Safety Evaluation of the Copper-Mediated Cross-Coupling of 2-Bromopyridines with Ethyl Bromodifluoroacetate

Article abstract of DOI:10.1021/acs.oprd.8b00261

The potential safety hazards associated with the copper-mediated cross-coupling of 2-bromopyridines with ethyl bromodifluoroacetate were evaluated. Thermal stability evaluation of the postreaction mixture of 50.6 mmol of 2-bromopyridine with 1.3 equiv of ethyl bromodifluoroacetate in the presence of 2.1 equiv of copper in 40 mL of dimethyl sulfoxide (DMSO) indicated a significant decomposition event with an onset temperature of 115.5 °C by accelerating rate calorimetry, which was significantly lower than that of neat DMSO. In contrast, the reaction mixture in N,N-dimethylformamide did not show any exothermic decomposition up to 400 °C by differential scanning calorimetry. Reaction calorimetry evaluation of this reaction in DMSO revealed a heat output (ΔH) of -13.5 kJ and an adiabatic temperature rise (ΔT_ad) of 129.5 °C, resulting in a maximum temperature of a synthesis reaction (MTSR) of 189.5 °C. The predicted heat of reaction using density functional theory with the BLYP functional was in good agreement with the experimental data. The scope studies with a variety of substituted 2-bromopyridines revealed similar magnitudes of ΔH and ΔT_ad compared to 2-bromopyridine when reacted at the same concentration. In all of the studied cases, the MTSR was significantly higher than the onset temperature of reaction mixture decomposition, indicating that in the absence of active cooling the system could quickly trigger the decomposition of the reaction mixture, resulting in a runaway reaction.

Full text of DOI:10.1021/acs.oprd.8b00261

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Full Paper
Safety Evaluation of the Copper-Mediated Cross-Coupling
of 2-Bromopyridines with Ethyl Bromodifluoroacetate
Qiang Yang, Pablo Cabrera, Xiaoyong Li, Min Sheng, and Nick X Wang
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00261 • Publication Date (Web): 18 Sep 2018
Downloaded from http://pubs.acs.org on September 18, 2018
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Safety Evaluation of the Copper-Mediated Cross-
Coupling of 2-Bromopyridines with Ethyl
Bromodifluoroacetate
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Qiang Yang,*,† Pablo J. Cabrera,† Xiaoyong Li, Min Sheng,ῼ and Nick X. Wang
†Process Chemistry, Dow AgroSciences, 9330 Zionsville Rd., Indianapolis, IN 46268, United
States
Process Development, Dow AgroSciences, 9330 Zionsville Rd., Indianapolis, IN 46268, United
States
ῼReactive Chemicals, Dow AgroSciences, Midland, MI 48667, United States
Discovery Chemistry, Dow AgroSciences, 9330 Zionsville Rd., Indianapolis, IN 46268, United
States
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Table of Contents Graphic:
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ABSTRACT
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The potential safety hazards associated with the copper-mediated cross-coupling of 2-
bromopyridines with ethyl bromodifluoroacetate were evaluated. Thermal stability evaluation of
the postreaction mixture of 50.6 mmol of 2-bromopyridine with 1.3 equiv of ethyl
bromodifluoroacetate in the presence of 2.1 equiv of copper in 40 mL of dimethyl sulfoxide
(DMSO) indicated a significant decomposition event with an onset temperature of 115.5 °C by
accelerating rate calorimetry (ARC), which was significantly lower than that of neat DMSO. In
contrast, the reaction mixture in N,N-dimethylformamide (DMF) did not show any exothermic
decomposition up to 400 °C by differential scanning calorimetry (DSC). Reaction calorimetry
evaluation of this reaction in DMSO revealed a heat output (H) of 13.5 kJ and an adiabatic
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temperature rise (Tad) of 129.5 °C, resulting in a maximum temperature of a synthesis reaction
(MTSR) of 189.5 °C. The predicted heat of reaction using the density functional theory (DFT)
method, BLYP, was in good agreement with the experimental data. The scope studies with a
variety of substituted 2-bromopyridines revealed similar magnitudes of H and Tad compared
to 2-bromopyridine when performed at the same concentration. In all studied cases, the MTSR
was significantly higher than the onset temperature of DMSO decomposition, indicating that in
the absence of active cooling the system could quickly trigger the decomposition of the reaction
mixture resulting in a runaway reaction.
Keywords: safety hazards, copper-mediated cross-coupling, reaction calorimetry, dimethyl
sulfoxide thermal decomposition, 2-bromopyridine, ethyl bromodifluoroacetate, 2-
bromopyridine homo-coupling.
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INTRODUCTION
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Incorporation of the difluoromethylene (CF2) group in bioactive molecules has become an
important area of research due to the significant enhancement of physical, chemical, and
biological properties.1 The CF2 group acts as an isosteric and/or isoelectronic replacement of an
ether oxygen atom or a carbonyl moiety, with increased metabolic stability and lipophilicity.2
Over the years, several important pharmaceutical products (e.g., Ledipasvir, Roflumilast,
Deracoxib, etc.) and agrochemicals (e.g., Isopyrazam, Fludioxonil, Fluxapyroxad, Thiazopyr,
Pantoprazole, etc.) containing the CF2 group have been developed.
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Common methodologies for the introduction of the CF2 group involve the deoxyfluorination of
aldehydes and ketones employing nucleophilic fluorinating reagents such as diethylaminosulfur
trifluoride (DAST), bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor), and sulfur
tetrafluoride (SF4).3 The gem-difluorination of the -position of carbonyl groups can be achieved
with a number of electrophilic fluorinating reagents (N-fluoroimides, N-fluorosultam, N-
fluoropyridinium salt, and Selectfluor, etc.).3c,4 Additional difluoromethylation strategies such as
the direct fluorination of C-H bonds,5 direct difluoromethylation of C-H bonds,6 cross-coupling,7
ring-opening of difluorocyclopropanes,8 and generation of difluorocarbene species,9 have also
been developed for the incorporation of CF2 groups. However, most of these conditions suffer
from the use of highly toxic and/or costly reagents, high temperatures, and/or unstable reactive
intermediates.
In the late 1980’s, the copper-mediated cross-coupling of alkenyl halides and aryl halides with
alkyl bromodifluoroacetate or iododifluoroacetate was developed for the synthesis of CF2-
containing compounds.10 The in-situ generation of Cu-CF2R species enables reactivity with a
wide range of aryl, vinyl and alkynyl halides under mild conditions.10b,11 The most frequently
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used solvent for this type of reaction is DMSO, while in some cases DMF, N-Methyl-2-
pyrrolidone (NMP), and hexamethylphosphoramide (HMPA) also provide the desired the
conversion. In particular, the copper-mediated cross-coupling of 2-bromopyridine with ethyl
bromodifluoroacetate has seen industrial application during the scale up of a thrombin
inhibitor.12 In this report the researchers noted potential safety hazards with this reaction in
DMSO; however, detailed information around these safety hazards was not disclosed. During our
recent research we observed a delayed exotherm during the heating of a mixture of 2-
bromopyridine, ethyl bromodifluoroacetate, and copper powder in DMSO. In a reaction
performed in a 125-mL reactor without active cooling, the reaction temperature rapidly spiked to
~100 °C from 55 °C upon the addition of 1.3 equiv of ethyl bromodifluoroacetate to a mixture of
50.6 mmol of 2-bromopyridine and 2.1 equiv of copper in 40 mL of DMSO. This observation,
coupled with the thermal stability hazards of DMSO, necessitated further investigation into the
potential safety hazards associated with this type of reaction (Scheme 1).
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Scheme 1. Copper-Mediated Cross-Coupling of 2-Bromopyridines with Ethyl
Bromodifluoroacetate.
RESULTS AND DISCUSSION
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Postreaction Mixture Thermal Stability Evaluation: Reaction mixture thermal stability is
an important component of safety evaluation of a chemical reaction. It is crucial to understand
the thermal stability of reaction mixtures and design strategies such that the reactions are
performed within a safe temperature window.13 DMSO has been widely used as a solvent in
chemical reactions due to its unique physical properties for solubilizing both organic and
inorganic chemicals; however, many recent reports disclosed concerns around the uncontrollable
thermal decomposition of DMSO.12,14 Further studies showed that in the presence of acids, bases,
and/or halogenated organic compounds, DMSO decomposition is autocatalytic and frequently at
much lower onset temperatures compared to the 268 °C onset temperature for the decomposition
of pure DMSO.15
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Preliminary evaluation of the postreaction mixture (after reaction completion was determined
by GC analysis) of the copper-mediated cross-coupling of 2-bromopyridine with ethyl
bromodifluoroacetate in DMSO was performed using DSC. The thermogram showed a sharp
exothermic event with 555.3 J/g energy release. The onset temperature of 158 °C was
significantly lower than the 268 °C onset temperature for neat DMSO (Figure 1). The evaluation
was further conducted with ARC to enable detection of slow initial decomposition, minor
exothermic events, and potential pressure buildup due to the release of non-condensable gases
during the decomposition. A major exothermic event with an onset temperature of 115.5 °C was
detected (Figure 2). This decomposition gave an estimated heat release of 597 J/g with a
maximum self-heating rate of 143 °C/min and a Tad of 284 °C. The ARC test reached the
maximum cut-off pressure during the evaluation with a cool down pressure of 414.6 psia at 29.4
°C. These results confirmed the formation of a significant amount of non-condensable gases
during the reaction mixture decomposition (Figure 3). The pressure “step-up” at 216 °C in Figure
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3 was most likely caused by a delayed temperature measurement during the rapid heat generation
since the thermocouple was positioned outside the ARC bomb and not immersed in the liquid
sample.
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Figure 1. Comparison of the DSC profiles of neat DMSO and the postreaction mixture in
DMSO.
Figure 2. ARC self-heat rate vs. temperature profile of the postreaction mixture in DMSO.
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Figure 3. ARC pressure vs. temperature profile of the postreaction mixture in DMSO.
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Reaction Calorimetry Evaluation: Initial reaction calorimetry evaluation was performed on
the coupling of 2-bromopyridine with ethyl bromodifluoroacetate. The thermal profile revealed a
significant exotherm upon the addition of 1.3 equiv of ethyl bromodifluoroacetate to a mixture of
50.6 mmol of 2-bromopyridine and 2.1 equiv of copper in 40 mL of DMSO at 60 °C (Procedure
A). The H was calculated to be 13.5 kJ with a Tad of 129.5 °C, resulting in a MTSR of 189.5
°C that was considerably higher than the onset temperature of the reaction mixture
decomposition (Figure 4). This heat profile suggested that without sufficient cooling, the system
could rapidly self-heat, trigger the decomposition of the reaction mixture, and result in a runaway
reaction.
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Figure 4. Heat flow profile of the copper-mediated cross-coupling of 2-bromopyridine with
ethyl bromodifluoroacetate in DMSO at 60 °C.
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In-Process Control (IPC) analysis by GC indicated full consumption of the starting material
and the exclusive formation of the desired product at the end of heat release. This was consistent
with in-situ ReactIR analysis as shown in Figure 5. The rate of the desired product formation
correlated very well with the rate of the starting material consumption, as well as with the heat
conversion. Notably, no product degradation was observed after the reaction was stirred under
the reaction conditions for a prolonged time after reaction completion.
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Figure 5. Reaction profile of the copper-mediated cross-coupling of 2-bromopyridine with
ethyl bromodifluoroacetate in DMSO at 60 °C by ReactIR.
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Heat of Reaction Calculation: First-principle methods to calculate thermodynamic
parameters has been routinely used for reaction design in chemical processes.16 We calculated
the heat of reaction for the copper-mediated cross-coupling of 2-bromopyridine with ethyl
bromodifluoroacetate using the BLYP method.
The geometry optimization was performed to generate the structures of all reactants and
products with BLYP/MIDIX method. The BLYP/MIDIX solution phase energy was calculated
for all molecules except for copper species based on the optimized structures in an implicit SM8
solvation model17 with DMSO as the solvent. The solution phase energy for copper and copper
(I) salt was calculated with BLYP/6-31G**+ method in the same solvation system. Frequency
calculations were also performed to generate relevant thermodynamic quantities including zero-
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point energy, thermal energy, and enthalpy at 333.15 K and 1 atm. All calculations were done
with Jaguar software in Maestro (Schrodinger Inc.). The enthalpy change for the reaction was
268.7 kJ/mol, giving a 13.6 kJ heat release on a 50.6 mmol scale that was in close agreement
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with the experimental data of 13.5 kJ.
Exotherm Scope Evaluation: A variety of substituted 2-bromopyridines was evaluated to
study the scope of this exothermic behavior (Table 1 and Figure 6). All experiments were
initially conducted with the same concentration following Procedure A, in which ethyl
bromodifluoroacetate was added to a mixture of the selected 2-bromopyridine derivatives and
copper in DMSO after calibration. With substrates that afforded high levels of homo-coupling
biaryl products 3 (Scheme 1), the experiments were repeated following Procedure B (copper was
added to a mixture of 2-bromopyridine and ethyl difluoroacetate at the specified temperature
after the 105 min calibration) to minimize the formation of the homo-coupling biaryl product
during the calibration. Similar magnitude exotherms were observed in all evaluated substrates
with the H ranging from 11.9 kJ with 2-bromo-3-trifluoromethylpyridine following Procedure
A (entry 4) to 13.9 kJ with 2-bromo-5-chloropyridine (Entry 10). The Tad was also similar
across the tested substrates, ranging from 119.2 °C with 2-bromo-3-trifluoromethylpyridine
following Procedure A (entry 4) to 141.1 °C with 2-bromo-5-chloropyridine (entry 10). In all
cases the MTSR was significantly higher than the onset temperature of the reaction mixture
decomposition, and could likely result in runaway scenarios if proper control strategies were not
implemented.
It is worthwhile to note that homo-coupling of substituted 2-bromopyridines was observed
with most of the 3-, 4-, and 5-substituted 2-bromopyridines (entries 39). Following Procedure
A, 2-bromo-3-trifluoromethylpyridine afforded the highest amount of homo-coupling biaryl
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product (32.9%, entry 4). This undesired side product formation was significantly suppressed to
14.8% when the reaction was performed following Procedure B (entry 5). All reactions with 6-
substituted 2-bromopyridines stalled even after prolonged stirring; however, no homo-coupling
was observed in any of these cases (entries 1114).
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Table 1. Copper-Mediated Cross-Coupling of 2-Bromopyridines with Ethyl
Bromodifluoroacetate.
GC (% AUC)
Temp.
(°C)
MTSR
(°C)
H
Tad
Entry
R
Solvent
Procedure
(kJ) (°C)
1
0
2
3
0
H
DMSO
DMF
60
60
40
60
60
40
60
40
60
60
A
A
B
A
B
B
A
B
A
A
>99.9
96.8
98.3
67.1
85.2
98.6
90.5
98.3
90.3
99.3
129.5 189.5
163.1 223.1
130.4 170.4
119.2 179.2
134.2 194.2
138.9 178.9
136.4 196.4
132.6 172.6
136.2 196.2
141.1 201.1
1
2
13.5
13.0
13.5
11.9
13.0
13.7
13.3
13.4
13.6
13.9
H
3.2
0
0
3-Me
3-CF3
3-CF3
4-Me
4-F
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1.7
32.9
14.8
1.2
9.5
1.7
9.7
0
3
0
4
0
5
0.2
0
6
7
5-Me
5-CF3
5-Cl
0
8
0
9
0.7
10
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6-OMe
6-OMe
6-CF3
6-Cl
DMSO
DMSO
DMSO
DMSO
40
60
60
60
B
A
A
A
9.6
8.1
90.4
91.9
85.6
92.2
0
0
0
0
128.6 168.6
133.8 193.8
121.8 181.8
121.7 181.7
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14
12.4
12.9
12.2
12.7
14.4
7.8
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Figure 6. Heat profiles of the copper-mediated cross-coupling of 2-bromopyridines with
ethyl bromodifluoroacetate.
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Potential Control Strategies: Controlled addition of reactive chemicals (e.g., reactants,
reagents) is one of the most frequently used strategies to control reaction exotherm. In our
attempt to control the exotherm, ethyl bromodifluroacetate was added to a mixture of 2-
bromopyridine and copper in DMSO at 60 °C over 3 h. The reaction progress was monitored by
GC analysis during the addition to ensure no accumulation of ethyl bromodifluoroacetate during
the addition. Upon completion of addition, the reaction was further stirred at 60 °C to achieve
complete conversion. The reaction temperature remained steady at 60 °C throughout the reaction
as a result of controlled release of heat coupled with active cooling. The reaction profile by GC
analysis was consistent with that following Procedure A. However, it is recommended that
researchers evaluate their specific reactions before implementing this strategy as elevated levels
of homo-coupling biaryl products were observed with some substituted 2-bromopyridines
(entries 39). More importantly, heat generated by this homo-coupling side reaction could also
pose potential safety hazards. In a control experiment to investigate the potential safety hazards
associated with this homo-coupling reaction, a mixture of 50.6 mmol of 2-bromo-3-
trifluoromethylpyridine and 2.1 equiv of copper in 40 mL of DMSO was heated at 60 °C for 3 h,
after which time GC analysis showed no reaction. Based on the observations during the reaction
calorimetry scope studies, we suspected that this reaction could be catalyzed by ethyl
bromodifluoroacetate or its copper complex. Thus, to the above reaction mixture was added 0.1
equiv of ethyl bromodifluoroacetate while maintaining the temperature at 60 °C. GC analysis at
the end of reaction indicated full consumption of starting material 1 and the formation of 9.9% of
2 and 90.1% of homo-coupling biaryl product 3. The heat flow profile revealed a H of 7.25 kJ
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and a Tad of 76.5 °C, indicating that without sufficient cooling the exotherm from the homo-
coupling reaction could still potentially trigger the decomposition of the reaction mixture.
DMF is also a frequently used solvent for this reaction. Operational safety testing by Merck
researchers indicated DMF was a safe solvent for the scale up of the copper-mediated cross-
coupling of 2-bromopyridine with ethyl bromodifluoroacetate; however, detailed information of
their safety testing was not disclosed.12 In our preliminary studies this reaction progressed at a
much slower rate in DMF than in DMSO, requiring a total of 9 h to achieve 96.8% conversion
compared to full conversion within 2 h in DMSO (Figure 5). Thermal stability evaluation of the
postreaction temperature by DSC indicated no exothermic decomposition up to 400 °C (Figure
7). Reaction calorimetry evaluation revealed similar magnitude exotherm (13.0 kJ) compared to
that in DMSO (entries 1 and 2). Although in this specific case the MTSR of 223.1 °C was higher
than the boiling point of DMF, the reaction temperature was easily maintained below the boiling
point as a result of the slow reaction rate and active cooling to remove heat generated from the
reaction.
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Figure 7. Comparison of the DSC profiles of the postreaction mixtures in DMF and DMSO.
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CONCLUSIONS
A significant exotherm was observed during the thermal stability evaluation of the postreaction
mixture of the copper-mediated cross-coupling of 2-bromopyridine with ethyl
bromodifluoroacetate in DMSO. The onset temperature of this decomposition was 115.5 °C by
ARC analysis, which was significantly lower than that of pure DMSO. Reaction calorimetry
evaluation revealed H of 11.9 kJ to 13.9 kJ and Tad of 119.2 °C to 141.1 °C in the studied
systems of 50.6 mmol of substituted 2-bromopyridines with 1.11.3 equiv of ethyl
bromodifluoroacetate in the presence of 2.1 equiv of copper in 40 mL of DMSO. Heat of
reaction from theoretical calculations using the density functional theory (DFT) method, BLYP,
was in good agreement with the experimental data. This exotherm posed potential safety hazards
as the MTSR exceeded the onset temperature for the reaction mixture decomposition. Strategies
such as controlled addition of reactive chemicals and use of more stable solvents could
potentially provide handle for controlling this exotherm. Researchers are encouraged to conduct
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safety evaluations and develop control strategies specific to their reactions to mitigate potential
safety risks.
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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 Intuvo 9000 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,
30°C/min to 200 °C then 5 °C/min to 250 °C, hold 2 min; maximum column temperature: 250
°C.
General procedures for the reaction calorimetry evaluation by EasyMax HF Cal: The
reaction calorimetry was evaluated using a Mettler-Toledo EasyMax 102 with HF Cal.14g,18 All
reactions were performed at a stirring rate of 400 rpm under a nitrogen blanket.
Procedure A: A stirred mixture of 2-bromopyridine (50.6 mmol) and copper powder (2.1
equiv, 1425 µm, from Sigma Aldrich) in DMSO or DMF (40 mL) was heated to 57 °C. The
virtual volume was recorded, followed by calibration to determine heat transfer coefficient (u)
and heat capacity (cpr) with 15 min waiting time and ∆Tr of 3 °C. Ethyl bromodifluoroacetate
(1.11.3 equiv) was added, and the reaction was heated at 60 °C until heat release subsided. The
virtual volume was recorded, and a second calibration was performed to determine u and cpr
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with 15 min waiting time and ∆Tr of 3 °C. The reaction was then cooled to 25 °C to complete the
experiment.
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Procedure B: A stirred mixture of 2-bromopyridine (50.6 mmol) and ethyl
bromodifluoroacetate (1.11.3 equiv) in DMSO (40 mL) was heated to 37 °C or 57 °C. The
virtual volume was recorded, followed by calibration to determine u and cpr with 15 min waiting
time and ∆Tr of 3 °C. Copper powder (2.1 equiv, 1425 µm, from Sigma Aldrich) was added,
and the reaction was heated at 40 °C or 60 °C (Table 1) until heat release subsided. 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.
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The exothermic event was integrated to determine H, which was then used for the calculation
of Tad and MTSR.
Procedure for DSC analysis: A Q2500 DSC from TA instruments was used for the constant
heating rate tests in this study. A ~2 mg postreaction mixture sample was loaded into a glass
capillary and then flame sealed with nitrogen as the headspace. During the flame sealing of the
glass, the sample containing portion of the glass capillary was cooled with liquid nitrogen. The
sealed capillary had a total internal volume of ~4 µL. The sealed capillary 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.19
Procedure for ARC analysis: An ARC manufactured by Thermal Hazard Technology was
used in this study. A 4.54 g postreaction mixture sample was loaded into a standard Hastelloy C
ARC sphere with nitrogen as the headspace. The ARC experiment was performed with a Heat-
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Wait-Search (HWS) mode. A heat step of 5 °C, waiting time of 20 min, and a detection threshold
of 0.02 °C/min were utilized. The Phi factor calculated from mass and heat capacity was 1.96.20
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AUTHOR INFORMATION
Corresponding Author
e-mail: qyang1@dow.com
Notes
The authors declare no competing financial interest.
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
ACKNOWLEDGMENT
Dow AgroSciences is acknowledged for support of this work. The authors also thank the Editor
and the anonymous reviewers for their helpful comments to help us in shaping this paper.
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