Potential Safety Hazards Associated with Using N,N-Dimethylformamide in Chemical Reactions

Abstract

N,N-Dimethylformamide (DMF) is frequently used as a solvent because of its unique physical properties that allow it to solubilize both organic and inorganic substances. It has also found broad applications as a catalyst for a variety of chemical transformations and as a donor for many functional groups in synthetic organic chemistry. However, DMF is incompatible with a wide variety of substances and has resulted in many incidents over the years. Analysis of literature information indicates that those incompatible substances can be categorized as acids, bases, halogenated reagents, oxidants, and reductants. This comprehensive review of the potential hazards of using DMF in chemical reactions will serve as an educational resource to promote awareness of such safety hazards in the broader chemistry community and encourage scientists to develop appropriate control strategies to mitigate the potential safety risks associated with the use of DMF in chemical reactions.

A Journey from June 2018 to October 2021 with N,N-Dimethylformamide and N,N-Dimethylacetamide as Reactants

“…Numerous procedures above documented have been used for syntheses with other amides as sources of building blocks; others could also be efficient. Another remark concern the alarm to the potential safety hazards associated with using DM in particular chemical conditions [161,162] and the toxicity of these solvents [163].…”

Tetramethylammonium Fluoride: Fundamental Properties and Applications in C-F Bond-Forming Reactions and as a Base

“…The initial catalytic screening was conducted in a high-throughput regime using an electron-deficient chloropyrimidine substrate (122), which is suitably activated to undergo S N Ar fluorination (Scheme 11a). Strongly polar aprotic solvents like DMF and DMSO, which are in the ideal solvation window to ensure optimum reactivities for ionic sources of nucleophilic fluorine such as TMAF (Section 2.2.3), were avoided in these studies due to the potential risks of explosion associated with their use in the presence of strong bases and temperatures as low as 50 • C [87,88,131]. To this end, MeCN offered the best compromise as a solvent between polarity, safety profile, and operational simplicity, allowing the removal of salt byproducts by filtration.…”

“…CAUTION: The highest temperatures reported in synthetic reactions using TMAF either in DMSO or DMF range between 80 and 100 • C. These solvents can violently decompose at elevated temperatures in the presence of a superbasic reagent such as NaH (which possesses comparable basicity to TMAF) [87,88]. It is advisable to conduct reactions requiring the most active anhydrous form of TMAF, especially in gram-scale, either at lower temperatures or in a different solvent.…”

Replacement of Less-Preferred Dipolar Aprotic and Ethereal Solvents in Synthetic Organic Chemistry with More Sustainable Alternatives

“…One potential reason for this trend may be that solvent selection in process chemistry and scale-up operations involves far more in-depth risk assessment, which may preclude DMF from use. This may be due to either physicochemical incompatibilities, for example, DMF is known to be incompatible with sodium hydride, 10 or due to regulatory concerns, which are described in the following section.…”

“…Thermal stability and potential safety hazards associated with the use of DMF as a reaction solvent have also recently been reviewed by Yang et al, highlighting a multitude of potential thermal safety issues including thermal runaway and explosive decomposition. 25 …”