Applied Catalysis A: General 189 (1999) 191204

The role of catalysis for the clean production of fine chemicals

Hans-Ulrich Blaser , Martin Studer
Novartis Services AG, Catalysis and Synthesis Services, WRO 1055.6, CH-4002 Basel, Switzerland

Abstract
The role of catalysis for the production of fine chemicals is reviewed. The following topics are discussed on a general
level: characteristics of the manufacture of fine chemicals, opportunities opened up by catalysis, critical factors for the
application of catalysts and the tools that are available to the catalytic chemist. The general part is illustrated by specific
examples from the catalysis group of Ciba-Geigy/Novartis such as chemoselective hydrogenations of aromatic nitro groups,
the combination of a homogeneous and heterogeneous Pd catalyzed reaction for the alkylation of aromatic systems, catalytic
systems for the enantioselective reduction of an -keto ester, different routes to an N-alkylated hindered aniline including the
(S)-metolachlor process, and the use of on-line monitoring of catalytic hydrogenations with ATR-probes. A short outlook on
future developments is also presented. 1999 Elsevier Science B.V. All rights reserved.
Keywords: Technical catalysis; Fine chemicals production; Catalyst development; Process optimization; On-line monitoring

1. Introduction
Traditionally, fine and specialty chemicals have
been produced predominantly using non-catalytic
organic synthesis. At least in the opinion of R. Sheldon, this is one important reason why besides the
desired product, between 20 and 100 times as much
waste is produced [1]. Of course many other factors
such as the complexity of the molecules (and consequently, the number of synthetic steps), as well as the
short development time for a (registered) technical
synthesis and also the high requirements concerning
purity of many fine chemicals are responsible for the
unfavorable ecological situation.
Nevertheless, the application of catalytic methods
in the fine and specialty chemicals industry has increased in recent years in part because both produc Corresponding author.
E-mail address: hans-ulrich.blaser@sn.novartis.com (H.-U. Blaser)

tion costs and waste minimization are of growing importance even for high value pharma and especially
agro chemicals. In this contribution we will first give
a short characterization of the problems in fine chemical production. Then we will describe the tools that
are available to solve some of these problems with
the help of catalysis and finally, we will present examples from our laboratory to illustrate some of these
points.

2. Problems and opportunities

2.1. Characteristics of the manufacture of fine
chemicals
The manufacture of fine chemicals and especially
of pharmaceuticals and agrochemicals can be characterized as follows (typical numbers are given in parenthesis):

0926-860X/99/$ see front matter 1999 Elsevier Science B.V. All rights reserved.
PII: S 0 9 2 6 - 8 6 0 X ( 9 9 ) 0 0 2 7 6 - 8

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H.-U. Blaser, M. Studer / Applied Catalysis A: General 189 (1999) 191204

Rather complex molecules (isomers, stereochemistry, several functional groups) with limited thermal stability.
Production via multistep syntheses (5 > 10 steps
for pharmaceuticals and 37 for agrochemicals)
with short product lives (often < 20 years). Usually
classical organic reactions, catalysis as exception.
Production usually in solution, at ambient pressure
and low to medium temperature in relatively small
(500 l10 m3 ) multipurpose batch equipment.
Relatively small scale products (11000 t/year for
pharmaceuticals, 50010 000 t/year for agrochemicals)
High purity requirements (usually >99% and
<10 ppm metal residue and ee > 98% in pharmaceuticals).
High value added and therefore, tolerant to higher
process cost (especially for very effective, small
scale products).
Short development time for the production process
(<few months to 12 years) since time to market
affects the profitability of the product.
Typically relatively high E-factor [1] with large
amounts of unwanted products (solvents, salts,
by-products etc, that must eventually be recycled
or discarded).
2.2. What can catalysis contribute
Catalysis can contribute on two levels to the clean
production of fine chemicals. First, by providing
improved production processes and second, by helping to remove or transform unwanted or even toxic
by-products. Here, we will only address the first
point: How the application of catalytic methods can
lead to a better, more environmentally friendly and
often cheaper production of fine chemicals. One can
distinguish the following cases:
2.2.1. Transformations that are only possible with
catalysts
(Fig. 1).
2.2.2. New selectivities
Enantioselective catalysis
New chemoselectivities (e.g. hydrogenation of
C=CC=O to CHCHC=O).

2.2.3. Combining several transformation in one step

Reductive alkylation of amines with carbonyl compounds (imine not isolated)
Hydrogenationacylation of nitro arenes to acylanilines
Direct alkylation of amines with alcohols via a
dehydrogenationcondensationhydrogenation sequence.
2.2.4. Replacing toxic or problematic reagents (and
reactants)
Alkylation of amines or aromatics with alcohols instead of alkyl halides (reduction of salt production)
Use of H2 instead of metals, metal hydrides or sulfides
Use of H2 O2 or O2 instead of metal oxides or
peracids
Solid acids and bases to replace soluble ones.
2.3. Critical factors for the application of catalysts
An impressively large number of highly selective
catalytic transformations is recorded in the literature
that in principle can be applied to the synthesis of fine
chemicals. However, quite many prerequisites must be
fulfilled in order to render a catalytic process technically viable and to really profit from the opportunities
described in the preceding chapter.
2.3.1. Catalyst performance
The selectivity of a catalyst is probably its most cited
property. Besides chemoselectivity, regio-, stereo- and
enantioselectivity play a role for the synthesis of fine
chemicals. Due to often high cost of starting materials
and intermediates as well as of separation steps, selectivities >95% are usually required to make a catalytic
method attractive. The catalyst productivity, given as
turnover number (ton) or as substrate/catalyst ratio
(s/c), determines catalyst costs. Here it is more difficult to give general numbers because both catalyst
prices and the value added by the catalytic transformation play an important role. For enantioselective catalysts, tons ought to be >1000 for high value products
and >50 000 for large scale or less expensive products
(catalyst re-use increases the productivity). The catalyst activity (turnover frequency (tof), h1 ), affects the
production capacity. As a rule of thumb, tofs ought to

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193

Fig. 1. Transformations that are only possible with metal catalysts.

be > 500 h1 for small and >10 000 h1 for large-scale

products.
2.3.2. Substrate specificity
Catalytic methods are often more substrate specific
than stoichiometric ones, i.e., even small changes of
the structure of the starting material can strongly affect
the catalyst performance of a given catalyst. This is
especially true for highly optimized stereo- and enantioselective catalysts, thereby leading to a low predictability for new substrates. This fact renders synthesis planning difficult for the synthetic chemist who
by definition must be a generalist and often does not
know the scope and limitations of catalytic methodologies. In our experience, catalytic methods are usually abandoned if they do not succeed almost at first
try because development time and costs for fine chemicals are limited.
2.3.3. Commercial availability of catalysts and
ligands
In many cases this is still a major problem for products where relatively small amounts of catalysts are
needed usually not enough to make it worthwhile
for a catalyst manufacturer to develop a tailor-made
catalyst that might be required. For homogeneous catalyst both (chiral) ligands and many metal precursors
can be expensive. Ligands often have unusual structures that are prepared via many step syntheses.

Heterogeneous catalysts can not be characterized on

a molecular level. The catalytic properties of two catalysts with the same description, e.g., 5% Pt/C, can vary
considerably. It is well known that even small variations in the preparation procedure or impurities can
alter the structural and chemical properties of a heterogeneous catalyst significantly. This might or might
not affect its catalytic or chemical activity. It is precisely this might or might not that leads to problems
of reproducibility and frustration.
2.3.4. Practical problems
Especially homogeneous catalysts are very sensitive to air, reactor materials, handling etc. Most catalytic processes are also sensitive to the presence of
impurities that can act as poisons or can modify the
selectivity of a catalyst. This is due to the fact that the
catalyst is present in very small concentration, that the
active species are very reactive and that quite often
oxygen sensitive ligands and complexes are employed.
The quality of the starting material as well as of the
reagents (solvent, gasses, etc.) is therefore, absolutely
crucial.
Catalyst separation from the reaction mixture is a
problem that has to be addressed for every homogeneous catalyst. Usually, the solution has to be tailored
to the substrate, solvent, catalyst type etc. Distillation,
crystallization, extraction or immobilization of the soluble catalyst are often successful approaches. Solid
catalysts can be separated from the reaction mixture

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H.-U. Blaser, M. Studer / Applied Catalysis A: General 189 (1999) 191204

by simple filtration. This allows easier work up and

isolation of the desired product and is the most obvious advantage of a heterogeneous catalyst. Leaching
of the active species such as noble metals can contaminate products and require an expensive purification.
2.4. The toolbox of the catalytic chemist
In the following chapter we sketch the tools that are
available for developing catalysts that make a desired
transformation technically feasible. We use the example of homogeneous and heterogeneous metal catalysts for this endeavor.
2.4.1. Design parameters for catalytic systems
2.4.1.1. Homogeneous catalysts For homogeneous
catalysts the most important elements are the type
of metal (very often used are Pd, Rh, Ru, Ir, Ni,
Cu, Ti) and the specific precursor complex, the type
(mono- and bidentate phosphines, amines, alcohols)
and structure of the organic (chiral) ligand, and in
some cases the presence of additional additives. Especially for the design of chiral ligands there is practically no limit and as illustration a number of important chiral PP-ligands used for preparing soluble hydrogenation and isomerization catalysts is depicted in
Fig. 2.
Most (chiral) ligands are not commercially available. Therefore, chemists in research and development
have to tap various sources to get the needed amounts
of a desired ligand. Collaboration with university labs
or industrial research groups is often useful for getting small amounts of experimental ligands. Own custom synthesis of ligand, especially of (chiral) phosphines requires considerable know how in organic synthesis and the handling of phosphor derivatives. For
large-scale applications, ligand synthesis will at the
moment be part of process development. Collaboration
with an external manufacturer might be the method of
choice for small and large quantities of ligand for long
term projects.

2.4.1.2. Heterogeneous catalysts Of the many parameters of a heterogeneous hydrogenation catalyst

that affect its catalytic performance, the following are

the most important ones: Type of metal (most often

used Pd, Pt, Ni, Cu, Rh, Ru) ; type of catalyst (supported, powders, skeletal); metal loading of supported
catalysts; type of support (active carbon, alumina, silica). Important parameters for the active metal are the
surface area, the dispersion (typically only 1060%
of the metal atoms are exposed), the size of the crystallites (typically in the range 20 to > 200 ), the location in the pores of the support and oxidation state
(reduced or unreduced). Important support parameters are the particle size (for slurry catalysts typically
1100 m), the surface area (typically in the range
of 1001500 m2 /g), the pore structure (pore volume,
pore size distribution) and acidbase properties. Many
types of heterogeneous catalysts are now available on
a commercial basis. In our experience, it is of advantage to develop a close working relationship with several catalyst producers that specialize in catalysts for
the fine chemical industry.
2.4.2. Catalyst modifiers or promoters
In cases where a commercially available catalyst
lacks a desired property or selectivity, the addition
of a modifier is an interesting option. Both organic
molecules (e.g. amines, chiral modifiers such as cinchona alkaloids or tartaric acid) or inorganic salts /
metals are known for this purpose. The modifier can
either be added to the catalysts before it is introduced into the reaction (often done with inorganic
compounds) or added directly to the reaction mixture
as process modifier. Factors that may be influenced are
catalyst selectivity, activity, reduction of intermediate
/ side product formation and catalyst recovery.
2.4.3. Reaction conditions
The catalyst performance can be optimized by
choosing a suitable reaction system and the proper
reaction conditions. Important parameters are the
solvent, the temperature, in case of hydrogenation
the hydrogen pressure, the concentration of the substrate and the catalyst, and process modifiers. Very
often, the choice of the solvent is the most important of these parameters. The optimal solvent can
improve catalyst performance. Furthermore, the separation of the catalyst and if necessary of the undesired enantiomer or racemate can be facilitated by
the proper solvent system (see below). Last but not

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195

Fig. 2. Structural characteristics of important chiral diphosphine ligands (P = PAr2 or PAlk2 ).

least the solvent also has to fit into the sequence of

reactions.
2.4.4. Reaction control (end point)
Monitoring the progress of a catalytic reaction can
be difficult, especially if the catalyst is air-sensitive or
the reaction carried out in an autoclave. Nevertheless,
in the laboratory it is usually possible to find a suitable
solution. This is by no means the case under the conditions of large scale production. There, one very often has to rely on relatively inaccurate measurements
or defined reaction times. On-line monitoring of substrate and/or product concentrations could be of great
help, especially for reaction where a precise end point
control is crucial for high yield and / or selectivity.
Here, ATR- and other in-line probes can sometimes
be very useful for on-line spectroscopy.

3. Examples and short case studies

3.1. Chemoselective hydrogenations of aromatic
nitro groups [2]
3.1.1. Development of the new catalytic systems
Until recently, only the Bchamp reduction was
available for the technical reduction of nitroarenes
with additional, easily reducible functional groups
(e.g., halide, C=C or C=O). When the catalysis process development team of Ciba-Geigy was faced with
the task of developing a process for the reduction
of the nitroallyl ester shown in Fig. 3, a completely
new solution had to be found. Finally, two new catalytic systems that are both technically feasible were
developed.

Both methods make use of catalyst modifiers. In the

first process, a newly developed PtPbCaCO3 catalyst was used. In the second process, H3 PO2 was used
as process modifier for a commercial PtC catalyst.
The PtPb-system gives the best results in methyl ethyl
ketone (MEK) in presence of FeCl2 and tetrabutylammonium chloride. The hypophosphorous acid modified Ptcharcoal catalyst works best in toluene-water
in the presence of VO(acac)2 as promoter. The iron
or vanadium promoters serve to suppress the accumulation of hydroxylamines. The Bchamp process was
used to make the first kg of material but was not developed further due to problems with filtration and
work-up. In addition, large amounts of product remained adsorbed on the iron oxide that would present
an enormous waste problem.
Comment: As shown in Table 1, for the hydrogenation of the nitroallyl ester, the PtC/H3 PO2 system is
clearly the most advantageous. It combines low waste
with high selectivity, activity and space time yield.
Furthermore, a relatively cheap commercially available PtC catalyst can be used and because toluene is
the solvent used in the steps before and after reduction,
no solvent change is necessary. The PtPbCaCO3
catalyst is of advantage when more polar solvents are
required.

3.1.2. Scope of the new systems

Both catalyst systems have a wide scope for related
substrates (see Fig. 4), for details see [2]. They are
for example able to hydrogenate aromatic nitro compounds containing functional groups such as iodide,
C=C, CN and even CC with high yield and high
selectivity.

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H.-U. Blaser, M. Studer / Applied Catalysis A: General 189 (1999) 191204

Fig. 3. Chemoselective hydrogenation of a nitroallyl ester.

Table 1
Comparison of important features of three reduction methods of nitro allyl esters

Reducing agent
Solvent
Reaction conditions
Catalyst
Modifiers
Selectivity for allyl
Yield
Reaction time
Important features

Critical factors

PtPbCaCO3

PtC with H3 PO2

Bechamp

Hydrogen
Aprotic polar solvent, best
results with MEK
140 C and 15 bar H2
Custom catalyst
Lead, FeCl2 and N(Bu)4 Cl
99.8%
>90%
5h
low space time yield
by-product formation
change of solvent

Hydrogen
apolar solvents, best
results in toluene
100 C and 5 bar H2
Commercial catalyst
H3 PO2 and VO(acac)2
99.9%
>98%
2h
no solvent change
high space time
yield

Iron
EtOH/HCl/H2 O

catalyst preparation
recycling of MEK

Fig. 4. Scope of the modified hydrogenation catalysts.

80 C

100%
ca. 90%
18 h
Contaminated iron oxide sludge
Two filtrations
Change of solvent
EtOAc extraction
Waste disposal

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197

Fig. 5. Important substrates for nitro reduction.

3.2. Lowering of hydroxylamine accumulation in the

hydrogenation of aromatic nitro groups [3,4]
The catalytic hydrogenation of aromatic nitro
groups proceeds via several intermediates and the
most important is the corresponding hydroxylamine.
Nitro compounds with electron withdrawing substituents, e.g., sulfonamide or halogen, accumulate
hydroxylamines in large amounts during the reaction.
This is especially critical when the hydrogenation
is carried out in batch reactors at low or medium
temperature because hydroxylamines are in many respects problematic (thermally unstable, explosions;
strong carcinogens; by-product formation). The maximum concentration of hydroxylamines is notoriously
difficult to predict. Here we show how with a process
modifier/promoter the hydroxylamine problem can
often be solved for a number of industrially important
substrates (Fig. 5).
A broad screening of transition metal salts showed
that the addition of vanadium salts drastically reduced
the accumulation of the hydroxylamine intermediate
without increasing the reaction time in the hydrogenation of 1 (See Table 2 and [3,4]).
This vanadium effect has a relative wide scope
and NH4 VO3 also works for Pt/C in the case of 2 or
for the nitroallyl ester described in 3.1.3.. In the case
Table 2
Hydroxylamine accumulation and reaction time for the hydrogenation of 1a
Additive

Hydrogenation
time (min)

Hydroxylamine
accumulation

None
NH4 VO3
V on Pd/C catalyst
VOSO4

150
120
120
180

41%
<1%
<1%
2%

a 5% Pd/C, AcOH, 0.006 mol% promoter relative to 1, 120 C,

20 bar.

of 3, where a Pt/Cu/C catalyst was used, the vanadium

had to be deposited on carbon for the desired effect.
Without this measure, the catalyst was deactivated.
Comment: This example shows how process-promoters allow to modify the properties of a catalyst to
get a safer reaction, less by-products and in some cases
shorter reaction times. Especially advantageous is the
fact the commercially available catalysts can be used.
3.3. Alkylation of aromatic ring: combination of
a homogeneous and heterogeneous Pd catalyzed
reaction [5,6]
3.3.1. Process development
Sodium 2-(3,3,3,-trifluoropropyl)-benzenesulfonate
is a key intermediate for the sulfonylurea herbicide
Prosulfuron (Fig. 6). This and analogous building
blocks were prepared in the Central Research Laboratories of Ciba-Geigy by the three step sequence diazotation, Matsuda arylation, hydrogenation. Attempts
failed to find a classical synthetic method such as
a Friedel-Crafts alkylation of benzenesulfonic acid.
Therefore, the process development team had to develop a technically feasible production process using
a technology that until that time was only used on a
laboratory scale.
In the end, a process was developed starting with
2-aminobenzenesulfonic acid and ending with sodium
2-(3,3,3-trifluoropropyl)-benzenesulfonate
without
isolation of the diazonium or olefin intermediates,
producing only 2 kg wastes/kg product over the three
consecutive synthetic steps equal to an E-factor of 2.
Moreover, the yield over these three steps is 93%,
i.e., an average of 98% per step (Fig. 7).
3.3.2. Important factors
The solvent had to be compatible with three
different chemical reactions, have high solubility for

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H.-U. Blaser, M. Studer / Applied Catalysis A: General 189 (1999) 191204

Fig. 6. Key intermediate and formula of Prosulfuron herbicide.

Fig. 7. Three step one pot reaction for the synthesis of sodium 2-(3,3,3-trifluoropropyl)-benzenesulfonate.

trifluoropropene and be easy to regenerate. Pentan-1-ol

showed these properties to a high degree. The cost
and separation of the Pd catalyst was another crucial factor. By careful optimization of the reaction
conditions catalyst loading for the arylation was lowered to 0.51.5% and the catalyst precursor Pd(dba)2
was prepared from readily available PdCl2 . The most
crucial idea however, was to add charcoal after completion of the arylation reaction and to produce a
heterogeneous hydrogenation catalyst in-situ that on
the one hand is able to catalyze the hydrogenation of
the C=C bond and at the same time allows an efficient
separation of the Pd by simple filtration.
Comment: By linking homogeneous and heterogeneous catalysis, and by using a one pot procedure for
three consecutive steps, it was possible to develop an
economically and ecologically sound process for the
production of Prosulfuron.

precursor, a chiral diphosphine ligand and H2

(20 bar) in MeOH.
3. The -keto acid was reduced to the corresponding a-hydroxy acid with a d-lactate dehydrogenase (d-LDH), a formate/formate dehydrogenase
(FDH) for the co-enzyme NAD regeneration and
formate in an aqueous buffer using an enzyme
membrane reactor.
4. The ,-unsaturated -keto acid was reduced
to the corresponding -hydroxy acid with the
microorganism Proteus mirabilis (immobilized), a co-factor and formate. The resulting ,
-unsaturated -hydroxy acid was hydrogenated
with Pd/C to the saturated acid.
Comment: The over-all performance and economy
for (1), (3) and (4) are comparable, but each process
has its specific problem(s) associated. Except for the
homogenous hydrogenation, they are all technically
feasible on a 1100 kg scale.

3.4. Enantioselective hydrogenation of an -keto

ester [7]
3.5. Routes to an N-alkylated hindered aniline [8]
(R)-2-Hydroxy-4-phenyl-butyric acid ethyl ester,
the so-called HPB-ester, is an important intermediate for the synthesis of several ACE inhibitors. It
can be synthesized from the corresponding -keto
acid derivatives via chemical or biochemical catalytic
methods as depicted in Fig. 8 (Table 3).
1. The -keto ester was catalytically hydrogenated
to the corresponding a-hydroxy derivative with a
Pt on Al2 O3 catalyst, a cinchona alkaloid (chiral
modifier) and H2 (60 bar) in toluene or AcOH.
2. The -keto ester was catalytically hydrogenated
to the corresponding a-hydroxy ester with a Rh(I)

3.5.1. Background
Metolachlor is the active ingredient of Dual ,
one of the most important grass herbicides for use
in maize and a number of other crops. It is an
N-chloroacetylated, N-alkoxyalkylated ortho disubstituted aniline. In this context it can serve as an
illustration how the requirements for the technical
production of a large scale agrochemical can evolve
(Table 4). The commercial product was introduced to
the market in 1976 as a mixture of four stereoisomers
(Fig. 9) and is produced via a Pt catalyzed reductive

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199

Fig. 8. Catalytic routes to HPB ester.

Table 3
Comparison of systems 14 for the synthesis of HPB ester
Pt-Cinchona

Rh-PP

Dehydrogenase

Proteus mirabilis

Catalytic system
Reducing agent
% ee
s/c (w/w)
s/c (mol/mol)
Ton
tof (h1 )
Space/time yield
Cat. cost ($/kg p)
Problems

Commercial heterogeneous catalyst

H2
8092
200
4000
4000
1000
210
12
Catalyst activation

Commercial enzymes
HCOOH, NAD
>99.9
25 000
N/A.
High
N/A.
7
Not known
Long development
time
Complicated work-up

Immobilized microorganism
HCOOH, co-factor
>99
50100
N/A.
Living
N/A.
512
Not known
Long development time

Economy

process very sensitive

to substrate purity
Ok

Custom diphosphine
H2
96
50
100
100
5
53
140400
ees drops at higher
s/c ratios
optimization not
successful
bad

Ok

Ok

Complicated work-up

Table 4
Milestones in the history of metolachlor
1970
1978
1982
1983
1987
1993
1993/19944
1995/1996
1996

Discovery of the biological activity of metolachlor (patent for product and synthesis)
Full-scale plant with a production capacity >10 000 t/year in operation
Synthesis and biological tests of the four stereoisomers of metolachlor
First unsuccessful attempts to synthesize (S)-metolachlor catalytically
CaSnPt catalyst for direct alkylation of MEA in the gas phase developed
Ir/ferrocenyl diphosphine catalysts and acid effect discovered
Patents for racemic-metolachlor expire
Pilot results for (S)-metolachlor: ee 79%, ton 1 000 000, tof >200 000 h, first 300 t produced
Full-scale plant for production of >10 000 t/year (S)-metolachlor starts operation

alkylation of 2-methyl-5-ethyl-aniline (MEA) with

aqueous methoxyacetone (MOA, made by dehydrogenation of methoxyisopropanol, MOIP) in presence
of traces of sulfuric acid followed by chloroacetylation [9] (see Fig. 10). A redox catalyst for the direct
alkylation of MEA with MOIP was developed but not

used commercially (see Fig. 9) [10]. Already in 1982

it was found that about 95% of the herbicidal activity
of metolachlor lies in the two (1S)-diastereomers
[11]. In 1997, after years of intensive research [12],
Dual Magnum with a content of approximately
90% (10 S)-diastereomers and with the same biologi-

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Fig. 9. Structure and stereoisomers of metolachlor.

Fig. 10. The production process for racemic metolachlor.

Fig. 11. Enantioselective MEA imine hydrogenation.

cal effect at about 65% of the use rate was introduced

in USA. To make this chiral switch possible, a new
technical process had to be found that allowed the economical production of the enantiomerically enriched
precursor of metolachlor. Key step of this new synthesis is the enantioselective hydrogenation of N-(2-

ethyl-6-methylphenyl)-N-(10 -methoxymethyl)-ethylidene-amine (see Fig. 11). The optimized process

operates at 80 bar hydrogen and 50 C with a catalyst
generated in-situ from [Ir(cod)Cl]2 and the ferrocenyldiphosphine ligand xyliphos at a substrate to
catalyst ratio (s/c) of >1 000 000. Complete conver-

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201

Table 5
Comparison of important features of three methods to make hindered N-alkyl aniline

Catalyst
Technology
Status
Reaction conditions
Modifiers
Conversion
Chemoselectivity
Important features
Critical factors

Reductive alkylation

Direct alkylation

Enantioselective hydrogenation

5% Pt/C, commercial catalyst

Liquid phase, batch
production
50 C, 5 bar H2
>98%
>98%
High space time yield
High catalyst recycling rate
catalyst filtration
recycling of starting material

Pt/SiO2 , custom catalyst

Gas-phase, continuous
laboratory
200 C, 1 bar H2
Sn, Ca
66%
>98%
one step reaction

Custom diphosphine
Liquid phase, batch
production
50 C, 80 bar H2
Acid, iodide
100
100% (80% ee)
high space time yield
extremely active catalyst
imine quality

sion is reached within 34 h, the initial tof exceeds

1 800 000 h1 and enantioselectivity is approximately
80%.
3.5.2. The production process for racemic
metolachlor [8,13]
For the reductive alkylation, several problems had
to be solved: Competing reduction of MOA, especially
when imine formation was slow; trace hydrogenation
of the aromatic ring and re-use and separation of the
Pt/C catalyst from the two-phase reaction mixture. After intensive development work, first in the laboratory
(comprising >1500 experiments) and later in the pilot
plant (also used for the production of the first commercial quantities), the production process depicted in
Fig. 10 was established in early 1978.
3.5.3. Alternatives processes [10]
Acid catalyzed alkylation of MEA with MOIP
gave complex mixtures of the desired product (NAA),
as well as N-methyl-, N-dimethyl, N-propyl- and
N-isopropyl-MEA as by-products due to cleavage of
the ether group of MOIP. More successful was the
development of a multifunctional bimetallic platinum
tin catalyst on a calcium treated silica support. This
catalyst is able to catalyze the dehydrogenation of
MOIP to MOA, the condensation to the MEA imine
and the subsequent hydrogenation to produce NAA.
It was shown that all three components as well as the
silica support are absolutely necessary to get a good
catalysts performance, i.e. there is a remarkable synergy between the various elements. At 200 C in the
gas phase NAA was produced with >98% selectivity

catalyst preparation
process control

at ca. 66% conversion over more than 1000 h. The

process was not commercialized because large investments would have been necessary and also because
the development of the catalyst would have been very
difficult.
3.5.4. (S)-Metolachlor process [12]
On the way to a successful process for the enantioselective hydrogenation of the imine intermediate (see
Fig. 11) the following milestones are worthy of note:
A rhodium diphosphine catalyst was found that
was able to produce S-NAA with about 70% ee
quite close to the desired selectivity of 80%. However, low temperatures and large amounts of catalyst
were needed to accomplish this. Iridium catalysts with
classical diphosphines proved to be as selective as
the best Rh catalyst, were about 100 times more active but tended to deactivate relatively fast. The final
breakthrough came in 1993: A new class of Ir ferrocenyl diphosphine complexes (see Fig. 11) turned
out to be stable and the discovery of an extraordinary
acid effect led to extremely active and productive
catalysts. Scale up presented little problems and now
the reaction is carried out on a scale of >10 000 t/year
(Table 5).
Comment: The three case histories demonstrate that
catalytic methods are very suitable for the production
of medium to large volumes fine chemicals even in an
enantiomerically enriched form. It is worthy of note
that the time for process development depends very
much on the state of the art of a given catalytic technology. It was quite short for the reductive alkylation,
a well known method already in 1972, whereas it took

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Fig. 12. Intermediates and by-products for the hydrogenation of 3-cyanopyridine.

Fig. 13. Dependence of 3-cyanopyridine concentration and ATR-response on hydrogen uptake.

more than 10 years to develop a suitable catalyst for

the enantioselective imine hydrogenation.
3.6. On-line monitoring of catalytic hydrogenations
with ATR-probes [14]
As described in Section 2.4.4., accurate end point
determination is often the key for obtaining high selectivity and therefore, high yield. Here, we describe
how this can be done on-line for catalytic hydrogenations with the help of ATR-probes under difficult technical conditions. In both examples the technical hydrogenation was carried out under pressure with heterogeneous catalyst in steel autoclaves, where sampling is time consuming and complicated. ATR probes
can also be very helpful for the development and optimization of a reaction and for identifying interme-

diates and by-products. Contrary to the examples below, an in-depth analysis of the data gathered is then
necessary.
3.6.1. 3-Cyanopyridine to 3-Pyridinecarboxaldehyde
3-Pyridinecarboxaldehyde is a valuable intermediate for a number of industrial processes but expensive
to buy. An inexpensive precursor is 3-cyanopyridine
which can be converted to the desired product according to Fig. 12. However, many side- and consecutive
reactions, e.g. the formation of primary and secondary
amines are possible. Furthermore, the reaction does
not stop on the aldehyde stage but slowly continues to
give the corresponding alcohol. To obtain a high yield
it is, therefore, essential to have a good method for
end point determination. Comparing the change in adsorption at 240 nm with the concentration of the start-

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203

Fig. 14. Hydrazone hydrogenation.

ing material reveals that a maximum in adsorption is

observed when the starting material has disappeared
completely (Fig. 13). This maximum coincides with
the maximum concentration of the desired aldehyde.
Therefore, the optimal end point can be determined
very easily.
3.6.2. C= N double-bond hydrogenation in a
acetyl-hydrazone derivative
The hydrogenation of the hydrazone depicted in
Fig. 14 is an important step in the production of a
Novartis fungicide. One key problem is the determination of the end point of the reaction because
prolonged hydrogenation leads to a cleavage of the
NN bond in the desired hydrazine. Again, the difference observed at 240 nm was shown to correlate
with the concentration of the hydrazone and was directly related to the hydrogen uptake (data not shown).
Therefore, the end point of the reaction was reached
when the adsorption reached a plateau. If the reaction was not stopped at this point, the hydrogen uptake continued slowly, leading to undesired cleavage
products.
Comment: In both examples, the relative simple measurement at a single wavelength provided
enough information for end point determination and
yield optimization. Due to the high sensitivity of
the method it is very important to carefully maintain the equipment and to critically analyze the data
produced.

4. Conclusions and outlook

We have illustrated with several examples how
catalysis can help to optimize existing processes or

to open up new syntheses. We are convinced that the

application of catalytic methods for the production of
fine chemicals will increase in the coming years. It
is clear, however, that due to the rather conservative
nature of most people involved in applying chemical
technology, on should not expect a radical change.
Some new developments that are already being described in the literature might help to accelerate the
rate of application:
Automated high through-put screening of catalysts
and reaction conditions
More readily accessible catalyst families (homogeneous, heterogeneous, enzymes) with tunable properties and well defined scope and limitations
In-situ process control and improved (micro)- analytical techniques
Specialized (small) companies offering catalyst and
process development to fine chemicals manufacturers [15].

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