Triethylamine trihydrofluoride: synthesis, applications in organic synthesis and safety

General Description

Triethylamine trihydrofluoride can be synthesized through a cost-effective process involving the addition of an organic solvent, HF liquid, and triethylamine in specific molar ratios and temperature ranges. The resulting complex, Et3N·nHF, is obtained in a two-step reaction using either triethylamine-HF complex or carbon tetrachloride as the solvent. This synthesis method offers simplicity, low production costs, and potential for continuous operation. In organic synthesis, Triethylamine trihydrofluoride is used to prepare heterocyclic compounds with applications in pharmaceuticals, particularly in antibacterial agents. It also plays a role in synthesizing perfluoroalkyl fluorophosphates for phosphorus compound synthesis. However, it is crucial to handle this compound with extreme caution due to its severe corrosive and acute toxic properties, including the risk of toxic pneumonitis.

Figure 1. Triethylamine trihydrofluoride

Synthesis

The synthesis of Triethylamine trihydrofluoride involves a straightforward and cost-effective process. Initially, an organic solvent is added to the first reactor, followed by the addition of HF liquid and triethylamine in a molar ratio ranging from 0.96-1.06:1. The reaction takes place at temperatures between -40°C to 15°C for a duration of 20-720 minutes. Subsequently, the resulting product is transferred to the second reactor where further reaction occurs at temperatures of 20°C to 120°C for 40-480 minutes, ultimately yielding the target complex Et3N·nHF, with n ranging from 2-12. The organic solvent used can be either triethylamine-HF complex (with n = 2.5-12) or carbon tetrachloride. The synthesis apparatus comprises an HF-feeding unit with a storage tank and distributor, a similar setup for triethylamine, and two interconnected reactors equipped with stirrers. Key advantages of this process include its simplicity, low production costs, and the potential for continuous operation. As a result, this method offers an efficient and economical means of synthesizing Triethylamine trihydrofluoride. ¹

Applications in organic synthesis

Triethylamine trihydrofluoride has applications in organic synthesis, particularly in the preparation of heterocyclic compounds. These compounds, which contain a 5-membered heterocycle linked to the structure by nitrogen (N), can be saturated, partially unsaturated, or aromatic and may include at least one quaternized nitrogen atom. The invention focuses on the synthesis of these heterocyclic compounds and their derivatives, including racemates, enantiomers, diastereoisomers, and geometric isomers, as well as their pharmaceutically acceptable salts. The compounds prepared using triethylamine trihydrofluoride have potential applications in the field of pharmaceuticals. They can be used alone or in combination with other antibacterial agents and beta-lactam compounds for the prevention or treatment of bacterial infections. In laboratory tests, these compounds showed significant inhibitory effects against various strains of bacteria, including those producing β-lactamase enzymes. The preparation method involves reacting triethylamine trihydrofluoride with sulfuryl halide in the presence of an inorganic base. This reaction leads to the formation of intermediate compounds, which can be further processed to obtain the desired heterocyclic compounds. Additionally, triethylamine trihydrofluoride is also utilized in the synthesis of perfluoroalkyl fluorophosphates, which are precursors for various phosphorus compounds. These fluorophosphates are synthesized by fluorinating perfluoroalkylphosphinates or perfluoroalkylphosphonates with hydrogen bifluorides in the presence of Bronsted acids. In summary, triethylamine trihydrofluoride finds applications in the synthesis of heterocyclic compounds and perfluoroalkyl fluorophosphates, with potential uses in pharmaceuticals and phosphorus compound synthesis, respectively. ²

Safety

Triethylamine trihydrofluoride  poses significant safety hazards, as indicated by its GHS classification. It is important to handle this compound with extreme caution due to its corrosive and acute toxic properties. When in contact with the skin or swallowed, triethylamine trihydrofluoride can be fatal, leading to acute toxicity. It can cause severe burns and damage to the skin and eyes, resulting in skin corrosion and irritation. Inhalation of this compound can also be lethal, causing burns and corrosive injuries to the upper respiratory tract and lungs. It is highly toxic through ingestion, inhalation, and skin absorption. Moreover, exposure to triethylamine trihydrofluoride may lead to toxic pneumonitis, which is inflammation of the lungs caused by inhaling metal fumes or toxic gases and vapors. In summary, triethylamine trihydrofluoride presents severe health hazards, including acute toxicity, corrosive effects, and the risk of toxic pneumonitis. Therefore, strict safety protocols must be followed to prevent accidents and minimize potential harm. ³

Reference

1. Continuous process and apparatus for preparation of triethylamine-hf complex. 2010, Patent Number: CN101648873.

2. Preparation of heterocyclic compounds, especially 1,6-diazabicyclo[3.2.1]oct-3-en-7-one derivatives, as β-lactamase inhibitors and their use in preventing or treating bacterial infections. 2018, Patent Number: WO2018060481.

3. Triethylamine trihydrofluoride. National Center for Biotechnology Information, 2023, PubChem Compound Summary for CID 175505.

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