Microfluidic combinatorial chemistryPaul Watts� and Stephen J Haswell
Microreactors are finding increasing application in the field of
combinatorial chemistry. In the past few years, microreactor
chemistry has shown great promise as a novel method on which
to build new chemical technology and processes. It has been
conclusively demonstrated that reactions performed within
microreactors invariably generate relatively pure products in high
yield. One of the immediate and obvious applications is therefore
in combinatorial chemistry and drug discovery.
AddressesDepartment of Chemistry, University of Hull, Cottingham Road,
Hull, HU6 7RX, UK�e-mail: [email protected]
Current Opinion in Chemical Biology 2003, 7:380–387
This review comes from a themed issue on
Combinatorial chemistry
Edited by Samuel Gerritz and Andrew T Merritt
1367-5931/03/$ – see front matter� 2003 Elsevier Science Ltd. All rights reserved.
DOI 10.1016/S1367-5931(03)00050-4
AbbreviationsDBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCC N,N-dicyclohexylcarbodiimide
DMF dimethylformamide
EOF electroosmotic flow
IntroductionMicroreactors consist of a network of micron-sized chan-
nels (typical dimensions are in the range 10–300 mm)
etched into a solid substrate (see, for example, [1–9]
for introductory overviews). They may be fabricated from
a range of materials including glass, silicon, quartz, metals
and polymers using a variety of fabrication techniques
including photolithography, hot embossing, powder blast-
ing, injection moulding and laser microforming [10]. For
glass microreactors, photolithographic fabrication of chan-
nel networks is performed as shown schematically in
Figure 1 [11,12].
For solution-based chemistry, the channel networks are
connected to a series of reservoirs containing chemical
reagents to form the complete device with overall dimen-
sions of a few centimetres, as illustrated in Figure 2.
Reagents can be brought together in a specific sequence,
mixed and allowed to react for a specified time in a
controlled region of the channel network using either
electrokinetic (electroosmotic and electrophoretic) or
hydrodynamic pumping. For electrokinetically driven
systems, electrodes are placed in the appropriate reser-
voirs to which specific voltage sequences can be delivered
under automated computer control [13–16]. This control
offers a simple but effective method of moving and
separating reactants and products within a microreactor,
without the need for moving parts. In comparison, hydro-
dynamic pumping uses conventional or microscale pumps
(notably syringe pumps) to manoeuvre solutions around
the channel network; however, this technique has the
disadvantage of requiring either large external pumps or
complex fabrication of small moving parts.
A concerted effort has now begun to establish the benefits
that microreactors can bring to the field of reaction
chemistry. For example, the ability to manipulate reagent
concentrations in both space and time within the channel
network of a microreactor provides an additional level of
reaction control that is not attainable in bulk stirred
reactors, where concentrations are generally uniform
[17��]. Consistent with this notion, many reactions have
been demonstrated to show altered reactivity, product
yield and selectivity when performed in microreactors as
compared with conventional bench-top glassware [18��].
To date, the outcome of the reported research has con-
firmed that microreactor methodology is applicable to
performing both gas- and liquid-phase reaction chemistry
[18��]. From the work cited in this article, the evidence is
that the unique modus operendi of microreactors, namely
the low-volume spatial and temporal control of reactants
and products in a laminar flow diffusive mixing environ-
ment in which distinct thermal and concentration gradi-
ents exist, offers a novel method for the chemical
manipulation and generation of products. In short, micro-
reactors are new, safe and more atom-efficient tools with
which to generate molecules and increase our knowledge
of complex chemical processes.
Reactions performed in microreactorsMost reactions that have been performed in microreactors
have been conducted simply to demonstrate proof of
principle. A summary of the reactions that have been
performed in microreactors to date is presented in Table 1
and these are reviewed in detail in [18��].
This section reviews reactions that have been performed
within microreactor systems specifically with combina-
torial applications.
Skelton and co-workers [19�,20�] have reported the appli-
cation of microreactors, prepared from borosilicate glass,
for the Wittig reaction. They used the microreactor to
380
Current Opinion in Chemical Biology 2003, 7:380–387 www.current-opinion.com
prepare the cis- and trans-nitrostilbene esters 1 and 2 using
the Wittig reaction (Figure 3a). Several features such as
stoichiometry and stereochemistry were investigated.
When two equivalents of the aldehyde 3 to the phospho-
nium salt 4 were used in the reaction, a conversion of 70%
was achieved. The microreactor demonstrated an
increase in reaction efficiency of 10% over the traditional
batch synthesis. The reaction stoichiometry was subse-
quently reduced to 1:1, but using continuous flow of
reagents, as above, the conversion was poor (39%). The
conversion was increased to 59% using an ‘injection’
technique, where ‘slugs’ of 4 were injected into a con-
tinuous flow of the aldehyde 3.
The research was further extended to investigate the
stereochemistry of the reaction. The ratio of isomers 1and 2 was controlled by altering the voltages applied to
the reagent reservoirs within the device, which in turn
affected the electroosmotic flow (EOF) and electrophore-
tic mobility of the reagents. The variation in the external
voltage subsequently altered the relative reagent concen-
tration within the device, producing Z/E ratios in the
region 0.57–5.21. In comparison, the authors report that
when a traditional batch synthesis was performed using
the same reaction time, concentration, solvent and stoi-
chiometry, a Z/E ratio of approximately 3:1 was observed.
This demonstrated that significant control was possible in
a microreactor compared with batch reactions. The
authors also demonstrated that the microreactor could
to used as a tool for the rapid reaction development and
optimisation based on analogue chemistry by using other
aldehydes in the reaction [19�,20�].
Carbanion chemistry is one of the most common methods
of C–C bond formation used in the pharmaceutical
industry. The temperature of the reaction often governs
the stereochemistry of the product, hence microreactors
have a considerable attraction because the reactor
enables excellent temperature control to be attained.
Wiles et al. [21�] have recently demonstrated the use
of silyl enol ethers in the aldol reaction within a micro-
reactor. Quantitative conversion of the silyl enol ethers to
Figure 1
PhotoresistMask
Metal layer
Photoresist exposedto light through mask
•
Top block thermally bondedto form microchannel
•
Photoresist andmetal removed
•
Exposed glassetched
•
Photoresist developedand exposed metaletched
•
Current Opinion in Chemical Biology
Photolithographic fabrication of microreactors.
Figure 2
A borosilicate glass microreactor.
Microfluidic combinatorial chemistry Watts and Haswell 381
www.current-opinion.com Current Opinion in Chemical Biology 2003, 7:380–387
Table 1
Reactions conducted in a microreactor.
Reaction Chip material Solvent Conversion (%) Comments Refs
Suzuki Glass Aq THF 67 EOF [28]Kumada coupling Polypropylene THF 60 Syringe pump [29]
Nitration Glass Benzene 65 EOF [30]
Enamine Glass MeOH 42 EOF [31]
Diazo coupling Glass MeOH 37 EOF [32]
MeCN 22
Diazotisation Glass DMF/H2O 52 Syringe pump [33]
Photocyanation Polymer Pyrene/H2O 73 Syringe pump [34]
Dehydration Glass/PDMS EtOH 85–95 EOF or syringe pump [35]
Esterification Glass/PDMS EtOH 30 Syringe pump [36]
Photochemical Silicon/quartz (CH3)2CHOH 60 Syringe pump [37]
Photochemical Glass MeOH 80 Syringe pump [38]
Phase transfer Glass EtOAc 100 Syringe pump [39]
Fluorination Ni or Cu Nitrogen gas 90–99 Syringe pump [40,41]
Fluorination Silicon/Pyrex MeOH 80 Syringe pump [42]
Oxidation Al None 75–99 Syringe pump [43]
Figure 3
PPh3.Br
NO2
CHO
CO2Et NO2CO2Et
NO2
CO2Et
4 3
OTMS
5
O
6
−O
Br
OH
8
OHC
Br
R R′ R R′
O O
EtO O10 R = Ph; R′ = Me11 R = Me; R′ = Me
12 R = Ph; R′ = Me13 R = Me; R′ = Me
EtO
O
9
iPr2EtN
1
2
+
+ NaOMe
MeOH
(a)
(b)
TBAF
THF
(c)
O O
Current Opinion in Chemical Biology
7
Reactions performed within microreactors. (a) The Wittig reaction. (b) The aldol reaction. (c) Michael addition.
382 Combinatorial chemistry
Current Opinion in Chemical Biology 2003, 7:380–387 www.current-opinion.com
b-hydroxyketones was observed in 20 min in the micro-
reactor, compared with traditional batch systems where
quantitative yields were only obtained when extended
reaction times of up to 24 h were employed. One example
involved the treatment of the trimethylsilyl enol ether 5with tetra-n-butylammonium fluoride (TBAF), to gener-
ate the tetra-n-butylammonium enolate 6 in situ, followed
by condensation with p-bromobenzaldehyde 7 to give the
b-hydroxyketone 8 in 100% conversion (Figure 3b). The
reaction has also been successfully achieved using a
variety of other silyl enol ethers and aldehydes, which
demonstrates that microreactors may be used in the
synthesis of combinatorial libraries.
Similarly, Wiles et al. [22�] have also reported the pre-
paration of the enolates from a series of 1,3-diketones
using an organic base and their subsequent reaction with a
variety of Michael acceptors such as 9 to afford 1,4-
addition products within a microreactor (Figure 3c).
When using a continuous flow of reagents 9 and 10, 15%
conversion to the adduct 12 was observed, compared with
56% when the diketone 11 was reacted with 9 forming the
Michael adduct 13. The authors, however, demonstrated
enhancements in conversions through the application of
the stopped-flow technique. This procedure involved the
mobilisation of reagents through the device for a desig-
nated period of time, using an applied field, and the flow
was subsequently paused by the removal of the applied
field, before re-applying the field. Using the regime of
2.5 s on and 5 s off, the conversion to the product 12 was
improved to 34%, whereas lengthening the stopped-flow
period to 10 s, resulted in a further increase to 100%. This
was compared to the preparation of 13, in which the
regime of 2.5 s on and 5 s off resulted in an increase in
conversion to 95%. This demonstrated that the enolate of
2,4-pentanedione 11 was more reactive than the corre-
sponding enolate of benzoyl acetone 10. The authors
propose that the observed increase in conversion, when
using the technique of stopped flow, was due to an
effective increase in residence time within the device
corresponding to the different kinetics associated with
these reactions. This approach is clearly relevant to those
wishing to study the kinetics of such reactions and the
results demonstrate the ease with which reactions may
be optimised in microreactors when conducting com-
binatorial synthesis.
Although the previous result demonstrates the ease with
which reaction conditions may be optimised, it is still
sometimes necessary to heat reactions to achieve high
yields of products. Industrially, special equipment is
required when performing large-scale reactions at ele-
vated temperature. However, Garcia-Egido et al. [23��]have demonstrated the synthesis of a series of 2-ami-
nothiazoles using a Hantzsch synthesis within a micro-
reactor. The paper represents the first example of a
heated solution-based organic reaction within a glass
microreactor under EOF conditions. The T-shaped
microreactor was heated to 708C using a Peltier heater,
which was aligned with the channels, and the heat gen-
erated by the device was applied to the base of the
microreactor. Reaction of a-bromoketones such as 14with a thiourea derivative such as 15, using N-methyl-
pyrrolidinone as solvent, resulted in the preparation of the
aminothiazoles 16 in up to 85% conversion (Figure 4a).
Fernandez-Suarez et al. have reported the synthesis of
cycloadducts in a microreactor using hydrodynamic dri-
ven flow [24�]. The reactions consisted of Knoevenagel
condensation of an aldehyde 17 with a 1,3-diketone 18with ethylenediamine acetate (EDDA) as catalyst, in
aqueous methanol as solvent. The reaction intermediate
underwent an intramolecular hetero-Diels-Alder reaction
to form cycloadduct 19 in 60–68% conversion (Figure 4b).
Initially, four different compounds were prepared indi-
vidually but the research was extended to a multi-reaction
experiment where all compounds were prepared in a
single run.
Watts et al. [25,26��] have recently demonstrated the first
example of a multi-step synthesis in a microreactor, using
their devices in peptide synthesis. The authors evaluated
the reactor using a carbodiimide coupling reaction of
Fmoc-b-alanine 20 with the amine 21 to give the dipep-
tide 22 (Figure 4c). When stoichiometric quantities of the
reagents were used, only ca 10% conversion to dipeptide
22 was achieved. By using two equivalents of N,N-dicy-
clohexylcarbodiimide (DCC), however, an increase in
conversion to ca. 20% was observed, and by applying a
stopped flow technique (2.5 s injection length with stopped
flow for 10 s) the conversion of the reaction was further
increased to approximately 50%. Using five equivalents of
DCC, a conversion of up to 93% of 22 was obtained using
the stopped-flow technique.
The authors also demonstrated that the dipeptide could
be prepared from pre-activated carboxylic acids [25,26��].They reported that the reaction of the pentafluorophenyl
(PFP) ester of Fmoc-b-alanine 23 with the amine 21 gave
the dipeptide 22 quantitatively in 20 min (Figure 4d).
This represented a significant increase in yield compared
with the traditional batch synthesis, where only a 50%
yield was obtained in 24 h.
Having demonstrated that peptide bonds could be suc-
cessfully formed when using a microreactor, the authors
then found that they could extend the methodology
to the preparation of longer-chain peptides. Using the
microreactor, the Dmab ester of Fmoc-b-alanine 24was reacted with one equivalent of piperidine or 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) to give the free
amine 21 in quantitative conversion. This is in compar-
ison with solid-phase peptide synthesis where 20%
Microfluidic combinatorial chemistry Watts and Haswell 383
www.current-opinion.com Current Opinion in Chemical Biology 2003, 7:380–387
piperidine in dimethylformamide (DMF) is frequently
employed, which demonstrates the atom efficiency of
reactions performed within the devices. The authors then
reacted the amine in situ with the pentafluorophenyl ester
25 to give the dipeptide 26 (Figure 5a) in 96% overall
conversion.
Having shown that more complex peptides could be
produced by removal of the N-protecting group, the
authors then demonstrated that they could remove the
Dmab ester using hydrazine. The reaction of the Dmab
ester 24 with one equivalent of hydrazine resulted in
quantitative deprotection, to afford the carboxylic acid 20(Figure 5b). This is in comparison to solid-phase peptide
synthesis where 2% hydrazine in DMF is generally
required to effect complete deprotection.
The authors have further extended the approach to the
synthesis of tripeptide 28 [26��]. Reaction of pentafluoro-
phenyl ester 23 with amine 21 formed dipeptide 22,
which was reacted with DBU to effect Fmoc deprotec-
tion. The amine 27 was then reacted in situ with another
equivalent of pentafluorophenyl ester 23 to prepare tri-
peptide 28 in 30% overall conversion (Figure 5c). The
approach clearly demonstrates that intermediates may be
generated in situ and used in subsequent reactions,
enabling the combinatorial synthesis of peptides, which
are of biological and pharmaceutical interest.
Having demonstrated that peptide bonds could be suc-
cessfully formed when using a microreactor, the authors
then investigated racemisation in peptides derived from
a-amino acids [27]. Reaction of the pentafluorophenyl
ester of R-2-phenylbutyric acid 29, at 0.1 M concentra-
tion, with a-methylbenzylamine 30, gave the product 31in quantitative conversion with 4.2% racemisation
(Figure 5d). Importantly, there was less racemisation than
observed in the batch reaction at the same concen-
tration and temperature. The reduced level of racemisa-
tion was attributed to the reduced reaction times
observed within the microreactors. This demonstrates
that there would be real advantages to performing com-
binatorial chemistry in microfluidic reactors compared
with traditional batch systems.
Figure 4
Br
O
NH
NH2
SO
NH
S
NO
H
O
N
N
O
OO
O N
N
O
O
H
H
14 15+
16
17
EDDA
19
FmocHN OH
O H2N ODmab
O
20
21
DCC, DMF
FmocHNH
O
22
ODmab
O
FmocHN OPFP
OH2N ODmab
O
FmocHH
O
ODmab
O
23
21
DMF 22
(a)
(b)
+
(c)
N
18
N
(d)
Current Opinion in Chemical Biology
Reactions performed within microreactors. (a) Hantzsch reaction. (b) Cycloadduct formation. (c,d) Peptide bond formation reactions.
384 Combinatorial chemistry
Current Opinion in Chemical Biology 2003, 7:380–387 www.current-opinion.com
ConclusionsMicroreactor chemistry is currently showing great pro-
mise as a novel method on which to build new chemical
technology and processes. Reactions performed in a
microreactor invariably generate relatively pure products
in high yield, in comparison to the equivalent bulk
reactions, in much shorter times and in sufficient quan-
tities to perform full instrumental characterisation. One of
the immediate and obvious applications is therefore in
combinatorial chemistry and drug discovery, where the
generation of compounds either with different reagents or
under variable conditions is an essential factor. An inter-
esting twist to the chemistry carried out to date is not just
the opportunity to separate reactants and products in real
time but also the capability to manufacture and use
reagents in situ.
The success of pharmaceutical companies resides largely
on the ability to synthesise novel chemical entities and to
optimise the production of marketable drugs. In an
Figure 5
FmocHN ODmab
O
24
DBU
DMFH2N ODmab
O
21
BocHN OPFP
O
25DMF
BocHN
O
26
ODmab
O
FmocHN ODmab
O
24
FmocHN OH
O
20
NH2NH2
DMF
FmocHN OPFP
O
23
H2N ODmab
O
21FmocHN N
H
O
22ODmab
O
DBU
FmocHN NH
O
NH
O
28
ODmab
OFmocHN OPFP
O
23
H2 N NH
O
27
ODmab
O
OPFP
O
Ph29
H2 Ph
Me30
NH
O
Ph31
Ph
Me
(a)
NH
(b)
(c)
(d)
N
Current Opinion in Chemical Biology
Peptide synthesis within microreactors.
Microfluidic combinatorial chemistry Watts and Haswell 385
www.current-opinion.com Current Opinion in Chemical Biology 2003, 7:380–387
industry where development costs are extraordinarily
high and attrition rates from lead generation onwards
are about 98%, careful lead selection and ruthless pres-
sure to shorten optimisation times are crucial for survival,
microreactor technology could certainly help meet these
criteria.
References and recommended readingPapers of particular interest, published within the annual period ofreview, have been highlighted as:
� of special interest��of outstanding interest
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17.��
Fletcher PDI, Haswell SJ, Zhang X: Electrokinetic control of achemical reaction in a lab-on-a-chip micro reactor:measurement and quantitative modelling. Lab on a Chip 2002,2:101-112.
This paper demonstrates the spatial and temporal control achievablewhen performing a reaction in a microreactor under electrokinetic flow.Specifically, Ni2þ ions are reacted with a ligand to produce a complex.The results demonstrate that Ni2þ ions have a greater electrophoreticvelocity than the neutral ligand.
18.��
Fletcher PDI, Haswell SJ, Pombo-Villar E, Warrington BH,Watts P, Wong SYF, Zhang X: Micro reactors: principles andapplications in organic synthesis. Tetrahedron 2002,58:4735-4757.
This review article gives a detailed account of the fabrication and opera-tion of microreactors. The paper gives a detailed account of all gas phase,liquid phase and catalysed reactions performed in microreactors to date.
19.�
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20.�
Skelton V, Greenway GM, Haswell SJ, Styring P, Morgan DO,Warrington B, Wong SYF: The generation of concentrationgradients using electroosmotic flow in micro reactors allowingstereoselective chemical synthesis. Analyst 2001, 126:11-13.
This paper uses a borosilicate glass microreactor, operating underelectrokinetic control, to prepare stilbenes using the Wittig reaction. Itdiscusses how the Z/E ratio of isomers changes depending on theelectrokinetic parameters used.
21.�
Wiles C, Watts P, Haswell SJ, Pombo-Villar E: The aldol reactionof silyl enol ethers within a micro reactor. Lab on a Chip 2001,1:100-101.
This paper illustrates how a selection of enolates may be prepared in situwithin microreactor devices. The enolates are subsequently reacted witha range of aldehydes to form a variety of aldol products in high yield.
22.�
Wiles C, Watts P, Haswell SJ, Pombo-Villar E: 1,4-Addition ofenolates to a,b-unsaturated ketones within a micro reactor.Lab on a Chip 2002, 2:62-64.
This paper prepares a range of Michael adducts by reaction of a selectionof diketones with an organic base in a microreactor. The paper illustratesthat microreactors may be used to study the kinetics of reactions.
23.��
Garcia-Egido E, Wong SYF, Warrington BH: Synthesis of athree-member array of cycloadducts in a glass microchipunder pressure driven flow. Lab on a Chip 2002, 2:170-174.
This paper demonstrates that an array of compound may be simulta-neously produced within microreactor devices operating under pressure-driven flow. This methodology may be used for a combinatorial library ofcompounds.
24.�
Fernandez-Suarez M, Wong SYF, Warrington BH: A Hantzschsynthesis of 2-aminothiazoles performed in a heatedmicroreactor system. Lab on a Chip 2002, 2:31-33.
This paper reports a convenient method of heating a reaction in amicroreactor by aligning a Peltier heating device with the fluidic channels.It is demonstrated how such devices may be applied to combinatorialchemistry.
25. Watts P, Wiles C, Haswell SJ, Pombo-Villar E, Styring P: Thesynthesis of peptides using micro reactors. Chem Commun2001:990-991.
26.��
Watts P, Wiles C, Haswell SJ, Pombo-Villar E: Solution phasesynthesis of b-peptides using micro reactors. Tetrahedron 2002,58:5427-5439.
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