Liquid-Assisted Ball-Milling Synthesis of Organic Carbonates as Aroma Compounds

Abstract

A new approach based on ball milling is introduced as an efficient and greener alternative to conventional solution-based methods for the synthesis of carbonate compounds, which typically require toxic solvents (e.g., dichloromethane) and bases such as pyridine. Following an initial proof-of-concept, the scalability of the method was demonstrated on gram scale using two representative reactions, including the synthesis of the fragrance molecule liffarome and the reaction of vanillin with isobutyl chloroformate, affording the desired products in 42% and 74% yield, respectively. Using this solvent-free methodology, a total of nine new carbonate-based aroma compounds were synthesized and fully characterized. Their olfactory properties were evaluated by an expert panel, revealing diverse and, in some cases, unexpected odor profiles, which were classified into floral, spicy, fruity, green, and gourmand categories. A comprehensive comparison with traditional and water-based methods showed that ball milling generally provides superior or comparable yields (up to 84%) while avoiding hazardous solvents. Green metrics further highlight the advantages of the ball-mill approach: atom economy values were higher for ball milling (72.2–78.9%) compared to the traditional method (63.2–71.2%), similarly real atom economy reached up to 0.580 for ball milling compared to 0.151 for the traditional method. Notably, the process mass intensity (PMI) was as low as 1.73 for ball milling, making it nearly seven times more resource-efficient than the conventional approach (PMI = 11.96). Furthermore, analysis of the liquid-assisted grinding (LAG) parameter (η) revealed that higher liquid-to-solid ratios, achieved in the absence of solid auxiliaries, lead to improved reaction efficiency. Overall, this study demonstrates that ball milling offers a practical, scalable, and sustainable strategy for the synthesis of fragrance-related carbonate compounds, while also enabling access to structurally diverse molecules with unique olfactory properties.