Process safety evaluation of a magnesium-iodine exchange reaction

Article abstract of DOI:10.1021/op060145b

An unexpected highly exothermic decomposition was observed during routine safety analysis of the magnesium-iodine exchange reaction of 2-iodo-4-fluorotoluene (3) with commercially available i-PrMgCl (2.0 M solution in THF). When the reaction mixture was scanned in an adiabatic calorimeter with the use of a 2 °C/min temperature ramp, a rapid exothermic decomposition with an onset temperature of approximately 80 °C was observed. The system temperature rapidly rose to 210 °C at a peak rate of 200 °C/min. Subsequent testing of three simplified substrates showed the same type of exothermic decomposition for all cases. Control experiments indicated that the decomposition requires both aryl iodide and i-PrMgCl (or arylMgCl and i-PrI). While the onset temperatures for all cases studied were generally well above the typical operating temperature for these reactions (0-10 °C), it is nonetheless important to cautiously evaluate these types of processes and install proper engineering controls for analogous decomposition events.

Full text of DOI:10.1021/op060145b

Organic Process Research & Development 2006, 10, 1258−1262
Process Safety Evaluation of a Magnesium-Iodine Exchange Reaction
Jonathan T. Reeves, Max Sarvestani, Jinhua J. Song,* Zhulin Tan, Laurence J. Nummy, Heewon Lee,
Nathan K. Yee, and Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Old Ridgebury Road/
PO Box 368, Ridgefield, Connecticut 06877-0368, U.S.A.
Abstract:
An unexpected highly exothermic decomposition was observed
during routine safety analysis of the magnesium-iodine ex-
change reaction of 2-iodo-4-fluorotoluene (3) with commercially
available i-PrMgCl (2.0 M solution in THF). When the reaction
mixture was scanned in an adiabatic calorimeter with the use
of a 2 °C/min temperature ramp, a rapid exothermic decom-
Figure 1.
Scheme 1. Magnesium-halogen exchange for generation of
Grignard 4
position with an onset temperature of approximately 80 °C was
observed. The system temperature rapidly rose to 210 °C at a
peak rate of 200 °C/min. Subsequent testing of three simplified
substrates showed the same type of exothermic decomposition
for all cases. Control experiments indicated that the decomposi-
tion requires both aryl iodide and i-PrMgCl (or arylMgCl and
i-PrI). While the onset temperatures for all cases studied were
generally well above the typical operating temperature for these
reactions (0-10 °C), it is nonetheless important to cautiously
evaluate these types of processes and install proper engineering
controls for analogous decomposition events.
is increasingly being employed in both academic laboratories
and industrial settings.
Introduction
The generation of aryl Grignard reagents has traditionally
been accomplished by treatment of aryl halides (Cl, Br, or
I) with magnesium metal in etheral solvents. In recent years,
however, an attractive alternative has emerged. Developed
by Knochel and co-workers,1 this procedure involves treat-
ment of an aryl bromide or iodide with commercially
available i-PrMgCl or the more powerful reagents i-PrMgCl‚
LiCl2 and i-Pr2Mg‚LiCl3 in THF at temperatures of -20 °C
to room temperature. Aryl and heteroaryl Grignard reagents
may smoothly and rapidly be generated and may contain
functional groups that are not tolerated by the traditional
magnesium metal-mediated process. The mild temperatures
and typically homogeneous solution composition of these
reactions are attractive features, particularly considering that
the magnesium metal-mediated processes often require
heating for Grignard formation, and the initiation may be
unpredictable. Due to the demonstrated generality, simplicity
of reaction conditions, and the excellent functional group
compatibility, the magnesium-halogen exchange reaction
In one of our recent process development programs, we
required 2-methyl-5-fluorophenylmagnesium bromide (1,
Figure 1). This reagent is commercially available as a 0.5
M solution in THF. However, the low concentration and high
cost of this reagent are not desirable for large-scale produc-
tion of the API. In the search for economical alternatives to
the commercial Grignard solution, we considered generating
this Grignard reagent through a magnesium-halogen ex-
change reaction.
We investigated the magnesium-halogen exchange reac-
tion using 2-bromo-4-fluorotoluene (2, Scheme 1) and
2-iodo-4-fluorotoluene (3) with commercially available i-
PrMgCl (2.0 M solution in THF). The reaction of bromide
2 with 1.0 equiv of i-PrMgCl or i-PrMgCl‚LiCl gave only
10-20% exchange after 24 h at 20-25 °C as monitored by
HPLC analysis of reaction aliquots quenched into MeOH.
The reaction of iodide 3 with i-PrMgCl (1.0 equiv), however,
was complete (g95% exchange) after 45 min at 0 °C
(Scheme 1). The resultant Grignard reagent 4 proved to be
suitable for use in our subsequent synthetic sequence. The
optimized procedure for Grignard formation consisted of
charging 1.0 equiv of i-PrMgCl (2.0 M in THF) to the
reactor, cooling the solution to 0 °C, and charging 3 at a
rate to maintain the temperature between 0 and 10 °C. The
reaction mixture was agitated for 45 min to 1 h at 0-10 °C
after completion of the addition of 3 to achieve complete
* jsong@rdg.boehringer-ingelheim.com.
(1) (a) Boymond, L.; Rottla¨nder, M.; Cahiez, G.; Knochel, P. Angew. Chem.,
Int. Ed. 1998, 37, 1701. (b) Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay,
D. M.; Vu, V. A.; Knochel, P. Synthesis 2002, 4, 565. (c) Knochel, P.;
Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis,
I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42, 4302.
(2) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333.
(3) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem., Int. Ed. 2006,
45, 159.
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10.1021/op060145b CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/09/2006

Figure 2. Thermal safety evaluation of Grignard 4 formation. Plots derived from ARSST calorimetry data. (a) Temperature vs
time plot. Heat-up and cool-down portions are shown here. (b) Temperature rise rate vs temperature plot. Only the heat-up portion
is shown here.
Scheme 2. Generation of Grignard reagents 7 and 8 for
(g95%) formation of 4. Since the commercial 2.0 M solution
testing substituent contributions to decomposition reaction
of i-PrMgCl was used as the solvent for the reaction, a ∼2
M solution of 4 was produced, and the overall volume
efficiency of this process was excellent. In addition, iodide
3 was readily available in bulk at a low price, rendering this
process economically attractive.
In preparation for scale-up of this procedure in the pilot
plant, a routine safety analysis was performed. To our
surprise, the safety study showed that there was a highly
exothermic decomposition process with an onset temperature
of ∼80 °C. This presented an unexpected process safety
approximately 80 °C was observed (Figure 2). The system
temperature rapidly rose to 210 °C at a peak rate of 200
°C/min. The system pressure also showed a sharp increase.
concern. The details of this study including our analysis of
related substrates are discussed in this paper.
As a control experiment, the commercial 0.5 M solution
of Grignard reagent 1 was also subjected to the same thermal
Results and Discussion
According to our internal standard operating procedures,
the process safety of every reaction must be evaluated prior
to scale-up in the kilo-lab and pilot plant. Routine safety
testing of the process described above for the i-PrMgCl
exchange reaction with 3 was performed as follows. A 10-
mL sample of the reaction mixture was taken after the
exchange reaction was complete (confirmed by HPLC after
aging at 0-10 °C for 45 min to 1 h) and was scanned in an
Advanced Reactive Systems Screening Tool4 (see Experi-
mental Section for details) at a rate of 2 °C/min. A rapid
exothermic decomposition with an onset temperature of
safety testing. In this case, no decomposition event was
observed, suggesting a dependence of the decomposition
event on both the aryl iodide 3 and i-PrMgCl (and/or the
products derived from their reaction). Dilution of the
magnesium-iodine exchange reaction 4-fold (to generate a
∼0.5 M solution of 4) still gave the decomposition event,
albeit with a reduced magnitude. In this case the onset
temperature was also 80 °C, but the peak rate of temperature
rise was lesser at 20 °C/min.
Given the above data obtained for Grignard reagents 1
and 4, we became interested in the generality of this
decomposition for magnesium-iodine exchange of other
substrates. In order to ascertain the effect of the methyl and
fluorine groups, 2-iodotoluene (5) and 3-fluoroiodobenzene
(4) Burelbach, J. P.; Theis, A. E. Thermal Hazards Evaluation Using the ARSST.
Third International Symposium on Runaway Reaction, Pressure Relief
Design and Effluent Handling, Cincinnati, OH, November 1-3, 2005.
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Figure 3. Thermal safety evaluation of Grignard 8 formation. Plots derived from ARSST calorimetry data. (a) Temperature vs
time plot. Heat-up and cool-down portions are shown here. (b) Temperature rise rate vs temperature plot. Only the heat-up portion
is shown here.
Figure 4. Thermal safety evaluation of Grignard 10 and mixture derived from mixing commercial PhMgCl and i-PrI. Plots derived
from ARSST calorimetry data. (a) Temperature vs time plot. Heat-up and cool-down portions are shown here. (b) Temperature
rise rate vs temperature plot. Only the heat-up portion is shown here.
(6) were subjected to the same magnesium-iodine exchange
reaction conditions as 3, producing the Grignard reagents 7
and 8, respectively, in >95% conversion by HPLC analysis
(Scheme 2). Thermal safety evaluation of aliquots of
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Table 1. Summary of Thermal Safety Evaluation Data
Scheme 3. Generation of Grignard reagent 10 by
magnesium-iodine exchange and mixing of a commercial
solution of 10 with i-PrI
magnitudes. For 7, the onset temperature of the decomposi-
tion was 80 °C, and the peak rate of the temperature rise
was 25 °C/min. For 8, the onset temperature was again 80
°C, while the peak rate of the temperature rise was much
larger at 410 °C/min (Figure 3).
These results prompted us to investigate the reaction
mixture derived from magnesium-iodine exchange of the
simplest substrate, iodobenzene (9), to give phenylmagne-
sium chloride (10) (Scheme 3). Again, a similar exothermic
event occurred. The onset temperature was slightly higher
at 110 °C, and the peak rate of the temperature rise was 105
°C/min. A series of control experiments were subsequently
conducted. It was found that a commercial phenylmagnesium
chloride solution (2.0 M in THF), commercial i-PrMgCl
Grignard reagents 7 and 8 were performed. In both cases,
similar thermal events were observed, although at different
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solution (2.0 M in THF), and pure isopropyl iodide (dissolved
in THF) were thermally stable. However, when a 1:1 molar
mixture of phenylmagnesium chloride (2.0 M in THF) and
isopropyl iodide was tested, the mixture ran away with an
onset temperature of 80 °C at a peak rate of 220 °C/min
(Figure 4).
consumption of 3. A ∼10 mL sample was withdrawn for
thermal safety analysis. The magnesium-iodine exchange
of iodides 5, 6, and 9 was performed in the same manner
and on the same scale (40.0 mmol). HPLC was used to
monitor the completion of the exchange, which generally
required 0.5-2.0 h. For the preparation of a mixture of
PhMgCl and i-PrI, 10.0 mL (20.0 mmol, 2.0 M in THF) of
commercial PhMgCl was cooled to 0 °C and treated with
i-PrI (2.0 mL, 20.0 mmol). The mixture was used directly
for thermal safety analysis. Samples of PhMgCl and i-
PrMgCl (10.0 mL, 20.0 mmol, both as commercial 2.0 M
THF solutions) were used directly for safety analysis, while
i-PrI (2.0 mL, 20.0 mmol) was dissolved in 10 mL of
anhydrous THF, and the resultant solution was used for
testing.
Collection of Thermal Safety Data. Experimental data
were collected on an Advanced Reactive Systems Screening
Tool (ARSST) manufactured by Fauske and Associates.4
ARSST is a quasi-adiabatic instrument that works on the
basis of the heat loss compensation principle. The basic
component of the ARSST includes a spherical 10-mL glass
test cell, its surrounding “bottom heater” jacket and insula-
tion, thermocouple, pressure transducer, and a 350-mL
containment vessel that serves as both pressure simulator
and safety vessel. Tests are performed in the open test cell
in closed containment. Nitrogen pressure in the containment
vessel is used to suppress the boiling point of the sample.
The sample temperature is measured by a thermocouple
inside the test cell. A magnetic stir bar is placed inside the
test cell and driven by an external magnetic stirrer. A key
feature of the apparatus is its low effective heat capacity
relative to that of the sample (low æ factor). Thus, the heat
released by chemical reaction goes to heat up the sample
with negligible energy absorbed by the test cell itself. A fill
tube is used to add the mixtures to the purged test cell.
ARSST containment including the reaction cell was purged
many times with nitrogen before introducing the reaction
mixtures to the system by syringe through the fill tube. All
ARSST data were collected with the use of a 2 °C/min
temperature ramp. In all experiments 10 mL of reaction
mixture was used.
These data seemed to suggest that the interaction of the
byproduct of the magnesium-iodine exchange reaction (i.e.,
i-PrI) with the aryl Grignard reagent was necessary for the
decomposition reaction to occur. This is consistent with the
observation that dilution slows down the decomposition and
reduces the severity of the event, as was observed for the
4-fold dilution in the preparation of Grignard reagent 4.
In summary, we have observed an unexpected thermal
event for simple magnesium-iodine exchange reactions of
a few substituted phenyl iodides with i-PrMgCl (Table 1).
It was interesting to note that even for the simplest substrate,
phenyl iodide, there was a thermal event starting at 110 °C.
Control experiments showed that i-PrI, generated in the
magnesium-iodine exchange reaction, is not simply an inert
byproduct. It might participate in certain decomposition
reactions at elevated temperatures, causing a process safety
concern. In view of our observation from this safety study,
it is strongly recommended that extra attention should be
paid to this class of reactions which are increasingly finding
industrial applications. Although the onset temperature is
above the operating temperature of this particular reaction,
the onset temperature is still well within the heating capability
of the equipment and the severity of the observed thermal
decomposition is considerable. Therefore, proper engineering
controls and vent sizing for credible upset scenarios (e.g.,
accidental dumping and overheating) must be put in place
before any scale-up.
Experimental Section
General. All reagents were purchased from commercial
sources and used without further purification. HPLC analysis
was performed on an Agilent 1100 series HPLC using a
Tosohass Super-ODS column; flow rate of 1.0 mL/min; UV
detection at 220 and 254 nm; mobile phase 10% MeCN in
water (0.05% TFA) to 90% MeCN in water in 15 min, hold
for 5 min, then back to 10% MeCN in water.
General Procedure for Magnesium-Iodine Exchange.
A nitrogen-purged flask with magnetic stir bar was charged
with i-PrMgCl solution (20.0 mL, 40.0 mmol, 2.0 M in THF).
The reaction mixture was cooled to an internal temperature
of 0 °C, and 3 (9.4 g, 40.0 mmol) was added over 10 min,
keeping internal temperature between 0 and 10 °C. The
reaction mixture was stirred at 10 °C for 45 min, at which
time HPLC analysis (aliquot into MeOH) showed g95%
Supporting Information Available
Corresponding time-pressure plots for all of the above
experiments and time-temperature plots for formation of
Grignard reagents 7 and 10. This material is available free
of charge via the Internet at http://pubs.acs.org.
Received for review July 20, 2006.
OP060145B
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