Process design and scale-up of the synthesis of 2,2′:5′,2′-terthienyl

Article abstract of DOI:10.1021/op020044n

The objective of this study was the design of a scaleable process for the synthesis of 3-4 mol of α-terthienyl from 2,5-dibromothiophene and thienylmagnesium bromide in a 10-L stirred tank reactor. In THF the Grignard reagent, thienylmagnesium bromide, was readily formed from 2-bromothiophene and magnesium. To avoid crystallization the maximal concentration was limited to 1.4 M. Furthermore, the novel combination of THF and NiCl₂[bis(diphenylphosphino)benzene] allows for fast double coupling of the Grignard reagent with 2,5-dibromothiophene. The concentration of catalyst could be limited to 0.5 mol % based on the amount of 2,5-dibromothiophene. An adapted workup procedure was developed, in which n-octane was used to separate the magnesium salts from the desired product. The reaction was performed in a (semi)batch-wise operated reactor. A global model for the coupling step proved to predict the results at 0.1-, 1-, and 10-L scales very accurately. The heat of reaction evolved in the coupling step was valorized and could be handled easily. Mixing of the feed stream and the reactor content proved to be another important factor in the scaling-up of the α-terthienyl synthesis.

Full text of DOI:10.1021/op020044n

Organic Process Research & Development 2003, 7, 10−16
Articles
Process Design and Scale-Up of the Synthesis of 2,2′:5′,2′′-Terthienyl
B. J. J. Smeets,† R. H. Meijer,† J. Meuldijk,‡ J. A. J. M. Vekemans,† and L. A. Hulshof*,†
EindhoVen UniVersity of Technology, Laboratory of Macromolecular and Organic Chemistry and Process DeVelopment
Group, P.O. Box 513, 5600 MB EindhoVen, The Netherlands
Abstract:
The objective of this study was the design of a scaleable process
for the synthesis of 3-4 mol of r-terthienyl from 2,5-dibromo-
thiophene and thienylmagnesium bromide in a 10-L stirred tank
reactor. In THF the Grignard reagent, thienylmagnesium
bromide, was readily formed from 2-bromothiophene and
magnesium. To avoid crystallization the maximal concentration
Figure 1. Selected two-step synthesis of r-terthienyl:
a
was limited to 1.4 M. Furthermore, the novel combination of
Grignard synthesis of thienylmagnesium bromide followed by
its Ni(0)-catalyzed coupling with 2,5-dibromothiophene.
THF and NiCl2[bis(diphenylphosphino)benzene] allows for fast
double coupling of the Grignard reagent with 2,5-dibromo-
thiophene. The concentration of catalyst could be limited to 0.5
mol % based on the amount of 2,5-dibromothiophene. An
adapted workup procedure was developed, in which n-octane
was used to separate the magnesium salts from the desired
product. The reaction was performed in a (semi)batch-wise
operated reactor. A global model for the coupling step proved
to predict the results at 0.1-, 1-, and 10-L scales very accurately.
The heat of reaction evolved in the coupling step was valorized
and could be handled easily. Mixing of the feed stream and the
reactor content proved to be another important factor in the
scaling-up of the r-terthienyl synthesis.
processes, the synthesis of 2,2′:5′,2′′-terthienyl (R-terthienyl)
was selected. This compound is one of the most general
building blocks in the field of conducting polymers.2
Many synthetic routes towards R-terthienyl are reported,3
but most of them are not applicable to large-scale production
since hazardous solvents or reactants or both, or too many
reaction steps with low yields are involved. A two-step
preparation involving the formation of thienylmagnesium
bromide and its subsequent Ni(0)-catalyzed coupling with
2,5-dibromothiophene (TBr2) was selected, see Figure 1.
The optimization comprised amongst other things the
selection of a suitable solventspreferably the same in both
steps, the concentration of the reactants, the reaction tem-
peratures and, in addition, an efficient catalyst for the
coupling step. Since both reaction steps are exothermic, a
reaction calorimetric study was performed to determine the
heat of reaction. With the results found during the optimiza-
Introduction
In the fine chemical industry most chemicals are produced
in (semi)batch-wise operated multipurpose plants. Short-
market life cycles and relatively low production volumes
characterize the wide variety of chemicals produced in these
plants. The demand for a short time-to-market of new
chemicals is a challenge for batch process design. A fast
and systematic approach is required in the scale-up that
allows an early recognition of scale-up issues before (pilot)
plant process implementation.1 To develop tools and a
methodology for fine chemical scale-up of catalytic batch
(2) (a) Roth, S. R. One-Dimensional Metals; VCH: Weinheim, 1995. (b) Miller,
J. S. AdV. Mater. 1993, 5, 587. (c) McQuade, D. T.; Pullen, A. E.; Swager,
T. M. Chem. ReV. 2000, 100, 2537. (d) Pei, J.; Yu, W. L.; Huang, W.
Macromolecules 2000, 33, 2462. (e) Semenikhin, O. A. Electrochim. Acta
2001, 47, 171. (f) Leclerc, M.; Donat-Bouillud, A. Chem. Mater. 1997, 9,
2815. (g) Buvat, P. Synth. Met. 1999, 101, 17. (h) Sicot, L.; Lorin, F. A.;
Nunzi. J. M.; Raimond, P. Synth. Met. 1999, 102, 991. (i) Miller, L. L.;
Mann, K. R. Acc. Chem. Res. 1996, 29, 417. (j) Gangopadhyay, R.; De, A.
Chem. Mater. 2000, 12, 608.
(3) Tourillon, G. Handbook of Conducting Polymers; Skotheim, T. A., Ed.;
Marcel Dekker: New York, 1986. R-Terthienyl has been prepared by ring-
closure of 1,4-bis(2-thienyl)-butane-1,4-dione14 and of 1,4-bis(2-thienyl)-
1,3-butadiyne.15 It has also been prepared by Pd-catalyzed aryl-aryl coupling
of the Stille16 and Suzuki type.17 Most frequently, however, the Ni-catalyzed
aryl-aryl Kumada coupling is selected.18 While Pd catalysts serve as aryl-
aryl coupling mediators with boronates and stannanes (Suzuki; Stille), the
use of nickel catalysts definitely is to be preferred with Grignard reagents
(Kumada). In comparison with other homogeneous aryl-aryl coupling
methods the described Ni-dppp-catalyzed coupling of 2-thienylmagnesium
bromide with 2,5-dibromothiophene in diethyl ether necessitates minor
quantities of catalyst, presumably reflecting the intrinsic high reactivity of
the system aryl Grignard-Ni0-aryl halide. The replacement of the solvent
(diethyl by dipropyl ether),19 of the halide (dibromide by diiodide)20 and of
the catalyst (Ni-dppp by Ni-dppf)21 has been investigated.
* Author for correspondence. E-mail: L.A.Hulshof@tue.nl.
† Laboratory of Macromolecular and Organic Chemistry.
‡ Process Development Group.
(1) (a) Hulshof, L. A. The Red Queen’s Race in Fine Chemical Scale-Up.
Presented at the 3rd International Conference on Organic Process Research
and Development, Montreal, Canada, July 10-12, 2000 (this article
describes the contours of a novel methodology in fine chemical scale-up as
derived from an analysis of the causes of various batch surprises upon scale-
up). (b) Nollen, E. A. C. Continuous Versus Batch in Fine Chemicals
Industry; Stan Ackermans Institute: Eindhoven, The Netherlands, 1999.
(c) Spanjers, M. A. J. C. M. A NoVel Approach for Fine Chemicals Process
DeVelopment; Stan Ackermans Institute: Eindhoven, The Netherlands, 2000
(examples of b and c are related to the production of R,S-â-acetylthio-
isobutyrate).
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Vol. 7, No. 1, 2003 / Organic Process Research & Development
10.1021/op020044n CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/05/2002

Figure 2. Yields of products in the formation of the Grignard reagent (right), and of r-terthienyl (left) respectively in various
solvents as a function of time, 1.5 mol % NiCl2(dppp) was used as catalyst in the coupling step. The temperature was at reflux for
diethyl ether (35 °C) and THF (67 °C); other solvents were heated to 90 °C. At 100% conversion the concentration of the Grignard
reagent was approximately 2 mol/L.
Figure 3. Various ligands screened to tune the selectivity and activity of the Ni catalyst.
tion of the reaction system and kinetic data for the coupling
reaction a semibatch process was designed for the production
of R-terthienyl on a 10-L scale in a fully automated (semi)-
batch-wise operated reactor.4
both steps since it gave reasonably high yields and is
commercially available in large quantities.
Glymes have been considered as solvent for this process.
However, it turned out that the ligating power of monoglyme
is so high that it stabilizes the active nickel catalyst, giving
rise to a colorless and inactive NiCl2‚monoglyme complex.
Hence, glymes were also abandoned for the formation of
the Grignard reagent.
Catalyst Selection. Variation of the phosphine ligands
attached to nickel changes the activity of the nickel catalysts.
Apart from steric and electronic effects of more or less
electron-rich ligands the bite angle of the ligand plays a
crucial role.6 Several ligands (Figure 3) were selected for
screening on selectivity and productivity. The results are
depicted in Figure 4.
Optimization Studies
Solvent Selection. Most nickel-catalyzed coupling reac-
tions between a Grignard reagent and a bromo compound
are carried out in diethyl ether in the literature.5 Since diethyl
ether is not appropriate for scale-up, a number of more
applicable solvents were selected. The selected solvent should
be cheap, not harmful to the environment, and easy to
recover. Additionally, the reactions should proceed with high
conversion rates in the solvent to increase productivity and
reduce production costs.
A substantial difference in activity of the catalysts in
different solvents was observed (see Figure 4). In THF the
best catalysts seem to be NiCl2(dppe) and particularly NiCl2-
Ethers are known to be good solvents for both the
Grignard and coupling reactions; therefore, a screen of
ethereal solvents was carried out. The length and type of
the ether alkyl chains influenced the results as is depicted in
Figure 2.
Several solvents performed well in the Grignard step as
becomes apparent from Figure 2. For the coupling step
diethyl ether remained the best solvent, with di-n-propyl ether
and THF as good alternatives.
(4) (a) This reactor is described in: Soldaat, A. Chemisch2weekblad 1999, 8,
18. (b) Hersmis, M. C.; Spiering, A. J. H.; Waterval, R. J. M.; Meuldijk, J.;
Vekemans, J. A. J. M.; Hulshof, L. A. Org. Process Res. DeV. 2001, 5, 54.
(5) (a) Langeveld-Voss, B. M. W. Chiral Polythiophenes; Universiteitsdrukkerij
Technische Universiteit: Eindhoven, 1999. (b) Wynberg, H. Recl. TraV.
Chim. Pays-Bas 1996, 115, 119. (c) Albers, W. Tetrahedron 1995, 51, 3895.
(d) Cunningham, D. D. J. Chem. Soc., Chem. Commun. 1987, 13, 1021. (e)
Tamao, K.; et al. Tetrahedron 1982, 22, 3347. (f) Carpita, A.; et al.
Tetrahedron 1985, 41, 1919.
The differences in yields are caused by variations in the
solubility of the catalysts and in stabilization by the solvent.
Finally, THF was selected as the most favorable solvent for
(6) Oosterom, G. E.; Reek, J. N. H.; Kramer, P. C. J.; van Leeuwen, P. W. N.
M. Angew. Chem., Int. Ed. 2001, 40, 1828.
Vol. 7, No. 1, 2003 / Organic Process Research & Development
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11

Figure 4. Screening tests for various catalysts in selected solvents (THF, di-n-butyl ether, di-n-propyl ether, and diethyl ether).
Except for the two at the right, NiCl2 is used as metal center. The procedure for the screening tests is given in the Experimental
Section.
(dppbenz). The bite angles of these ligands are comparable.
In di-n-butyl ether and di-n-propyl ether several catalysts
showed a similar but inferior activity.
Optimization of the Reaction System. In the screening
tests for the solvent and catalyst the combination of THF
with NiCl2(dppbenz) gave remarkably high yields of the
desired R-terthienyl. This system was selected for further
optimization tests. Factors such as concentration of the
catalyst, concentration of 2,5-dibromothiophene in the reac-
tion mixture, temperature of the reaction mixture, and the
addition rate of the Grignard reagent have been included in
this study.
Figure 5. Influence of the temperature in K, [TBr2]0 ) 0.4 M,
0.5% NiCl2(dppbenz), tadd (Grignard) ) 15 min.
In Figures 5-10 the yields are given as a function of time.
Higher temperatures increased the reaction rate as ex-
pected. In experiments at low temperatures the activity of
the catalyst started to decrease when the conversion reached
about 60%. At elevated temperatures this fall in performance
was not observed. This is presumably due to product
inhibition by a reversible coordination of R-terthienyl to the
Ni center.
At room temperature an optimum addition time of 15 min
for the Grignard reagent was determined on 0.1-L scale.
Faster addition resulted in product inhibition again, while
slower addition diminished the concentration of the Grignard
reagent and hence the reaction rate. When the temperature
was increased, this effect disappeared. At this addition rate
Figure 6. Influence of the addition time of the Grignard
reagent, [TBr2]0 ) 0.4 M, 1.5% NiCl2(dppbenz), 25 °C.
of the Grignard reagent the rate of heat production was
modest, and no severe precautions had to be taken to control
the reaction temperature.
reagent used. To guarantee a high selectivity the excess of
Grignard reagent was set at 5%.
Conclusions of the Optimization Study. The coupling
reaction should be performed at reflux temperature (see
Figure 5). The addition rate is not important for the final
yield when a sufficiently high temperature is applied, and it
allows control of the temperature (see Figure 6). The amount
of catalyst can be reduced to 0.5 mol % (see Figure 7) at
reflux, and the catalyst cannot be recycled. Recycling of the
catalyst at higher loadings was not considered. Finally, a
concentration above 0.4 M of the starting material gives
lower yields (see Figure 8).
The results in Figure 7 demonstrate that the reaction rate
with decreasing amounts of catalyst decreases more than
proportionally. The lower productivity with 0.5 mol %
catalyst could be improved by an increase in temperature.
The concentration of the TBr2 influenced the reaction rate,
see Figure 8. Another effect of high concentration was a
decrease in selectivity, giving more 2,2′-bithiophene as the
major byproduct. Therefore, the maximal concentration of
TBr2 was fixed at 0.4 M.
Increasing the excess of the Grignard reagent favored the
reaction rate. Unfortunately, the formation of undesired 2,2′-
bithiophene was also related to the amount of Grignard
On the basis of the above-mentioned conclusions a
reaction procedure was developed at 100-mL scale (see
Experimental Section).
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Vol. 7, No. 1, 2003 / Organic Process Research & Development

recrystallization either from n-octane, n-hexane, or n-butanol
as depicted in Figure 10.
Two crystallization cycles from n-octane yielded R-ter-
thienyl with the desired purity.
Scale-Up of the r-Terthienyl Synthesis. In the scale-
up of the R-terthienyl synthesis three aspects proved to be
important. First the mixing of the feed stream, second the
heat transfer to remove the heat of reaction, and finally the
handling of the suspension containing magnesium salts
during workup.
The desired degree of feed-stream mixing was determined
by visual inspection and was accomplished at a stirring speed
of 400 rpm at 1-L scale. At this stirring speed the heat
transfer between the reactor content and the jacket was
sufficient to remove the heat of reaction. The heats of
reaction for the Grignard synthesis and the coupling step were
measured with a Mettler Toledo RC1/e reaction calorimeter.
The results are shown in Table 1. The adiabatic temperature
rise (∆Tad) was calculated in the usual way.8
Figure 7. Influence of the amount of catalyst, [TBr2]0 ) 0.4
M, tadd (Grignard) ) 15 min, 25 °C.
By feeding the Grignard reagent to a solution of 2,5-
dibromothiophene the heat that had to be removed could be
controlled. The feeding time was calculated by simultaneous
solution of the mass and energy balances:
dV(t)
dt
) Fin
(1)
(2)
Figure 8. Influence of [TBr2]0, 0.5% NiCl2(dppbenz), tadd
(Grignard) ) 15 min, 25 °C.
d(V(t)CA)
dt
) FinCA,in + V(t)RA
d(Trm(t)Cp(t))
dt
) FinFinCp,in(Tin - Tr) + UA(Tj - Tr) +
(-∆RHRAV(t)) (3)
where
Fin ) feed stream (m3/s)
CA ) concentration of the feed (kmol/m3)
m
) reaction mass (kg)
Figure 9. Influence of the excess of the Grignard reagent,
[TBr2]0 ) 0.4 M, 0.5% NiCl2(dppbenz), tadd (Grignard) ) 15
min, 25 °C.
RA ) reaction rate of the feed (kmol/m3‚s)
Cp ) heat capacity of the reactor contents (1200 J/kg‚K)
∆rH ) reaction heat production (kJ/kmol)
/lp;&-2q;1
U
A
) heat exchange coefficient (45 J/m2‚K‚s)
) heat exchange area (m2)
Workup
Tj ) temperature of the jacket (K)
The traditional workup for reactions involving Grignard
reagents is the addition of water, followed by an extraction
step.7 This method could not be used for a scaleable process
since it was found that THF formed soluble complexes with
magnesium salts. These complexes remained in the organic
phase and led to an off-spec product. A new workup method
had to be developed. Addition of n-octane, removal of THF
by distillation, and heating the n-octane to reflux led to
dissolution of all R-terthienyl. After siphoning off the
R-terthienyl solution, the precipitated magnesium salts were
washed with hot n-octane (110 °C) twice. The total volume
of n-octane (approximately 1.5 times the original amount of
THF) was allowed to cool to room temperature, yielding
bright yellow R-terthienyl as product (95% yield). The purity
of the R-terthienyl could be improved from 95 to 99% by
Tr ) temperature of the reaction mass (K)
The feeding time is governed by the requirement that the
temperature of the reaction mixture should be 67 °C. This
is theoretically met when the addition times for the Grignard
reagent were 35 min at 1-L and 65 min at 10-L scale,
respectively. In practice the addition times were shorter.9
The magnesium salts formed during the reaction precipi-
tated when n-octane was fed to the reactor. These salts
showed a tendency to stick to the reactor wall when mixing
was not efficient. A pitched-blade impeller was used, and
according to measurements the lowest stirring rate to keep
∆rHC0
(8) ∆Tad
) -
mCp
with ∆rH ) heat of reaction (kJ/mol), C0 ) total amount of the starting
material (mol of 2-bromothiophene and 2,5-dibromothiophene in the
Grignard synthesis and the coupling step, respectively), m ) total mass
of the reaction mixture (kg), Cp ) heat capacity of the reactor contents
(kJ/kg‚K).
(7) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. In Vogel’s
Textbook of Practical Organic Chemistry, 5th ed.; Vogel, A. I., Ed.;
Longman Scientific & Technical: Harlow, UK; Wiley: New York; 1989.
Vol. 7, No. 1, 2003 / Organic Process Research & Development
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13

Figure 10. Purity of r-terthienyl obtained after repeated crystallizations (A) and the fraction of isolated product, compared to the
initial amount of crude r-terthienyl (B).
Table 1. Reaction enthalpies and the adiabatic temperature rise for both reaction steps
C0 (mol)
∆rH (kJ/mol)
M (kg)
Cp (kJ/kg‚K)
∆Tad (°C)
Grignard synthesis
coupling step
0.84 (2-bromothiophene)
0.40 (2,5-dibromothiophene)
-471.90a
-248.13b
0.650
0.900
1.85
2.03
329.64
54.32
a Based on 2-bromothiophene. b Based on 2,5-dibromothiophene.
the solids in suspension was 360 rpm. According to the
The filterability and cake resistances of various suspen-
sions shown in Table 2 indicate that a good separation
between the solid and liquid phases is possible by pressure
filtration or centrifugation.
“Zwietering” relation 4 a just-suspended stirring rate (Nmin
)
of 380 rpm was predicted.10
0.45
0.13
Fs - Fl
Fl
ms
T
Nmin ) S1υ0.1d0p.2
g
100
S2D-0.85 (4)
The synthesis of R-terthienyl was performed on 1-L scale
according to the optimized recipe as mentioned before. The
yields were comparable to the small-scale experiments, and
the reaction heats could be handled smoothly. The results
of the 1-L experiments are summarized in Table 3.
To ensure the control of the temperature in the reactor
the Grignard reagent was fed over 40 min. In the first run it
was noticed that mixing between the feed stream and the
reactor content was very poor. In the second and third run,
mixing was improved by higher impeller speeds and an
increased clearance between the pitched-blade impeller and
the reactor bottom. The overall yield of isolated R-terthienyl
after crystallization was in all cases between 90 and 92%
based on 2,5-dibromothiophene (98% purity).
( (
)) ( m ) (D)
l
where
Nmin ) lowest stirring rate (rpm)
) diameter of the impeller (m)
D
S1, S2 ) constants(forthe Rushton turbine: S1 ) 1.4,
S2 ) 1.5; pitched-blade: S1 ) 0.9, S2 ) 1.5)
ν
) kinematic viscosity (m2/s)
) particle diameter (m)
) gravity constant (m/s2)
dp
g
Fs, Fl ) density of the solid and liquid phase (kg/m3)
ms, ml ) total mass of solids and liquid, respectively (kg)
T
) reactor diameter (m)
Ten-Liter Experiment. On 10-L scale4 the recipe was
identical to the procedure used at 1-L scale multiplied by a
factor of 6 (maximal filling of the reactor). The stirring speed
during the reaction was scaled according to eq 713
The following relations for the cake resistance (r) and
filterability (k) could be used to predict the behavior of a
suspension upon filtration,11 and this could be used in the
selection of a proper filtration unit:
2∆PA
(9) The addition time of the 10-L run was estimated from the mass and energy
balances to be 65 min and turned out to be 60 min, whereas the addition
time for 1-L scale was estimated to be 35 min, and in practice 40 min. The
addition times for the Grignard reagent were estimated under the requirement
that the temperature of the reaction mixture was 67 °C (reflux). For 1000-L
scale the addition time was estimated to be 4 h. No chances of accumulation
in the experimentals were ever observed. The temperature rise after additions
was complete before heating to reflux was started. On larger scale when
the Grignard would be added at higher temperatures, reflux would be
advantageous for even a shorter addition time due to the removal of heat
by improvement of the heating transfer capacity of the condenser.
(10) Zwietering, Th. N. Chem. Eng. Sci. 1957, 8, 244.
(11) (a) Svarovsky, L. Kirk-Othmer Encyclopedia of Chemical Technology; John
Wiley & Sons: New York, 1994. (b) Meeten, G. H.; Smeulders, J. B. A.
F. Ind. Eng. Chem. Res. 1996, 35, 4810. (c) Motta Raimondo (Oxon Italia
Spa.). CH623057, May 15, 1981.
(12) (a) Personal communications from Van Buel, M.; Christis, H. DSM Fine
Chemicals, Venlo, The Netherlands. (b) Jennings, J. R. J. Organomet. Chem.
1987, 325, 25. (c) Klokov, B. A. Org. Process Res. DeV. 2000, 4, 122.
(13) Custers, J. P. A.; Hersmis, M. C.; Meuldijk, J.; Vekemans, J. A. J. M.;
Hulshof, L. A. Org. Process Res. DeV. 2002, 6, 645.
r ) t
(5)
(6)
filter HVη
HV
Atfilter∆P
k )
where
tfilter ) filtration time (s)
∆P ) pressure drop (9 × 104 Pa)
A
H
V
) filtration area (2 × 10-3 m2)
) cake height (m)
) filtration volume (1 × 10-4 m3)
In Table 2 the cake resistance and filterability are collected
for three different suspensions. The cake resistance and
filterability determine the filtration type at different scales.12
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Vol. 7, No. 1, 2003 / Organic Process Research & Development

Table 2. Filtration times, cake heights, cake resistance, and filterability for different suspensions
run
filtration times (s) cake heights (m) cake resistance (m-2
)
filterability (m3/kg)
magnesium salts in a solution of R-terthienyl in THF
magnesium salts in n-octane at 110 °C
R-terthienyl in n-octane at room temperature
64
28
16
0.024
0.014
0.013
1.92 × 1012
1.36 × 1012
6.38 × 1012
1.88 × 10-9
2.91 × 10-9
5.23 × 10-9
Table 3. One-liter synthesis of r-terthienyl, 200 mL of THF with TBr2 in the reactor, 600 mL of 1.4 M Grignard solution is
added in 40 min, pitched-blade impeller
[Br2T]
% catalyst
(NiCl2[dppbenz])
excess of Grignard
reagent (%)
temperature
stirring speed
(rpm)
yield T3
run
(mol/dm3)
(°C)
(%)a
1
2
3
0.5
0.5
0.3
0.5
0.5
0.25
10
5
5
30-67
40-67
40-67
300
400
400
95
95
98
a After 1.5 h, based on 2,5-dibromothiophene and determined by GC analysis.
Nmin
D-0.85
Nmin
D-0.85
) C
(7)
(
)
(
)
s
l
where C ) correction factor, C ) 0.9 for V < 10 L, and C
) 1 for V > 10 L for a pitched-blade impeller.
With eq 7 the stirring speed needed for the suspension of
particles formed during the reaction was calculated to be at
least 280 rpm on a 10-L scale. The actual stirring rate applied
in the 10-L experiment was also 280 rpm.
The Grignard reagent was fed to the 2,5-dibromothiophene
solution in 60 min. The heat of reaction was used to heat up
the reactor content as could be calculated from eqs 1-3.
After addition of the entire amount of Grignard reagent, the
reaction mixture was stirred for another 30 min at reflux
temperature, leading to complete conversion of the 2,5-
dibromothiophene.
The conversion of 2,5-dibromothiophene at different
scales could be described very accurately by simultaneous
solution of eqs 1-3 as becomes obvious in Figure 11.
When the reaction was complete, THF was distilled off;
in the meantime n-octane was added slowly. The n-octane
solution was heated to reflux temperature. The impeller was
stopped, and the magnesium salts that settled on the bottom
were separated from the R-terthienyl solution by siphoning
off the latter into another vessel to crystallize. The final
conversion was 100% with a selectivity of 92%. The main
byproduct was 2,2′-bithiophene. After a second crystallization
the yield of bright yellow colored R-terthienyl was 85% with
a purity of 98.7%.
Figure 11. Conversion of 2,5-dibromothiophene as a function
of time at different reaction scales. T ) 60 °C, [T3] ) 0.4 M,
0.5 mol % NiCl2(dppbenz), addition time Grignard reagent (1.4
M): 15 min (0.1 L), 40 min (1 L), and 60 min (10 L).
catalyst combination in the coupling of 2,5-dibromothiophene
with 2 equiv of thienylmagnesium bromide. THF is ap-
plicable as solvent in the large-scale production of R-ter-
thienyl since it gives a high yield and purity.
In addition, the optimization study includes concentration
of the reactants, reaction temperature, addition rate of the
Grignard reagents, and excess of the Grignard reagent. The
highest conversions are 99% with a selectivity of 92%. This
means that some of the byproduct formation occurs via a
parallel reaction.
A workup procedure has been developed to obtain the
desired purity (99%). In this procedure THF is distilled off
while hot n-octane is fed to the reaction mixture. The
magnesium salts precipitate while R-terthienyl stays in
solution. After filtration/siphoning off the solution, it is
cooled, and the R-terthienyl is obtained in good yields. A
simple model for the semibatch reactor is able to describe
the coupling step adequately. Finally, the scale-up to 10 L
has been successful.
Conclusions
A novel combination of THF and NiCl2(dppbenz) has
proven to be very efficient in the coupling as a solvent/
(14) Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S.-O. Bull. Soc.
Chim. Belg. 1978, 87, 223.
(15) Carpita, A.; Rossi, R.; Veracini, C. A. Tetrahedron 1985, 41, 1919.
(16) (a) Yui, K.; Aso, Y.; Otsubo, T.; Ogura, F. Bull. Chem. Soc. Jpn. 1989, 62,
1539. (b) Crisp, G. T. Synth. Commun. 1989, 19, 307.
(17) Gronowitz, S.; Peters, D. Heterocycles 1990, 30, 645.
(18) Kumada, M.; Tamao, K.; Sumitani, K. Org. Synth. 1978, 58, 127.
(19) Morand, P.; Leitch, L. C.; Mac Eachern, A.; Arnason, J. J. Can. Patent
1267904, 1990.
(20) Tamao, K.; Kodana, S.; Nakajima, M.; Kumada, M.; Minato, A.; Suzuki,
K. Tetrahedron 1982, 38, 3347.
(21) Rossi, R.; Carpita, A.; Ciofalo, M.; Houben, J. Gazz. Chim. Ital. 1990, 120,
793.
Experimental Section
General Experimental. NiCl2‚6H2O was obtained from
Aldrich. 2,5-Dibromothiophene (95% pure), and 2-bromo-
thiophene (97% pure) were also purchased from Aldrich.
Ligands for the preparation of the catalysts were purchased
from different suppliers in purity varying between 95 and
98%. All chemicals were used without further purification.
All solvents were distilled prior to use and stored under dry
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argon gas on activated molecular sieves. H and 13C NMR
In the coupling reactions the Grignard reagent (50 mL,
1.4 M) was added in 15 min to a solution of 2,5-
dibromothiophene (0.030 mol, 7.26 g) in THF (20 mL) at
room temperature. In the latter solution the catalyst, NiCl2
[dppbenz] (0.15 mmol, 60 mg) was dispersed. After addition
of the Grignard reagent the temperature was raised to reflux
temperature.
In the workup n-octane (50 mL) was added in 2 min, and
the THF was distilled off. The resulting suspension of
magnesium salts and R-terthienyl in n-octane was heated to
110 °C followed by siphoning of the hot n-octane solution.
The magnesium salts were washed twice with 25 mL of hot
n-octane, and the combined n-octane fractions were cooled
to room temperature, yielding R-terthienyl as a bright yellow
product after smooth filtration and drying under vacuum
(6.72 g, yield 90%).
spectra were recorded in CDCl3 with a Varian Gemini 300,
400, or 500 MHz. The proton chemical shifts were calibrated
to tetramethylsilane (TMS), whereas the carbon chemical
shifts are reported in ppm downfield of TMS using the
resonance of the deuterated solvent as the internal standard.
GC analyses were performed using a Zebron ZB-35 column
on a Perkin-Elmer autosystem. Conversion and yields were
determined with the aid of 1,3,5-tri-tert-butylbenzene as the
internal standard. Reaction calorimetric tests were performed
on 1-L scale in a RC-1. Large-scale reaction was carried
out in a 10-dm3 fully automated (semi)batch-wise operated
reactor. This Belatec reactor is able to perform under a
variety of conditions: a temperature range from -50 to 200
°C, solvent distillation, different agitator types, a pressure
range from 0.03 to 1.1 bar. The reactor is controlled by a
PLC, a special computer, which monitors physical data (batch
history) and secures optimal process and safety conditions.4
Procedure for Screening Tests. An oven-dried 40-mL
Radley Carousel reaction tube was flushed with argon before
it was charged with 2,5-dibromothiophene (10 mL of 0.4
M) dissolved in the solvent of choice, mixed with catalyst
(1.5 mol %) and 2-thienylmagnesium bromide (10 mL 0.9
M). This mixture was stirred at room temperature during 5
h. Small aliquots were taken for GC analyses.
Syntheses of Different Catalysts. In a 100-mL flask
NiCl2‚6H2O was dispersed in methanol. The dispersion was
thoroughly purged with argon for 2 h. The different ligands
were added (1.1 equiv), and the resulting dispersions were
stirred during 24 h at reflux temperature. The color of the
solid in the dispersion changed from green to orange/red
(except for the synthesis of NiCl2[dppf], where a purple solid
was formed). After filtration and drying under vacuum the
solids were stored under argon and used without further
purification. Yields varied around 95% for all syntheses. The
purity was checked by elemental analysis and UV absorption.
Original Procedure for the Synthesis of r-Terthienyl.
A solution of 2.5 equiv of 2-thienylmagnesium bromide in
diethyl ether was reacted with 2,5-dibromothiophene in the
presence of a catalytic amount NiCl2[dppp]. After 5 h at
reflux, 0.1 M HCl was added, and the mixture was extracted
with toluene. The volume of toluene was reduced by
distillation, and the product was obtained by the addition of
cold methanol. After recrystallization yields up to 60% were
reported.5b
1H NMR (CDCl3, 300 MHz): δ ) 7.20 (s, 2H), 7.11 (s,
2H), 7.06 (s, 2H), 7.01 (s, 2H). 13C NMR (CDCl3, 300
MHz): δ ) 137.07, 136.14, 127.84, 124.26, 77.00.
Ten-Liter Scale. During the formation of the Grignard
reagent 2-bromothiophene (7 mol, 1141 g) was added in 4
h to a slurry of 1.3 equiv of magnesium turnings in THF
(4.5 L). Addition was carried out at reflux temperature. After
addition of all 2-bromothiophene the mixture was kept at
reflux temperature during 1 h. The stirrer was stopped, the
Grignard reagent was filtered to remove the excess of
magnesium, and the resulting solution was kept under argon
prior to use.
In the coupling reactions the Grignard reagent (4.5 L, 1.56
M) was added in 45 min to a solution of 2,5-dibromo-
thiophene (3 mol, 726 g) in THF (2 L) at room temperature.
In this solution the catalyst, NiCl2 [dppbenz], (14 mmol, 8.29
g) was dispersed. After addition of the Grignard reagent the
temperature rise was complete (Tr,max ) 338 K), and the
reaction mixture was heated to reflux temperature for another
hour.
In the workup n-octane (5 L) was added, and the THF
was distilled off at atmospheric pressure. The resulting
suspension of Mg salts in n-octane was heated to 110 °C.
The hot n-octane solution was siphoned off, and the salts
were washed twice with hot n-octane (2.5 L). The combined
n-octane fractions were cooled to room temperature, yielding
R-terthienyl as a bright yellow product after a smooth
filtration and drying under vacuum (678.5 g, yield 90.8%).
A second crop could be obtained by cooling the n-octane to
253 K (50.6 g, total yield 97.5%).
New Procedure for the Synthesis of r-Terthienyl (100-
mL Scale). During the formation of the Grignard reagent,
2-bromothiophene, (0.07 mol, 11.41 g) was added in 1 h to
a slurry of 1.3 equiv of magnesium turnings in anhydrous
THF (50 mL). Addition was carried out at reflux temperature.
After addition of all 2-bromothiophene the mixture was kept
at reflux temperature during 1 h. The stirrer was stopped,
the Grignard reagent was filtered to remove the excess of
magnesium, and the resulting solution was kept under a
blanket of argon prior to use. Treatment of a sample of
2-thienylmagnesium bromide with water revealed the disap-
pearance of 2-bromothiophene by GC and NMR.
Acknowledgment
We thank DSM Fine Chemicals and the departments SMO
and SPD of the Eindhoven University of Technology for
financial support. Also the excellent assistance by Tim Baks
is gratefully acknowledged.
Received for review April 19, 2002.
OP020044N
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