Chemical Engineering Science 56 (2001) 305}322

Chemical reaction engineering aspects of "ne

chemicals manufacture
K. J. Carpenter
Process Studies Group, Zeneca Agrochemicals Huddersxeld Works, Leeds Road, Huddersxeld HD2 IFF, UK

Abstract

Reaction engineering in "ne chemicals manufacture is an integral part of the process development and design. It requires
a multidisciplinary collaboration to implement complex organic chemistry within tight time and cost pressures. The commercial
viability of a chemical route can be determined by the ability to handle complex mixtures and to obtain maximum selectivity and yield
in multi-phase reaction mixtures where reaction rates, mass transfer rates and dispersion and coalescence rates all interact. Whilst
much of the equipment used may appear super"cially to be rather simple, in practice, where development is carried out at
a world-leading level, the underlying principles and understanding of the dynamics of the competing rate processes and the
fundamental mechanisms can be very complex. Examples of reactor selection and design on cost and safety grounds are described and
the techniques used to address problems of competing reaction and mass transfer, dispersion and coalescence and competing fast
reactions are illustrated. A number of opportunities for improved reactor design are discussed to meet ever more demanding capital
and operating cost constraints and chemical e$ciency requirements, driven by the desire to reduce the impact of the manufacture and
use of "ne chemicals on the environment and by increasing competition.  2001 Elsevier Science Ltd. All rights reserved.

Keywords: Fine chemicals; Agrochemicals; Process development; Competing reactions; Mass transfer; Multi-phase reactions

1. Introduction In order to understand the role of reaction engineering

Fine chemicals manufacture means many di!erent
things to di!erent people, but most will agree that the
common elements are; the products are complex organic
molecules, with molecular weights in the hundreds,
manufactured at relatively low annual rates, kilograms to
perhaps a thousand tonnes. There are exceptions, but for
the purpose of this paper, these are the important charac-
teristics we will assume. The products are sold into a very
wide range of industry sectors. Here we will concentrate
on Pharmaceutical intermediates, Agrochemicals, speci-
ality industrial chemicals and biocides. By speciality
industrial chemicals we mean colours for electro-
photographic applications and printer inks, chemicals for
other electronic applications, additives and formulating
agents for a range of industries and complexing agents
for metal extraction. Many of the comments apply
equally to the "nal stages of pharmaceutical active ingre-
dient manufacture, although in that business there is less
opportunity for engineering innovation and less incen-
tive, because of the restrictions imposed by product and
process registration and validation, and the relatively
small impact of manufacturing on the "nal product cost.
in "ne chemicals process development and manufacture,
it is important to understand the nature of the chemistry
and materials involved, the development time scale and
product cost structures. These will be discussed brie#y
and illustrated by examples. The current approach to
reactor selection and design will be reviewed, along with
areas of current di$culty, leading to ideas for potential
future developments and opportunities. Along the way
several lessons regarding collaboration between chemists
focused on synthesis, chemical engineers and phys-
ical}organic chemists will be highlighted and areas for
improved education and research noted.
2. The nature and impact of the chemistry
Three typical molecular structures are presented in
Fig. 1. On inspection, it is immediately obvious that for
any given molecule, there are many possible synthesis
routes, that potentially each route can contain many
reaction stages and that the molecules and intermediates
contain very many reactive sites. Reaction engineering
can have a major impact on the commercial viability and

0009-2509/01/$ - see front matter  2001 Elsevier Science Ltd. All rights reserved.
PII: S 0 0 0 9 - 2 5 0 9 ( 0 0 ) 0 0 2 3 1 - 1
306 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322
Fig. 1. Three typical "ne chemical molecular structures (Atherton & Carpenter, 1999; Tessier, 1984).
Fig. 2. Simple electrophilic substitution.
the selection of the best synthesis route and the develop-
ment of a safe and successful manufacturing process,
minimising any adverse impact on the environment and
human health.
Many of the impurities will have very similar struc-
tures to the target molecules. As an extreme example, the
synthetic pyrethroid shown is deltamethrin. It is sold as
a single enantiomer, but is one of eight potential
stereoisomers. Of the other seven, six have no biological
activity. A process which produced a mixture of the
active compound along with seven `impuritiesa in similar
amounts, which then required separation and destruc-
tion or disposal, would clearly be very wasteful and
unproductive. Similarly, although it is possible to sell the
mixture in its entirety, for example the commercial insec-
ticide cypermethrin is a mixture of eight stereoisomers, it
is much less desirable than the single active. The manu-
facturing process therefore has to be based on very
stereo-speci"c chemistry, to attach the active groups in
exactly the desired position and orientation. Tessier
(1984) describes the development of an industrial process
for the manufacture of the single enantiomer deltameth-
rin. Robson, Cheetham, Fettes, and Crosby (1984)
describe the development of the Zeneca compound j-
cyhalothrin. This is a very e!ective synthetic pyrethroid
insecticide, manufactured by a process involving multiple
reaction stages and sold as a mixture of two enantiomers.
The implications for the reaction engineer are clear:
(1) there will be very many potential by-product reac-
tions, generating many impurities,
(2) the relative amounts of impurities will depend on the
inherent reactivity of the molecules as well as the
reactor selection and detailed design; the best pro-
cess will be the result of a collaboration between the
synthetic chemist and the reaction engineer,
(3) there will be many options to synthesise the molecule
from a variety of building blocks,
(4) no single stage can be considered in isolation and
(5) the feasibility and commercial viability of a complete
chemical route may be determined by the feasibility,
selectivity, yield or ease of operation of any single
stage.
2.1. The problem of impurities
It would be extremely rare for even the simplest of
organic reactions to be totally speci"c. In real systems
there will be many parallel and consecutive reactions
which will take place, such that less than 100% yield will
be obtained in even the most well engineered reactor. For
example, Cox (1994) describes the selectivity of simple
electrophilic substitution into mono-substituted aro-
matic rings (Fig. 2).
 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322
Fig. 3. Benzoylation of ethylene diamine.
Table 1
Benzoylation of ethylene diamine with benzoyl chloride at !783C (%
yield based on benzoyl chloride, 5 M excess of diamine)
Conc. of diamine Conc. of PhCOCI % dibenzoylamine
solution (M) solution (M)
0.67 0.4 99
0.033 0.02 22
In this case the selectivity is high, 95% towards the
p-derivative, 5% to the o- with a trace of the m-com-
pound. In a nine-stage synthesis, even with a high recov-
ery in each stage and a remarkable 95% yield per stage
a total yield of 63% would be obtained. In practice a real
process would have a very much lower overall yield than
this due to losses in puri"cation stages and lower reac-
tion selectivity, even before deviations from ideality due
to the practical limitations of the reactor design are taken
into account. Consecutive by-product reactions also oc-
cur. These can be intrinsic in the relative reactivity of the
species, but also a!ected by the reagent concentrations,
the reactor type, local mixing e!ects and inhomogeneity.
For example, Jacobson, Makris and Sayre (1987) made
some interesting observations on the yield obtained in
the benzoylation of ethylene diamine with benzoyl chlor-
ide at a mol ratio of 5:1 diamine to benzoyl chloride at
!783C. The amine groups can be considered to be
independent of each other and it is, therefore, possible to
calculate the yield expected from the chemical rates.
With this excess of amine it is 90% mono- and 10%
di-benzoylamine (Fig. 3).
In practice, when they actually carried out the experi-
ment, they obtained the results in Table 1.
There are no reported kinetic data at !783C, but at
room temperature King, Rathore, Lam, Guo, and Klas-
sen (1992) measured the rate constant for the reaction of
benzoyl chloride with aliphatic amines to be about
10 M\ s\, so it is still expected to be a very rapid
reaction. This reaction clearly shows the symptoms of
micromixing controlled rather than kinetically control-
led selectivity, i.e. the selectivity depends on mixing by
local turbulence rather than the intrinsic chemical kine-
tics. The e!ects of mixing on reaction selectivity are
discussed in more detail later in this paper.
The presence of impurities produces something of a di-
lemma. Carrying them forward to the next reaction stage
will generate more impurities and consume raw materials
as they themselves will be reactive. However purifying at
each stage will generate large amounts of waste and yield
307
loss, and require additional expensive equipment. In
practice, in many industry sectors a compromise is reach-
ed where the "rst research route used in the discovery of
the molecule will include puri"cation after every reaction
stage. During the development of a viable manufacturing
process some of the inter stage separations will be re-
moved, leaving puri"cations only at key stages. It is,
however, extremely important to identify where puri"ca-
tion really is necessary for a viable process, by under-
standing which impurities, when carried forward, will
have a dramatic e!ect on the yield or feasibility of opera-
tion of downstream stages. Carpenter (2000) describes an
example where the presence of an impurity at 0.1% in
solution inhibited crystal growth so badly that it was not
possible to isolate and purify the product by conven-
tional means. The problem could only be resolved by
introducing an intermediate puri"cation stage earlier in
the process, with a consequent loss of overall yield, an
increase in e%uent load and signi"cant expenditure on
additional new equipment.
2.2. Directing synthesis * protection and leaving groups
Another feature of the complex organic chemistry is
that many intermediate compounds are used which have
constituent groups that do not appear in the "nal prod-
uct molecule. Understanding the e!ect on the reactivity
of the various sites on the whole molecule by the inclu-
sion of a particular group and the addition of protecting
groups to prevent reaction at a particular site, and later
removed, are part of the synthetic organic chemist and
the physical organic chemist's art. Using that knowledge
to build up a complex synthesis step by step in combina-
tion with reaction engineering to provide the necessary
local conditions in a full scale reactor are at the heart of
the development of an industrially viable process. The
chemistry used for the manufacture of red azo dyes based
on H-acid (Brennan, 2000) is a good example. Here the
aromatic amine group is protected then released for
further reaction, and the protecting group directs the
reaction towards the desired position on the ring (Fig. 4).
The protection prevents the amine from reaction with
the diazonium, which could produce an explosive impu-
rity. It would also produce an alternative diazonium in
the amine position and an amine species from the diazo
which could react further. The protection also enables
the OH to direct the substitution to the 2-position (rela-
tive to the OH). Without it a mixture with the azo group
in the 2- and 7-positions would be obtained, because of
the in#uence of the amine, giving a complete mixture of
308 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322

Fig. 4. Azo dye chemistry involving protection of the amine on H-acid.

Fig. 5. Avecia route to #uorobenzene.

Fig. 6. Reactions used for the manufacture of aniline from benzene via nitrobenzene.

products. The selectivity of this chemistry depends criti-
cally on the ionic equilibrium hence on local pH condi-
tions in the reactor. There is therefore a very important
interaction betweeen the reaction engineer and the syn-
thetic chemist. The chemist provides the understanding
of the important parameters to control and design for, in
this case very good overall pH control and rapid mixing
to control pH local to the point of addition of the
reacting species, and the reaction engineer provides the
reactor design which will achieve the necessary mass and
heat transfer.
Another example of an overall route which looks more
complicated and ine$cient at "rst glance than would be
thought it should be, is the commercial process for the
manufacture of #uorobenzene. Although not really a "ne
chemical it demonstrates the principle very well. Super"-
cally the simplest route would appear to be from benzene
and #uorine. However, the true situation is not quite that
simple, the benzene itself would be derived from catalytic
reforming of hydrocarbons or transalkylation of toluene,
and the #uorine from KF.HF by electrolysis, with the KF
from KOH and HF, and the HF from CaF and H SO ,
  
and so on. Unlike Cl and Br , the direct aromatic
 
substitution with F gives violent reactions involving

ring scission, coupling, addition and polymerisation
(Boudakian, 1994). The commercial route therefore has
been developed via diazotisation of aniline, and a num-
ber of patents exist for various processes. One process,
operated very successfully by Avecia is via diazotisation
in aqueous HF and decomposition of the diazonium
#uoride (Fig. 5).
This process is selective, gives a clean product, and can
also be used for other #uoroaromatic species. It seems
ironic that the aniline itself will have been manufactured
from benzene via nitrobenzene (Fig. 6). Puri"ed aniline
and nitrobenzene are manufactured at the millions
 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322
Fig. 7. Schematic of the development process for an agrochemical product.
of tonnes scale world-wide in dedicated continuous
plant.
The reaction engineering for the #uorobenzene process
is a good example of the speci"cation of a reactor type
based on safety grounds and is considered in more detail
later in this paper.
A key message for reaction engineers is to interact very
closely with the chemistry during process development in
order:
(1) Not to go down the track of a complex route if
a more direct simple reaction is possible, but not
recognised because of experimentation in inappro-
priate laboratory equipment. There are many exam-
ples of reactions thought not to work simply because
of a lack of understanding of the rate controlling step
and/or mechanism and not using the necessary reac-
tion or mass/heat transfer conditions.
(2) To appreciate that there are many potential solu-
tions to a synthesis problem. It may be appropriate to
use what may seem at "rst to be a roundabout route
in the interests of safety, integration with other pro-
cesses on site or other process stages, or even cost.
(3) To be able to consider the whole manufacturing
chain and to make judgements with little informa-
tion. Route decisions must be taken early in develop-
ment and the reaction engineering is an integral part
of the route selection.
2.3. Development costs and time scales
The major impact of the reaction engineering on the
overall process development is at the route selection
309
stage, ensuring that the best overall route is selected to be
carried forward into the "nal stages of development and
process design. The various types of business in the "ne
chemicals sector will have di!erent development
processes and time scales, however, there are many
similarities and a typical agrochemical is used here for
illustration.
Fig. 7 is a schematic of the overall development pro-
cess for an agrochemical product, from a research route
to a developed product, operating process and plant
design (Carpenter, 2000). Entering the "nal stages of
development there will be a research route with an early
formulation and an understanding of the requirements of
the delivery system. The development will proceed
through alternative route generation to initial route se-
lection based on a number of product, SHE and business
criteria. Very many synthetic routes will be considered.
A large number will be rejected as infeasible or un-
economical, but a smaller number will be worthy of
serious investigation. At this stage little information on
much of the proposed chemistry will be available, but it is
important to "rm up on a route or a small number of
competing routes, quickly. It is, therefore, necessary for
reaction engineers to be able to apply basic principles
with limited data to ensure, as far as is possible, that the
routes selected will be those best placed to achieve the
business and SHE targets, and to ensure that the scouting
chemical experiments are not misinterpreted due to inap-
propriate experimental equipment or conditions. From
here, on, the reaction engineering and chemical develop-
ment will be fully integrated to ensure that the reaction
conditions, reaction and extraction solvents, reactor
selection and overall process design will achieve the
310 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322
Table 2
A typical agrochemical development chain (after Plant, 1999)
Phase Activity
Phase 1 * invention Investigates interesting activity
Phase 2 * evaluation Clari"es the preferred candidate
Phase 3 * development Answers critical questions
Table 3
New agrochemical product development costs (after Plant, 1999)
Activity % of total cost
Research 13
Biology (R&D) 13
Field biology (e$cacy, environmental) 24
Environmental sciences, toxicology 23
Formulation development 7
Process technology 15
Administration (inc. patents, planning) 5 intermediates, which will most likely be part of the same
Total 100
required performance at manufacturing scale. Even-
tually, the engineers will go on to provide the design data
for the manufacturing plant or plants. As the process
"rms up, it will become most important to design for the
detailed mixing, mass and heat transfer necessary to
achieve the target selectivity in the full-scale reactor.
The time scales for the development of pharmaceut-
icals and agrochemicals are not exactly analogous, but
there are many similarities. From initial discovery to
product launch can take 10 or even 15 years, and involves
a huge investment. For example AstraZeneca spent
£2.2bn on research and development in 1998, a similar
sum to most of the world's leading pharmaceutical based
companies, and 21% of sales. It has been reported (ABPI,
1998) that the chance of discovering a molecule which
will be a commercial success is 1 in 5000. Even after
molecules with recognised activity have been discovered,
many fall by the wayside during development. Plant
(1999) has reviewed the number of active molecules on
average coming from discovery to reach the end of devel-
opment, in a typical agrochemicals business (Table 2).
Plant (1999) has also outlined the cost distribution of
new agrochemical product development (Table 3).
Coming at the end of this time scale and with very
large amounts investment already made, it is imperative
that a process is developed, which will operate success-
fully at full scale. However, the time to market is extreme-
ly important, such that very little time will be available
for the "nal stages of development. There is, therefore,
tremendous pressure on the chemist}engineer develop-
ment team to deliver. Although this example concerns
agrochemical development, the same comments apply to
Time (yr) Number per year required for one product
Could be 5}10 12
2 4
4 1
Fig. 8. Vapour phase route to chlorothalonil.
pharmaceuticals. They also generally apply to chemical
development process, simply outsourced to the chemical
manufacturer by the company developing the "nal
product.
2.4. Physical characteristics of materials
Having reviewed the impact of the chemistry on the
reaction engineering and with an understanding of the
pressures to deliver successfully, it is also important to
understand the nature of the materials which will be
handled.
For almost all reactions, especially the larger molecu-
les in the later stages of the process, the reaction will
proceed via a continuous liquid phase. There are some
exceptions, for example the two stage process to the
fungicide chlorothalonil uses continuous vapour-phase
catalytic #uid-bed reactors (Fig. 8), but these are rela-
tively rare:
For the majority of "ne chemicals processing, the reac-
tion will be carried out in a solvent, although it is by no
means unusual for one of the reagents itself to be the
liquid phase, even if it is the melt phase of a material
which would be a solid at room temperature. The solvent
can have a dramatic e!ect on the rate and selectivity of
the reaction. A good example is the aromatic nuc-
leophilic substitution of the azide ion with 4-#uoronit-
robenzene (Cox & Parker, 1973; Cox, 1994), where the
rate changes by six orders of magnitude depending upon
the solvent (Fig. 9).
It is also very common to control selectivity by trans-
ferring reagents, intermediates or reaction products be-
tween phases. For example the acylation of an amine or
phenol, the Schotten}Baumann reaction, can be carried
out successfully even though the half-life of the acid
chloride in water is less than a second (Atherton &
Carpenter, 1999) (Fig. 10).
 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322 311

Fig. 9. E!ect of solvent on rate constant.

Fig. 10. Two-phase Schotten}Baumann reaction.

In this reaction, mass transfer is part of the rate-
determining mechanism and in order to achieve the de-
sign rate at full scale, it will be necessary to provide the
required interfacial area. It will also be important to
control which is the dispersed and which the continuous
phase to ensure stability of operation, subsequent separ-
ation and the correct rate of mass transfer (Atherton
& Carpenter, 1999). Another common practice is to `pro-
tecta the products of a reaction by simultaneous extrac-
tion into another liquid phase or bringing the products
out of solution into a solid phase.
Many starting materials for reactions will be solids or
pastes. In some cases, they will be supplied by external
companies, in others they will simply be from an earlier
reaction stage. One major feature of "ne chemicals re-
action engineering is handling solids and pastes and
reactions with multiple phases. A particular di$culty is
the ability to know the strength of a feed material in paste
form. Many intermediates will not be puri"ed and dried,
but handled as pastes. In addition, the reaction masses
will very often be non-Newtonian slurries. As will be
discussed later, a major reduction in environmental im-
pact can be achieved by reducing the amount of solvent,
or removing it altogether, so that the feeds and products
will often largely be out of solution. Obviously, if the
reaction goes via the liquid phase; once the liquid phase is
saturated, the rate will not be a!ected by further increase
in solids content, but the productivity of the reactor
certainly will, and the amount of solvent to recover or
dispose of per unit of production will be reduced.
In summary, the challenge for the reaction engineer is
to be able to develop a process and design a reaction
stage which will perform at full scale when handling
multiple phases with complex reactions, where the trans-
port between the phases can have a signi"cant e!ect on
the selectivity, and the reaction mass may well be viscous
and probably non-Newtonian.
3. Current technology
In much of the "ne chemicals industry a super"cial
look at the reactors will give the impression that they are
all very similar, predominantly batch agitated vessels in
the 5}20 m range. There are obviously exceptions. In
AstraZeneca for example, we have continuous and semi-
continuous reactors of di!erent types as well as
batch reactors up to 60 and 70 m. However this "rst
312 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322
impression will be misleading, for two main reasons:
(1) there will be very many reactors of other types
`hiddena amongst the agitated vessels, which actual-
ly may be reactor feed vessels and
(2) the agitated vessel reactors will all be designed very
di!erently and have major di!erences in their inter-
nal design.
3.1. The batch agitated vessel } a cheap and yexible friend
It is worth considering why so many reactors are
operated in batch or more commonly fed-batch mode.
The traditional view from outside of the industry is that
conservatism and chemists dominate and there is, there-
fore, resistance to adopting other types of equipment,
particularly as an agitated reactor can be operated like
and can look like a laboratory reaction #ask. However,
in reality, although in some sectors, particularly pharma-
ceuticals, regulation tends to favour traditional ap-
proaches, the truth is that often an agitated vessel is the
best choice, and will have been selected as a result of in
depth consideration of alternatives, by the engineers and
chemists working together in the development team.
Sometimes a fed batch reactor is the best choice or even
the only choice which can be made to work and some-
times other designs are more appropriate. Examples of
reactor selection on the grounds of safety, reaction selec-
tivity and cost are described in the following section.
The major advantages of batch reactors for products
of this type are cost, ability to cope with uncertainty,
#exibility and ability to control.
In cost terms, for the relatively low production rates
required in "ne chemicals manufacture, the trade o!
between continuous operation which requires more but
smaller plant items, and batch operation requiring fewer
but larger items usually shows that batch is cheaper.
There are however exceptions, in particular, where con-
tinuous or more likely semicontinuous operation gives
bene"ts on the grounds of intrinsic safety, or reaction
selectivity. Examples of these are described later in this
paper.
Considering the ability to cope with uncertainty, one
advantage of the batch reactor and its associated ancil-
lary equipment is that in many cases it is relatively easy
and cheap to over-design. An example when this is a very
positive advantage is where there are signi"cant by-
product reactions and the rate determining steps change
between mass transfer, mixing and intrinsic chemical rate
control during a reaction. In this case, although it is
possible to know what the minimum design criteria are,
for example, the minimum mixing performance, the max-
imum rheology and the minimum mass transfer coe$c-
ient, it is prudent to ensure that they are exceeded; e.g.
design for higher mass transfer rates than estimated to be
the minimum from laboratory reactions, or provide
additional volume to allow for an increased batch size in
case of extended reaction times, and still achieve capa-
city, or install a more robust agitation system to cope
with variable and highly non-Newtonian rheology.
Whilst this should never be taken as an excuse to avoid
the need to understand the fundamentals of the system in
question, it does allow the development team to have
con"dence in a workable design in the minimum time
and with limited information. An additional uncertainty
is how di!erent the actual manufacturing process will be
when the reactor is "nally installed and commissioned
compared to the process at the outset of development
and at the time the reactor design is "xed. With a good
grasp of the fundamentals and sound judgement, a batch
reactor system can be designed to cope with a wide
divergence of the process parameters. In this way, the
time required to complete the detailed design, procure-
ment and installation of the plant can be used to develop
and optimise the process, reducing the development time
as compared to a totally consecutive procedure by typi-
cally 18 months. For a seasonal product like an ag-
rochemical, this gives an extra two years early sales
advantage over competition (Ward, 2000).
Flexibility is a similar consideration to robustness.
A continuous reaction stage will be designed for a very
speci"c set of physical parameters, for example physical
properties and reaction kinetics; whereas although
a batch agitated vessel has some limitations, it can cope
with a very wide range of materials and is generally very
easy and cheap to modify to handle new conditions. The
only really di$cult variable to change can be pressure, as
a vessel will have a speci"c maximum operating pressure
which cannot be exceeded. For example, it is relatively
easy to intensify an existing, operating reaction stage by
increasing concentration, reducing solvent and increas-
ing viscosity. For a continuous reaction this may be
much more di$cult or even impossible, depending upon
the speci"c reactor design. It is also very easy to `bolt ona
modular designed ancillary equipment, for example com-
pact semi-continuous mixer-settler units for liquid ex-
traction of reaction products, distillation, centrifugation
or "ltration equipment, membrane units or dryers.
The ability to control reaction selectivity in "ne chem-
icals manufacture is very closely linked to the nature of
the materials and the chemistry. There are many issues
associated with accurate feeding of solids and pastes,
particularly when the composition may be variable, as it
is very di$cult to control the solid/liquid ratio in a paste,
and representative sampling for analysis is di$cult. How-
ever, the most obvious problem, and one where there
must be potential for new opportunities, is in on- and
at-line chemical analysis. In many examples the progress
of a reaction currently can only be monitored by complex
o! line chemical analytical techniques, although develop-
ments in infra-red spectroscopy hold great promise for
the future (Etienne & Weaver, 2000). The advantage of
 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322
Fig. 11. Plug #ow diazotisation reactor and train of CSTR decomposers for FB manufacture.
batch reactor technology in this case is the ability to
de"ne `safea holding positions, where the operation can
be temporarily held in a state where further reaction and
by-product formation is negligible, providing time to
analyse and resolve problems, avoiding wasting or hav-
ing to reprocess valuable materials. Holding will increase
the cycle time. At the worst, this will increase the reactor
size for a given design rate, which in most cases will have
a negligible overall e!ect on process economics.
3.2. Reactor selection * on safety grounds
The Avecia route to #uorobenzene provides a good
example of reactor selection based on safety grounds, and
will be used here even though it is not strictly a "ne
chemical under our de"nition and there are also many
alternative processes patented in this area. As described
in Fig. 5 the manufacture involves the formation of the
benzene diazonium #uoride (bdf) and decomposition in
aqueous HF to produce #uorobenzene, which as a separ-
ate organic phase, is then separated by gravity and puri"-
ed. A major consideration in reactor selection is that
when the unstable diazo decomposes, it generates heat
and nitrogen gas. Under normal circumstances, the
N carries with it HF, and the heat of reaction is re-
 tubular reactor.
moved by the heat of vaporisation. At the correct temper-
ature and pressure the overall reaction and evaporation
are approximately thermally neutral, but at higher tem-
peratures, without adequate cooling, the reaction will run
away generating very large quantities of gaseous N and

HF. At low temperatures the reaction will proceed only
extremely slowly. A key criterion in the selection of the
reactor type is to minimise the potential for a very high
HF vapour rate to the emergency scrubbing system.
Batchwise operation would clearly be the least attractive
option. At the end of a batch diazo reaction and at the
start of a batch decomposition, the reactor would be full
of unusable bdf, which would then require heating to the
reaction temperature to get the decomposition to go. In
313
contrast continuous operation would minimise the in-
ventory of the bdf. The reactor train would have a small-
er overall capacity and the only time when a reactor full
would be heated would be on start up. The design capa-
city of the protective scrubber system will still be deter-
mined by the worst case, which even for a train of CSTRs
is a reactor full of unreacted diazo or even the reactor
train full, with the heating then switched full on and
runaway decomposition, but the potential frequency is
much reduced, as is the amount of diazo present in
normal operation.
The diazotisation is controlled by the dissolution of
NaNO , and subsequent reaction which is second order.

For constant volume the reaction rate in solution is
d
[bdf]"k [NO \][anilineHF].
dt  
There are by-product reactions whose activation energies
are such that operation at 03C gives the optimum selec-
tivity. The rate constant k is 17 m kmol\ s\ at this

temperature and the preferred residence time pro"le is
plug #ow. In practice, as the NaNO is a solid, the

reactor design is a small agitated vessel, with a complex
solids feeding and control system, followed by a long
The decomposition is "rst order in diazo
d
[FB]"k [diazo].
dt 
At the optimum reactor temperature and pressure, the
rate constant is 2.67;10\ s\ and the residence time
required for 99.99% conversion is 6 h. Therefore, a train
of continuous stirred tanks is used to approximate plug
#ow. In practice three followed by a gravity separator
(Fig. 11) provide a cost-e!ective design.
In this example, the reactor selection is determined by
the inherently safer continuous design, even though it
may not be as #exible nor able to operate at a range of
314 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322
Fig. 12. Bromination example after Atherton (1999).
production rates as well as a semi-batch system and is
limited to the manufacture of FB or very similar com-
pounds with similar reaction kinetics and physical
properties.
3.3. Reactor selection * for selectivity
Often, it is possible to use a batch reactor and by
chemists and reaction engineers developing the process
together, to select operating conditions and procedures
which provide the desired selectivity. Occasionally how-
ever, adopting a batch reactor and `"ttinga a process can
lead to an over complicated or di$cult synthesis, when
using an alternative reactor design could provide the
selectivity in a much simpler way. A good example of this
is given by Atherton (1999) (Fig. 12).
The reaction is known to proceed via the intermediate
brominated species. The product forming reaction is
rapid in the presence of HBr which acts as an acid
catalyst. The original laboratory process gave a high
yield by brominating the starting material rapidly in cold
ethyl acetate solvent. The bromo-intermediate was then
poured into ethanol, rapidly forming the solid product
which was "ltered o!. The two-stage process was oper-
ated in the laboratory in a few minutes. However, upon
further investigation, it was shown that the intermediate
is unstable in the presence of HBr, which is generated by
the reaction. At the time-scale expected in normal full
scale process operation in a batch reactor, little of the
intermediate would survive and a very poor yield would
be obtained. The possibility of using ethanol as a solvent
for the "rst reaction, in order to allow the reactions to
proceed together directly to product was unsuccessful.
Instead, it was shown that a rapid "rst stage could be
obtained by using a continuous stirred tank, which
allows the backmixed HBr generated to catalyse the
reaction so that a very short residence time is required.
The reactive intermediate could then be fed straight on to
a second reactor where the HBr is quenched with
K CO suspended in ethanol, as shown in Fig. 13. The
 
study of the kinetics and mechanism showed that a resi-
dence time of 40 s in the "rst stage would be optimum
and operating in this way is reported to generate product
at 96% yield.
Fig. 13. CSTR feeding to semi-batch quench for bromination example
(Atherton, 1999).
Fig. 14. Hydrogenation example after Muller (1996).
3.4. Reactor design for gas}liquid mass transfer
Very many of the reactions developed in "ne chemicals
synthesis are multi-phase and involve gas}liquid mass
transfer. The example used here is that of an hydrogen-
ation of a solid starting material using gaseous hydrogen
and a solid catalyst to produce a solid product, a very
common and typical situation. Muller (1996) describes
the reaction engineering models used to establish the
sensitivity of the yield and productivity to the particle
size of the starting material for the reaction described in
Fig. 14.
The reactor used is a purpose designed stirred tank
with an agitator and ba%e system designed to allow fresh
hydrogen to be dispersed within the liquid phase as well
as hydrogen from the reactor head space to be drawn
back through the liquid surface, thereby, avoiding the
need for gas re-compression. These reactors typically
operate on pressure control, fresh hydrogen being taken
in on demand. The exothermic reaction is cooled by
a coil with very high surface area. In some cases, the
reactor can be so packed with cooling surface that special
attention must be paid to the details of the coil design
a prevent it from forming a `false walla and a!ecting the
performance of the agitation system. The control system
includes the feature that if the cooling goes to full on, but
the temperature continues to rise, the hydrogen pressure
and #ow will the be cut back. The whole system works
well provided the required mass and heat transfer rates
 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322
Fig. 15. Typical hydrogenator design.
can be achieved, therefore, considerable care and atten-
tion are paid to the details of the agitator system design.
An energy input of around 5 W kg\ would not be un-
common. The typical approach to design is described by
Carpenter (1997), and Lines (2000) describes alternative
detailed designs and gives a number of examples. The
detailed design of the agitator itself is very important as
the presence of gas e!ects the ability of the agitator to
perform. Special curved blade turbine agitators are used
to maintain optimum performance even at high gas rates.
An outline of the reactor is shown in Fig. 15. Muller
(1996) describes a real industrial problem where the plant
throughput was bottlenecked at the hydrogenator.
Through an analysis of the reaction rates and mechanism
and the use of dynamic simulation to predict the progress
of the reaction from the reaction kinetics, mass and heat
transfer rates, he was able to show that the extended
reaction times taken to complete the reaction at the full
plant scale were caused by the particle size distribution of
solid feed, which in turn was related to the conditions
used in an upstream isolation step. By modifying the
upstream process stage to produce a narrow and control-
led particle size distribution, the time required for the
hydrogenation was dramatically reduced, thereby, pro-
viding extra capacity at little cost.
3.5. Reactor design for two liquid phases
Almost all "ne chemicals reaction involve two liquid
phases. The major business area where this is not the case
is aqueous dyestu!s manufacture, where traditionally
solvents have not commonly been used. Whereas for
gas}liquid mass transfer the e!ect of the gas on the
315
agitator performance complicates the design, for two
liquid phases it is the fact that often either phase could be
dispersed, and either continuous, which requires special
attention. Consider the example of adding an organic
light solvent to a heavier aqueous phase in an agitated
vessel with no stabilising surfactant species present. As
the solvent is added it will disperse to form a solvent
dispersed * aqueous continuous dispersion. Gradually,
the volume fraction of the droplet solvent phase will
increase until it reaches a point where the drops are in
permanent contact, coalescence predominates and even-
tually the whole system phase inverts to become solvent
continuous and aqueous dispersed. This is shown sche-
matically in Fig. 16 by the line C}D where D is the point
at which phase inversion takes place. The line through
D is the phase inversion boundary. If the experiment is
carried out the other way round, starting with the light
solvent in the vessel and adding the heavier aqueous
phase, the aqueous phase will disperse initially and its
volume fraction will increase until inversion occurs, this
time from the light solvent continuous system to the
heavier aqueous continuous dispersion, as shown by the
line A}B in Fig. 17. B is the point of inversion and lies on
the boundary for a light continuous to heavy continuous
inversion. Between the boundaries is the ambivalent re-
gion where either phase can be dispersed depending upon
how that particular composition was reached and the
mode of operation. In solvent mixtures which have not
been stabilised with surfactants deliberately, the ambiva-
lent region will typically be between 35 and 65% by
volume dispersed phase.
Many laboratory processes will be developed with
volume fractions within the ambivalent region, and
316 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322
Fig. 16. Phase boundary diagram (heavy continuous to light continuous inversion).
Fig. 17. Phase boundary diagram (light continuous to heavy continuous inversion).
unless speci"cally looking for the e!ect, the development
team may well not account for control of continuity, i.e.
may not know which phase is preferred as continuous. In
processes where the physical properties of the two phases
do not di!er widely and reaction rates are slow relative to
mass transfer, the selectivity and reactor productivity will
most likely be similar whichever dispersion is used. How-
ever, where there are fast competing reactions and mass
transfer, the selectivity could well depend upon which
phase is dispersed and the laboratory development
should speci"cally investigate the e!ect. In semi-batch
operation where one phase is added to the other during
the reaction, there is a distinct possibility of phase inver-
sion when the "nal volume fraction of the dispersed
phase is close to the inversion boundary. The result can
be an unexpected instantaneous change in physical prop-
erties and reaction rates. Atherton (1993) describes an
industrial example of the development of an exothermic
reaction between a low volume of aqueous solution and
a larger volume of higher viscosity mixed organic phase.
In the early phase of development the reaction was car-
ried out with no solvent in the organic phase, with the
organic added to the aqueous and the addition rate
controlled to maintain the reactor temperature at a "xed
point, with full cooling on the reactor. However, it was
observed that part way through the reaction, the control
system suddenly and unpredictably reduced the feed rate
to an extremely low level, with the process consequently
taking many hours to complete. The cause was a phase
inversion from aqueous to organic continuous, with
a sudden increase in viscosity from around 5;10\ to
1 N s m\ and a consequent dramatic fall in heat transfer
coe$cient, as shown in a reaction calorimeter. The or-
ganic continuous mixture was an almost totally stable,
high viscosity dispersion of "ne droplets around 2 lm.
Although there were many attractions to the solvent-free
route, Atherton (1993) reports that eventually the di$-
culty in controlling the inversion and handling a viscous
reaction mass led to the use of a solvent based process in
the longer term at full scale.
One of the major di$culties in handling two liquid-
phase systems and one of the main reasons for determin-
ing the preferred phase continuity in development is the
unpredictable nature of droplet coalescence. Whilst there
are many guidelines and rules of thumb and some very
good analyses of the underlying theories, for example,
Chesters (1991), it is not possible to predict coalescence
rates from physical properties for real systems. In addi-
tion, because small amounts of impurities, changes in
drop size and drop size distribution and of interfacial
properties can all have major e!ects on coalescence rates,
they can be very variable even for a supposedly `con-
stanta system. For a given pair of immiscible liquids,
there can be very large di!erences in rates of coalescence
between one phase continuous and the other. Atherton
and Carpenter (1999) describe an example of the
 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322
Fig. 18. Example of the e!ect coalescence rate on reaction pH control.
extraction of an organic acid where the presence of sur-
face-active impurities in the aqueous phase, derived from
an upstream biotransformation reaction, caused the
aqueous continuous dispersion e!ectively to be stable, at
least not able to coalesce within 15 h, whereas, the same
liquid pair with the clean organic phase continuous
would coalesce within 15 s. There can be unexpected
e!ects on reaction selectivity and rate when the rate of
coalescence is relatively slow and is part of a reac-
tion/mass transfer mechanism. Consider the very simple
example of adding an aqueous alkali to a dispersion to
maintain pH at a controlled level during a reaction which
generates protons, as illustrated in Fig. 18. In the "rst
case, where the reaction mass is organic continuous, with
the reaction in the aqueous dispersed phase, the droplets
will become acidic as the reaction proceeds. The alkali
will disperse into drops as it is added and the pH within
the drops can only be controlled if they coalesce with the
drops of aqueous alkali. There will, therefore, be a distri-
bution of pH within the reactor, depending upon the
coalescence rate. If it is slow relative to the reaction rate,
then there will be a very wide distribution from un-
neutralised drops right through to fresh undiluted alkali.
In the second case, the reaction takes place in the
continuous aqueous phase, the added alkali will mix
rapidly with the aqueous phase in the reactor, provided
the agitation system is well designed. The slow coales-
cence rate will have no e!ect on the reaction selectivity in
this case.
In summary, for reactions between immiscible liquids,
it is very important to establish the sensitivity of the
reaction to phase continuity and to design the reactor
and operating procedure to ensure that the required
continuity can be achieved, controlled and maintained.
3.6. Reactor design to handle fast competing reactions
One of the most common problems in "ne chemicals
317
Table 4
Reaction time constants and relevant mixing regimes (after Carpenter
in Atherton & Carpenter, 1999)
Reaction time constant Mixing regime
10 mins to hours Independent of mixing
seconds to minutes Macromixing
ms Micromixing
manufacture which the reaction engineer has to address,
is that of fast competing reactions. There have been very
many publications and a large amount of research into
the various aspects of predicting selectivity, particularly
in low viscosity media, over the years. Atherton and
Carpenter (1999) present a brief overview of the most
relevant "ndings with some simple examples. Baldyga
and Bourne (1999) present a comprehensive review with
a thorough and detailed analysis.
In practice, one of the major tasks for the reaction
engineer is to help the development chemists to under-
stand that it is possible for the way in which reagents are
added and mixed to have a signi"cant e!ect on reaction
selectivity and yield, even in laboratory reactors. Al-
though the detailed analysis of turbulence in reactors is
a rather specialised topic and outside the experience of
development chemists, and even many reaction engin-
eers, the basic concepts and semi-theoretical approaches
to design are relatively simple. As a "rst step, an under-
standing of the relevant mixing regime can be obtained
by the magnitude of the competing reaction time con-
stant. A convenient de"nition for semi-batch operation
with equal stoichiometry is
1#a
q " ,
0 KC

where a"< /< and < and < are the volumes of the
reagents added.
Meso-mixing falls between micro- and macro-mixing
(see Table 4).
A great deal of information can be obtained from
laboratory experiments supported by an understanding
of the relevant mixing regime. For example, for a reaction
where selectivity is determined by macro-mixing or bulk
circulation within the reactor, it is possible to calculate
what the minimum scale is for reliable laboratory opera-
tion, to give a required mixing time for the full scale
design. An example calculation is given by Atherton and
Carpenter (1999). Having determined the minimum scale,
it is a simple matter to establish the relationship between
yield and mixing time, thus enabling a full-scale design
directly from laboratory scale experimental data. In
a similar way for a micro-mixing dominated system of
reactions, it is the turbulent energy dissipation rate rather
318 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322

Table 5
Energy dissipation rates and micromixing time constants for typical
equipment

Equipment e (W kg\) Micromixing

(to an order time constant
of magnitude) in water (ms)

Tubular reactor or 5 8
centrifugal pump
Well-agitated stirred-tank 0.2}50 40}2.4
reactor
Static in-line mixer 1000 0.5 Fig. 19. Example reaction of alcohol and dihalo compound.
(e.g. Kenics)
Rotor}stator mixer device
(e.g. Silverson mixer) 5000 0.25

than mixing time, which determines selectivity and the

relationship between them can be established experi-
mentally (see Atherton & Carpenter, 1999). The most
appropriate equipment can then be selected and designed
on that basis (see Table 5).
For a given reaction system where the competing reac-
tion is much faster than micro-mixing, if this analysis
shows that an available piece of equipment is not suit-
able, then there are simple techniques for moving away
from micro-mixing control, principally by slowing the
reactions down either by dilution or manipulation of
pre-equilibria.
In a semi-batch reactor, meso mixing-comes in be-
tween micro- and macro-mixing depending upon the rate
of feeding reagents. In this case the details of the feed
pipe, the turbulence characteristics of the feed and reac-
tor contents at the addition point are all important and
the design to achieve a required selectivity becomes more
di$cult. It is not possible to match the performance of
a full-scale reactor exactly at small scale and more de-
tailed analysis is required if the reactions cannot be
manipulated to move into macro rather than meso mix-
ing control.
A recent example of what should have been a relatively
simple reactor design for a known set of fast competing
reactions gives a clear lesson to pay attention to the
details. The reaction in question is between a dihalo
compound and an alcohol in the presence of a methoxide
species (Fig. 19).
The methoxide also reacts with the dihalo compound
(Fig. 20).
At the reaction conditions, the time constants for these
reactions are: 2.3 s for the dihalo and 0.2 s for the prod-
uct-forming reaction. These should be free of any e!ect of
micro- and meso-mixing provided a local energy dissipa-
tion rate (e) of 0.75 W kg\ is achieved and even reason-
ably free for e'7.5;10\ W kg\. The full-scale
reactor design easily delivered this level of turbulent
energy, but no commissioning, the full-scale yield was
poor compared to the laboratory. On further inspection,
Fig. 20. Competing reaction of methoxide and dihalo.
it was established that the dip leg used to direct the
reagent addition into the high-intensity region inside the
stirred tank reactor was manufactured from large dia-
meter pipe in order to achieve the necessary mechanical
strength. In practice it was established that the reaction
was taking place mainly through back di!usion into the
almost stagnant feed pipe and not in the turbulent liquid
in the vessel. A simple modi"cation rapidly overcame the
problem, but the message is clear * in many cases, the
details of the reactor design do matter.
4. Looking to the future
So far in this paper we have reviewed the state of the
art in current technology; why reactors are like they are,
what the shortcomings and problems are, what the time
and cost constraints on development and design are. It is
now useful to look at what technologies could enable
major advances, but "rstly what the pressures driving the
need for change are.
4.1. Drivers for change
The overriding pressures for change are very obvious:
(1) The desire to keep ahead of changes in environ-
mental, safety and health legislation and to set the
agenda for improvement.
(2) The need to retain competitive advantage in order to
maintain a healthy business and to retain the ability
to provide future investment, secure employment
and improve the quality of life for society.
These are both very broad statements and very laudable,
but what do they mean in practice and why do they
generate pressure for change?
 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322
The desire to keep ahead of legislation is fairly obvi-
ous. Whilst it is a legal duty to keep within the require-
ments, by anticipating change and keeping ahead it is
possible to put pressure on competition, and to have
a very positive in#uence on the direction and speed of
change. There is, obviously, a business case to be ana-
lysed concerning the level of retrospective investment
which can be justi"ed in support of improvements to the
impact on the environment of the manufacture and use of
existing products. However, for new products there is an
opportunity to implement new and improved techno-
logy. It is clear that the allowable levels of emissions of
materials to the environmental and the levels of impu-
rities in products reduces steadily as developments in
analytical techniques improve the ability to quantify im-
purities to lower and lower levels with accuracy. The
implications on reaction engineering are:
(1) More speci"c chemistry, producing fewer by-prod-
ucts and at lower levels.
(2) Greater control over reaction selectivity, to go hand
in hand with more speci"c chemistry, by improved
reactor selection and design.
(3) Introducing fewer molecules into the supply chain,
which do not appear in the "nal product.
(4) Enhanced levels of containment and reduced fugitive
emissions.
(5) The ability to recover and even process by-products
into products.
(6) Where by-products are formed, the ability to ensure
that they are not harmful in themselves nor trans-
form to harmful materials on further processing, in
e%uent treatment systems nor in the product.
Maintaining competitive advantage involves more cost
e!ective manufacturing, whilst still keeping ahead of the
legislative SHE requirements. All of the above comments
concerning legislative pressures apply here. In addition, it
is necessary to:
(1) Reduce variable costs, usually this means improving
raw materials e$ciency, i.e. higher yields, and using
low cost materials.
(2) Improve capital productivity, i.e. less capital invest-
ment per unit of capacity.
(3) Develop and implement the most cost e!ective pro-
cess; a combination of the chemical route, i.e. the raw
materials and solvents, and the processing, i.e. the
equipment design, the losses to e%uent in recovery
and puri"cation stage, the use of recycled materials,
the robustness and control.
4.2. Potential useful technologies
With these targets in mind, what advances in techno-
logy will be useful in moving forward?
319
4.3. Telescoped process and isolation stages
This is a general heading rather than a speci"c piece of
technology, but is of such great potential importance that
it is worthy of discussion in its own right. At the broadest
level, every isolation and puri"cation stage generates
e%uent, no matter how `e$cienta it is. Simplistically
therefore, reducing the number of stages automatically
reduces the e%uent load. Whilst this approach does not
in any way address the nature of the e%uent generated,
nevertheless it is a good general rule of thumb that
technology which removes the need for separations or
enables reactions to be operated together or `in situa will
have a positive e!ect on the cost of minimising the SHE
impact. However, there will be examples where removing
inter stage separation can lead to drastic problems, espe-
cially where an impurity carried forward from an early
process stage can react to produce a particularly prob-
lematic impurity later in the process. Carpenter (2000)
describes an industrial example where an impurity at
0.1% in solution inhibited the crystal growth of the
product so badly that isolation by crystallisation and
conventional separation became impossible. Without the
impurity, large, easily handled product crystals could be
formed with no di$culty. Tools which facilitate the rapid
evaluation of process options and allow the prediction of
potential cost savings and e%uent reduction within very
tight time scales with limited laboratory data would be
very useful here.
4.4. Ability to select processing options
In a similar way tools to facilitate the rapid selection of
a process and route option close to the best with very
limited information very early in the development phase
would be valuable. The ability to develop options rad-
ically di!erent to `conventional technologya for any
given organisation becomes less and less feasible the
further the development has proceeded down the project
plan. The ability to generate route and process options
and compare them, considering the total supply chain for
the product, enables the reaction engineer to focus on
developing those options closest to the best rather than
optimising a process which is inherently inferior to an
alternative which had not been identi"ed, or had been
ruled out because of lack of ability to make a sound
judgement on limited information.
4.5. Catalysis
The most likely means of progressing towards more
speci"c chemistry, producing fewer by-products and at
lower levels is via developments in catalysis, both the
availability of novel catalysts and the ability to design
catalysts for their ability to hold the target molecule in
the exact position necessary for regio-speci"c synthesis.
320 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322
There are currently many advances in this area. For
example, the work of Gellman and co-workers (McFad-
den, Cremer & Gellmann, 1996; Buelow & Gellmann,
1998) developing the potential to design `chirala metal
surfaces could, in the long term, form the basis of a novel
approach to developing solid catalysts for regio-speci"c
chemistry. There have also been recent signi"cant ad-
vances in the development and use of liquid-phase homo-
geneous catalysts, for example, the catalytic asymmetric
transfer hydrogenation technology developed by Blacker
(1998) using group VIII metal cyclopentadienes for the
manufacture of optically active alcohols and secondary
amines. Blacker (1998) also describes the development of
a large scale process using organozinc reagents with
an optically active catalyst for asymmetric alkylation
reactions.
Some years ago, biocatalysis became a very popular
topic for research and there were great hopes for its use in
enabling shorter synthesis routes, getting to `di$culta
molecules directly in one step given the right biocatalyst.
Although the high costs of development and generally
high e%uent loads have meant that many otherwise
promising biotransformations have not been able to
compete with synthetic chemistry alternative routes,
there are still cases where a biotransformation provides
the most cost e!ective and occasionally the only real
feasible route particularly when developed together with
the up and downstream chemical stages. Blacker and
Holt (1997) describe the combined development of
a chemical and biological route to an optically active
intermediate for an anti-glaucoma drug. This was prefer-
red over a prior purely synthetic alternative.
4.6. Supported reagents
The use of reagents supported, for example, on poly-
mer beads, has been developed as a very e!ective means
of assembling amino-acids into peptides. Atherton and
Sheppard (1989) give a comprehensive review of the tech-
nology and a comparison to solution-phase chemistry.
A potentially attractive extension of the peptide techno-
logy is to move to the synthesis of small molecules by this
technique, a major advantage being that with the advent
of automated laboratory synthesis, the initial samples of
an active compound will most likely have been made this
way and therefore the development process may be
shortened if a cost e!ective supported route can be de-
veloped in stead of a traditional wet chemistry route.
However, there are many potential disadvantages with
the technique, not least the very large quantities of waste
solvents generated by the multiple washings and the
many protecting groups which are added and removed.
There must be potential for improved operation and
reduced e%uent loading by more e!ective reactor design.
The current technology is e!ectively simply a large scale
version of the laboratory glassware. One di$culty is the
solvent swelling of the polymer support. In practice, this
facilitates rapid di!usion to the active sites. The current
supports used for synthesis will commonly swell to 10
times their dry volume, i.e. in the swollen state the di!er-
ence between the solvent and polymer phases is only
10% polymer holding the gel phase together. A greater
understanding of the swelling properties and the physical
properties of the swollen gel phase could lead to im-
proved reaction engineering and reactor development.
4.7. Reduced solvent and solvent free processing
Whilst in most reactions the presence of a solvent
phase is necessary for a speci"c chemical function, for
example, to provide a solvated intermediate suitable for
the desired reaction selectivity or rate, in many examples,
the actual amount of solvent is potentially a matter of
choice. It would not be uncommon for the development
team to arrive at a concentration of solvent which in their
judgement can be handled easily in a traditional stirred
tank reactor. Given the very great incentive to reduce the
amount of solvent in a synthesis chain, and preferably to
remove solvents altogether, there is signi"cant potential
for improved processes by a greater understanding of the
ability to handle non-Newtonian high-viscosity reaction
masses in traditional equipment. There is also scope for
further development of specialised high-viscosity reac-
tion processing equipment. One severe limitation on the
development of higher viscosity processes is the very
limited availability of laboratory equipment suitable for
such materials.
4.8. Selectivity through reactor design
Selecting the most appropriate reactor type to obtain
maximum selectivity should be regarded as a normal part
of the reaction engineer's and development team's role,
and not really `looking to the futurea. However, it is
worth noting two areas: the problem of traditionally
narrow approach of the organic chemist with research
and chemical focus; and the potential impact of new
reactor technology. In the former case, the task is one of
education and collaboration; ensuring that where a reac-
tor type has a signi"cant impact on the selectivity and
potential feasibility of a chemical; route, it is recognised
in order not to rule out potentially attractive options
simply through the use of inappropriate laboratory
equipment. In the latter case, two reactor types have
promise for improved "ne chemicals processing; pulsatile
#ow and membrane-reactors.
Although pulsatile #ow technology has been well re-
searched (e.g. Stonestreet & van der Veeken, 1999) and in
liquid extraction columns, used at large scale for many
years, it has had little impact to date on reactor techno-
logy in most of the chemical industry. In the case of "ne
chemicals manufacture, however, it opens up the
 K. J. Carpenter / Chemical Engineering Science 56 (2001) 305}322
potential to operate reactions which have signi"cant resi-
dence time requirements, i.e. minutes to hours, in simple
pipe work, with relatively small pumps and feed vessels.
The bene"ts could well be improved selectivity by close
control of residence time and temperature/concentration
pro"les, along with improvements capital e$ciency, or at
least at no higher cost than current semi-batch stirred
tank, or multiple CSTR technology. Here the challenge
appears to be directed more towards industry to imple-
ment what is known, rather than necessarily requiring
further academic research. In the simplest case, the pul-
satile #ow reactor is a very useful laboratory or semi-
technical scale device, being able to give plug #ow and
well controlled RTD without having to use high #ow
rates and large quantities of materials, which would,
otherwise, be required to achieve turbulence in small
scale equipment.
Similarly much research has been carried out on the
application of coupled membrane separators and reac-
tors, particularly in biotransformations. They o!er the
ability to remove reaction products from the reaction
mass, thereby, avoiding the possibility of further reaction,
catalyst poisoning, or inhibition of the biocatalyst by the
product. In many ways, they o!er an alternative to the
transfer of reaction products into another liquid or solid
phase in more traditional reaction chemistry, but poten-
tially removing excess solvent phases. In this case, the
obstacle to further implementation in "ne chemicals
manufacture appears to be the high installed cost of the
equipment and a concern over the robustness of mem-
branes, with potential high replacement costs or poor
reliability in chemical service. There has also been to date
potential restrictions on the reaction conditions which
many commercially available membrane systems can
tolerate.
4.9. Other enabling technologies
There are many other technologies where advances in
the state-of-the-art could facilitate improvements in "ne
chemicals reactor design and development, too numer-
ous to cover here. However, worthy of a brief mention are
the potential for advances in on- and at-line analytical
techniques leading to closer control of reactor conditions
and reactant concentrations, improved understanding of
selectivity in multi-phase systems and the use of novel
solvent systems, e.g. supercritical or near-critical ma-
terials, which may open up new chemical synthesis
opportunities or facilitate solvent recover or product
puri"cation or control over physical form.
5. Conclusions
Fine chemicals reaction engineering requires a good
appreciation of the complex organic chemistry involved,
321
and is only really at its best where there is close collab-
oration and mutual understanding between the engin-
eers, organic chemists and physical chemists along with
experience in analysis and control.
There are tight time and cost constraints on the pro-
cess development, which the selection and design of reac-
tors is an integral part of. Although the reactor
technology is at the heart of the chemical process, it
cannot be developed in isolation from the rest of the
manufacturing, nor indeed from the rest of the total
product supply chain.
There are many reasons why current reactor techno-
logy is as it is, which are understandable on the grounds
of cost, SHE impact, ease of operation, robustness and
#exibility. However, there are still signi"cant problems to
be overcome and areas for improvement driven by in-
creasing cost pressures, and the desire or even necessity
to force down the impact of the manufacture and use of
"ne chemicals on the environment. There are a number of
examples where further academic research or better im-
plementation of known but novel technology could lead
to signi"cant improvements and real practical bene"ts.
Acknowledgements
Permission to publish from Zeneca Agrochemicals is
gratefully acknowledged. Avecia are acknowledged for
permission to publish information concerning #uoroben-
zene manufacture.
Thanks to a great many friends and colleagues for
advice and information, especially:
Dr. Brian Cox, Dr. Colin Brennan, Dr. Alan Hall of
Zeneca Agrochemicals Process Studies Group.
Dr. John Crosby of AstraZeneca Pharmaceuticals.
Jim Amodeo of GB Biosciences.
Dr. Steve Brown, Dr. Jacqui Campbell of Zeneca
Agrochemicals Process Technology Department.
Dr. Peter Plant recently retired from Zeneca Ag-
rochemicals Manufacturing and Supply.
Neil Ward of Zeneca Agrochemicals International
Engineering.
Dr. John Atherton and Dr. John Blacker of Avecia
Process Technology.
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