Continuous-flow generation of anhydrous diazonium species: Monolithic microfluidic reactors for the chemistry of unstable intermediates

Article abstract of DOI:10.1021/op025586j

Monolithic microfluidic reactors for the safe, expedient, and continuous synthesis of products involving unstable intermediates were fabricated and assessed. The formation of diazonium salts in anhydrous conditions and their subsequent in situ chlorination within microfiuidic channels under hydrodynamic pumping regimes is presented. Significant enhancements in yield were observed due to enhanced heat and mass transfer in microfluidic systems. Analysis performed using off-line GC and GC-MS was compared with on-line, on-chip Raman spectroscopy for the direct determination of analytes.

Full text of DOI:10.1021/op025586j

Organic Process Research & Development 2003, 7, 762−768
Technology Reports
Continuous-Flow Generation of Anhydrous Diazonium Species: Monolithic
Microfluidic Reactors for the Chemistry of Unstable Intermediates
Robin Fortt, Robert C. R. Wootton, and Andrew J. de Mello*
Department of Chemistry, Imperial College London, Exhbition Road, South Kensington SW7 2AZ, U.K.
-
1
Abstract:
velocity (m s ), A is the cross sectional area of channel
2
Monolithic microfluidic reactors for the safe, expedient, and
continuous synthesis of products involving unstable intermedi-
ates were fabricated and assessed. The formation of diazonium
salts in anhydrous conditions and their subsequent in situ
chlorination within microfluidic channels under hydrodynamic
pumping regimes is presented. Significant enhancements in yield
were observed due to enhanced heat and mass transfer in
microfluidic systems. Analysis performed using off-line GC and
GC-MS was compared with on-line, on-chip Raman spectros-
copy for the direct determination of analytes.
(m ), P is the wetted perimeter (m), and µ is the absolute
-
1
-1
fluid viscosity (kg m s ). When Reynolds numbers are
greater than 2000, turbulence is dominant, whereas at
Reynolds numbers below 100, laminar flow is the norm.
Between these extremes lies a transitional region showing
both behaviours. In exceptional laminar flow systems the
degree of mixing can vary with Reynolds number, even at
values below 100. This is only the case where the reactor
channel is designed to invoke nondiffusive mixing, as
2
demonstrated recently by Liu et al. who employed the use
of chaotic advection for mixing at low Reynolds numbers.
In most microfluidic systems the channel design provides a
stable laminar flow environment, and consequently, mixing
of reagents is achieved by random molecular diffusion alone.
Knowledge of diffusion rates provides accurate information
on the degree of mixing and therefore allows a high degree
Introduction
The development of synthetic chemistry utilising micro-
fluidic devices or microfluidic reactors has been of increasing
interest in recent years. The term microfluidic reactor herein
describes reactors with characteristic dimensions most con-
veniently measured in micrometers with instantaneous reac-
tion volumes measured in the nanoliter to microliter range.
Miniaturisation of reaction systems offers several advantages
over the macroscale. These include improved mixing ef-
ficiencies and increased thermal transfer, leading to improved
reaction selectivities, low sample consumption, and higher
3
of control over the quantities and location of reagents. This
control can be understood by a comparison of reaction rates
and diffusion rates. In reactions with rates that are fast
compared to the rate of mixing, the reaction rate is
independent of the rate constant (k) and is entirely dependent
on the rate of mixing. The volume available for reaction is
reduced from the volume of the entire reaction vessel to a
plane between reacting streams. In this situation, designated
the diffusion regime, the potential for the formation of
secondary products is the greatest. In comparison, the mixing
time in the chemical regime is fast compared to the reaction
rate, and therefore mixing is complete before significant
amounts of products are present. The entire reaction vessel
is available for reaction, and the smallest amounts of
secondary products are formed. By employing techniques
1
sample throughput per unit volume.
In most conventionally scaled reactor vessels, mixing is
achieved by turbulence or eddy flow. Fluid elements of
varying sizes induced by inertial forces create a mixture that
is highly segregated with a finely dispersed structure but still
heterogeneous at the molecular level. The amalgamation of
these fluid elements is then achieved by molecular diffusion
over short intra-element distances. In typical microfluidic
systems viscous forces outweigh inertial forces, and flow
operates in the laminar flow regime. The transition between
turbulent and laminar flow is conveniently characterised by
the Reynolds number (equation 1), a dimensionless ratio of
the inertial and viscous forces.
4
such as multilamination, microfluidic reactors can perform
complete mixing in milliseconds, opening the way for
extremely efficient high-throughput synthesis.
The scale-up of processes from the laboratory to bulk and
fine chemical industries is often a complex and expensive
operation where precautions must be taken to guard against
F(4(A/P))ν
Re )
(1)
µ
(
2) Liu, R. H.; Stremler, M. A.; Sharp, K. V.; Olsen, M. G.; Santiago, O. J.;
Adreian, R. J.; Aref, H.; Beebe, D. J. J. Microelectromech. Syst. 2000, 9,
-
1
Here F is the fluid density (kg m ), ν is the average linear
190-197.
*
Author for correspondence. Fax: +44 (0) 207 594 5833. Telephone:
44 (0) 207 594 5820. E-mail: a.demello@ic.ac.uk.
1) Matlosz, M. Microreaction Technology: Industrial Prospects; Springer:
(3) Crank, J. The Mathematics of Diffusion, 2nd ed.; Clarendon Press: Oxford,
+
(
1975.
(4) Bessoth, F. G.; de Mello, A. J.; Manz, A. Anal. Commun. 1999, 36, 213-
Verlag: 2002.
215.
7
62
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Vol. 7, No. 5, 2003 / Organic Process Research & Development
10.1021/op025586j CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/31/2003

Scheme 1. Synthetic transformations from a diazonium function
reactive hazards and loss of reaction specificity. This is
especially true when the process involves the use of reactive
intermediates and events such as thermal runaway can lead
to catastrophic consequences. By operating within micro-
fluidic, continuous-flow regimes, precise manipulation of
reagent concentration, temperature, and reaction times are
possible, allowing greater control over the reaction. This
reaction control is achievable due to the large surface area-
to-volume ratios encountered on the microscale, allowing
ultrafast heating and cooling of reactants. Manipulation of
hazardous (e.g. toxic, pyrophoric, explosive, or unstable)
compounds on the microscale also allows chemical reactions
to be undertaken with increased safety due to the small
instantaneous reaction volumes involved. These advantages
have previously been demonstrated in the application of
microfluidic reactor technology to the safe generation of
singlet oxygen for the continuous-flow synthesis of ascaridole
contain all the components of a conventional catalyst test
station (feed gas manifold, reactor feed manifold, reactors,
and control circuitry) but with a dramatically smaller
footprint and a greatly reduced capital expenditure when
compared with conventional reactor plants. This may not only
decrease development time and costs but also create enough
production flexibility for on-demand, on-site production,
removing the need for storage of large quantities of danger-
ous chemicals. The application of microfluidic reactors to
industrial processes has previously been shown by Krum-
mradt et al. who examined an established multistage process
for the generation of a fine chemical from the exothermic
reaction between a carbonyl compound and an organo-
7
metallic reagent. In their study a microfluidic reactor pilot
scheme was compared to a 0.5 L flask and a technical-scale
vessel of 6000 L. The batch process was successfully
transferred to a continuous flow, miniaturised reactor process,
and increased yields were obtained. The production plant
consisting of five parallel miniaturised reactors has been used
in place of the conventional approach since August 1998.7
Motivated by these advantages, we describe herein the
application of microfluidic reactor technology to the safe,
efficient, continuous-flow chemistry of unstable intermedi-
ates. As a demonstration reaction for this study we chose
the generation of diazonium reactive intermediates in anhy-
drous conditions and their subsequent on-chip reactive
quenching. The diazotisation of aromatic amines is an
5
from R-terpinene. Studies employing a microfluidic reactor
showed that transformations of 85% or more were achievable
with irradiation times of 5 s and the use of a low intensity
light source. Furthermore, oxygenation and irradiation took
place on-chip, leading to greatly enhanced safety.
Clearly dangerous reactions can be undertaken within
microfluidic reactors in relative safety due to the small
reacting volumes involved. These reactors can also be
operated to produce large amounts of material if required.
This is achieved using the concept of “scale-out”; where
multiple microfluidic reactors are run in parallel to simulate
a large-scale flow reactor without the usual problems
associated with scaling. Scale-out can be seen as an answer
to such problems as decreased yields on scale-up, low rate
of maximum heat extraction, and the expense of high-
pressure reaction vessels. The issues of microfluidic reactor
scale-out have recently been addressed by researchers at MIT
and DuPont who have begun construction of multiple reactor
8
industrial process of vast importance, being useful for the
synthesis of a wide range of species including azo com-
pounds, biphenyls, hydroxyarenes, and chloroarenes (Scheme
1). The dangers of diazotisation are well-known: diazonium
salts being sensitive to physical agents such as heat, light,
(5) Wootton, R. C. R.; Fortt, R.; de Mello, A. J. Org. Process Res. DeV. 2002,
6, 187.
(
6) Quiram, D. J.; Patrick L.; Mills, J. F. R.; Wetzel, M. D.; Ashmead, J. M.;
Delaney, T. M.; Kraus, D. J.; McCracken, J. S.; Jensen, K. F.; Schmidt,
M. A. Technical digest of the 2000 solid-state sensor and actuator
workshop; Transducer Research Foundation: Hilton Head Island, SC, 2000.
7) Krummradt, H.; Koop, U.; Stoldt, J. Microreaction Technology: Industrial
Prospects; Springer: Berlin, 2000; p 181.
6
test stations for gas-phase systems. These microfluidic
reactor test stations contain not only microfabricated reactors
but also other micro-engineered mechanical systems (MEMS)
components for microfluidic control. A typical system may
(
(8) Zollinger, H. Diazo Chemistry I; VCH: Weinheim, 1994.
Vol. 7, No. 5, 2003 / Organic Process Research & Development
•
763

Scheme 2. Chloro-dediazotisation, the Sandmeyer reaction
shock, static electricity, and dehydration that can lead to
9
rapid, uncontrollable decompositions and explosions. Con-
ventionally diazonium chemistry is performed on the bulk
scale in quenching aqueous conditions. Diazonium chemistry
can be performed on the bulk scale in anhydrous conditions
but only by using diazonium tetrafluoroborates, certain
arenediazonium sulfonates or in the presence of complex
anions, e.g. zinc double chlorides and hexafluorophos-
Figure 1. Schematic of microfluidic reactor chip channel
pattern used in all syntheses. Identities of components A-E
provided in the text.
preformed diazonium tetrafluoroborates for the formation of
azo dyes under electrooosmotic flow (EOF) control.16
Furthermore, a fast-flowing microfluidic reactor utilizing
mixer vanes and heat exchangers for temperature control has
also been patented by Clariant where azo dyes are produced
in suspension by combination of a diazonium salt and
10
phates. Incidents of explosive decomposition of diazonium
salts caused by salt deposition or vapour-phase reaction have
been reported, and use of diazonium intermediates in industry
1
1,12
is normally subject to stringent safety procedures.
1
7
coupling agent.
For processes that occur in two or more distinct steps,
such as in the Sandmeyer reaction, the high degree of reaction
control and increased safety mentioned above makes mi-
crofluidic reactors attractive for reaction optimisation and
operation in a continuous-flow format. The difficulties
involved in large-scale Sandmeyer syntheses are numerous
Results and Discussion
In the current contribution, we demonstrate that hazardous,
reactive diazonium salts, can be generated on-chip and used
in situ in a safe and simple protocol. Initial experiments were
undertaken using two separate microfluidic devices. First,
the reagents for diazotisation were combined in a microfluidic
mixer. The resulting fluid was then transported via a fused
silica capillary interconnect to a heated microfluidic reactor
for chloro-dediazonation. Although this approach exhibits
the traditional advantages of modularity, the increased
transport distances led to precipitation and furring of the
capillary. A simpler and more elegant approach to performing
sequential reaction operations is to minimise transport
distances by incorporating both generation of the unstable
intermediate and reactive quenching into a monolithic chip
(Scheme 2). These include the thermal instability of the
diazonium intermediate, the evolution of large volumes of
gas and the difficulties raised by interaction between mixed
and unmixed strata in large vessels that can lead to unwanted
coupling reactions. Furthermore, the aqueous conditions
usually employed in diazonium synthesis limit the applicabil-
ity of the reaction to some substrates. On a large-scale precise
temperature control of process operations is needed. At
temperatures above 283 K hydroxy-dediazonation is pro-
13
moted to form the phenol in aqueous media. In the case of
reactive diazonium salts higher temperatures can lead to
1
8
design, as previously demonstrated.
reaction of the parent arene in an explosive manner even
under aqueous conditions.14 However, at low temperatures
the Sandmeyer reaction is often slow, leading to an increased
likelihood of intermediate decomposition and cross-coupling
reactions.
By incorporating reagent mixing, quench addition, and
heated decomposition operations onto a single device,
transport distances and dead volumes are minimised prevent-
ing precipitation. This is realised in the current device (Figure
1
) in the following way. The chip consists of a “tee” shaped
By using a microfluidic reactor the initial mixing of the
nitrite and an amine can be carried out in complete safety.
In addition, operating under continuous flow allows increased
reaction control, which may lead to facile process optimi-
sation, increased yields, and higher throughput per unit
volume. For example, single-function reactor chips have
inlet (A), a serpentine primary reaction sector 80 mm in
length (B), a second inlet channel (C), a 280-mm long
serpentine reaction sector at elevated temperature (D), and
an exhaust (E) at which samples may be collected for
analysis. The etched channels have an average depth of 50
µm and an average width of 150 µm and a total volume of
1
5
previously been used to react preformed diazonium salts.
In addition, Harrison et al. described a system utilising
2.55 µL. In the current system incorporating localised heaters,
a given fluid element can experience temperature variations
-
1
(
9) (a) Engel, A. In Houben-Weyl, 4th ed; Klamann, D., Ed.; Thieme-Verlag:
Stuttgart, 1990; Vol. 16a, Part 2, p 1052. (b) Wulfmann, D. S. In The
Chemistry of Diazonium and Diazo Groups, Part 1, Patai, S., Ed.; Wiley:
New York, 1978. (c) Roe, A. In Organic Reactions; Adams, R., Ed.;
Wiley: New York, 1949; Vol 5.
in excess of 100 K s . By virtue of the size of the channels
used, the convective heat-transfer coefficient is extremely
4
-2
-1
high (6 × 10 W m K ). Although glass is not normally
considered an efficient thermal conductor (thermal conduc-
tivity ) 0.937 W m K ), the overall heat-transfer
(10) Rutherford, K. G.; Redmond, W. Organic Syntheses; Wiley & Sons: New
-
1
-1
York,1973; Collect. Vol. 5, p 133.
(
(
(
(
11) Doyle, W. H. J. Loss PreV. Process Ind. 1969, 3, 14.
12) Anon. Sichere Chemiearbeit 1993, 45(1), 8.
(16) Salimi-Moosavi, H.; Tang, T.; Harrison, D. J. J. Am. Chem. Soc. 1997,
13) Hodgson, H. H. Chem. ReV. 1947, 40, 251.
14) Science of synthesis: Houben-Weyl methods of molecular transformations;
Thieme: Stuttgart, 1965; Vol. 10.3, p 1.
119, 8716.
(17) Jung, R.; Nickel, U.; Saitmacher, K.; Unverdorben, L. (Clariant). U.S. Patent
6,469,147, 2002.
(15) Greenway, G. M.; Haswell, S. J.; Petsul, P. H. Anal. Chim. Acta 1999,
(18) Wootton, R. C. R.; Fortt, R.; de Mello, A. J. Lab-On-A-Chip 2002, 2 (1),
3
87, 1.
5.
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Vol. 7, No. 5, 2003 / Organic Process Research & Development

Scheme 3. Formation of azo dyes via diazonium salts
-
2
coefficient of the device remains competitive (740 W m
-
1
K ) when compared to bulk scale reaction vessels. Micro-
fluidic reactors are also routinely fabricated from thermally
conductive materials such as silicon, silver, and nickel. The
combination of small channels and these thermally conduc-
tive materials provides extremely efficient heat dissipation
-
2
-1
(41 000 W m
K
for a silicon microfluidic reactor) and
thus allows highly exothermic reactions to occur without risk
of thermal runaway.
Figure 2. Effect of amine concentration on product yield for
the aromatic diazotisation/hydro-dediazonation reactions of
aniline, o-toluidine, and m-toluidine. Isoamyl nitrite concentra-
tion ) 10 mM.
In a previous study we investigated the formation of
diazonium salts by their in situ transformation into the azo
dye Sudan 1 and its analogues (Scheme 3). Conversions
ranging between 9 and 52% were calculated from the parent
amine by extinction coefficient, where the extent of conver-
sion is dependent on residence time and the substrate
diazotised. These initial reactions were not optimised for the
diazotisation reaction.18 GC-MS data showed a close
concordance between the extent of diazotisation of the
aminoarenes and the conversion given above. This was
ascertained from the presence of unreacted amine and
insignificant amounts of byproducts from cross-coupling
reactions, suggesting that optimisation of the diazotisation
step would lead to enhanced reaction yields. This is ad-
ditionally noteworthy as in continuous flow processing,
nitrogen evolution during the chloro-dediazonation step has
a considerable effect on the overall residence time of the
reaction but has little effect on the more significant rate-
determining diazotisation step.
Table 1. Effect of amyl nitrite concentration on product
yield for aromatic diaszotisation/hydrodiazonation reactions
substratea
amyl nitrite (mM)
yield (%)
aniline
aniline
aniline
aniline
o-toluidine
o-toluidine
o-toluidine
o-toluidine
m-toluidine
m-toluidine
m-toluidine
m-toluidine
1.0
2.0
4.0
10.0
1.0
2.0
4.0
10.0
1.0
2.0
4.0
21.7
24.0
30.0
50.5
7.7
12.6
20.8
44.8
6.7
9.5
14.5
33.2
10.0
a
Substrate concentration ) 10 mM.
The ability of the current microfluidic reactor to make
available a range of previously restricted syntheses to the
industrial chemist is confirmed by performing both the hydro
and chloro-dediazonations in anhydrous conditions. Com-
monplace hydroxy-dediazonation is eliminated, and applica-
tion to a far wider range of substrates becomes possible. The
optimisation of the diazotisation step was studied by forming
diazonium salts in anhydrous conditions with varying
concentrations of isoamyl nitrite (1-15 mM) and amine (2-
Inspection of Figure 2 and Table 1 shows that the extent
of diazotisation is heavily dependent on both substrate
concentration and isoamyl nitrite concentration. Higher
concentrations of isoamyl nitrite were not studied due to the
prohibitive viscosities of the reaction mixtures. Crude
material from the microchip effluent was submitted to GC-
MS analysis and demonstrated benzene and toluene as the
majority products. Utilising optimised concentration condi-
tions as determined for the diazotisation and hydro-dedia-
zonation above, chloro-dediazonation was subsequently
performed for three separate arylamines, each being diazo-
tised by isoamyl nitrite under identical conditions. The
ensuing reduction of the diazonium ion to the aryl radical
and its halogen abstraction from cupric chloride was observed
to be extremely efficient, resulting in conversion efficiencies
of nearly 100%, as evidenced by GC-MS analysis of the
chip effluent. This indicates that the extent of diazotisation
of the aminoarenes and the conversion rates are closely
related. Since the aim of this report is to demonstrate the
utility and versatility of microfluidic reactors for synthetic
optimisation, a full process optimisation of the Sandmeyer
reaction was not performed. Furthermore, no attempt to
optimise temperature conditions was made during this study,
10 mM), followed by thermal hydro-dediazonation to the
aryl substrate (Figure 2 and Table 1). To effect diazotisation,
isoamyl nitrite was chosen which is often used on a
laboratory scale to perform diazotisations on water-sensitive
substrates.19 Alkyl nitrites are thermally unstable and may
20
readily decompose or explode on heating; lower alkyl
nitrites have even been known to decompose and burst the
container in refrigerated storage. This has limited their use
in large-scale synthesis. By using microfluidic reactor
components, however, such materials can be utilised for
industrial processes in relative safety.
(
19) Doyle, M. P.; Siegfried, B.; Dellaria, J. F., Jr. J. Org. Chem. 1977, 42,
426.
20) SORB: safety releVant characteristic data of chemical materials 1968, 146.
2
(
Vol. 7, No. 5, 2003 / Organic Process Research & Development
•
765

Table 2. Vibrational exciton spectrum of aniline in DMFa
nor was an acid catalyst employed. It should be noted that
Sandmeyer syntheses employing alkyl nitrites can result in
yields inferior to those utilising sodium nitrite. In addition,
substrates containing alkyl groups such as the toluidines used
Raman shift (cm-1
)
molecular origin
1662
1630
solvent (DMF)
solvent (DMF)
aniline (NH
aniline (ring stretch a )
aniline (ring stretch a )
aniline (ring stretch a )
solvent (DMF)
1
9
in these experiments often result in disappointing yields.
1622
1603
1501
bend a1)
2
Although attractive as a detection method, GC is an
indirect and off-line approach to product analysis, results are
typically obtained after transfer from the reaction vessel with
analysis times typically in excess of 30 min. Direct monitor-
ing techniques such as UV-vis absorption and FT-IR could
be employed for monitoring the extent of diazotisation.
However, as glass is the favoured medium for developmental
organic chemistry these methods are impractical due to high
extinction coefficients of glass in the UV and IR regions of
the electromagnetic spectrum.
1
1
1
1
1468
1443
1408
1279
1176
solvent (DMF) 1
aniline (x-sens a )
11
aniline (CH bend ip a )
aniline (CH bend ip a )
solvent (DMF)
1
1
1155
095
1
a
1
11
Key: a ) In plane of symmetry, a ) normal to plane of symmetry, x )
2
, sens ) sensitive, ip ) in plane.
NH
Raman spectroscopy utilises monochromatic light usually
in the visible region of the spectrum and is an established
real-time, on-line fingerprinting tool for chemical identifica-
tion.21 The combination of glass microfluidic reactors and
Raman spectroscopy allows for the direct on-line detection
of analytes in situ, without need of reaction quenching.
Indeed, Raman spectroscopy has previously been used in
microfluidic systems as a detection technique for electro-
phoretic separations in both capillaries and microfabricated
channels.2 It should be noted that, due to the curved nature
of conventional capillary walls, scattered photons are in-
creasingly dispersed, generally leading to a weakened Raman
signal. However, the flat, uniform nature of microchannels
and substrate surfaces in chip-based systems reduces scatter
dispersion and ensures that scattered photons are collected
directly assess the extent of chloro-dediazonation as a
function of reaction time (inset Figure 2). Interestingly, the
disappearance of the in-plane ring-stretch band is shown to
be complete after a residence time of 600 s. This is
significantly longer than the residence time required for
complete mixing on a microfluidic reactor as defined by the
Fourier number for the system (0.55 for a flow rate of 3.1
µL min through each inlet at A). This indicates that the
reaction is occurring in the chemical domain, rather than the
diffusive domain. The utility of Raman spectroscopy for
direct detection is further demonstrated by the speed of
optimisation. The work required to establish the optimum
residence time for the chloro-dediazonation on-chip using
Raman spectroscopy involves a single reaction being moni-
tored over 600 s. Spectral acquisition times are minimal, and
data can be fed back to the pump very rapidly for the next
run. In comparison, residence time optimisation by GC
requires a series of reactions using significantly more
reagents, each monitored in series over a range of reaction
times taking up to 3 h to complete.
-
1
2,23
2
3
only from the solution and not from the glass substrate.
To demonstrate the use of Raman spectroscopy for the
direct detection and dynamic optimisation of reaction condi-
tions in microfluidic structures, solutions of aniline and
isoamyl nitrite in N,N-dimethylformamide were infused into
the microfluidic reactor at a variety of flow rates (Figure 2).
Both aniline and N,N-dimethylformamide have strong char-
In terms of safety, the range of synthetic methods
available, and the facility of optimisation, the advantages of
microfluidic reactors can be clearly seen by comparison to
a traditional laboratory-scale synthesis. In addition to these
advantages, an increase in yield by utilisation of microfluidic
reactors is also possible due to the high heat- and mass-
transfer coefficients already mentioned. To compare and
contrast reaction efficiency in a microfluidic reactor with a
traditional laboratory method, a small-scale reaction flask
of appropriate dimensions was employed, utilising the same
-
1
acteristic Raman bands between 200 and 1700 cm ,
providing ample information for sample identification (Table
2
4
2
). By monitoring for the extent of diazotization by the
disappearance of aniline bands as opposed to the formation
of the product, the reaction can be monitored in the forward
mixing section, B. The problem of disruption of the Raman
signal by evolved nitrogen bubbles is thus avoided.
For the reaction between aniline and amyl nitrite, inspec-
-
1
tion of the spectral region between 1050 and 1750 cm
1
9
illustrates direct evidence for the disappearance of aniline
as a function of time. This is possible because, as stated
above, the chloro-dediazonation reaction is near quantitative
with respect to the parent diazonium salt. Thus, any direct
monitor of the conversion of aniline serves as a marker for
the extent of chloro-dediazonation. In particular, analysis of
the in-plane ring-stretch band at 1603 cm-1 can be used to
solutions and reaction conditions. In each case significant
enhancement in yields on a microfluidic reactor (15-20%)
were obtained in contrast to bulk solutions (Figures 3 and
4). Despite the relatively low flow rate used for the reaction,
-
3
-1
a space-time yield of 75 000 mol m
h
is obtained due
to the extremely small volume of the reactor.
Microfluidic Reactor Fabrication. The glass microchip
(
footprint 40 mm × 20 mm) was made in-house using direct-
(
(
(
(
21) Van den Brink, M,; Van Herk, A. M.; German, A. L. Process Control and
Quality, 1999, 11, 265.
22) Walker, P. A.; Kowalchyk, W. K.; Morris, M. D. Analytical Chemistry
write laser lithography, wet chemical etching and bonding
techniques as previously described. Briefly, soda lime glass
substrate precoated with a positive photoresist (AZ 1518)
25
1
995, 67, 4255.
23) Walker, P. A.; Morris, M. D.; Burns, M. A.; Johnson, B. N. Analytical
Chemistry 1998, 70, 3766.
24) Tripathi, G. N. R. J. Chem. Phys, 1980, 73, 5521.
(25) Sirichai, S. C.; de Mello, A. J. Analyst 2000, 125, 133.
766
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Vol. 7, No. 5, 2003 / Organic Process Research & Development

Figure 3. Raman spectra of in-channel diazotisation reaction mixtures at various times after initial mixing. Inset shows the variation
of the integrated area of the 1603 cm-1 peak as a function of reaction time.
microfluidic devices presented herein range between 1 and
2
.1. This and the channel design ensure that only diffusive
processes mediate mixing. To allow for complete diffusion
-
1
over the serpentine sections, flow rates of 3.2 µL min
through the first two inlets were used with a balancing flow
-
1
of 6.4 µL min through the third inlet.
Experimental Section
Reagents and solvents were obtained from commercial
sources and dried using 3 Å molecular sieves.
General Method for the Continuous-Flow Synthesis
of Chloroarenes. Solutions of amine (0.1 mL, 1.1 mmol)
in N,N-dimethylformamide (2 mL) and 97% isoamyl nitrite
(0.35 mL, 2.6 mmol) in N,N-dimethylformamide (2 mL) were
prepared. These solutions were introduced into inlets A of
-
1
the reactor chip at a flow rate of 3.2 µL min using a PHD
2000 syringe pump (Harvard Apparatus, Kent, U.K.). A
solution of anhydrous copper (II) chloride (0.17 g, 1.3 mmol)
in N,N-dimethylformamide (4 mL) was introduced into inlet
Figure 4. Comparative product yields for the aromatic
diazotisation/hydro-dediazonation reactions of aniline, o-tolui-
dine, and m-toluidine using the microfluidic reactor and
conventional bulk syntheses.
-
1
B of the reactor chip at a flow rate of 6.4 µL min , and the
secondary serpentine section of the device was heated to 338
K. Heating of the secondary section was achieved by
contacting the microfluidic reactor to a heated metal block.
A continually moving stream of air cooled the first section
of the device over both upper and lower surfaces. Product
analysis was performed by GC without further purification
by comparison to spiked standardised solutions giving a
conversion by area analysis of 55-71%. GC-MS spectra
were also obtained and showed concordance.
and a low reflective chromium layer (Microfilm, Westlake
Village, California) was exposed using a DWL system
(DWL2.0, Heidelberg Instruments, Heidelberg, Germany) to
transfer the channel design. After the photoresist was
developed (Microposit 351, Shipley Europe Ltd, Coventry,
UK), the channels were etched into the glass substrate using
a buffered oxide etching solution (HF/NH
access holes were drilled. To form enclosed channels, a glass
cover plate cleaned with concentrated H SO was thermally
4
F), and external
2
4
bonded in a furnace (Heraeus Instruments GmbH, Hanau,
Germany) at 858 K. The reactor channel pattern is schemati-
cally described in Figure 1. Reynolds numbers for the
2-Chlorotoluene was prepared and analysed as above from
o-toluidine (0.1 g, 1.1 mmol) in N,N-dimethylformamide (0.5
mL), isoamyl nitrite (0.35 mL, 2.6 mmol), and anhydrous
Vol. 7, No. 5, 2003 / Organic Process Research & Development
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767

copper (II) chloride (0.17 g, 1.3 mmol) in N,N-dimethyl-
formamide (2 mL).
standardised solutions (Lancaster Synthesis Ltd, Morecambe,
U.K.). Traces were accumulated over a 42-min period and
displayed using HP Chemstation software. The LabRam
Infinity Raman microscope (Jobin Yvon Ltd. Middlesex
U.K.) consisted of a 632-nm excitation laser, an inverted
microscope, and a 50×/0.5 numerical aperture objective. The
microfluidic reactor was secured to an XY translation stage
and aligned with the excitation beam. Spectra were ac-
cumulated over a period of 30 s and displayed using Labspec
V 4-02 software (Jobin Yvon Ltd., Middlesex, U.K.) running
on a Pentium computer.
3-Chlorotoluene was prepared and analysed as above from
m-toluidine (0.1 g, 1.1 mmol) in N,N-dimethylformamide (0.5
mL), isoamyl nitrite (0.35 mL, 2.6 mmol), and anhydrous
copper (II) chloride (0.17 g, 1.3 mmol) in N,N-dimethyl-
formamide (2 mL).
General Method for the Laboratory Synthesis of
Chloroarenes.19 To a solution of isoamyl nitrite (3.5 mL,
26 mmol) and anhydrous DMF (5 mL) heated at 338 K was
added the aromatic amine (1 g, 11 mmol) dissolved in 5 mL
of DMF. The reaction was performed in a 50-mL three-
necked round-bottomed flask equipped with a reflux con-
denser, addition funnel, a gas outlet tube, and a magnetic
follower. The vessel was heated by immersion in an oil bath
in turn heated on an IKA magnetic stirrer hot plate equipped
with a PT-100 probe with Fuzzy logic for self-optimising
temperature control. Anhydrous copper (II) chloride (1.7 g,
Conclusions
The application of microfluidic reactor technology to
multistage reactions has been demonstrated. Utilising a
continuous flow methodology the advantages of microscale
reactors were illustrated by the intrinsically safe anhydrous
diazotisation and chloro- and hydro-dediazonation of a
variety of simple arenes, resulting in increased yields over
those from similar reactions undertaken on a traditional scale.
The simple structures described and the safe nature of the
procedure show clear advantages over bulk-scale syntheses
with significant yield increases and facile optimisation,
offering a viable alternative to the industrial route.
The utility of online optical detection using Raman
spectroscopy has also been demonstrated for the first time
in microfluidic reactor systems. Reaction monitoring was
undertaken in real time with data acquisition rates shown to
be ideally suited for on-line reaction feedback and control.
The advantages of on-line monitoring over traditional off-
line GC monitoring and the advantages of on-chip rather than
capillary monitoring were elucidated.
13 mmol) in N,N-dimethylformamide (20 mL) was then
added. Upon this addition, the reaction solution turned from
the initial green copper (II) chloride colour completely black
as nitrogen was evolved. Generally, gas evolution was
complete within 10 min following the addition of the amine.
After complete gas evolution the product was analysed by
GC giving a conversion by area analysis of 40-49%. GC-
MS spectra were also obtained and showed concordance.
2-Chlorotoluene was prepared and analysed as above from
o-toluidine (0.1 g, 1.1 mmol) in N,N-dimethylformamide (0.5
mL), isoamyl nitrite (0.35 mL, 2.6 mmol), and anhydrous
copper (II) chloride (0.17 g, 1.3 mmol) in N,N-dimethyl-
formamide (2 mL).
3-Chlorotoluene was prepared and analysed as above from
m-toluidine (0.1 g, 1.1 mmol) in N,N-dimethylformamide (0.5
mL), isoamyl nitrite (0.35 mL, 2.6 mmol), and anhydrous
copper (II) chloride (0.17 g, 1.3 mmol) in N,N-dimethyl-
formamide (2 mL).
Acknowledgment
We thank EPSRC U.K. and the Department of Trade and
Industry (DTI) for financial support. R.F. is grateful to
SmithKlineBeecham Pharmaceuticals for an EPSRC CASE
studentship.
Reaction Monitoring. Optical monitoring was performed
on an inverted microscope (Leica DMIL: Leica Microsys-
tems Ltd, Milton Keynes, U.K.) with a CCD camera (SONY,
CCD XC-999P) mounted onto the microscope and connected
to a TV/VCR (Samsung/Panasonic). Transformation was
monitored using a Hewlett-Packard (HP) 6890 capillary gas
chromatograph (GC) utilising a HP Innowax stationary phase.
Samples were introduced using a HP 6890 autosampler and
autoinjector array to minimise operator errors. Samples were
analysed without further purification by comparison to spiked
Supporting Information Available
Experimental details. This material is available free of
charge via the Internet at http://pubs.acs.org.
Received for review August 30, 2002.
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