Safety Case Study. Intrinsic Instability of Concentrated Solutions of Alcoholic Hydrogen Chloride: Potential Hazards Associated with Methanol

Abstract

Methanolic hydrochloride is a commonly used reagent on the lab scale and on larger scales as well. It is commercially available or can be prepared by bubbling gaseous hydrogen chloride in methanol. After we experienced an incident using a concentrated solution, observations and data were collected. This allowed us to implement a few recommendations to prevent the recurrence and alert of a potential hazard that to our knowledge has not been clearly reported in the literature.

Chlorinated Solvents: Their Advantages, Disadvantages, and Alternatives in Organic and Medicinal Chemistry

“…With literature precedent of more sustainable, non-chlorinated solvents being employed successfully for Boc deprotection, chemists may be able to move away from traditional methods employing DCM and 1,4-dioxane especially with the commercial availability of HCl solutions in EtOAc, IPA, EtOH, MeOH, 1-butanol, and CPME . Regarding the use of methanolic HCl, a recent incident report has highlighted its intrinsic instability on storage leading to spontaneous degassing and spraying out of a bottle leading to a near miss incident . Ethanolic HCl was examined for the same behavior and was found to be a much safer alternative …”

“…Regarding the use of methanolic HCl, a recent incident report has highlighted its intrinsic instability on storage leading to spontaneous degassing and spraying out of a bottle leading to a near miss incident . Ethanolic HCl was examined for the same behavior and was found to be a much safer alternative …”

“…174 Regarding the use of methanolic HCl, a recent incident report has highlighted its intrinsic instability on storage leading to spontaneous degassing and spraying out of a bottle leading to a near miss incident. 175 Ethanolic HCl was examined for the same behavior and was found to be a much safer alternative. 175 Thermal deprotection in batch or flow offers multiple benefits in that aqueous workup or free-basing of amines can be avoided, thus reducing waste and allowing for the compounds to be used directly in multistep reaction sequences, 176 as long as the compound undergoing deprotection is otherwise thermally stable to the heating conditions.…”

“…175 Ethanolic HCl was examined for the same behavior and was found to be a much safer alternative. 175 Thermal deprotection in batch or flow offers multiple benefits in that aqueous workup or free-basing of amines can be avoided, thus reducing waste and allowing for the compounds to be used directly in multistep reaction sequences, 176 as long as the compound undergoing deprotection is otherwise thermally stable to the heating conditions. 161 Thermal deprotection can also be conducted under solvent-free conditions.…”

Development of an Intrinsically Safer Methanolysis/Aromatic Nitro Group Reduction for Step 1 and 2 of Talazoparib Tosylate

“…12.4 wt %) . HCl in MeOH is well-known to be unstable and decomposes slowly to give MeCl, dimethyl ether, and water at or below 25 °C; this can pose a significant handling and safety risk from the off-gassing of extremely flammable MeCl (bp −24 °C, fp −45.5 °C, LEL 8.1%, UEL 17.2%) and dimethyl ether (bp −25 °C, fp −4 °C, LEL 2%, UEL 50%) and the interaction of such gaseous vent streams with scrubbers and/or thermal oxidizers. In the laboratory, off-gassing was observed throughout the reaction using this 30% methanolic HCl solution.…”