
1. The attack of a non-coordinated water molecule, or
2. Insertion of alkene into a Pd – OH or Pd – OH2 bond.
The observed rate law is consistent with both mechanisms, so in order to try and
ascertain which is more likely a number of elegant experiments have been devised using
isotopic labelling.
The first was reported by Stille
Cis-dideuterioethene undergoes hydroxy-palladation followed by CO insertion to give a
lactam product. The deuterium atoms are trans- to one another in the product, which
implies that an inversion of configuration has occurred. However, CO insertion is known
to proceed with retention of configuration, so inversion must have occurred during the
attack of H2O. This would imply that an external nucleophile has attacked the π-ligand
(alkene).
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A second, similar, series of experiments were performed by Bäckvall and Åkermark.
They took a trans-deuterioethylene complex of palladium and reacted it in the presence
of a high concentration of chloride ions. The resulting product was an epoxide in which
the deuterium atoms are cis to one another. The scheme below shows how this must
occur:
The trans-deuterioethylene complex again undergoes a nucleophilic attack by water
leading to the hydroxyalkyl species. In the presence of a high concentration of chloride
undergoes an SN2 cleavage reaction to give the threo-chlorohydrin product, with
inversion of configuration. Finally, in order for the geometry to be correct for the
displacement of chloride to give the epoxide it is necessary for a rotation about the C – C
bond to occur. This results in the cis-deuterio epoxide as shown.
So we have two pieces of evidence which support the external nucleophilic attack of a
water molecule. However, there is also some evidence to suggest that this may not
necessarily be the mechanism which occurs under the conditions most commonly used
in the Wacker synthesis!
A third, cleverly devised reaction, uses an allylic alcohol which prevents β-elimination
and thus aldehyde formation from occurring. At high concentrations of chloride (as
used in Bäckvall’s experiment) the external nucleophlic attack by water occurs, which
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Dr M.D. Spicer
leads ultimately to the R-isomer, whereas, at low concentrations of chloride ion (similar
to the conditions of the industrial process) an internal nucleophilic attack by
coordinated water leads to observation of the S-isomer as shown in the following
scheme:
A great deal of effort has been expended in trying to understand this step of the
reaction, but the fact that no firm conclusion can yet be drawn illustrates how difficult it
can be, even in relatively simple systems, to obtain definitive answers to mechanistic
questions.
Setps (c), (d) and (e): these comprise of halogen loss (c), β-elimination (d) and olefin
insertion (e). It might be thought that after step (d) the enol could be displaced from the
metal centre followed by a tautomerisation to the aldehyde product as shown below.
However, this is not the case. The evidence for this is that if the reaction is run in D2O
there is no incorporation of deuterium into the product, which would be expected if the
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tautomerisation was taking place. So the metal based rearrangement (olefin insertion
followed by elimination) seems more plausible.
This reaction can also be used on a lab scale for the preparation of ketones.
In addition, the reaction is selective, as terminal alkenes react very substantially quicker than
internal alkenes, for instance:
3.3: Alkene Hydrogenation by Wilkinson’s Catalyst
Wilkinson’s catalyst, [Rh(PPh3)3Cl], is a 16 electron square planar complex which is a
highly useful catalyst for a number of reactions. We will consider briefly its use as a
hydrogenation catalyst. It is able to catalytically add hydrogen across the double bond of
an alkene at room temperature, 1 atmosphere pressure of H2 and at millimolar
concentration of catalyst. In other words it is highly efficient.
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A great deal of effort has been expended in trying to understand this catalytic reaction.
It has been discovered that the rate of hydrogenation increases both with alkene
concentration and with H2 pressure. This is shown in the figure below, which displays
plots of reciprocal rate vs 1/[alkene] and vs 1/[H2] where the alkene is cyclohexene.
The straight line plots confirm that the reaction rate is inverse first order with respect
to both alkene and hydrogen concentration.
The dependence of the rate on the catalyst concentration is somewhat more complex,
and is subject to variation on addition of free PPh3. A number of rate laws have been
advanced, for example:


b[ PPh3 ] c[ PPh3 ] 
d [alkene]

 [ Rh ]total  a 

dt
[H 2 ]
[alkene] 

27 | P a g e
The dependence of rate on addition of phosphine suggests that there are chemical
reactions of the catalyst taking place. The catalytic solution have been studied
extensively by spectroscopic means and the presence of a considerable number of
species can be observed or inferred. The species identified thus far are:
The concentrations of the hydride containing species increase with increasing H2
pressure (as might be expected), while the dimers decrease in concentration as the
concentration of phosphine increases and at higher temperature.
The
dimer
C
is
also
a
good
hydrogenation catalyst, but is not
particularly
soluble
and
is
very
sensitive to O2 poisoning. Addition of
small amounts of phosphine to the
reaction give a small increase in rate of
H2 uptake, but addition of large
amounts of phosphine inhibit the
reaction (see figure above). This is
presumably because the excess phosphine inhibits the dissociation equilibria which are
necessary for the catalyst to take up the alkene and for the reaction to proceed.
Consider the catalytic cycle which has been proposed:
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It can be seen that, in line with the number of observed complexes in this reaction, there
are a large number of possible peripheral reactions that can be undergone by the
catalyst. Many of these can be studied relatively easily. For instance, Halpern has
studied the reactions of H2 with Wilkinson’s catalyst:
At low PPh3 concentrations the phosphine dissociation process (1) dominates, and
below 0.15M PPh3 the uptake of H2 by this species (reaction (4)) is preferred. However,
at higher concentrations of PPh3 the direct reaction of H2 with Wilkinson’s catalyst
(reaction (2)) is most important since equilibrium (1) is pushed back towards the
starting material. The phosphine dissociated compound, [Rh(PPh3)2Cl] has not been
observed to date, but the related PCy3 complex is known, demonstrating the feasibility
of this reaction.
Reaction (3) in the scheme has been very nicely followed by
31P
NMR spectroscopy as
shown in the figure below:
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The top spectrum is of [Rh(PPh3)3Cl]. There are two different PPh3 ligands in the
complex, 2 which are mutually trans to one another and one which is trans to chlorine.
The one trans to chlorine is seen as a doublet of triplets arising from coupling to 103Rh (I
= ½, 100%) and to two 31P nuclei (I = ½, 100%). The two phosphine ligands which are
mutually trans appear as a doublet of doublets due to coupling to 103Rh and to the other
phosphine ligand.
The spectra labelled B show what happens when H2 is introduced into the system. The
starting complex is completely consumed and a new complex is formed. The difference
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Dr M.D. Spicer
in the spectra at 30 °C and at -25 °C suggest dynamic exchange is taking place. It can be
assumed that the following equilibrium is occurring:
At 30 °C the exchange is fast and the unique phosphine ligand is being lost leaving a
doublet due to coupling of the two equivalent,non-exchanging phosphines to 103Rh. The
third, unique phosphine appears as a broad line – the coupling to Rh is disrupted by the
exchange. At -25 °C the exchange is slowed and the full coupling is now seen. So we have
confirmation of the exchange processes which are proposed in the catalytic cycle.
The final spectrum shows the effect of bubbling N2 through the reaction mixture. The
result is that the starting complex is partially reformed, suggesting that the hydride
complex and H2 are in equilibria with one another, and that H2 is carried out of the
system on the N2 stream. This implies that step (2) of the cycle is in fact an equilibrium.
Step (6) of the reaction has also been the subject of considerable study. In particular, if
an isotopic labelling experiment is performed using D2 instead of H2, and using
cyclohexene as the alkene, while the main product is the expected d2-cyclohexane,
products which include 0 – 4 deuterium atoms are obtained! This suggests that this step
of the reaction is in fact an equilibrium as well.
We can see again that the reactions are not as simple as they may seem at face value.
There are many competing reactions which require careful control of concentrations of
various reagents to ensure that the appropriate species are present for the most
efficient catalytic reaction. It’s a detective puzzle, trying to track down all the pieces of
information and putting them together to deduce a likely pathway for the reaction.
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4. Immobilisation of Homogeneous Catalysts
We have seen that, while there are many advantages to homogeneous catalysis in terms
of selectivity, activity, tuneability and mechanistic understanding. However, the major
stumbling block remains the problem of separation of the catalyst from the reaction
products.
One strategy which has been adopted to address this problem is to immobilise
homogenous catalysts on solid phase supports. This allows the molecular nature of the
catalyst to be retained, with all the advantages that entails, but also facilitates
separation. A number of different types of support have been investigated and we will
take a brief overview of these.
4.1 Polymer Bound Catalysts
This was probably the first class of immobilised catalyst to be extensively studied and a
vast array of systems has been investigated. Catalyst immobilisation is achieved by
introducing appropriate metal ligating functions into an organic polymer. We will only
consider phosphines, but a wide range of different ligand types have been used in this
capacity. There are at least two different strategies which are used for introduction of
these groups.
4.1.1 Modification of Pre-formed Polymers
This is the most popular method. A commercially available polymer is treated to
introduce ligating groups which then form complexes with metal ions in order to
generate catalytically active species. The major advantage of this method is that the
physical properties, such as pore size, surface area, swelling properties, are already
known.
Polystyrene (right) is most commonly used. It is
readily available in several forms and it has
limited chemical reactivity (enough to enable
functionalisation, but not so much that it is
damaged under catalytic conditions).
There are three main classes of polystyrene which are used in this application:
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(i) Uncrosslinked Polymers. These polymers are soluble, and hence apparently
homogenous with the reaction mixture. However, they can be readily separated either
by membrane filtration or by precipitation.
(ii) Gel (or Microporous) Polymers. These have a low degree of cross-linking
(typically < 2%). In organic solvents these swell to open up their internal volume to
allow both solvents and reagents which allows reasonably high catalyst loading and
efficient diffusion of reagents and products to catalytic sites.
(iii) Macro-reticular (or Macro-porous) Polymers. These are polymers with a
high degree of crosslinking (common commercially available examples have 20, 40 or
60% crosslinker) and have high surface areas. However, diffusion is highly restricted by
the rigidity of the polymer and so the majority of the catalyst will be located on, or close
to the surface.
Some examples of phosphine functionalisation of polystyrene are shown below:
Functionalisation requires in the first instance that the aromatic ring be substituted to
allow appropriate reactivity. Aryl phosphines are generally prepared by either by
reaction of aryl lithium or aryl Grignard reagents with halophosphines, or by reaction of
33 | P a g e
lithium diphenylphosphide (LiPPh2) with an alkyl or aryl halide. Various examples are
seen in the scheme above.
It is also possible to do something similar with polyvinyl chloride (and indeed other
polymers as well) :
The substitution reactions are less efficient with PVC and the strong nucleophile used
can also lead to polymer breakdown.
4.1.2. Polymerisation of Phosphine Containing Monomers
A second approach is to prepare phosphine monomers which can then be polymerised.
An example of this is:
The catalyst loading is controlled by the
ratio
of
styrene
to
diphenylstyrylphosphine and the degree
of crosslinking by the amount of divinyl
benzene added. A variety of metals can
then
be
incorporated
into
these
polymers.
Such metal functionalised polymers are
used in a range of catalytic reactions.
These
can
be
reasonably
well
characterised by a variety of analytical and structural techniques, although there is
always some conjecture as to the exact nature of the active site. However, as the
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Dr M.D. Spicer
catalytic reactions seem to proceed in much the same fashion as with the simple
molecular catalysts it is generally assumed that very similar catalytic species are
present.
4.1.2 Functionalised Inorganic Polymers
Inorganic polymers have been used for a long time as a part of heterogeneous catalysts,
and in more recent times have also been used to support homogeneous type catalysts as
well. Examples of such polymers include Zeolites, clays, alumina and magnesia;
however, the most widely used is silica. We will briefly look at how catalysts may be
attached to silica surfaces. Silica, as you will know from other courses, has hydroxylgroups on the surfaces, and it is the chemistry of these groups which allows
functionalisation. Two approaches may be used:
(i) Direct Attachment. Here the metal complex is allowed to react directly with the
surface hydroxide. For example:
Here, molybdenum hexacarbonyl is reacted with the silica surface. Carbon monoxide is
released and the Mo(CO)5 fragment is believed to insert into the O-H bond to form a
surface bound carbonyl hydride. The problem with this approach, however, is that it is
difficult to ascertain what the true nature of the surface bound species is.
(ii) Attachment via a Spacer Group. This generally employs alkoxy-substituted
organosilanes, which react with the suface Si – OH groups, eliminating an alcohol and
covalently attaching to the surface.
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The metal complex is then added and is immobilised on the surface by exchanging a
labile ligand with the surface bound phosphine. The main problem is controlling the
distribution of the phosphine ligand on the silica particle surface. If there is a high
concentration of ligand on the surface the metal complex may be tethered by two or
even three surface bound phosphines, while if the concentration is low then maybe only
one phosphine will bind to the metal. One way to circumvent this problem is to use a
preformed metal complex instead. An example of this is:
The triethoxysilane substituted phosphine ligand is complexed to rhodium, forming an
analogue of Vaska’s complex, which is then immobilised on the silica surface. Since the
orientations of the silane groups are essentially fixed, the metal complex will normally
be transferred essentially unchanged to the silica surface and thus the identity of the
catalytic species can be known with some degree of confidence.
5. Biphasic Catalysts
As an alternative method of catalyst immobilisation it has fairly recently been
discovered that, instead of a solid supported catalyst in either a liquid or gaseous
medium, a liquid-liquid biphase can be used. In such a system the catalyst is in one
liquid phase, while the substrates and products are in a second, immiscible, liquid
phase. The process relies on transfer of substrate and product at the liquid-liquid
interface. There are two main realisations of these types of processes, namely Aqueous
Biphasic Catalysis and Fluorous Biphasic Catalysis. These will be considered in turn.
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Dr M.D. Spicer
5.1 Aqueous Biphasic Catalysis.
As the name suggests, this method uses a homogeneous catalyst dissolved in water as a
mobile phase, while the reactants and products are carried in an organic phase which is
immiscible with water and in which the catalyst is insoluble. The catalyst is thus
“immobilised” and rendered heterogeneous on what may be thought of as a liquid
support. Also, the catalyst, though immobilised, is not anchored to a surface and thus
loses none of the advantages of homogeneous catalysts, since it is a truly molecular
species.
In a truly biphasic system there should be no need for additives of any sort (e.g. phase
transfer catalysts) to ensure phase separation. Normally the miscibility of the reactants
and products is controlled by changes in temperature and pressure alone. In addition,
the ease of separation enhances the ease of catalyst recycling.
In order to generate water soluble catalysts, complexes bearing ligands with highly
polar (often ionisable) functional groups are used. Some examples include:
The polar substitutents such as carboxylates, sulfonates alcohols and ammonium salts
enhance the solubility of the ligands and their complexes in water. In some casesthe
number of groups can be increased to increase partition. Thus, triphenylphosphine can
be sulfonated on either one (above, bottom right), two or three or the phenyl rings
depending on the reaction conditions used. Also, variation of the spacers can also lead
to improved solubility properties or separation of the two layers.
The advantages of biphasic catalysis include:
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1. Generally heating is not required (e.g. distillation) to separate the products,
hence catalyst lifetimes are increased as less degradation occurs. This can also be
helpful if sensitive organic groups are being used.
2. Catalyst leaching is not observed. With supported catalysts, because the
complexes can be susceptible to ligand exchange, some leaching of the metal into
the liquid phase can be observed. Because the catalyst is already in solution the
problem does not exist in biphasic catalysis.
3. Easy separation of the pahses.
However, the major disadvantage of aqueous biphasic catalysis arises when the
substrate or product is moisture sensitive. Some types of catalyst are also moisture
sensitive, and so certain types of reaction may be hard to do in aqueous media. Another
drawback can be that many organics are not highly soluble in water, so problems of
mixing and phase transfer can arise leading to slow reaction rates.
The classic example of aqueous biphasic catalysis is the hydroformylation of ethene by a
sulfonated analogue of the standard rhodium catalyst, with P(m-C6H4SO3Na)3 replacing
PPh3. The reaction takes place in the aqueous layer. The reaction conditions and
outcomes (selectivity etc) are similar, or slightly better than the standard rhodium
system as shown in the table below.
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Dr M.D. Spicer
Process
Cobalt catalyst
Phosphine
modified cobalt
catalyst
Catalyst Precursor
HCo(CO)4
HCo(CO)4 +
PnBu3
HRh(CO)(PPh3)3
HRh(CO)(PAr3)3
(Ar = m-C6H4SO3Na)
PR3 : Metal ratio
-
2:1
50 : 1 to 100 : 1
50 : 1 to 100 : 1
Pressure (bar)
200 – 300
50 – 100
15 – 25
40 – 60
Temperature (ºC)
110 – 160
160 – 200
80 – 120
110 – 130
Catalyst
Concentration
(% metal/olefin)
0.1 – 1.0
0.6
0.01 – 0.05
0.001 – 1.0
Linear : branched
ratio
4:1
7:1
8 : 1 – 16 : 1
7 : 1 – 19 : 1
Alkene
Hydrogenation (%)
<2
15
5
<2
Higher B.Pt.
Products (%)
5
5
2
< 0.5
Catalyst Recovery
Difficult
Simple
Simple (for C3 and
C4 alkenes)
Facile
Rhodium
phosphine catalyst
Rhodium Phosphine
Biphasic Catalyst
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5.2 Fluorous Biphasic Catalysis
(Short Perspective Article: R.H. Fish, Chem. Eur. J., 1999, 5(6), 1677-1680)
This is an alternative to aqueous biphasic catalysis. Perfluorinated organic s make ideal
carriers for the catalysts. They are poorly miscible with a range of organic solvents (e.g.
toluene, THF, acetone, alcohols) and they are chemically rather inert, thus rarely react
with either the catalyst or the substrate and product. So, the catalyst is dissolved in a
suitable fluorous solvent. These are usually perfluorinated alkanes, ethers or tertiary
amines, of types CF3(CF2)nCF3, N((CF2)nCF3)3, and O((CF2)nCF3)2. The organometallic
complex can be solubilised in the fluorous phase by attachment of “fluorous ponytails”,
(long fluorocarbon or hydrofluorocarbon chains) to ligands such as phosphines or
diketonates:
One problem which can arise with attachment of the fluorous ponytails is that the
fluorinated hydrocarbons are highly electron withdrawing, which can lead to adverse
effects on the reaction rates. This can be ameliorated by placing two or three methylene
(CH2) groups between the ligand functionality and the fluorous ponytail to act as a
buffer.
An example of the use of fluorous biphasic catalysis is in the epoxidation of alkenes by a
ruthenium tris(perfluoroheptyldiketonate) complex.
The O2 and aldehyde are thought to react in the presence of the catalyst to give a
peroxyacid performs the epoxidation. The big advantage of this reaction is that O2 is
highly soluble in fluorocarbons.
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6. Organocatalysis.
When we think of catalysts our thoughts invariably turn to transition metals and their
complexes, which have dominated the scene for many decades. There have, however,
been rapid advances in enzyme based catalysis in recent years. A third approach, namely
Organocatalysis, has also become significant in the last decade or so. While organic
catalysts have been known for some time, the term organocatalysis was coined by David
MacMillan in 2000 (A Scot from Bothwell, now Prof at Princeton) and brought focus and
impetus to the area of chemistry.
As the name suggests, Organocatalysts are purely organic compounds (containing C, H
and heteroatoms such as N, O, P and S) which are able to enhance reaction rates.
Organocatalysis is not new. One of the first examples in the literature was reported by
Justus von Liebig, one of the early fathers of organic chemistry, who described the
reaction of cyanogen with water, catalysed by acetaldehyde (ethanal) to give oxamide
The acetaldehyde catalyst presumably activates the carbon atoms to nucleophilic attack
by water. The work of MacMillan has raised the profile of organocatalysis and has
brought focus to research in this area of chemistry.
Organocatalysts have a number of significant advantages over metal based catalysts.
1. They are robust. This is in contrast to many organometallic catalysts which are
typically air or moisture sensitive. Organocatalysts are normally inert to both O2 and
H2O. Consequently, inert atmosphere conditions and dry solvents are unnecessary
making manipulation much more straightforward.
2. They are inexpensive. Precious metal catalysts (with Rh/Ir/Pt etc..) are typically
between £50 and £500 per gram. Organocatalysts are mostly less that £10 per gram
(and often much less).
3. They are readily available – Most organocatalysts can be bought “off the shelf”, and
thus little or no synthesis is required. In contrast only the most basic transition metal
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catalysts can be purchased (and at considerable expense), so normally they will need to
be prepared.
4. Low molecular weight This means that only a small mass of material is required.
5. Low product contamination – Organocatalysts are easily separated from unreacted
reagents and from the products by chromatography. – metal catalysts are less easily
separated and are prone to leaving trace contaminants, which are undesirable,
especially in pharmaceutical products!
6. Chiral catalysts are readily available from the “chiral pool”. These are cheap and
abundant sources of pure chiral materials.
7. Most have low toxicity.
Organocatalyst Classes.
Organocatalysts fall into two
broad
classes,
those
which
operate by the formation of
covalent bonds, and those which
operate
by
non-covalent
interactions (such as hydrogen
bonding). We will concentrate
on
the
former
type.
Most
organocatalysts of this class
react by one of four general
mechanistic types shown in
schematic cycles in the figure on
the left (where A = Acid, B =
Base, S = Substrate, P = Product). In Lewis base catalysis, the catalyst is a Lewis base
which can react with the substrate to form an intermediate. This is then converted to the
product and is lost, regenerating the catalyst.
For reasons of time, and the fact that they predominate, we will consider Lewis base
catalysts in a bit more detail. In particular there are three major types of Lewis base
catalyst:
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1. Iminium Catalysis. Iminium catalysis can be
summed up in the scheme below. The condensation
of a secondary amine/ammonium salt with an
aldehyde or ketone gives rise to an iminium salt.
The original carbonyl carbon is now activated
towards nucleophilic attack.
An example of such a reaction is the piperidine catalysed Knoevenagel Condensation:
The mechanism can be summarised as follows:
2. Enamine Catalysis. Secondary amines (below) can also
catalyse reactions via enamine formation. The enamine is
formed by deprotonation of an iminium ion. These enamines
can react with electrophiles or undergo pericylic reactions.
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An example of an enamine reaction is shown below:
The key mechanistic step can be summarised as follows:
The proline forms an enamine with the ketone which is then sufficiently activated to
react with the lighly electrondeficient alkene
3. Carbene Catalysis. The so called N-heterocyclic carbenes, which are derived from
heterocyclic salts such as imidazolium (left), triazolium (centre) or thiazolium (right)
salts by deprotonation (below) are relatively stable and active catalysts in a range of
reactions.
The catalysts work by nucleophilic reaction with a variety of substrates, including
aldehydes as shown below:
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An example of an imidazolium catalysed reaction is the benzoin condensation:
The mechanism can be summarised as follows:
The N-heterocyclic carbene acts as a nucleophile towards the aldehyde to form the 2substituted imidazolium salt, which rearranges to the very electron rich N,N’-alkene.
This in turn is a good nucleophile for the second aldehyde and leads to the coupling
product. Finally, the product dissociates to regenerate the carbene catalyst.
In all of the examples we have seen, the key is the reversible formation of a C-C bond.
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4. Enzyme Organocatalysts.
It should be noted that many (metal-free)
enzyme catalysts behave in a very similar
fashion to these organocatalysts. An example
is shown on the right. This is a comparison of
the catalytic mechanisms of the class I
aldolase enzymes and the proline catalysed
aldol reaction. It can be seen that the steps are
completely in parallel.
It is thought that enzyme catalysts will inspire
new generations of organocatalysts, while
mechanistic insights from the small molecule
analogues will aid understanding of the
enzymatic
processes.
A
synergistic
relationship.
5. Chiral Organocatalysis.
By far the most important reactions in this class are the proline
catalysed reactions. Proline (right) is a naturally occurring,
enantiomerically pure chiral compound which is cheap ( < 30 pence
per gram) and readily available. It is able to support both iminium
and enamine type reactions. A second type of readily available chiral
catalysts are the imidazolidinone catalysts (right), which are
prepared in a one-pot reaction from readily available and
enantiomerically pure amino acids.
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The chiral induction arises from the control of transition states. In the case of proline
reactions this arises by hydrogen bonding from the acid to the substrate:
In the case of the imidazolidinones, steric effects and π-π interactions between the
proximal aryl group and the substrate control the stereochemistry of the intermediate:
The intermediate on the left is stabilised in preference to the one on the right because of
π-π interactions between the phenyl group and the alkene on the substrate. This
controls the face which is attackedin the next step and thus the handedness of the chiral
centre generated.
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