Thermal hazards of the Vilsmeier-Haack reaction on N,N-dimethylaniline

Article abstract of DOI:10.1021/op0580116

From literature data and a preliminary calorimetric study it is clear that the Vilsmeier-Haack reaction poses specific thermal hazards as both the Vilsmeier-Haack intermediate (1) in N,N-dimethylformamide (2) and the reaction mixture with N,N-dimethylanil

Full text of DOI:10.1021/op0580116

Organic Process Research & Development 2005, 9, 982−996
Thermal Hazards of the Vilsmeier-Haack Reaction on N,N-Dimethylaniline
Marcus Bollyn*
Chemical Process DeVelopment, Agfa-GeVaert N.V., 2640 Mortsel, Belgium
Abstract:
relative position of the following parameters: process tem-
From literature data and a preliminary calorimetric study it is
clear that the Vilsmeier-Haack reaction poses specific thermal
hazards as both the Vilsmeier-Haack intermediate (1) in N,N-
dimethylformamide (2) and the reaction mixture with N,N-
dimethylaniline (3) are thermally unstable and can generate
high and fast temperature and pressures rises when heated.
Therefore alternatives were investigated for their thermal
hazards. The stability of Vilsmeier intermediates generated from
a series of other formamides was investigated. In principle the
Vilsmeier intermediate could be generated and converted in
situ, thus avoiding large amounts of an unstable intermediate
in the process vessel and yielding the same reaction mixture.
This concept could also be applied to the other formamides
studied, and this option was also included in the investigation.
perature (T ), boiling temperature of the reaction mixture (T ),
p
b
maxiumum temperature of the synthesis reaction (MTSR),
and the temperature with a time to maxiumum rate of 24 h
TMR24 or MaxTsafe247).
(
Process temperature and boiling point can quite easily be
obtained, but MTSR should be calculated from calorimetric
data, and MaxTsafe24 values come from adiabatic thermal
stability testing. For the readers not familiar with reaction
r
calorimetry, the heatflow (Q ) is a measure for the heat
generated by the process(es) at any time; integrating this
signal over the whole process yields the total process
enthalpy (∆H). The combination of these data with other
process information allows the calculation of other param-
eters which are important for risk assessment of the process.
These comprise:
(
1) MAT: Maxiumum Adiabatic Temperature is the
Introduction
The Vilsmeier-Haack reaction1-3 is widely used for
formylations. It can be applied to introduce an aldehyde
group on activated aromatic compounds, but many other
conversions can be achieved with this technology. In general
N,N-dimethylformamide (DMF) and phosphorus oxychloride
temperature that can be achieved when all the process
enthalpy is converted to temperature rise.
(2) MTSR: Maxium Temperature of the Synthesis Reac-
tion is the calculated temperature that will be achieved when
the dosing is stopped at the time of a cooling failure; it is a
measure for the accumulation in a semi-batch process during
the process.
3
(POCl , 4) are used to generate the Vilsmeier-Haack
intermediate. Within Agfa this reaction is used for the
production of N,N-dimethylaminobenzaldehyde (DMAB, 5),
from N,N-dimethylaniline (DMA), as an intermediate for
dyes (Scheme 1).
In the European Union the Seveso II directive requires
that the hazards of chemical processes are identified to
control the risks and avoid major incidents. One of the
common hazards of chemical reactions performed in a (semi)
batchwise process is a runaway resulting in a thermal
explosion. It is imperative to have the appropriate experi-
mental data to evaluate the risk of this possible event.
Reaction and adiabatic calorimetry testing are the techniques
used to acquire these data.
(3) FHR: Fraction of Heat Released is a measure for the
accumulation of reagent at the end of the dosing.
This concept is used in the risk assessment of all our
chemical processes. In this report we discuss the results of
the study of the process for DMAB production.
In this work the “Runaway index 2” and “Runaway
index 5” are most relevant. In Runaway index 2 the follow-
ing scenario can be envisaged: when cooling fails at a
certain stage of the process (worst case is at maximum
accumulation), the temperature will risesby definitionsto
the value of the MTSR, but the MaxTsafe24 will not be
attained (the MaxTsafe24 value should be 20 °C higher
than the MTSR), nor will the reaction mixture start to boil
because the boiling point is even higher. In “Runaway index
Batch and semi-batch processes can be classified into five
types of runaway scenarios4 (Figure 1), depending on the
,5
6
*
To
whom
correspondence
should
be
addressed.
E-mail:
marcus.bollyn@agfa.com.
5
” the same scenario will have other consequences: loss of
(
(
(
1) Vilsmeier, A.; Haack, A. Ber. 1927, 119-122.
2) Hazebroucq, G. Ann. Pharm Fr. 1966, 793-806.
cooling will trigger the temperature to rise to the MTSR
value, but in the meantime the MaxTsafe24 is also attained
or surpassed, and the decomposition can be initiated. In
general it is recommended to redesign this type of process
or build several well-designed independent layers of protec-
tion (pressure relief valves or bursting disks, inhibition or
quenching, ...).
3) Marson, C. M.; Giles, P. R. Synthesis Using Vilsmeier Reagents; CRC
Press: Boca Raton, FL, 1994.
(
(
(
4) Gygax, R. Chem. Eng. Sci. 1988, 43, 1759-1771.
5) Stoessel, F. Chem. Eng. Progress 1993, 89, 1068-1075.
6) Thematic Network on Hazard Assessment of Highly Reactive Systems,
HARSNET; http://www.harsnet.de: HarsBook is a source of background
and reference material on the subject of exothermic reaction hazards.
7) We prefer to use the expression MaxTSafe24 rather than TMR24, because
the physical meaning is a temperature, rather than a time.
(
9
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10.1021/op0580116 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/03/2005

Scheme 1. General reaction scheme of the Vilsmeier-Haack reaction on N,N-dimethylaniline
Figure 1. Runaway indices: classes of thermal runaway scenarios.
Literature Information
Scale-Up of a Vilsmeier Formylation Reaction: Use of
There are only limited literature data on the thermal
hazards of the Vilsmeier-Haack reaction.8,9 These two
articles have been examined, and although the information
is interesting, these data were not sufficient to identify the
hazards of a similar process. Other references on this topic
were unavailable in the time allowed for this study.
Thermal Hazard Evaluation of Vilsmeier Reaction
with DMF and MFA. In this article the authors studied
the Vilsmeier reaction under specific experimental condi-
tions: short addition times (less than 2 min) and high dilution
HEL Automate and Simulation Techniques for Rapid
9
and Safe Transfer to Pilot Plant from Laboratory. In this
3
article the Vilsmeier reaction is run with DMF/POCl and
an additional solvent at a temperature of -5 °C either with
or without the substrate in the reaction mixture at the time
of addition. It is claimed that the best chemical results are
obtained with preformed Vilsmeier intermediate in the
solvent mixture. Calorimetric data were used to model the
reaction to support the scale-up of the process. A comparison
of the data obtained from the AutoMate and Simular was
also discussed. The potential for decomposition of the
reaction mixture is not mentioned.
The literature information presented here was not suf-
ficient to identify all the hazards associated with our process.
Therefore, an initial calorimetric study was performed in the
RC1 according to the parameters of the production process.
This intitial study indicated that high-energy potentials were
involved; therefore, a more in-depth study was required to
fully characterize the thermal hazards of this process.
8
(DMF/POCl
3
) 24/1, MFA/POCl ) 15/1 in mass ratio).
3
Both of these parameters are outside of the range of our
process operations. In our opinion it is required that
calorimetric data are obtained under conditions as close as
possible to plant conditions; the conditions mentioned are
quite different from those of our process. A reaction enthalpy
value of -57 kJ/mol is reported. The authors state that there
is a high potential hazard of thermal decomposition of the
Vilsmeier complex in the cases where this is formed without
substrate present. This can be avoided by running the process
in a different way: mix the substrate with DMF and feed
Results and Discussion
Our intitial objective for studying the DMAB process was
to measure the reaction heat and determine the thermal
stability of the reaction mixture at different stages to establish
the “Runaway index”. The results confirmed the findings of
previous studies in that there is a significant problem with
thermal instability. This prompted us to investigate the
POCl
as it is formed.
3
to it, and the Vilsmeier complex is consumed as soon
(
8) Miyake, A.; Suzuki, M.; Sumino, M.; Iizuka, Y.; Ogawa, T. Org. Process
Res. DeV. 2002, 6, 922-925.
(
9) Dyer, U.; Henderson, D.; Mitchell, M.; Tiffin, P. Org. Process Res. DeV.
2
002, 6, 311-316.
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thermal hazards of potential alternative methodologies:
integration of the process stages, use of other formamides,
and a combination of both.
1
. The Two-Stage DMF Process. In the standard
production process the Vilsmeier intermediate is generated
in and from DMF by dosing POCl to excess. Subsequently,
3
this is allowed to react with a feed of DMA. The product is
then transferred to a mixture of water and sodium acetate to
hydrolyse and isolate the DMAB. This is called the two-
stage process since there are two feed sequences.
Reaction Calorimetry. To facilitate the interpretation and
avoid extrapolation of the results, the reaction calorimetry
was performed using, as far as possible, the production
conditions (see Experimental Section). The reactor was
charged with DMF, this was cooled to the process temper-
3
Figure 3. DMF + POCl w Vilsmeier: safety parameters.
profile was applied. The measured data are summarised in
Table 2 and illustrated in Figures 4 and 5.
3
ature, and POCl was added to it, followed by the DMA. As
shown, an aging period was used to ensure complete reaction.
This yielded results that are listed in Table 1 for the formation
of the Vilsmeier intermediate.
3
Table 2. ARC results: DMF + POCl at 5 °C
parameter
value
comments
The graphical representation of measured and calculated
parameters allows more in-depth interpretation of the calo-
rimetry information and results (Figures 2 and 3).
It can be concluded that the rate of the reaction is fast
compared to the dosing rate and generates only a moderate
amount of heat. The conversion is essentially complete at
the end of the dosing, and within 60 min of stirring, all heat
production has ceased.
onset T
67 °C
temperature at which the first heat
production above the sensitivity
threshold is detected
temperature at which the maximum
rate of temperature rise is detected
T @ max rate 173 °C
max T rate
max P rate
MaxTsafe24
28 °C/min the maximum temperature rate; this value
can be considered a high rate
48 bar/min the maxiumum pressure rate; this value
can be considered a high rate
49 °C
this rather low value is the result of
low onset temperature and the short
time to thermal explosion.
Table 1. Calorimetry results: DMF + POCl
3
at 5 °C
parameter
value
comments
Q
r
22 W/mol
at the start there is an interaction with the
water present in the technical
grade DMF (0.3%)
5
W/mol
heatflow of the expected reaction
∆
H
-46 kJ/mol total reaction enthalpy, including the
interaction with water which has a
contribution of about -10 kJ/mol,
leaving about -36 kJ/mol for the
Vilsmeier reaction
MAT
73 °C
MAT including the interaction with water,
MAT ) 61 °C for the Vilsmeier reaction
indicates an addition limited process
nearly no accumulation
MTSR
FHR
6 °C
98%
Figure 4. ARC: T,P graph.
The sample starts to self-heat above the threshold value
from 67 °C. This exotherm continues to around 195 °C where
the temperature and pressure stalls. Around 140 °C there is
a rapid temperature increase accompanied by a sharp pressure
rise, comparable to an explosion. A MaxTSafe24 value of 49
°
C is obtained after extrapolation to 1440 min and correction
for the φ-factor (the φ-factor is the ratio of the total mass
bomb + sample) over the mass of the sample; the lower
(
the value, the better).
3
Figure 2. DMF + POCl w Vilsmeier: profile.
The Runaway index for the Vilsmeier intermediate
Adiabatic Calorimetry. A sample taken from a reaction
mixture after the dosing of POCl to DMF was transferred
to the ARC (ARC ) Accelerating Rate Calorimetry) test cell
formation is illustrated in Figure 6. Although the MaxTSafe-
3
24 value is quite low, this is still a Runaway index 2 process
because of the slow dosing, the strong feed control, and the
low temperature rise in case of cooling failure.
(usually called ARC bomb), and the “heat-wait-seek”
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Figure 7. Vilsmeier + DMA profile.
Figure 5. MaxTSafe24 graph.
Figure 6. Runaway index for the formation of the Vilsmeier
intermediate in DMF.
Figure 8. Vilsmeier + DMA safety parameters.
For the reaction calorimetry of the Vilsmeier intermediate
with DMA, Table 3 and Figures 7 and 8 show the results
A sample of the final reaction mixture was subjected to
the same ARC test procedure as the intermediate and yielded
the data shown in Table 4 and graphed in Figures 9 and 10.
The exothermic activity in the sample starts at 48 °C and
proceeds to a temperature of 300 °C, which terminated the
test, and a pressure of 77 bar. From 120 °C on there is a
strong pressure increase over a short period. The first
exotherm switches to a second one around 175 °C.
A Runaway index of 5 is obtained for the reaction of the
Vilsmeier intermediate with DMA (Figure 11).
Table 3. Calorimetry results: Vilsmeier intermediate +
DMA at 15 w 40 °C
parameter
value
comments
Q
r
(12 W/mol the heatflow starts at 4 W/mol and
increases to (12 W/mol after 20 min.
∆
H
-107 kJ/mol this value includes the phase at higher
temperature, required to finish the process
MAT
112 °C
this high value is the result of high
reaction enthalpy and high
The combination of the high accumulation during the feed
and the low onset temperature for the reaction mixture results
in a Runaway index of 5. It is recommended to avoid this
type of process which therefore should be revised.
2. The One-Pot DMF Process. From both in-house
concentration of the process,
but for a semi-batch process
this is not particularly significant
a 30 °C increase due to accumulation
in the process can be considered
as a high value
MTSR 46 °C
FHR 70%
this also indicates a substantial
accumulation of the energy potential
of the process;
8
experience and literature information it was clear that an
alternative method of running the same process should be
the reaction is slower than the feed
possible. As indicated earlier, POCl
mixture of DMF and DMA at the required process temper-
ature. Since the reaction between DMF and POCl is fast, it
3
could be added to a
recorded by the RC1. This reaction profile is more complex
as there seems to be some induction period before the heat
production reaches a constant value. Although the heatflow
drops substantially at the end of the dosing, after 90 min
and during the temperature rise from 15 to 40 °C there is
still heatflow. Further reaction is observed, including a sharp
peak possibly due to crystallisation. At the final temperature
an aging time of 180 min is required to complete the thermal
conversion. It seems that 15 °C is too low a temperature to
maintain full control on the process via the dosing. This is
indicated by both the MTSR and FHR results. A higher
process temperature could avoid this accumulation, but it
should be confirmed that this change leaves the product
quality unaffected.
3
can be assumed that the Vilsmeier intermediate is generated
in situ and could immediately react with the DMA. In this
way the build-up of large amounts of the Vilsmeier inter-
mediate could be avoided. It is difficult to predict if this
would also result in a more thermally stable reaction mixture.
To adress this issue, the calorimetric study was extended,
and the one-pot process was investigated. The initial condi-
tions chosen were close to those of the existing process in
that the temperature was set at 15 °C, the temperature at
which the DMA reaction is run in the two-stage process.
The reactant feed time was extended to the sum of the two
feed periods because more heat generation is expected. In
the following experiments an analytical grade of DMF with
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Table 4. ARC results on the reaction mixture Vilsmeier +
DMA
Table 5. Calorimetry results: Vilsmeier intermediate +
DMA at 15°C
parameter
value
48°C
comments
parameter
value
comments
onset T
the start of the exothermic activity
in the sample
Q
r
13 W/mol
21 W/mol
initial plateau first 60 min
peak value, probably due to
crystallization
T @ max rate
max T rate
max P rate
MaxTsafe24
238°C
4.6°C/min
4.2bar/min
30°C
4 W/mol
final plateau from 150 to 240 min
∆H
-142 kJ/mol this corresponds to the sum of the
this rather low value comes from
the low onset temperature and the
high velocity of the decomposition.
two-stage process
MAT
165°C
high value due to high reaction enthalpy
p
and low C value; not relevant for a
controlled semi-batch process
8 °C potential temperature rise
near end of feed period
MTSR
FHR
23°C
95%
only small amount of accumulation
Figure 9. ARC: T,P graph.
3
Figure 12. DMF, DMA + POCl w Iminium salt: profile.
Figure 10. MaxTSafe24 graph.
3
Figure 13. DMF, DMA + POCl w Iminium salt: safety
parameters.
dosing for more than 5 h there is still thermal activity
detected. The data indicate that 73% of the total heat is
generated with only 50% of the POCl added, and during
3
the addition of the remaining 50% only 27% of the reaction
enthalpy is released.
Since there are indications that the reaction between the
Vilsmeier intermediate and DMA requires a higher temper-
ature, additional experiments were run. The results from the
test at 25°C are contained in Table 6 and Figures 14 and 15.
The result of this experiment is nearly a copy of the
previous one at 15 °C with only a minor change in profile
due the higher temperature.
Another experiment was run at 40 °C, the final temper-
ature of the original process. The results of this experiment
are again close to the previous ones (see Table 7 and Figures
16 and 17). The heatflow profile shows the same general
form, but there are apparent differences: the first plateau lasts
longer and is more constant, and the peak appears at a later
Figure 11. Runaway index.
low water content was used to confirm that the initial
heatflow peak comes from the interaction with water, as it
is not present. The results of the first experiment are
summarized in Table 5, and the profiles are represented in
Figures 12 and 13.
The heatflow and hence the reaction enthalpy show an
unexpected profile: after an initial plateau at about 14 W/mol
a peak of nearly 21 W/mol is followed by a decay and ends
in a second plateau at about 4 W/mol. After the end of the
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Table 6. Calorimetry results: Vilsmeier intermediate +
DMA at 25 °C
Table 7. Calorimetry results: Vilsmeier intermediate +
DMA at 40 °C
parameter
value
comments
parameter
value
comments
Q
r
13 W/mol
initial plateau first 70 min
peak value, probably due to
crystallization
Q
r
13 W/mol
23 W/mol
initial plateau first 80 min
peak value, probably due to
crystallization
2
1 W/mol
4
W/mol
final plateau from 150 to 240 min
4 W/mol
final plateau from 150 to 240 min
∆
H
-146 kJ/mol this corresponds to the sum of the
∆H
-151 kJ/mol this corresponds to the sum of the
two-stage process
two-stage process
MAT
166 °C
high value due to high reaction enthalpy
MAT
170 °C
high value due to high reaction enthalpy
and low C
p
value; not relevant for a
p
and low C value; not relevant for a
controlled semi-batch process
10 °C potential temperature rise
near end of feed period
controlled semi-batch process
7 °C potential temperature rise
near end of feed period
MTSR
FHR
35 °C
MTSR
FHR
47 °C
93%
only small amount of accumulation
95%
only small amount of accumulation
3
Figure 16. DMF, DMA + POCl w Iminium salt: profile.
3
Figure 14. DMF, DMA + POCl w Iminium salt: profile.
3
Figure 17. DMF, DMA + POCl w Iminium salt: safety
parameters.
3
Figure 15. DMF, DMA + POCl w Iminium salt: safety
parameters.
Adiabatic Calorimetry. A sample of the reaction mixture
with dosing at 15 °C, after the required stirring time, was
transferred to the ARC cell, and the heat-wait-seek temp-
erature profile was applied (Table 8 and Figures 18, and 19).
It was decided to start the test at room temperature, and
the results indicate that there was thermal activity at the start
of the test. This could be due to some residual conversion.
After the first heat stage further thermal activity was detected,
but this stopped around 40 °C. From 42 °C on the exotherm
leading to total decomposition of the sample started, and this
resulted in a temperature rise to 180 °C over 450 min and a
sharp pressure rise. The test was terminated by the instrument
to avoid damage. A high residual pressure of 77 bar was
observed after cooling. This indicates that noncondensable
gases are formed in the decomposition. A MaxTSafe24 of 31
point in time. Surprisingly the accumulation is nearly the
same as those in the experiments at lower temperatures.
On the basis of only the thermal information, it is difficult
to draw conclusions on the progress of the reaction. As far
as we know, there is no mechanistic information on the
progress of the reaction in case the substrate is present when
the Vilsmeier intermediate is generated.3 It would be
interesting to have online analytical data to elucidate the
course of the chemical conversions. This would help to
understand the thermal profile. These data could then be used
in reaction-modelling software to build a reaction model and
kinetic expressions. The model could then be used to design
a safe and controllable process,10 also taking into account
the decomposition under thermal stress.
°
C was calculated.
Figure 20 illustrates the runaway index of the one-pot
(10) Bollyn, M.; Van den Bergh, A.; Wright, A. Chem.-Anlagen Verfahren 1996,
2
9, 95-100.
process at different temperatures. It can be questioned if the
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987

Table 8. ARC results of the one-pot synthesis reaction
mixture
then transferred by gravity to the hydrolysis-reaction vessel
m lower. For over more than 500 batches there were no
3
parameter
value
35 °C
comments
reported incidents of unexpected temperature or pressure
rises, foaming, or gas formation.
onset T
the onset recorded is even lower
than in the two-stage process !
this value is lower than for the separate
stages
This prompted us to further investigate the adiabatic
calorimetry. A sample from the one-pot DMF process was
prepared and transferred to a Hastelloy ARC bomb and
heated. It can be expected that Hastelloy is more resistant
to HCl attack; therefore, it was also used to study the
Vilsmeier intermediates. The Hastelloy ARC bombs have a
higher weight compared to that of the titanium cells, which
results in a higher φ-factor, and therefore is further from the
adiabatic ideal when φ ) 1. To test the hypothesis that there
is chemical interaction between the reaction mixture and the
test cell material we also decided to usesfor the first times
glass cells. These have an even higher φ-factor and a lower
pressure resistance but can be considered as chemically inert
to an acidic reaction mixture (except when HF is present).
We set the pressure limit to a lower value than that for the
metal bombs to avoid bursting these vessels.
T @ max rate 150 °C
max T rate
max P rate
max Tsafe24
8 °C/min
18 bar/min
31 °C
this result indicates that the
one-pot process is not better than
the original one
The results of the test in Hastelloy bombs are shown in
Table 9 and Figures 21 and 22. On heating, the sample shows
a different decompostion profile: exothermic activity is not
observed until 90 °C (at 600 min test time), and this takes
the temperature to about 130 °C and the pressure to 66 bar
after 1500 min, where further heating induces the second
exotherm which is terminated by the safety setting at 300
Figure 18. ARC: T,P graph.
°C and 120 bar pressure. The test took about 2900 min. This
indicates that the decomposition is much slower and also
less violent than in the titanium test cell. For this sample,
and taking the first exotherm into account, a MaxTSafe24 value
of 90 °C is calculatedsthis value is not obtained by
extrapolation but fits within the experimental measured data.
There is a remarkable difference between the results in
the titanium and Hastelloy bombs. It appears that there is
some catalytic interaction of the titanium with the reaction
mixture which starts the decomposition at lower temperature
and makes it more violent (higher pressure). The report in
Figure 19. MaxTSafe24 graph.
8
the literature was based on titanium bombs and thus should
same MaxTSafe24 value would have been obtained from the
reaction mixtures at higher temperatures; this was not tested
experimentally.
The MaxTSafe24 values of the two-stage and the one-pot
process are the same; hence, there is a problem of instability
of the reaction mixture.
The results from the adiabatic calorimetry are not congru-
ent with practical observations. In production the reaction
mixture is heated to 80 °C to produce a solution, which is
be considered with care.
The results of the test in a glass bomb are presented in
Table 10 and Figures 23 and 24. These results are comparable
to and confirm the findings of the tests in Hastelloy bombs.
In the temperature range of 40-60 °C some exothermicity
can be observed, probably due to further chemical conver-
sion. From about 90 °C and 940 min of test time on, self-
heating is observed, and this takes the temperature to about
125 °C and 35 bar pressure over a period of about 900 min.
Figure 20. Runaway index of one-pot process at different temperatures.
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Table 9. Hastelloy ARC cell
Table 10. Glass ARC bomb
parameter
value
comments
parameter
value
comments
onset T
85 °C
compared to 35 °C in Ti cell
compared to 150 °C in Ti cell
compared to 8 °C/min in Ti cell
compared to 18 bar/min in Ti cell
compared to 31 °C in Ti cell
onset T
93 °C
comparable to the test in Hastelloy
the decomposition slows down
immediately after the start
T @ max rate
max T rate
max P rate
max Tsafe24
121 °C
T @ max rate
94 °C
0.1 °C/min
0.2 bar/min
90 °C
max T rate
max P rate
max Tsafe24
0.08 °C/min
0.29 bar/min
77 °C
only a limited number of datapoints
are available, because the test was
terminated to protect the bomb
Figure 21. ARC: T,P graph.
Figure 23. ARC: T,P graph.
Figure 22. MaxTSafe24 graph.
Figure 24. MaxTSafe24 graph.
At this stage the test was terminated because the pressure
limit set for the glass bombs was reached. There is a high
residual pressure in the bomb after cooling to room temper-
ature. From this incomplete experiment a MaxTSafe24 value
of 77 °C is obtained by extrapolation. The test in the glass
ARC bomb was also run for the reaction mixture made at
3. Screening Study of Formamides. Since the alternative
process method (before the ARC tests in Hastelloy and glass
bombs) did not yield the desired resultsa more thermally
stable reaction mixturesit was decided to investigate the role
of DMF in the decomposition process. A. Miyake et al.8
indicated that the Vilsmeier intermediate of N-methylfor-
mamide (6) shows a decomposition behaviour comparable
to that of DMF, but no other information is available from
25 °C, and this provided the same values as for the previous
reaction mixture (MaxTSafe24 of 80 °C).
On the basis of these results the runaway index can be
calculated (Figure 25).
Figure 25. Runaway index.
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989

the literature. A set of potentially interesting formamides was
selected for further testing: N-methylformamide (MFA, 6),
N,N-diethylformamide (DEF, 7), N,N-dibutylformamide (DBF,
eliminated because of the practical problems encountered
with the high viscosity.
4. The Two-Stage DEF Process. The Argonaut AS3400
tests indicated that DEF could be used to run the Vilsmeier-
Haack reaction on DMA, and therefore a calorimetry study
was initiated.
8), N-formylpiperidine (PIF, 9), and N-formylmorfoline
(MOF, 10).
Reaction Calorimetry. The standard conditions for the
Vilsmeier reaction with DMF were also applied to DEF, and
this yielded the results shown in Table 11 and Figures 27
and 28.
The heatflow shows a profile comparable to that of DMF;
here also there is an additional peak due to the interaction
of the water present in the technical DEF (0.3%). It would
have been possible to use analytical grade of DEF to avoid
this, but the technical grade provides a more realistic sim-
ulation of the final “plant” process. The reaction is fast and
with addition control within the parameters of this experi-
ment.
Before running the calorimetric tests in the RC1, the
Argonaut AS3400 parallel synthesizer was used to test the
interaction of POCl with the formamides in two series of
four experiments. All formamides show an exothermic
reaction on adding POCl (molar ratio of 3.88 to 1), but the
3
3
reaction mixture of MFA became unstirrable, and 100% more
MFA was required to get the solids in solution and get a
viscous liquid.
Adiabatic Calorimetry. A sample of the previous reaction
mixture was transferred to an ARC Hastelloy bomb and
subjected to the heat-wait-seek temperature profile (Table
The reaction mixtures were subjected to the standard
hydrolysis process, and although the mixture could not be
worked up in all cases, we were able to confirm with TLC
that DMAB had been formed in each reaction using the
standard methodology. Samples of the final reaction were
screened for thermal activity on heating in the Radex
instrument, using Hastelloy vials. In this case we were
especially interested in the pressure profile, as shown in
Figure 26.
The results from this thermal screening led to the
following conclusions: all reaction mixtures show decom-
position with pressure build-up from around 100 °C in the
following series sequence: MOF, DMF, PIF, DEF, DBF, and
MFA. Only DEF and DBF do not generate pressures >100
bar at 190 °C, and the pressure rise is clearly slower than
that for the other formamides. From these results it was
decided to limit further study to DEF and DBF. MFA was
1
2 and Figures 29 and 30).
Thermal acitivity is recorded from 63 °C ending around
55 °C with a sharp pressure rise to around 85 bar around
00 °C. On further heating a second exotherm starts around
05 °C, but this was terminated at 225 °C because the set
1
1
2
pressure limit (130 bar) was reached. The data from the first
exotherm were used to calculate the MaxTSafe24, and this
yielded a value of 47 °C, which is close to the DMF value.
It appears that the thermal stabilities of the Vilsmeier
intermediates of DMF and DEF are comparable.
On the basis of these results the runaway index can be
calculated (Figure 31). In a semi-batch process with a long
feed time this process has a Runaway index of 2. Control of
the dosing is essential to ensure safety.
5. The One-Pot DEF Process. As part of the systematic
study of the different combinations of process modes and
Figure 26. Pressure versus temperature of reaction mixture with different formamides.
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Table 11. Calorimetry results: DEF Vilsmeier intermediate
at 25 °C
Table 12. ARC results: DEF Vilsmeier intermediate
parameter
value
comments
parameter
value
comments
onset T
63 °C
this is for the first exotherm,
a second exotherm is detected
at >200 °C
Q
r
38 W/mol
these peak comes from the interaction
with the water in DEF (0.3%)
2
0 W/mol
(
5 W/mol
this is the average value of the reaction
T @ max rate 135 °C
this exotherm stalls at 155 °C
between DEF and POCl
water has reacted
3
, once the
max T rate
max P rate
max Tsafe24
0.46 °C/min
1.05 bar/min
∆
H
-52 kJ/mol
this value includes the interaction
with water
47 °C
value obtained for the first exotherm
MAT
MTSR
83 °C
26 °C
limited accumulation near end
of the feed
nearly complete conversion at the
end of the dosing
FHR
99%
Figure 29. ARC: T,P graph.
Figure 27. DEF + POCl
3
w Vilsmeier profile.
Figure 30. MaxTSafe24 graph.
Figure 28. DEF + POCl
3
w Vilsmeier: safety parameters.
formamides, the one-pot process was subjected to the test
procedure.
Reaction Calorimetry. The one-pot Vilsmeier reaction
with DEF was also run in the RC1 calorimeter. To obtain
additional information on the accumulation during the dosing,
two “stop-start” sequences were incorporated. A stop-start
sequence means that the dosing is halted during a certain
time, and hence the reaction of the reagent stops. In case
there is a fast reaction (dosing control), the heatflow will
drop sharply and should attain the baseline shortly after the
interruption of the dosing. Once the dosing is restarted, it is
expected that the reaction simply continues and the heatflow
signal should come back to the value before the stop. If the
heatflow signal diminishes only slowly and/or does not fall
to 0, then dosing control is limited and accumulation is
observed. This could, of course, be due to parallel slower
reactions.
Figure 31. Runaway index.
3
production from the interaction of POCl and water, but
overall the reaction profile is comparable to that of DMF.
In this case the peak in the heatflow is smaller. The response
of the system to the stop of the feed indicates that there is
no full feed control on the heat production. Although there
is a substantial drop in the heatflow signal, it never reaches
0 within the “stalled” period.
Adiabatic Calorimetry. A sample of the reaction mixture
was transferred to the ARC bomb, and the heat-wait-seek
temperature profile was imposed (Table 14). The sample
showed thermal activity from 45 °C and heated over a period
The results of this experiment are presented in Table 13
and Figures 32 and 33. At the start there is additional heat
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•
991

Table 13. Calorimetry results: DEF Vilsmeier intermediate
DMA at 25 °C
Table 14. ARC results: DEF Vilsmeier intermediate in Ti
bomb
+
parameter
value
comments
parameter
value
45 °C
comments
Qr
23 W/mol
peak value due to the interaction
with water
average heatflow during first
part of the dosing
peak heatflow, due to crystallization
average heatflow during second part
of the dosing
total reaction enthalpy lower than in
DMF process
onset T
temperature at which the first
exotherm starts
1
3 W/mol
T @ max rate
max T rate
max P rate
max Tsafe24
157 °C
1.6 °C/min
1.9 bar/min
44 °C
2
4
0 W/mol
W/mol
this indicates that there is
thermal instability for the DEF
reaction mixture
∆H
-126 kJ/mol
MAT
MTSR
139 °C
32 °C
some accumulation near the end of the
dosing (low heatflow)
this confirms the accumulation
FHR
90%
Figure 34. ARC: T,P graph.
3
Figure 32. DEF, DMA + POCl w iminium salt: profile.
Figure 35. MaxTSafe24 graph.
3
Figure 33. DEF, DMA + POCl w iminium salt: safety
parameters.
of 220 min to 50 °C. At 50 °C one heat step was applied,
and a second exotherm initiated, leading to a slow decom-
position with a pressure peak of >50 bar at 150 °C, which
terminated the test. The adiabatic temperature profile yields
a MaxTSafe value of 44 °C for the DEF reaction mixture
(Figures 34 and 35).
On the basis of these results the runaway index can be
Figure 36. Runaway index.
calculated (Figure 36). The MaxTSafe24 value is close to the
MTSR, and this is a borderline case between index 2 and 5.
The same sample was also tested in an Hastelloy cell,
and this showed a different decompostion behaviour. Some
thermal activity below the detection of the instrument can
be observed from 70 °C onwards, but a first real exotherm
starts at 95 °C (after 700 min test time) and takes the sample
temperature to 102 °C. The next heat pulse initiates another
exotherm which ends around 122 °C. In the meantime, there
is already a pressure of 50 bar. After six heat pulses, around
to 200 °C and 120 bar, at which the test is terminated to
protect the instrument (Table 15 and Figures 37 and 38.).
This was the first time a difference between the results
obtained within different materials was observed. This
prompted us to extend the study on the DMF samples (see
above).
On the basis of these new results the runaway index can
be recalculated (Figure 39).
1
57 °C a third exotherm start and takes the temperature up
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Table 15. ARC results: DEF Vilsmeier intermediate in
Hastelloy bomb
Table 16. Calorimetry results: DBF Vilsmeier intermediate
+ DMA at 25 °C
parameter
value
70 °C
comments
parameter
value
comments (DVD246)
onset T
other exotherms start at
6 and 108 °C
Q
r
(22 W/mol peak region due to interaction with
9
water present (max 29 W/mol)
T @ max rate 95 °C
(5 W/mol
flat region: expected reaction
max T rate
max P rate
max Tsafe24
0.04 °C/min
0.1 bar/min
91 °C
∆H
-51 kJ/mol about -10 kJ/mol can be attributed
to the reaction with water
this is considerably higher than
in the titanium bomb
MAT
MTSR
FHR
61 °C
26 °C
99%
including the interaction with water
dosing controlled reaction
dosing controlled reaction
Figure 37. ARC: T,P graph.
Figure 40. DBF + POCl
3
w Vilsmeier profile.
Figure 41. DBF + POCl
3
w Vilsmeier: safety parameters.
Figure 38. MaxTSafe24 graph.
In this case also we used technical DBF, and the batch used
contained 0.6% water. This causes some side reactions, but
unfortunately this off-spec was the only material available
at that time (our technical grade should have <0.3% water).
It can be seen (see Table 16 and Figures 40 and 41) that
this reaction shows the same profile as DMF and DEF:
initially the interaction with the water, followed by a constant
heatflow of 5 W/mol which stops at the end of the feed
period.
Adiabatic Calorimetry. A sample of the reaction mixture
was tested in the ARC (Hastelloy bomb) and provided the
results shown in Table 17 and Figures 42 and 43.
The sample shows thermal activity on heating to around
58 °C, and this exotherm takes the temperature to 92 °C
over 750 min with a limited pressure rise of around 3 bar.
Two additional heating steps start a further exotherm, which
generates substantial pressure, (22 bar at 110 °C). The test
was terminated at 160 °C when the pressure limit of 120
bar was reached (not shown in the graph). From these data
a MaxTSafe24 value of 56 °C was calculated.
Figure 39. Runaway index.
Now there is a substantial difference between MTSR and
MaxTSafe24, and this is clearly a process with Runaway index
2.
6. The Two-Stage DBF Process. DBF was subjected to
the same tests as DMF and DEF. It should be noted that we
use the same molar ratio of reagents, but with the higher
molecular weight of DBF this results in a larger mass.
Reaction Calorimetry. The standard calorimetry test in
3
the RC1 was applied to DBF and POCl over 2 h at 25 °C.
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•
993

The combination of these experimental results yields a
Runaway index 2.
Table 18. Calorimetry results: Vilsmeier intermediate +
DMA at 40 °C
parameter
value
comments
Table 17. ARC results: DBF Vilsmeier intermediate
Q
r
17-22 W/mol additional heatflow due to the
parameter
value
comments
interaction with water
1
1
4 W/mol
average value over the first 80 min
onset T
T @ max rate 59 °C
max T rate
max P rate
max Tsafe24
58 °C
start of a slow decomposition
this can be considered a low value
in same range as DMF and DEF
4 w 5 W/mol decline in heat production
(5 W/mol
average value over the last
90 min of the dosing
including about -10 kJ/mol for the
reaction with water
including the effect of the
reaction with water
0.1 °C/min
0.013 bar/min
56 °C
∆H
-150 kJ/mol
130 °C
MAT
MTSR
FHR
43 °C
97%
some slow residual reaction after the
end of dosing over a period of 240 min
Figure 42. ARC: T,P graph.
3
Figure 45. DBF, DMA + POCl w iminium salt: profile.
Figure 43. MaxTSafe24 graph.
3
Figure 46. DBF, DMA + POCl w iminium salt: safety
parameters.
potential accumulation during the feed of POCl
and Figures 45 and 46).
3
(Table 18
The one-pot reaction in DBF exhibits the same profile as
DMF and DEF: additional heatflow at the start due to the
presence of water, then a plateau around 15 W/mol, after
50% of the feed is complete; in the second half of the dosing
the heatflow gradually drops to a value of (5 W/mol. Once
the dosing is stopped, there is a small heatflow for an
additional 240 min, even at 40 °C. Taking into account the
contrubution of the interaction with water, the total reaction
enthalpy is lower than that in DMF and DEF.
Figure 44. Runaway index.
The difference in MTSR and MaxTSafe is large enough to
make sure that the Runaway index is indeed 2.
7
. The One-Pot DBF Process. To complete the study, a
Adiabatic Calorimetry. A sample of the reaction mixture
was heated in a Hastelloy bomb (Table 19 and Figures 47
and 48). During the first 720 min with a stagewise temper-
ature rise from 25 to 105 °C there is no exothermic activity
and no pressure generation. Above this temperature several
weak exotherms occur to take the temperature to 120 °C
one-pot experiment with DBF was run in the RC1 instrument.
Reaction Calorimetry. Since previous experiments indi-
cated that the reaction is run best at higher temperature to
increase the reaction rate, this test was run at 40 °C, and the
start-stop procedure was applied to get information on
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and the pressure to 25 bar. On further heating, small
exotherms are detected in until 300 °C is reached. During
this period the pressure reaches 84 bar; however, the profile
suggests that this measurement is not reliable, probably due
to some material blocking the tubing to the pressure
transducer. A MaxTSafe24 value of 91 °C is obtained for the
first weak exotherm.
Conclusions
From this study of the thermal behaviour of the Vils-
meier-Haack reaction the following conclusions can be
drawn regarding the thermal hazards (other process hazards
are not within the scope of this discussion).
Reaction Calorimetry. The results from the reaction
calorimetry experiments indicate clearly thatsunder the
On the basis of these results the runaway index can be
calculated (Figure 49).
experimental conditions used heresthe interaction of POCl
3
with the three studied formamides is fast and exhibits a
moderate exothermicity (-45 ( 5 kJ/mol). These reactions
can be considered dosing controlled, with almost no ac-
cumulation when run in semi-batch mode with sufficient feed
time (which should be adapted to the cooling capacity of
the reactor used). As a result, the MTSR is close to the
process temperature.
Table 19
parameter
value
102 °C
comments
onset T
start of a small exotherm; around
70 °C another exotherm starts
1
T @ max rate 193 °C
max T rate
max P rate
max Tsafe24
0.23 °C/min
0.07 bar/min
The reaction of the Vilsmeier intermediate with DMA is
quite exothermic ((100 kJ/mol,) but relatively slow at 15
91 °C
calculated from the first weak exotherm
°
C compared to the feed time of 2 h, which leads to a
substantial accumulation of reagent and a substantial differ-
ence between process temperature and MTSR.
The reaction profile of the one-pot process, where the
3
substrate DMA is already present when POCl is added to
generate the Vilsmeier intermediate, appears to be different
from the sum of the individual processes. When DMA is
added to the Vilsmeier intermediate, the heatflow is ap-
proximately constant until the end of the feed, whereas in
the one-pot process there seems to be a changeover in the
course of the reaction around the time where 50% of POCl
3
is added (and only 50% of Vilsmeier intermediate is expected
to have been formed). The total reaction enthalpy ((140 kJ/
mol) corresponds to the sum of the reaction enthalpy of the
individual transformations, and also the isolated yield of the
product is comparable to that in case of DMF. Formally there
is only limited accumulation at the end of the dosing (FHR
Figure 47. ARC: T,P graph.
>
90%, adiabatic temperature rise of <10 °C), but the stop-
start procedure indicates that at certain stages during the
dosing the process is not completely dosing controlled.
In this type of process DEF and DBF exhibit a reaction
profile and enthalpy comparable to DMF.
Further research is required to understand and explain the
reaction profile observed, but this is outside the scope of
this study.
Adiabatic Calorimetry. The first conclusion from this
study is that great care should be taken in the selection of
the test cell material. It is clear that in this case there is an
interaction between the reaction mixture and titanium which
accelerates the decomposition and lowers the onset temper-
ature. The decomposition profile itself does not indicate that
there is a catalytic effect, and the ARC tests reported in the
literature were also run in titanium cells. Only by testing
other materials did this issue become clear. This was
triggered by the discrepancy between the ARC test results
and those of practical experience. Without this observation
we would have come to a wrong Runaway index (index 5
instead of index 2).
Figure 48. MaxTSafe24 graph.
The results of the tests conducted in inert test cells indicate
that the Vilsmeier-Haack reaction can be considered as
hazardous because of the high pressures associated with the
Figure 49. Runaway index.
Vol. 9, No. 6, 2005 / Organic Process Research & Development
•
995

decomposition. There are clear indications that permanent
gases are formed.
the flask on the balance over the programmed feed period
at the set temperature. The reaction mixture is stirred for
the required time at the set temperature. DMA (248 g, 1.01
The thermal stability of the Vilsmeier intermediatesas a
solution in the corresponding formamidesshows thermal
decomposition starting around 60 °C, but the profile of
decomposition is different. It would be required to run
additional tests under carefully controlled conditions (e.g.
identical concentration and/or solvent-free sample) to be able
to compare the results and draw unambiguous conclusions.
From a practical point of view, DMF and DEF have the same
MaxTSafe24 value ((48 °C), and the stability seems to be a
little better for DBF (56 °C).
3
mol per mol POCl ) is added from a separate flask on a
second balance over the programmed feed period at the set
temperature, and then the mixture is stirred for the required
time at the set temperature. Calibrations and CP determina-
tions are performed preprogrammed as required to obtain
the calorimetry data. The reaction mixture is withdrawn from
the reactor and added to a mixture of water and sodium
acetate for hydrolysis and further work-up. DMAB is isolated
by filtration, washed with water, and dried. In general a yield
of (75% is obtained.
Both the two-stage and the one-pot processes lead to the
same final reaction mixture, which starts to self-heat from
(
2) One-Pot Process. DMF (564 g, 3.78 mol per mol
POCl ) and DMA (248 g, 1.01 mol per mol POCl ) are
charged to the reactor and thermostated at the initial
temperature. POCl (312 g) is added from the flask on the
(
90 °C. All the formamides used in this process lead to a
thermally unstable reaction mixtureswhich generates gas and
hence pressure in a closed cell or vesselsat a temperature
of (100 °C. From a pure thermal point of view, DMF is
much more reactive than DEF, which is more reactive than
DBF. Despite the different rate and the adiabatic temperature
rises, for all reaction mixtures a MaxTSafe24 value of 90 °C
was calculated.
On the basis of the combination of reaction and calorim-
etry a Runaway index of 2 is obtained for all combinations
tested. At first sight the process can be considered as
acceptable. This is only because the runaway index takes
exclusively the temperature effects into account and not the
pressure generated during the decomposition.
3
3
3
balance over the programmed feed period at the set temper-
ature, and then the mixture is stirred for the required time at
the set temperature. Calibrations and CP determinations are
performed preprogrammed as required to obtain the calo-
rimetry data. The reaction mixture is withdrawn from the
reactor and added to a mixture of water and sodium acetate
for hydrolysis and further work-up. DMAB is isolated by
filtration, washed with water, and dried.
(
3) Screening Experiments. The formamide (1.16 mol) is
charged to the reactor and thermostated at the initial
temperature (25 °C). POCl (0.30 mol) is added to the
Experimental Section
3
Equipment. For the reaction calorimetry a Mettler Toledo
RC1 with a standard AP01 reactor with anchor stirrer was
used in combination with the WinRC V7.11 (SR6) software.
Prominent pumps with PTFE head and PTFE tubing was
used for the dosing from a Mettler balance. The quickcal
option was used for the calibrations. Data files were exported
to Microsoft Excel 97 for further calculations and charting.
Adiabatic calorimetry experiments were run in an Eu-
roARC from Thermal Hazard Technology with EuroARC
software V1.1, and ARCCal (based on Origin 3.53) was used
for data processsing and charting. The following types of
test cells were used: ARCTC-Ti-LCQ (titanium), ARCTC-
HC-MCQ (Hastelloy), and ARCTC-GL-LMSQa (glass with
metal stem, in which a PTFE tubing was mounted to isolate
the reaction mixture with the metal of the stem). Sensitivity
threshold was set to 0.02 °C/min).
reaction mixture over the programmed period (1 h). After a
stirring period, DMA is added over the programmed period
(1 h) and stirred for 1 h; after heating to 40 °C the mixture
is stirred for 3 h, cooled to room temperature, and hydrolysed
in a water/sodium acetate mixture. In this experiment a yield
of 68% was recorded.
(
4) For Experiments with DEF and DBF. A molar ratio
of 3.88 mol per mol POCl is used. The reaction mixture is
hydrolysed and then discarded without further work-up.
5) ARC Tests. Samples of 5-6 g of the reaction mixture
3
(
are transferred with a pipet to a preweighed test cell. This is
mounted in the calorimeter and fastened. After closing the
instrument the initial data are entered, and the heat-wait-
seek temperature program is started. At the end of the test
the data are transferred to the ARCCal software package,
and the sample is collected as chemical waste.
For the screening of the chemical reactivity the Argonaut
AS3400 with four 250-mL reactors was used; one feed unit
3
was used for POCl and the other for DMA.
Thermal stability testing was also done using the Systag
RADEX instrument, with 3-mL Hastelloy vials.
Chemicals. DMF and DBF were obtained from bulk
suppliers and used without drying, in some experiments dry
DMF was obtained from Acros Fine Chemicals (Belgium),
Acknowledgment
Experimental assistance of D. Van Dromme is gratefully
acknowledged. This work was the subject of the apprentice-
ship of K. Lauwers from the Karel De Grote Hogeschool in
Hoboken (Belgium). Thanks to P. Sears of Thermal Hazard
Technologies for his contribution.
3
POCl , MFA, MOF, and PIF were obtained from Acros Fine
Chemicals (Belgium) and used without pretreatement.
Experiments. (1) Two-Stage Process. DMF (564 g, 3.78
Received for review August 1, 2005.
OP0580116
mol per mol POCl
3
) is charged to the reactor and thermo-
(312 g) is added from
stated at the initial temperature. POCl
3
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•
Vol. 9, No. 6, 2005 / Organic Process Research & Development