Evaluation of Potential Safety Hazards Associated with the Suzuki-Miyaura Cross-Coupling of Aryl Bromides with Vinylboron Species

Article abstract of DOI:10.1021/acs.oprd.8b00001

The potential safety hazards associated with the Suzuki-Miyaura cross-coupling of aryl bromides with vinylboron species were evaluated. In the Suzuki-Miyaura cross-coupling of 1-bromo-3-(trifluoromethyl)benzene with potassium vinyltrifluoroborate in the presence of potassium carbonate (K₂CO₃) in 9:1 dimethyl sulfoxide (DMSO)/water at 80 °C, the thermal profile revealed a significant exotherm upon the addition of catalytic 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride [Pd(dppf)Cl₂]. Further investigations indicated that the exotherm was consistently higher and the reactions were faster in the studied aqueous systems compared to anhydrous conditions. Although under anhydrous conditions the exotherms were comparable among the studied cases, the rate of the exotherm was highly dependent on the choice of aryl electrophile, solvent, base, catalyst, as well as vinylboron species. In many of the studied cases the maximum temperature of a synthesis reaction (MTSR) was considerably higher than the boiling point of the solvent and/or the onset temperature of the DMSO decomposition, indicating that in the absence of active cooling the system could quickly exceed the boiling point of the solvent or trigger the decomposition of the reaction mixture to result in a runaway reaction.

Full text of DOI:10.1021/acs.oprd.8b00001

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Full Paper
Evaluation of Potential Safety Hazards Associated with the Suzuki-
Miyaura Cross-Coupling of Aryl Bromides with Vinylboron Species
Qiang Yang, Belgin Canturk, Kaitlyn C. Gray, Elizabeth McCusker, Min Sheng, and Fangzheng Li
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00001 • Publication Date (Web): 01 Feb 2018
Downloaded from http://pubs.acs.org on February 1, 2018
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Evaluation of Potential Safety Hazards Associated
with the Suzuki-Miyaura Cross-Coupling of Aryl
Bromides with Vinylboron Species
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Qiang Yang,*,† Belgin Canturk, Kaitlyn Gray, Elizabeth McCusker, Min Sheng, and
†
†
†
ῼ
Fangzheng Li†
†Process Chemistry, Dow AgroSciences, 9330 Zionsville Rd., Indianapolis, IN 46268, USA
ῼReactive Chemicals, Dow AgroSciences, Midland, MI 48667, USA
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ABSTRACT
The potential safety hazards associated with the Suzuki-Miyaura cross-coupling of aryl bromides
with vinylboron species were evaluated. In the Suzuki-Miyaura cross-coupling of 1-bromo-3-
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(
trifluoromethyl)benzene with potassium vinyltrifluoroborate in the presence of potassium
carbonate (K CO ) in 9:1 dimethyl sulfoxide (DMSO)/water at 80 °C, the thermal profile
revealed significant exotherm upon the addition of catalytic 1,1′-
bis(diphenylphosphino)ferrocene palladium(II) dichloride [Pd(dppf)Cl ]. Further investigations
2
3
a
2
indicated that the exotherm was consistently higher and the reactions were faster in the studied
aqueous systems compared to anhydrous conditions. Although under anhydrous conditions the
exotherms were comparable among the studied cases, the rate of exotherm was highly dependent
on the choice of aryl electrophile, solvent, base, catalyst, as well as vinylboron species. In many
of the studied cases the maximum temperature of a synthesis reaction (MTSR) was considerably
higher than the boiling point of the solvent and/or the onset temperature of the DMSO
decomposition, indicating that in the absence of active cooling the system could quickly exceed
the boiling point of the solvent or trigger the decomposition of the reaction mixture to result in a
runaway reaction.
Keywords: safety hazards, Suzuki-Miyaura cross-coupling, reaction calorimetry, thermal
decomposition, aryl bromide, vinylboron species.
INTRODUCTION
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The Suzuki-Miyaura cross-coupling reaction is undeniably one of the most powerful reactions
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in modern organic synthesis for the construction of carbon-carbon bonds. The development of
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new metal/ligand systems significantly broadened the scope of this reaction and consequently it
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has found wide use both in academia and industry. The Suzuki-Miyaura cross-coupling has been
frequently used in large scale production of active pharmaceutical ingredients3 and
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agrochemicals. The key advantages of this reaction include mild reaction conditions, relatively
low toxicity of the boron byproducts, tolerance to a wide array of functional groups, and wide
availability of organoboron species.1
The Suzuki-Miyaura cross-coupling reaction has been extensively used to access
functionalized styrene derivatives via the reaction of nucleophilic vinylboron species with
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various aryl electrophiles, including aryl halides, pseudo halides, and diazonium salts. Of the
various vinylboron species, potassium vinyltrifluoroborate is the preferred reagent because it is
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easily prepared, atom economical, and stable for handling and storage. Vinylation reactions
involving potassium vinyltrifluoroborate are typically performed in protic solvents (e.g., water,
ethanol, propanol) or a mixture of water and aprotic solvents (e.g., dioxane, tetrahydrofuran).5,6
However, some recent reports disclosed that this reaction could also be performed in anhydrous
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aprotic solvents. Frequently the reaction is conducted in an all-in fashion at elevated
temperature, which provides poor control over potential reaction exotherms.
In a recent study, an unexpected exotherm was observed during the coupling of an aryl
bromide with potassium vinyltrifluoroborate in the presence of Pd(dppf)Cl
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and K
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CO in a
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mixture of 9:1 DMSO/water at 80 °C. Potential safety hazards associated with the Pd-catalyzed
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
-arylation has been reported in the literature, but to our knowledge, no evaluations of the
potential safety hazards associated with the Suzuki-Miyaura cross-coupling of aryl bromides
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with vinylboron species has been disclosed in the public domain. This observation warranted
further investigation into the potential safety hazards associated with the Suzuki-Miyaura cross-
coupling of aryl bromides with vinylboron species in the presence of various bases, solvents, and
catalysts to better understand the scope of this exothermic behavior.
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RESULTS AND DISCUSSION
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The reaction calorimetry was evaluated using a Mettler Toledo EasyMax 102 HF Cal. The
initial reaction calorimetry evaluations involved the Suzuki-Miyaura cross-coupling of 1-bromo-
3-(trifluoromethyl)benzene with potassium vinyltrifluoroborate. These reactions were performed
in five volumes of solvent relative to aryl bromide rather than more diluted for the convenience
of work-up and product isolation, as removal of high boiling solvents such as DMSO, N,N-
dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), etc. on large scale can be
problematic. For each experiment, a mixture of 37.2 mmol of aryl bromide, 1.5 equivalents of
vinylboron species, and 2.5 equivalents of base in 42 mL of solvent was heated to 80 °C. To this
mixture was added 0.07 equivalents of catalyst (unless otherwise stated) in one-portion, and the
reaction was maintained at 80 °C until complete conversion was observed by GC analysis. It is
worthwhile to note that no noticeable exotherms were observed prior to the addition of catalyst
in any of the studied cases. The exothermic event was integrated to collect H of the reaction,
which was then used for the calculation of adiabatic temperature rise (Tad) and MTSR.
The thermal profile revealed a significant exotherm upon the addition of Pd(dppf)Cl
mixture of 1-bromo-3-(trifluoromethyl)benzene, potassium vinyltrifluoroborate, and K CO
9:1 DMSO/water at 80 °C (Figure 1). The total heat output was calculated to be 14.67 kJ
2
to a
2
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in
(393.5 kJ/mol) over only 6 min with a Tad of 141.0 °C, resulting in a MTSR of 221.0 °C that
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is considerably higher than the boiling point of the solvent. This heat profile suggests that in the
absence of sufficient cooling the system could quickly exceed the boiling point of the solvent
and result in a runaway reaction. In comparison, the same reaction in anhydrous DMSO
progressed relatively milder, generating a H of 9.44 kJ (253.8 kJ/mol) over 80 min and a
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Tad of 93.8 °C. This reaction started fast and decayed toward the end of reaction with 73% of
the total heat released in the first 20 min of reaction (Figure 2).
Figure 1. Heat flow profile of the Suzuki-Miyaura cross-coupling of 1-bromo-3-
(trifluoromethyl)benzene with potassium vinyltrifluoroborate in 9:1 DMSO/water.
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Figure 2. Heat flow profile of the Suzuki-Miyaura cross-coupling of 1-bromo-3-
(trifluoromethyl)benzene with potassium vinyltrifluoroborate in anhydrous DMSO.
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In addition to the desired heat of reaction, potential causes of the exotherm can be attributed to
the polymerization of the desired styrene products,10 decomposition of potassium
vinyltrifluoroborate under the reaction conditions, and/or decomposition of components of the
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reaction mixture. Quantitative In-Process Control (IPC) analysis by GC correlated very well
with the heat conversion during the course of the reaction and afforded >90% in-pot yield at
reaction completion, indicating that the product was stable during the reaction. This was further
supported by in-situ ReactIR analysis as shown in Figures 3 and 4. The product concentration
increased rapidly with the decrease of the starting material upon the addition of catalyst,
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Pd(dppf)Cl
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, and also corresponded well with the heat conversion. Further stirring of the reaction
mixture under the reaction conditions for a prolonged time after reaction completion did not
show decrease of the product concentration, confirming that polymerization of the desired
styrene product did not occur under the reaction conditions. Unfortunately, the signals of
potassium vinyltrifluoroborate were buried under other signals, thus precluding monitoring the
fate of potassium vinyltrifluoroborate by ReactIR. No noticeable heat was observed in a control
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experiment in which Pd(dppf)Cl
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exotherm was contributed by the decomposition of potassium vinlytrifluoroborate even if
decomposition occurred during the reaction.
Figure 3. Reaction profile of the Suzuki-Miyaura cross-coupling of 1-bromo-3-
(trifluoromethyl)benzene with potassium vinyltrifluoroborate in anhydrous DMSO at 80
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Figure 4. Three-dimensional plot of ReactIR monitoring of the Suzuki-Miyaura cross-
coupling of 1-bromo-3-(trifluoromethyl)benzene with potassium vinyltrifluoroborate in
anhydrous DMSO at 80 °C.
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It is a good safety practice to understand the thermal decomposition behavior of a reaction
mixture prior to scale-up and develop control strategies to ensure that the reaction is conducted at
a safe temperature (e.g., 100 °C below the detected onset temperature of the thermal
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decomposition ). Decomposition events are generally characterized with differential scanning
calorimetry (DSC), thermal screening unit (Tsu), accelerating rate calorimetry (ARC), and/or
vent sizing package (VSP).
The thermal decomposition of DMSO has been a growing concern in the chemistry
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temperature of 273 °C by DSC analysis (Figure 5), the decomposition of DMSO in a reaction
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mixture frequently occurs at a much lower onset temperature. This thermal decomposition can be
autocatalytic in the presence of acids, bases, and/or halogenated organic compounds.14
Initial evaluation of the stability of the post-reaction mixtures in DMSO and 9:1 DMSO/water
was performed using DSC. The thermograms of the post-reaction mixtures along with the
thermogram of neat DMSO are shown in Figure 5. In both experiments, significantly lower onset
temperatures (~223 °C) were detected compared to that of neat DMSO (273 °C). In the case of
the reaction mixture in 9:1 DMSO/water, the peak temperature representing the main DMSO
decomposition reaction was shifted to a much lower temperature, which was likely caused by the
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presence of water in combination with a weak base (K
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Figure 5. DSC analysis of the post-reaction mixtures of the Suzuki-Miyaura cross-coupling
of 1-bromo-3-(trifluoromethyl)benzene with potassium vinyltrifluoroborate.
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Further thermal decomposition evaluations were performed using ARC to enable detection of
the slow initial decomposition and/or other minor exothermic events. Two independent
exothermic events were detected for the reaction mixtures in anhydrous DMSO and 9:1
DMSO/water (Figure 6). According to the onset temperature, mass ratio, and total released
energy, the small exothermic events (around 150 °C) in both reaction mixtures were consistent
with the polymerization of the styrene product. The major exothermic events recorded by ARC
were comparable for the reaction mixtures in anhydrous DMSO and 9:1 DMSO/water, with a
detected onset at 190.7 °C and 196.0 °C, respectively (Figure 6). Both ARC tests were
terminated because the maximum cut-off pressure was reached and both tests had a significant
cool down pressure, confirming that the DMSO decomposition resulted in significant amount of
gas (Figure 7).
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For the reaction in 9:1 DMSO/water, the reaction mixture could self-heat to as high as its
MTSR of 221 °C, which would be much higher than the onset temperature of the DMSO
decomposition. With insufficient cooling and fast reaction rate, a close-to-adiabatic condition
would result, and the decomposition of DMSO would most likely promote a runaway reaction.
Although the MTSR of the reaction in anhydrous DMSO (173.8 °C) is below the solvent boiling
point and the onset temperature of the DMSO decomposition, if this temperature is reached it
will induce the heat release from the polymerization of the styrene product, which in turn will
further increase the temperature of the reaction mixture to potentially trigger the decomposition
of DMSO.
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Figure 6. ARC heat rate vs. temperature profile of the post-reaction mixture of the Suzuki-
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vinyltrifluoroborate.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 7. ARC pressure vs. temperature profile of the post-reaction mixture of the Suzuki-
Miyaura cross-coupling of 1-bromo-3-(trifluoromethyl)benzene with potassium
vinyltrifluoroborate.
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2
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2
3
3
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3
3
3
3
3
3
4
4
4
4
4
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4
4
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5
5
5
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5
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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1
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4
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8
9
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1
2
3
4
5
6
7
8
9
0
The effect of key parameters on the reaction heat profile was also evaluated (Table 1 and
Figure 8). The reactions conducted in DMF solvent systems followed the same trends as those in
anhydrous DMSO as well as 9:1 DMSO/water, generating a H of 9.39 kJ (252.4 kJ/mol)
over 46 min and a Tad of 100.6 °C in anhydrous DMF (Entry 4), and a H of 13.96 kJ (375.3
kJ/mol) over 5 min and a Tad of 138.6 °C in 9:1 DMF/water (Entry 2). In both cases, the MTSR
(180.6 °C in anhydrous DMF and 218.6 °C in 9:1 DMF/water) exceeded the boiling point of the
solvent and would result in runaway reaction without a sufficient cooling mechanism. The heat
profile of this reaction system at 80 °C in 9:1 dioxane/water, a frequently used solvent for the
Suzuki-Miyaura cross-coupling, revealed a H of 13.87 kJ (372.8 kJ/mol) over 55 min and a
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
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5
5
5
5
5
5
5
6

T
ad of 131.5 °C (Entry 3). This exotherm resulted in a MTSR of 211.5 °C that poses a potential
runaway hazard without active cooling during the reaction, especially given that the boiling point
of dioxane is only 101 °C. The use of a relatively weaker base, potassium hydrogen phosphate
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(K
2
HPO
4
), caused the reaction to progress at a much slower rate compared to K
2
CO , but
3
generated a comparable H of 9.35 kJ (251.3 kJ/mol) over 365 min and Tad of 93.3 °C in
anhydrous DMSO (Entry 6).
Table 1. Effect of base and solvent on the heat profile of the Suzuki-Miyaura cross-coupling
of 1-bromo-3-(trifluoromethyl)benzene with potassium vinyltrifluoroborate.
Time
(min)
Conversion
(% by GC)
H
(kJ/mol)
Tad
(°C)
MTSR
(°C)
Entry
Base
Solvent
H (kJ)
1
2
3
4
5
6
K
K
K
K
K
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
DMSO/water
DMF/water
Dioxane/water
DMF
6
5
98.7
>99.9
99.1
98.8
98.7
99.1
14.64
13.96
13.87
9.39
393.5
375.3
372.8
252.4
253.8
251.3
141.0
138.6
131.5
100.6
93.8
221.0
218.6
211.5
180.6
173.8
173.3
55
46
80
365
DMSO
9.44
K
2
HPO
4
DMSO
9.35
93.3
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Figure 8. Effect of base and solvent on the heat profile of the Suzuki-Miyaura cross-
coupling of 1-bromo-3-(trifluoromethyl)benzene with potassium vinyltrifluoroborate.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
14
12
Base: K2CO3, Solvent:
9
:1 DMSO/water
1
0
8
6
4
2
0
Base: K2CO3, Solvent:
9:1 DMF/water
Base: K2CO3, Solvent:
9
:1 dioxane/water
Base: K2CO3, Solvent:
DMF
Base: K2CO3, Solvent:
DMSO
Base: K2HPO4, Solvent:
DMSO
-
2
48
98
148
198
248
298
348
Time (min)
Moreover, upon switching to a more active catalyst, 1,1′-bis(di-tert-butylphosphino)ferrocene
palladium(II) dichloride [Pd(dtbpf)Cl or Pd-118], we observed complete conversion to the
2
desired styrene product in only 6 min (Figure 9) when the reaction was performed in anhydrous
DMSO at 80 °C with a H of 9.22 kJ (247.8 kJ/mol) and a Tad of 93.3 °C (Table 2, Entry 2).
When the Pd-118 loading was reduced to 0.01 equivalents, the reaction rate was marginally
reduced, but a similar exotherm was produced [H: 9.04 kJ (243.0 kJ/mol), Tad: 93.2 °C]
(Table 2, Entry 3) affording complete conversion in 13 min. However, it is worthwhile to note
that 93% of the total heat was released within the first 3 min of the reaction, which was
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
comparable to the 96% heat conversion in the same timeframe when 0.07 equivalents of Pd-118
was used (Figure 9). Slow reaction initiation was observed when the Pd-118 loading was further
reduced to 0.002 equivalents; however, the reaction ramped up drastically upon initiation to give
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
9
7% heat conversion within 11 min, achieving reaction completion in a total of 26 min (Figure
). The H [9.04 kJ (243.0 kJ/mol)] and Tad 98.4 °C of this reaction (Table 2, Entry 4) were
comparable with those with Pd(dppf)Cl
using tetrakis(triphenylphosphine)palladium(0) [Pd(PPh
C achieving only 4.1% conversion after 80 min, and reached 95.4% conversion after stirring at
2
and Pd-118 under anhydrous conditions. The reaction
3 4
) ] as the catalyst was very slow at 80
°
100 °C for 17 h with no integrable exotherm (Table 2, Entry 5).
Table 2. Effect of catalyst on the heat profile of the Suzuki-Miyaura cross-coupling of 1-
bromo-3-(trifluoromethyl)benzene with potassium vinyltrifluoroborate.
Loading Temperature
Time
(min)
Conversion
(% by GC)
H
(kJ)
H
(kJ/mol)
Tad
(°C)
MTSR
(°C)
Entry
Catalyst
(equiv)
(°C)
1
2
3
4
5
Pd(dppf)Cl
Pd-118
2
0.07
0.07
0.01
0.002
0.07
80
80
80
6
98.7
99.8
>99.9
99.6
95.4
9.44
9.22
9.04
9.04
ND
253.8
247.8
243.0
243.0
ND
93.8
93.3
93.2
98.4
ND
173.8
173.3
173.2
178.4
ND
Pd-118
80
13
Pd-118
80
26
Pd(PPh
3
)
4
100
17 h
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Figure 9. Effect of catalyst on the heat profile of the Suzuki-Miyaura cross-coupling of 1-
bromo-3-(trifluoromethyl)benzene with potassium vinyltrifluoroborate.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
0
9
8
7
6
5
4
3
2
1
0
0
.07 eq Pd-118
.01 eq Pd-118
0.002 eq Pd-118
.07 eq Pd(dppf)Cl2
0
0
-
2
18
38
58
78
Time (min)
A variety of substituted aryl bromides ranging from electron-deficient to electron-rich systems
were evaluated to study the scope of this exothermic behavior (Table 3 and Figure 10). All the
reactions were performed at 80 °C in anhydrous DMSO in the presence of Pd(dppf)Cl
2
and
K
2
CO . Similar magnitude exothermic behaviors were observed in all evaluated substrates, with
3
the heat of reaction ranging from 241.1 kJ/mol with 4-bromoacetanilide (entry 5) to 289
kJ/mol with ethyl 4-bromobenzoate (Entry 1). Both heat conversion and GC analysis supported
that the reaction progressed faster with the electron-deficient substrates than with electron-rich
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
substrates, with complete conversion ranging from 20 min with ethyl 4-bromobenzoate (Entry 1)
and 4-bromoacetophenone (Entry 2) to 100 min with 1-bromo-3-methoxybenzene (Entry 7). The
exothermic behavior of these substrates under aqueous conditions (i.e., 9:1 DMSO/water) was
not studied, but it is reasonable to speculate that these reactions should progress faster with
higher levels of heat generated than those under anhydrous conditions based on the observations
described in Table 1.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 3. The Suzuki-Miyaura cross-coupling of substituted aryl bromides with potassium
vinyltrifluoroborate.
Time
Conversion
(% by GC)
H
H
Tad
MTSR
(°C)
Entry
1
ArBr
(
min)
(kJ)
(kJ/mol)
(°C)
20
98.3
>99.9
98.8
10.75
9.70
9.28
289.0
260.8
249.5
88.5
80.8
89.2
168.5
160.8
169.2
2
3
20
80
4
5
80
90
98.7
9.44
8.97
253.8
241.1
93.8
89.5
173.8
169.5
>99.9
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90
>99.9
>99.9
9.48
9.59
254.8
257.8
111.0
90.4
190.0
170.4
100
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 10. Heat profiles of the Suzuki-Miyaura cross-coupling of substituted aryl bromides
with potassium vinyltrifluoroborate.
1
0
8
6
4
2
0
R = 4-COOEt
R = 4-COMe
R = 4-CF3
R = 3-CF3
R = 4-NHAc
R = 4-OMe
R = 3-OMe
0
20
40
60
80
100
Time (min)
Variation of the vinylboron species was also explored to determine if the observed exotherm
was specific to potassium vinyltrifluoroborate (Table 4 and Figure 11). The reaction of 1-bromo-
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
-(trifluoromethyl)benzene with potassium iso-propenyltrifluoroborate generated a similar heat
profile compared with potassium vinyltrifluorborate, giving a H of 9.46 kJ (259.1 kJ/mol)
over 70 min and a Tad of 90.4 °C in anhydrous DMSO (Entry 2). It is worthwhile to note that
the reactions with pinacol vinylboronate (entry 4) and iso-propenylboronate (entry 5) also
produced similar heat profiles in anhydrous DMSO [9.42 kJ (253.2 kJ/mol) and 9.33 kJ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(250.8 kJ/mol), respectively] compared to those with potassium vinyltrifluoroborate. The Tad
of 96.3 °C for pinacol vinylboronate and 94.2 °C for pinacol iso-propenylboronate were also
comparable with the Tad using potassium vinyltrifluoroborate. The reaction time for pinacol
vinylboronate was significantly longer than that of pinacol iso-propenylboronate (130 min vs. 70
min), which was suspected to be caused by poor mass transfer as a thick suspension was
observed during the reaction with pinacol vinylboronate. The heat profile with (E)-styrylboronic
acid in anhydrous DMSO was also comparable to other studied organoboron reagents under
anhydrous conditions, with a H of 9.04 kJ (243.0 kJ/mol) and a Tad of 89.0 °C (Entry 6).
Interestingly, when we switched to potassium allyltrifluoroborate, the reaction was much slower
and milder, requiring 180 min to achieve completion with a H of 7.1 kJ (190.9 kJ/mol) and a
Tad of 78.7 °C (Entry 3).
Table 4. The Suzuki-Miyaura cross-coupling of 1-bromo-3-(trifluoromethyl)benzene with
various organoboron species.
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Conversion (%
Tad
MTSR
(°C)
Entry
1
Borate
Time (min)
H (kJ)
9.44
H (kJ/mol)
253.8
by GC)
(°C)
80
98.7
93.8
90.4
78.7
173.8
170.4
158.7
2
3
70
>99.9
96.9
9.64
7.10
259.1
190.9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
180
4
130
99.7
9.42
253.2
96.3
176.3
5
6
70
50
>99.9
98.7
9.33
9.04
250.8
243.0
94.2
89.0
174.2
169.0
Figure 11. Heat profiles of the Suzuki-Miyaura cross-coupling of 1-bromo-3-
(
trifluoromethyl)benzene with various organoboron species.
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
0
9
8
7
6
5
4
3
2
1
0
(
E)-styrylboronic acid
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Potassium
isopropenyltrifluoroborate
Pinacol
isopropenylboronate
Potassium
vinyltrifluoroborate
Pinacol vinylboronate
Allyl trifluoroborate
0
20
40
60
80
100
120
140
160
180
Time (min)
CONCLUSIONS
Significant exothermic events were observed during the Suzuki-Miyaura cross-coupling of aryl
bromides with potassium vinyltrifluoroborate in the studied systems. The exotherm was more
significant and much faster in aqueous systems compared to anhydrous conditions. This
exotherm posed potential safety hazards as in many reaction systems, especially in the presence
of water, the MTSR exceeded the boiling point of the solvent and/or the onset temperature of the
decomposition of DMSO. The effects of key parameters such as solvent, catalyst, and base, etc.
were evaluated, and it was found that these systems produced exotherms of comparable
magnitude, but at different reaction rates. The scope studies revealed similar exotherms with
different aryl bromides and various vinylboron species, with faster reactions occurring with
electron-deficient aryl bromides. Researchers are encouraged to conduct safety evaluations and
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develop control strategies accordingly to mitigate potential safety risks prior to practicing similar
chemistry, especially on large scale. Although only aryl bromides were studied in this work,
similar precautions should be taken with the Suzuki-Miyaura cross-coupling of other aryl
electrophiles.
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EXPERIMENTAL SECTION
General: All reagents were commercially available and used as purchased without further
purification. Reaction conversion and product formation were confirmed by spiking with an
authentic sample of the desired product purchased from commercial suppliers and/or GCMS
analysis. GC analysis was performed on an Agilent 6850 equipped with Agilent DB-WAX
column (30 m × 320 m × 0.5 m, P/N 1237033); Inlet 250 °C; FID, 250 °C; helium constant
flow: 3 mL/min; hydrogen flow: 40 mL/min; air flow: 450 mL/min; nitrogen makeup: 30
mL/min; injection volume: 1 L; split ratio: 25; temperature programming: 50 °C: 0 min,
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0°C/min to 200 °C then 5 °C/min to 250 °C, hold 2 min; maximum column temperature: 250
C.
General procedure for the reaction calorimetry evaluation by EasyMax HF Cal: The
°
reaction calorimetry was evaluated using a Mettler-Toledo EasyMax 102 with HF Cal. All
reactions were performed under a nitrogen blanket. For each experiment a stirred (at 300 rpm)
mixture of aryl bromide (37.2 mmol), organoboron reagent (1.5 equiv), and base (2.5 equiv) in
solvent (42 mL) was heated to 77 °C. The virtual volume was recorded, followed by calibration
to determine heat transfer co-efficient (u) and heat capacity (cpr) with 15 min waiting time and
∆Tr of 3 °C. The catalyst (see tables for specific catalyst and amount) was added in one-portion,
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and the reaction was heated at 80 °C until complete conversion was observed by GC analysis.
The virtual volume was recorded, and a second calibration was performed to determine u and cpr
with 15 min waiting time and ∆Tr of 3 °C. The reaction was then cooled to 25 °C to complete the
experiment. The exothermic event was integrated to determine H, which was then used for the
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calculation of Tad and MTSR.
Procedure for DSC analysis: A Q2000 DSC from TA instruments was used for the constant
heating rate tests in this study. A 1 mg sample was loaded into a glass capillary and then flame
sealed with air as the headspace. During the flame sealing of the glass, the sample containing
portion of the ampoule was cooled with liquid nitrogen. The sealed ampoule had a total internal
volume of ~25 µL. The sealed ampoule can withstand pressures up to 3000 psi at 400 °C and
therefore effectively prevents the escape of any tested chemical or the products from reaction.15
Procedure for ARC analysis: An ARC manufactured by Thermal Hazard Technology was
used in this study. A 4.0 g sample was loaded into a standard Titanium ARC sphere with air as
the headspace. The ARC experiment was performed with a Heat-Wait-Search (HWS) mode. A
heat step of 5 °C, waiting time of 30 min and a detection threshold of 0.02 °C/min was utilized.
The Phi factor calculated from mass and heat capacity was 2.04.16
AUTHOR INFORMATION
Corresponding Author
e-mail: qyang1@dow.com
Notes
The authors declare no competing financial interest.
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Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
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ACKNOWLEDGMENT
The authors thank Dr. Gregory T. Whiteker for helpful discussions during this investigation and
Dr. Shawn Chen for assisting with the interpretation of ReactIR data. Dow AgroSciences is
acknowledged for support of this work.
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1. Quantitative GC analysis was performed using octanophenone as an internal standard.
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