Mizoroki–Heck Cross-Coupling of Bromobenzenes with Styrenes: Another Example of Pd-Catalyzed Cross-Coupling with Potential Safety Hazards

Abstract

The potential safety hazards associated with the Mizoroki–Heck cross-coupling of bromobenzenes with styrenes were evaluated. The heat output from the reaction in various solvents was comparable in a variety of solvents; however, the rate of reaction was significantly faster in the presence of water. Thermal stability evaluation of the postreaction mixtures in DMSO and 3:1 DMSO/water by differential scanning calorimetry indicated that the onset temperatures of thermal decomposition were significantly lower than that of neat DMSO. Evaluation of the substrate scope revealed that the substitution pattern on the bromobenzene did not affect the heat output. The reaction rate of electron-deficient bromobenzenes was slower than that of the electron-rich bromobenzenes. In general, substituted styrenes afforded similar magnitudes of exotherms; however, the reaction rate of bromobenzene with 2-methylstyrene was significantly slower than the other studied styrenes. The predicted heat of reaction using the density functional theory method, B3LYP, was in good agreement with the experimental data. Such excellent agreement suggests that this calculation method can be used as a preliminary tool to predict heat of reaction and avoid exothermic reaction conditions. In many of the studied cases, the maximum temperature of a synthesis reaction was considerably higher than the solvent boiling point and thermal decomposition onset temperatures when the reaction was performed in DMSO or 3:1 DMSO/water. It is crucial to understand the thermal stability of the reaction mixture to design the process accordingly and ensure the reaction temperature is maintained below the onset temperature of decomposition to avoid potential runaway reactions.

Potential Explosion Hazards Associated with the Autocatalytic Thermal Decomposition of Dimethyl Sulfoxide and Its Mixtures

“…In a separate report, Yang et al at Corteva Agriscience evaluated the thermal stability of the postreaction mixtures for the Mizoroki–Heck cross-coupling of bromobenzene ( 41 ) with styrene ( 42 ) in the presence of catalytic [1,1′-bis­(di- tert -butylphosphino)­ferrocene]­palladium­(II) dichloride [Pd­(d t bpf)­Cl 2 or Pd-118] and N , N -diisopropylethylamine (DIPEA) as the base in DMSO systems, in which KBr was again one of the byproducts (Scheme ). DSC analysis of the postreaction mixture in DMSO exhibited three exothermic decomposition events with onset temperatures of 89.1, 196.9, and 275.4 °C, respectively. These exothermic events afforded a combined Δ H of −586 J/g and Δ T ad of 344.4 °C.…”

“…DSC profiles of postreaction mixtures for the Mizoroki–Heck cross-coupling of bromobenzene with styrene in DMSO and 3:1 DMSO/water. Reproduced from ref . Copyright 2019 American Chemical Society.…”

On the Use of Differential Scanning Calorimetry for Thermal Hazard Assessment of New Chemistry: Avoiding Explosive Mistakes

“…There are other thermal hazard tests available, such as accelerating rate calorimetry (ARC), reaction calorimetry, impact sensitivity or explosivity tests, but none are as ubiquitous or simple to use as the humble DSC. Recently, there have been studies seeking to characterise and compare the thermal and process hazards of compound classes, such as peptide‐coupling reagents, oxidisers, N‐heterocyclic iodanes, diazo compounds, and cage alkyl motifs; or processes such as Pd‐catalysed cross‐coupling, TIPS‐EBX and NaH with DMF/DMSO/DMAc …”

Discovery, Synthesis, and Scale-up of Efficient Palladium Catalysts Useful for the Modification of Nucleosides and Heteroarenes

“…Recognizing the importance of Pd catalysis in the chemical modification of nucleosides, our One of the earliest examples of nucleoside modification using the Pd-catalyst was accomplished by Bergstrom in 1976 during the Heck reaction [28]. Subsequently, several protocols have been reported by varying Pd-precursors, ligand and coupling partners for the modification of nucleosides via Suzuki, Heck, Sonogashira, Stille, Negishi, Buchwald-Hartwig, and Tsuji-Trost reactions [29][30][31][32]. Recognizing the importance of Pd catalysis in the chemical modification of nucleosides, our group was inspired to develop sustainable (green) mild, efficient protocols with scalability at the forefront [18].…”