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Rapid determination of reaction order and rate constants of an imine

synthesis reaction using a mesoscale oscillatory bafed reactor


Fatimah R. Mohd Rasdi, Anh N. Phan

, Adam P. Harvey
School of Chemical Engineering & Advanced Materials (CEAM), Newcastle University, Newcastle upon Tyne NE1 7RU, UK
h i g h l i g h t s
" Reduce 75% the amount of reagent required when using a mesoOBR.
" Highly reproducible kinetic data compared to typical beakers.
" Produce more data per volume of reactants at steady state than batch screening.
" Reduce 50% process development time compared to beaker batch screening.
a r t i c l e i n f o
Article history:
Received 6 November 2012
Received in revised form 1 February 2013
Accepted 18 February 2013
Available online 28 February 2013
Keywords:
Reaction kinetics
Imine synthesis
Rate constant
Mesoscale-OBR
Steady-state
Dynamic screening
a b s t r a c t
The reaction of benzaldehyde with n-butylamine to form the imine (1-butanamine, N-(phenylmethyl-
ene)) was chosen to demonstrate the ability of the mesoscale OBRs to rapidly screen process conditions
and obtain kinetic data in both continuous multi-steady state and dynamic screening manner. The
two methods give 98% degree of agreement, with clear step-changes between different residence times.
In situ FTIR spectroscopy was used to determine concentrations in real time. The results showed that the
average rate constant was 2.0 10
1
0.006 mol
0.9
L
0.9
s
1
with about 1.0% different between the
methods. In determining such kinetic information, the meso-OBR was able to reduce the process devel-
opment time by about 50% of, and required 75% less reagent, compared to batch screening using standard
beaker. Furthermore, the data was more reproducible with the average deviation three times lower
across all the data points.
Crown Copyright 2013 Published by Elsevier B.V. All rights reserved.
1. Introduction
Organic synthesis and reaction kinetics investigation are com-
monly conducted at laboratory scale in batch standardized glass-
ware [1,2]. This normally involves general mixing apparatus such
as the magnetic stirrer or upright impeller mixer without bafes
to break up the mixing ow. This leads to inconsistencies with
regard to mass transfer, energy transfer and agitation during
scale-up to pilot and industrial scale, necessitating time-consum-
ing re-optimisation [3]. Laboratory- and pilot plant scale data can
be very different. Furthermore, screening in typical laboratory ves-
sels (50500 mm diameter) leads to substantial reagent usage and
waste generation [4].
One screening/process development laboratory-scale reactor
that may address some of these problems is the Mesoscale Oscil-
latory Bafed Reactor (meso-OBR). Typically Mesoscale-OBRs
consist of 5 mm inner diameter tubes containing equally spaced
bafes [5,6]. The mixing inside the reactor is achieved by superim-
posing an oscillatory ow upon a net ow. The oscillatory ow can
be created by the movement of piston and diaphragm placed at the
bottom of the reactor, or various other designs. The uid acceler-
ates and decelerates, usually following a sinusoidal velocity time
function, as shown in Fig. 1, in which as the ow accelerates up-
wards or downwards, the vortices are formed downstream of the
bafes. When the ow decelerates, these vortices are swept into
the bulk uid and subsequently unravel as ow accelerates in
the opposite direction.
Several bafe designs have been developed, including the
smooth periodic bafe (SPC), integral bafe, centrally (axially)
bafe and helical bafe. The SPC and integral bafe designs are
suitable for shear-sensitive applications, such as in bioprocessing
applications [7,8] whereas the sharp-edged centrally bafed design
provides high shear, and which aids mixing in 2-phase liquidli-
quid systems. This design has been demonstrated for biodiesel
screening, where it demonstrates more uniform mixing than
smooth round helical wire bafes [9]. The helically bafed design
has advantages for solidliquid reactions as the main ow is less
1385-8947/$ - see front matter Crown Copyright 2013 Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.cej.2013.02.080

Corresponding author. Tel.: +44 191 222 5747; fax: +44 191 222 5292.
E-mail address: anh.phan@ncl.ac.uk (A.N. Phan).
Chemical Engineering Journal 222 (2013) 282291
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constricted, thereby reducing particle clogging. This design also
provides more exibility of operation than other designs, because
a high degree of plug ow can be achieved over a wide range of
oscillation conditions [1012]. Generally, the uid mixing in these
meso-bafed reactors is strongly affected by oscillation amplitude
(x
o
) but little by oscillation frequency (f) [5,8]. Fluid dynamics in
these reactors are governed by geometrical (bafe spacing, L and
bafe open area, S) and dynamic parameters (oscillatory Reynolds
number, Re
o
, net ow Reynolds number, Re
n
, and Strouhal number,
St) [13] as described from Eqs. (1)(6).
L 1:5D 1
S
d
2
0
D
2
Typically in the range 0:2 0:4 2
Re
0

2pfx
o
qD
l
3
Re
n

qDu
l
4
St
D
4px
0
5
W
Re
0
Re
n
6
where u (m/s) is the supercial velocity; d
o
is the bafe diameter; D
is the tube diameter; l (m
2
/s) is the viscosity; x
o
(m) is oscillation
amplitude (centre to peak); f (Hz) is the oscillation frequency and
q (kg m
3
s
1
) is uid density.
The geometric parameters inuence the size and shape of ed-
dies generated in bafe cavities [14]. The bafe open area (S) con-
trols the width of the vortices created, whereas the optimal
distance of the bafe spacing (L) ensures full expansion of eddies
generated so that they will spread effectively throughout. The
oscillatory Reynolds number (Re
o
) is a measure of the intensity of
the mixing in the system. It is similar to the net ow Reynolds
number Re
n
, but the supercial velocity (u) is replaced by the max-
imum oscillatory velocity (2pfx
o
). The Strouhal number (St) is a
measure of the effectiveness of the eddy propagation in relation
to the tube geometry. The velocity ratio (w) is the ratio of
oscillatory ow (Re
o
) to net ow (Re
n
), and is strongly related to
the quality of the plug ow in the reactor. OBRs are usually de-
signed such that w is between 2 and 12.
Due to the small volume of mesoscale-OBRs, they require only
small amounts of feedstock, and produce small volumes of waste.
This is a particular advantage for processes when expensive re-
agents are required or hazardous waste is produced. Good radial
mixing, due to the vortices, results in a well-mixed regime in each
bafed cavity [8]. In addition, the mesoscale-OBRs can maintain
plug ow behaviour at very low net ow rates (0.3 ml/min, cor-
responding to Re
n
= 1.25) which gives a particular process advan-
tage: that OBRs are suitable for performing continuous reactions
with long residence times with plug ow [6].
Extensive studies on mesoscale OBRs have been carried out, in
terms of characterisation of the uid mixing and behaviour
[5,6,8,10,15,16], biodiesel production [9,17,18] and bioprocessing
reactions [7]. Most of the work was conducted in continuous mode,
which can overcome some of the disadvantages of batch scale-up
by maintaining the dynamic parameter factor with the OBR system
[1921]. Evidence on the scale-up was shown with OBR reactor for
tube diameters of 24 mm laboratory scale to 150 mm pilot plant
scale [19,21]. This was conducted over a wide range of oscillation
conditions (Re
o
) at a xed Re
n
= 107 that show similar axial disper-
sion coefcient at different tube diameter. MesoOBRs have a great-
er exibility of operation with which to control the desired product
compared to batch processes [9] by e.g. simply modifying a net
ow according to the desired residence time (as this will not sub-
stantially affect the mixing, within the plug ow operating win-
dow). However, there is little research into obtaining reaction
kinetic parameters using mesoscale OBRs.
The objective of this work was to demonstrate the mesoscale
OBR as a tool for quickly and logically obtaining kinetic data of a
chemical reaction in continuous mode. Its purposes are to reduce
process development time, by allowing optimal conditions to be
determined rapidly, reduce the amount of chemicals required
and waste generated. Because plug ow behaviour is easily
achieved over a wide range of at low net ow rates [5,6], it has
advantages in collecting data at different residence times (s) to
represent a reaction process. This is important in obtaining repre-
sentative kinetic information for chemical reactions of interest.
Furthermore, the oscillatory mixing inside the system allows good
control of reagent stoichiometry. This is not the case in microlitre
reactors, as the mixing is obtained through diffusion, which is dif-
cult when substrate dispersion becomes signicant [1]. The Schiff
reaction between aromatic aldehyde and primary amine was cho-
sen as a case study due to its simplicity, and because it has several
applications in biological processes, polymer synthesis and dy-
namic combinatorial chemistry [2225]. The kinetic parameters
and product yield of the imine reaction has previously been inves-
tigated in batch mode using volumetric asks and analytical meth-
ods such as Raman and Infrared (IR) Spectroscopy [2628]. In this
work, in situ IR was used to monitor real-time quantitative and
qualitative characteristics of the reaction system.
2. Experimental methods
2.1. Chemicals
The chemicals used in this study were n-butylamine (C
4
H
11
N)
and benzaldehyde (C
7
H
5
O) with purication percentage >98%
(SigmaAldrich). n-Hexane (n-C
6
H
14
) with >95% purity was used
as a solvent for kinetics experiments. Benzaldehyde was diluted
in n-hexane to 0.25 mol dm
3
whilst n-butylamine was prepared
at a set of various concentrations of 0.25, 0.50, 1.00 and
1.50 mol dm
3
.
Fig. 1. Schematic eddy motion in a bafed tube.
F.R. Mohd Rasdi et al. / Chemical Engineering Journal 222 (2013) 282291 283
2.2. Reaction in a meso-OBR
The experimental set-up for the imine synthesis is shown in
Fig. 2. It includes a meso-bafed reactor, Mettler Toledo ReactIR
4000 equipped with DiComp (diamond) probe with Mercury cad-
mium telluride (MCT) band detector and a set of three syringe
pumps. The IR probe was immersed in the outow of the reactor
to monitor the reaction progress.
The mesoreactor consists of a 350 mm length and 5.0 mm inner
diameter glass tube inserted with central bafes (axial bafes)
[5,6]. These central bafes are hexagonal stainless steel solid discs
(approximately 4 mm diameter) placed periodically at a distance
of 1.5 tube diameters along a 2 mm narrow rod (Fig. 3), giving a
reactor volume of approximately 6 ml. Two syringe pumps (Euro-
dyne Ltd.) were used for providing net ows and a third was used
for oscillating the reaction mixture in the reactor. The oscillation
frequency was obtained by adjusting the speed of the piston move-
ment whilst the amplitude was determined by the amount of vol-
ume dispensed. These parameters were controlled via a computer.
Prior to experiments, the oscillation conditions (via frequency and
amplitude) and net ows of the reagents (Re
n
) were set to the de-
sired conditions.
2.2.1. Batch reactions in the mesoOBR
At a temperature of approximately 25 C, reaction in batch was
performed by dispensing n-butylamine and benzaldehyde into the
reactor at the same ow rate (obtaining a stoichiometric ratio of
1:1) until the reactor was lled and the IR probe tip was covered
with the reaction mixture. The mixing condition was set at an
oscillatory Reynolds numbers (Re
o
) of between 35 and 400, which
represents mixing regimes from low to high intensity. The highest
ow rate possible with this design of syringe pump was used
(1800 ml/h) for the individual reagents to minimise the lling
time. As soon as the reaction mixture reached the tip of the IR
probe (about 15 s), the IR started recording the spectra of the
reaction. Each spectrum was taken at 15 s intervals for 60 min.
The same procedure was applied for investigating the reaction at
various molar ratios of benzaldehyde to n-butylamine, e.g. 1:2,
1:4 and 1:6.
2.2.2. Steady state and dynamic screening
In the ow reactions, only the 1:1 stoichiometric molar ratio
was considered. The mixing condition was chosen at Re
o
= 62, cor-
responding to an oscillation amplitude of 1 mm and frequency of
1 Hz, because it provided highly plug ow behaviour [5]. Both re-
agents (n-butylamine and benzaldehyde) were supplied to the
reactor at different ow rates to obtain various residence times re-
quired as illustrated in Table 1. Nine consecutive step changes of
residence time were investigated, each lasting for approximately
4 min for the steady state mode. In dynamic screening, the rst
step was maintained for approximately 4 min to obtain a steady
state prole, whilst each subsequent step change in the residence
time lasted only 20 s.
2.3. Batch reactions in beakers
The reaction was also carried out in a typical beaker set-up for
comparison (see Fig. 4: Experimental set-up for imine synthesis
using a 100 ml beaker, below). The temperature was maintained
at 25 C. Approximately 40 ml of n-butylamine and 40 ml benzal-
dehyde at equal concentration of 0.25 mol dm
3
were added into
a 100 ml beaker. The reaction mixture was agitated using a mag-
netic stirrer set at speed ranges in the range 2001200 rpm. The
spectra of the reaction were taken continuously at intervals of
15 s for 60 min by immersing the IR probe at the middle of the bea-
ker, as shown.
2.4. Analysis
The spectrometer and data was recorded using iC-IR vers. 4.2.26
software. The IR spectra were recorded in the absorbance mode
Fig. 2. Experimental set-up for imine synthesis using a mesoscale-OBR.
Fig. 3. A central bafed reactor.
Table 1
Flow rates at each residence time in ow reaction using
the mesoscale-OBR.
Flow rates (ml/h) Residence time (s), s
840 30
420 60
280 90
210 120
168 150
140 180
105 240
53 480
42 600
284 F.R. Mohd Rasdi et al. / Chemical Engineering Journal 222 (2013) 282291
from 4000 to 650 cm
1
at a resolution of 8 cm
1
. All collected spec-
trum data were treated using a second derivative method (Eq. (7))
to improve the detectability of small and/or overlapping peaks on a
main band [2,4]. This method also reduces baseline movement and
errors in the analysis [29,30].
A
~
V a
~
Vlc
dA
2

~
V
d
~
V
2

d
2
a
~
V
d
~
V
2
lc 7
where A
~
V is the wavenumber dependent absorbance, a
~
V wave-
number dependent absorption coefcient, l is the absorption path
and c is the concentration of the interest reagent.
As is apparent in Fig. 5a, the reduction of benzaldehyde (see
peak at 1714 cm
1
) and imine formation (1652 cm
1
) obtained
during reaction were difcult to determine without derivative
treatment. In 6a the baseline shifts between measurements, and
the peaks of benzaldehyde and imine overlapped with other peaks.
However, when using the second derivative data treatment as
shown in Fig. 5b, the peaks were isolated with clear and sharp
shape on the same baseline.
3. Results and discussion
3.1. Reaction mechanism
This imine synthesis is an additionelimination reaction, is
comprised of a nucleophilic attack by the amine species, followed
by an elimination process producing a C@N bond. The reaction
mechanism of benzaldehyde and n-butylamine reaction is pro-
posed in Fig. 6, starting with the attack of n-butylamine on the
benzaldehyde carbonyl carbon.
An acidic environment was not used to protonate the carbonyl
group in this case because n-butylamine is a strong nucleophile
and will readily attack the electrophile. No peak formation was ob-
served (Fig. 7 below) in the CAO region (11201080 cm
1
) or the
CANAC stretching region (11901130 cm
1
) for the intermediate.
This agrees with other ndings that conclude that the tetrahe-
dral intermediate (carbinolamine) is unstable and reactive, result-
ing in a negligible accumulation at any point in the reaction
[31,32]. The peaks observed in the region 11901130 cm
1
are as-
signed to the CAC of the aliphatic and aromatic structures of the
benzaldehyde. The product formation of the 1-butanamine (N-phe-
nylmethylene) was monitored and followed at the peak of
1652 cm
1
(C@N). This nding from the IR method was conrmed
using HNMR analysis, as shown in Fig. 8.
However, mass balance calculations from the benzaldehyde
reduction and imine formation data indicate that an intermediate
was formed (Fig. 9). The amount formed was about 20% but disap-
pears after approximately 200 s towards the product formation.
The reduction proles for benzaldehyde shown in Fig. 9 also
show that the imine synthesis was virtually complete after 600 s.
The reverse rate constants (k
1
and k
2
) should be negligible be-
cause the product was formed concurrently with the formation
of the intermediate. This effect will be vice versa if the reverse rate
constant was dominant. Therefore, the kinetic model for 1-butan-
amine (N-phenylmethylene) synthesis was described as follows
(Eqs. (8)(13)).
A B!
k
1
C !
k
2
D E 8
dA
dt
k
1
A
m
B
n
9
dB
dt
k
1
A
m
B
n
10
dC
dt
k
1
A
m
B
n
k
2
C
o
11
dD
dt
k
2
C
o
12
dE
dt
k
2
C
o
13
where A, B, C, D and E represent benzaldehyde, n-butylamine, inter-
mediate, imine and water, respectively. m, n, o, p and q are reaction
orders.
Fig. 4. Experimental set-up for imine synthesis using a 100 ml beaker.
Fig. 5. Reaction spectrum of imine synthesis (a) without second derivative
treatment and (b) with second derivative treatment.
F.R. Mohd Rasdi et al. / Chemical Engineering Journal 222 (2013) 282291 285
Fig. 6. Reaction mechanisms of benzaldehyde and n-butylamine reaction.
Fig. 7. The peaks observed at (a) 11201180 cm
1
for CAO stretching for alcohol and (b) 11901130 cm
1
for CANAC of secondary amine in the formation of the
intermediate in the synthesis of 1-butanamine, N-(phenylmethylene).
286 F.R. Mohd Rasdi et al. / Chemical Engineering Journal 222 (2013) 282291
Fig. 8. Evidence of the 1-butanamine (N-phenylmethylene) formation using (a) IR at the peak of 1652 cm
1
(C@N) and (b) H NMR at 8.3 ppm (HAC@N).
Fig. 9. Imine reaction synthesis proles in hexane at (a) 1:1 benzaldehyde:n-butylamine and (b) 1:4 ratio of benzaldehyde to n-butylamine.
F.R. Mohd Rasdi et al. / Chemical Engineering Journal 222 (2013) 282291 287
3.2. Kinetic determination
3.2.1. Experimental kinetics parameter
Reaction order and rate constant were determined at ambient
temperature (25 C) and pressure. The reaction was monitored
continuously by following the reduction in the carbonyl peak asso-
ciated with benzaldehyde at 1714 cm
1
.
As shown in Table 2, various molar ratios of benzaldehyde and
n-butylamine were investigated to determine the initial reaction
rate. Increasing the amount of n-butylamine had a small effect
on the initial rate: it only increased by 20% as the molar ratio of
benzaldehyde to n-butylamine increased from 1:1 to 1:4. The cal-
culated order of n-butylamine was therefore 0.22.
At an equal initial concentration of benzaldehyde (A
o
) and
n-butylamine (B
o
), the rate expression of benzaldehyde (Eq. (9))
simplies to:
dA
dt
k
1
A
m0:22
14
Integration of Eq. (14) gives the order for benzaldehyde (m) at
1.7 with the rate constant (k
1
) at 2.1 10
1
mol
0.9
L
0.9
s
1
. The
regression value (R
2
) was 0.9610. The total reaction order of 1.9
(1.7 for benzaldehyde and 0.22 for n-butylamine) obtained for
1-butanamine-(N-phenylmethylene) synthesis in hexane agrees
with the general ndings in the literature. Schiff base formation
from aromatic aldehydes or ketone with primary amine in polar
solvent, e.g. methanol has been shown to exhibit second order
kinetics, either with [33,34] or without [35] acid catalysts. How-
ever, these ndings did not state the reaction order for each
component.
3.2.2. Mathematical modelling
Kinetic modelling is a useful method for obtaining kinetics
parameters through analysis of several species on the concentra-
tion prole together. It has been used to investigate many chem-
ical reactions such as cyclometallation reactions between imines
and palladium acetate (combining hard and soft modelling pro-
cess) [36], hydrosilylation [37] and acetylsalicylic acid synthesis
[38].
The benzaldehyde n-butylamine imination reaction was mod-
elled on Matlab software (Ver. R2011a) with the reaction mecha-
nisms shown in Eq. (8). The experimental rate constant and
reaction orders calculated were initially used for the modelling
data. These data were adjusted until the best t between experi-
mental and modelling results was achieved qualitatively. As shown
in Fig. 10, there was little difference in the concentration proles of
the reduction of benzaldehyde and the formation of imine at all
tested molar ratios of benzaldehyde and n-butylamine.
Table 3 shows the kinetics parameters obtained from the mod-
elling output. The rate constant and reaction orders were similar to
Table 2
Initial reaction rate of at various molar ratios of benzaldehyde to
n-butylamine.
Benzaldehyde
concentration
(mol dm
3
)
N-butylamine
concentration
(mol dm
3
)
Initial rate
(M s
1
)
0.25 0.25 4.7 10
3
0.25 0.50 5.7 10
3
0.25 1.00 5.9 10
3
0.25 1.50 7.0 10
3
Fig. 10. Concentration proles obtained from Matlab modelling (solid lines) and experimental results (dotted lines) using the mesoscale reactor for benzaldehyde reduction
and imine formation at molar ratios of benzaldehyde:n-butylamine of (a) 1:1, (b) 1:2 and (c) 1:4.
288 F.R. Mohd Rasdi et al. / Chemical Engineering Journal 222 (2013) 282291
those obtained from experiments, e.g. the modelling rate constant
was 2.3 10
1
mol
0.9
L
0.9
s
1
compared to experimental result of
2.0 10
1
+ 0.006 mol
0.9
L
0.9
s
1
. The modelling reaction order of
benzaldehyde was 1.751.80 compared to the experimental data of
1.7. This shows that the modelling supports the reaction mecha-
nism proposed in Eq. (8). The suggested reaction path in previous
studies which involve with reversible scheme between the reagent,
intermediate and product was not obeyed due to the different
group of solvent used [22,39]. This referred to the polar solvent
with methanol as the preferred choice.
3.3. Effect of mixing conditions on reaction kinetics
The effect of mixing conditions on rate constant was studied at
a molar ratio of benzaldehyde and n-butylamine of 1:1 in the
100 ml beaker and mesoscale-OBR over a wide range of mixing
conditions (Re
o
= 50350 for the meso-OBR and 2001100 rpm
for the 100 ml beaker). As shown in Fig. 11, the rate constant
was identical for both reactor systems, k
1
= 2.0 10
1
mol
0.9
L
0.9
s
1
. This implies that mixing has no effect on the rate constant in
both systems in tested conditions. However, the mesoscale-OBR
exhibited a higher reproducibility than the beaker: the average er-
ror across all the data points was three times lower for the meso-
scale OBR. As presented in Table 4, an average standard deviation
of the rate constant for the mesoscale OBR was 5.5 10
3
mol
0.9
L
0.9
s
1
compared to 1.8 10
2
mol
0.9
L
0.9
s
1
for the beaker. Bet-
ter reproducibility was obtained with the meso-OBR system be-
cause it offers more uniform mixing without any localised region
compared to the beaker system. This led to sufcient interaction
between the reagents each time. In addition, the total volume of
chemicals used in this screening was 75% lower in the meso-
scale-OBR than in the beaker due to the much smaller volume of
the mesoscale OBR (6 ml) compared to that of the beaker
(80 ml). Smaller beaker volumes were not used due to the IR probe
size, which could have resulted in the formation of swirl vortices
that cause misleading readings.
3.4. Reaction kinetics in a continuous mesoscale OBR
Imine synthesis was conducted in multi-steady state and dy-
namic screening modes at an oscillation condition of Re
o
= 62
(x
o
= 1 mm, f = 1 Hz) in the continuous meso-OBR reactor. The mo-
lar ratio of benzaldehyde and n-butylamine was chosen at 1:1 over
a range of residence times of 30600 s. Nine consecutive residence
times were imposed on the reactor. For the multi-steady state
mode, each residence times was maintained for 200 s. As shown
in Fig. 12, a clear step-change between residence times was ob-
served, as would be expected, as each plug of material at a newres-
idence time emerged. This showed that the mesoscale-OBR
exhibited a high degree of plug ow behaviour. This behaviour
has been observed previously in multiphase reaction screening,
Table 3
Kinetic parameters obtained from modelling.
Ratio 1:1 1:2 1:4
Benzaldehyde concentration (mol dm
3
) 0.25 0.25 0.25
N-butylamine concentration (mol dm
3
) 0.25 0.50 1.00
Rate constant (k
1
), s
1
0.23 0.23 0.23
Rate constant (k
2
), s
1
0.04 0.04 0.04
Benzaldehyde order 1.80 1.75 1.80
N-butylamine order 0.22 0.22 0.22
Fig. 11. Rate constant of imine synthesis using (a) centrally bafed mesoscale-OBR (b) 100 ml beaker.
Table 4
Comparison of standard deviation of rate constant using different reaction vessel.
Beaker Mesoscale OBR
rpm Standard deviation Re
o
Standard deviation
229 1.2 10
2
31 1.6 10
2
337 2.5 10
3
62 3.9 10
3
537 3.6 10
2
123 1.1 10
3
684 3.1 10
2
185 0.0
1119 7.1 10
3
246 9.5 10
3
369 2.9 10
3
Fig. 12. Steady-state step change of residence time and dynamic screening of imine
synthesis at a molar ratio of benzaldehyde: n-butylamine of 1:1 at an oscillation
condition of Re
o
= 62 using centrally bafed mesoscale-OBR.
F.R. Mohd Rasdi et al. / Chemical Engineering Journal 222 (2013) 282291 289
e.g. biodiesel productions at various ratios of methanol to rapeseed
oil [9]. Each clear and consistent step contains a number of data
points, so is equivalent to numerous batch reactions conducted
in series. The average of a series of data points (r = 1.2 10
3
mol dm
3
) at each reaction time is more accurate than one data
point conducted in batch. The consistency and the clear step
change indicate that further processing advantages are possible,
such as introducing additional or third reagent into the ow
stream at precisely the time point to generate further reaction. This
was a challenge when operating using microreactor system on a
segmented ow [40]. The series of short reaction plugs conducted
in a constant stream of solvent only allows the microreactor to
briey reach steady-state condition at a point of time. This was
overcome by using excess volume of the third reagent which re-
sulted in substantial purication process later at the end of the
reaction.
For the dynamic screening, each set of residence time was held
for only 20 s to allow high throughput screening to be conducted.
This was the best approximation to a real linear ramp possible with
the existing syringe pump system. The results showed that the
concentration of benzaldehyde at the same residence time was in
agreement for both dynamic and steady-state mode, e.g. concen-
tration of benzaldehyde was 0.10 mol dm
3
at a residence time
(s) of 30 s and 0.02 mol dm
3
at s = 240 s for both methods. The
degree of the agreement was 98% between both method (stea-
dy-state and dynamic) when compared to the regression value ob-
tained. It can be concluded that the meso-scale OBRs can be used
for dynamic screening with a substantial reduction in processing
time of about 25% compared to the multiple steady state method.
The results also indicate that screening by changing individual
parameters, e.g. molar ratios, or multiple variables, e.g. molar ra-
tios, residence time, catalyst, etc., can also be done.
Fig. 13 shows the average results obtained from dynamic
screening, steady state and batch beaker at different residence
time for benzaldehyde reduction prole. As shown in Table 5, the
rate constant obtained via the different methods differed by
only 0.200.22 10
1
mol
0.9
L
0.9
s
1
about 10% in percentage
different.
4. Conclusion
The reaction of benzaldehyde with n-butylamine to form imine
(1-butanamine, N-(phenylmethylene)) was chosen as a case study
to demonstrate the ability of a continuous mesoscale Oscillatory
Bafed Reactor (OBR) to rapidly screen process conditions. Here,
the reactor was coupled to online FTIR, in order to rapidly deter-
mine kinetic data (rate constants and reaction orders).
The meso-OBR was operated in three modes:
(i) Multi-steady state mode, in which a sequence of different
residence times was imposed, each for a prescribed period of
time.
(ii) Dynamic mode in which the residence time was continu-
ously varied.
(iii) Batch operation.
The results were compared to each other, and to those achieved
using a conventional beaker in batch mode. It was demonstrated
that:
1. The rate constants obtained in both continuous ow
(multi-steady state, or dynamic) and batch (beaker) agreed
well. The average rate constant, regardless of method, was
2.2 10
1
mol
0.9
L
0.9
s
1
.
2. The process development time when using continuous
dynamic screening was 50% lower than that required for
batch screening using beakers, and 25% lower than that
required when using the multi-steady state method.
3. Multi-steady state and dynamic modes agree well, imply-
ing that in this technology, dynamic screening can reliably
be used in place of multi-steady-state. The caveats to this
are that here this is only proven for a homogeneous liquid
system, and that this only holds at a high degree of plug
ow. In multiphase systems, it would have to be ensured
that both phases have the same residence time
distribution.
4. In multi-steady state mode, more data is produced per vol-
ume of reactants used than in batch mode (meso-OBR or
beaker). This is because each data point at a given steady
state was equivalent to one batch reaction. Hence the num-
ber of data points was determined by the time resolution of
the FTIR and the time period of the steady state. This, in
practice, equates to a much smaller volume of uid per data
point than in conventional batch screening.
5. Operation of the mesoscale-OBR system in batch mode:
Reduced the amount of reagent required by 75% (compared
to standard laboratory glassware).
Resulted in more reproducible data: the standard deviation
in the batch mesoOBR was 5.5 10
3
mol
0.9
L
0.9
s
1
, com-
pared to 1.8 10
2
mol
0.9
L
0.9
s
1
for the beaker.
Overall, these results represent strong evidence that this reactor
can be the basis of a dynamic process screening platform, certainly
for homogeneous liquid systems with online analysis.
There are a variety of other scenarios to be investigated, partic-
ularly multiphase operation (multiple reactant phases and/or het-
erogeneous catalysis), and staged addition. Staged addition should
be easily achieved in this technology, given the mixing character-
istics, but can be a signicant problem for technologies such as
microchannel reactors, when trying to achieve this via e.g. seg-
mented ow. Investigation of various multiphase systems is under-
way, including biodiesel synthesis (two liquid phases, initially),
with both homogeneous and heterogeneous catalysts, and various
crystallizations.
Fig. 13. Benzaldehyde reduction proles obtained at ow and batch reaction
method at an oscillation condition Re
o
of 62.
Table 5
Rate constant of imine synthesis obtained from various methods.
Method Regression (R
2
) Rate constant (s
1
)
Beaker batch 0.96 0.20 0.020
Meso-batch 0.97 0.20 0.006
Flow (steady state) 0.95 0.22 0.006
Flow (dynamic) 0.97 0.20 0.006
290 F.R. Mohd Rasdi et al. / Chemical Engineering Journal 222 (2013) 282291
Acknowledgment
The authors would like to thank the Malaysian Rubber Board
(MRB) for their nancial support in this work.
References
[1] G. Jas, A. Kirschning, Continuous ow techniques in organic synthesis,
chemistry, Eur. J. 9 (2003) 57085723.
[2] C. Wiles, P. Watts, Improving chemical synthesis using ow reactors, Expert
Opin. Drug Discovery 2 (2007) 14871503.
[3] M. Ehly, P.J. Gemperline, A. Nordon, D. Littlejohn, J.K. Basford, M. De Cecco,
Scale-up of batch kinetic models, Anal. Chim. Acta 595 (2007) 8088.
[4] J.F. Hall, M. Barigou, M.J.H. Simmons, E.H. Stitt, Just because its small does not
mean its well mixed: ensuring good mixing in mesoscale reactors, Indus. Eng.
Chem. Res. 44 (2005) 96959704.
[5] A.N. Phan, A. Harvey, Development and evaluation of novel designs of
continuous mesoscale oscillatory bafed reactors, Chem. Eng. J. 159 (2010)
212219.
[6] A.N. Phan, A. Harvey, J. Lavender, Characterisation of uid mixing in novel
designs of mesoscale oscillatory bafed reactors operating at low ow rates
(0.3-0.6 ml/min), Chem. Eng. Process.: Process Intens. 50 (2011) 254263.
[7] N. Reis, C. Gonalves, M. Aguedo, N. Gomes, J. Teixeira, A. Vicente, Application
of a novel oscillatory ow micro-bioreactor to the production of c-decalactone
in a two immiscible liquid phase medium, Biotechnol. Lett. 28 (2006) 485490.
[8] N. Reis, A.P. Harvey, M.R. Mackley, A.A. Vicente, J.A. Teixeira, Fluid mechanics
and design aspects of a novel oscillatory ow screening mesoreactor, Chem.
Eng. Res. Des. 83 (2005) 357371.
[9] A.N. Phan, A.P. Harvey, M. Rawcliffe, Continuous screening of base-catalysed
biodiesel production using New designs of mesoscale oscillatory bafed
reactors, Fuel Process. Technol. 92 (2011) 15601567.
[10] A.N. Phan, A.P. Harvey, Effect of geometrical parameters on uid mixing in
novel mesoscale oscillatory helical bafed designs, Chem. Eng. J. 169 (2011)
339347.
[11] J.P. Solano, R. Herrero, S. Espn, A.N. Phan, A.P. Harvey, Numerical study of the
ow pattern and heat transfer enhancement in oscillatory bafed reactors
with helical coil inserts, Chem. Eng. Res. Des. 90 (2012) 732742.
[12] A.N. Phan, A.P. Harvey, Characterisation of mesoscale oscillatory helical bafed
reactorexperimental approach, Chem. Eng. J. 180 (2012) 229236.
[13] X. Ni, P. Gough, On the discussion of the dimensionless groups governing
oscillatory ow in a bafed tube, Chem. Eng. Sci. 52 (1997) 32093212.
[14] X. Ni, G. Brogan, A. Struthers, D.C. Bennett, S.F. Wilson, A systematic study of
the effect of geometrical parameters on mixing time in oscillatory bafed
columns, Chem. Eng. Res. Des. 76 (1998) 635642.
[15] N. Reis, A.A. Vicente, J.A. Teixeira, M.R. Mackley, Residence times and mixing of
a novel continuous oscillatory ow screening reactor, Chem. Eng. Sci. 59
(2004) 49674974.
[16] M. Zheng, M. Mackley, The axial dispersion performance of an oscillatory ow
meso-reactor with relevance to continuous ow operation, Chem. Eng. Sci. 63
(2008) 17881799.
[17] M. Zheng, R.L. Skelton, M.R. Mackley, Biodiesel reaction screening using
oscillatory ow meso-reactors, Process Saf. Environ. Prot. 85 (2007) 365371.
[18] A.N. Phan, A.P. Harvey, V. Eze, Rapid production of biodiesel in mesoscale
oscillatory bafed reactors, Chem. Eng. Technol. 35 (2012) 12141220.
[19] X. Ni, Y.S. De Glicourt, M.H.I. Baird, N.V. Rama Rao, Scale-up of single phase
axial dispersion coefcients in batch and continuous oscillatory bafed tubes,
Can. J. Chem. Eng. 79 (2001) 444448.
[20] H. Jian, X. Ni, A numerical study on the scale-up behaviour in oscillatory
bafed columns, Chem. Eng. Res. Des. 83 (2005) 11631170.
[21] K.B. Smith, M.R. Mackley, An experimental investigation into the scale-up of
oscillatory ow mixing in bafed tubes, Chem. Eng. Res. Des. 84 (2006) 1001
1011.
[22] E.H. Cordes, W.P. Jencks, The mechanism of hydrolysis of schiff bases derived
from aliphatic amines, J. Am. Chem. Soc. 85 (1963) 28432848.
[23] A.F. De Carvalho Alcntara, D. Pil-Veloso, D.L. Nelson, A study of the
formation and stability of N-alkylbutanimines by
1
H-NMR spectroscopy, J.
Braz. Chem. Soc. 7 (1996) 225232.
[24] V. Saggiomo, U. Lning, On the formation of imines in water a comparison,
Tetrahedron Lett. 50 (2009) 46634665.
[25] A. Murugesan, T. Vidhyadevi, S.S. Kalaivani, M.P. Premkumar, L. Ravikumar, S.
Sivanesan, Kinetic and thermodynamic studies on the removal of Zn
2+
and Ni
2+
from their aqueous solution using poly(phenylthiourea)imine, Chem. Eng. J.
197 (2012) 368378.
[26] M. Lee, H. Kim, H. Rhee, J. Choo, Reaction monitoring of imine synthesis using
Raman spectroscopy, Bull. Korean Chem. Soc. 24 (2003) 205208.
[27] H. Namli, O. Turhan, Background dening during the imine formation reaction
in FT-IR liquid cell, Spectrochim. Acta Part A: Mol. Biomol. Spectrosc. 64 (2006)
93100.
[28] H. Namli, O. Turhan, Simultaneous observation of reagent consumption and
product formation with the kinetics of benzaldehyde and aniline reaction in
FTIR liquid cell, Vib. Spectrosc. 43 (2007) 274283.
[29] L. Rieppo, S. Saarakkala, T. Nrhi, H.J. Helminen, J.S. Jurvelin, J. Rieppo,
Application of second derivative spectroscopy for increasing molecular
specicity of Fourier transform infrared spectroscopic imaging of articular
cartilage, Osteoarthr. Cartilage 20 (2012) 451459.
[30] M.M. Pierce, R.L. Wehling, Comparison of sample handling and data treatment
methods for determining moisture and fat in cheddar cheese by near-infrared
spectroscopy, J. Agric. Food Chem. 42 (1994) 28302835.
[31] D.A. Evans, G. Borg, K.A. Scheidt, Remarkably stable tetrahedral intermediates:
carbinols from nucleophilic additions to N-acylpyrroles, Angew. Chem. Int.
Ed. 41 (2002) 31883191.
[32] T. Iwasawa, R.J. Hooley, J. Rebek Jr, Stabilization of labile carbonyl addition
intermediates by a synthetic receptor, Science 317 (2007) 493496.
[33] G.M. Santerre, C.J. Hansrote Jr., T.I. Crowell, The reaction of aromatic aldehydes
with n-butylamine. Acid catalysis and substituent effects, J. Am. Chem. Soc. 80
(1958) 12541257.
[34] R.L. Hill, T.I. Crowell, Structural effects in the reactivity of primary amines with
piperonal, J. Am. Chem. Soc. 78 (1956) 22842286.
[35] T.I. Crowell, D.W. Peck, Kinetic evidence for a Schiff base intermediate in the
knoevenagel condensation, J. Am. Chem. Soc. 75 (1953) 10751077.
[36] A. de Juan, M. Maeder, M. Martinez, R. Tauler, Combining hard- and soft-
modelling to solve kinetic problems, Chemom. Intell. Lab. Syst. 54 (2000) 123
141.
[37] N.C. Imlinger, M. Krell, M.R. Buchmeiser, Modeling the kinetics of
hydrosilylation based polyaddition, Monatsh. Chem./Chem. Mon. 138 (2007)
285291.
[38] N.C. Imlinger, C. Blattner, M. Krell, M.R. Buchmeiser, Hard-modeling of reaction
kinetics by combining online spectroscopy and calorimetry, J. Chemom. 22
(2008) 758767.
[39] E. Rotondo, R. Pietropaolo, G. Tresoldi, F. Faraone, F. Cusmano, Mechanism of
formation of Schiff base complexes. Part. I. Reaction of Ni(bis-salicylaldehyde)
with primary amines, Inorg. Chim. Acta 17 (1976) 181191.
[40] C.J. Smith, C.D. Smith, N. Nikbin, S.V. Ley, I.R. Baxendale, Flow synthesis of
organic azides and the multistep synthesis of imines and amines using a new
monolithic triphenylphosphine reagent, Org. Biomol. Chem. 9 (2011) 1927
1937.
F.R. Mohd Rasdi et al. / Chemical Engineering Journal 222 (2013) 282291 291