Lessons in Knoevenagel method adaptation: Reaction yields of ferulic acid and alternative product synthesis

Authors: RHEAY, HANAH - Orise Fellow; Compton, David; Brownstein, Korey; Skory, Christopher

Submitted to: Illinois Heartland American Chemical Society (ACS) Regional Conference
Publication Type: Abstract Only
Publication Acceptance Date: 10/26/2024
Publication Date: N/A
Citation: N/A

Interpretive Summary:

Technical Abstract: Chemical synthesis of ferulic acid via the Knoevenagel reaction is prone to over decarboxylation into its styrene derivative. The proposed mechanism occurs via a highly reactive quinone methide (QM) intermediate. The resulting QM compound subsequently participates in various polymerization/cyclization with other reaction products. The initial goal of adapting the previously reported green Knoevenagel reaction (solvent-free, ammonium-catalyzed) to reactive extrusion techniques in effort to combat styrene formation and QM polymerization was hindered by the inability to replicate the original results reported in previous research. Revisiting optimization revealed that the reaction yield of ferulic acid could not be increased beyond 50% (w/w), while calculated purities remained consistently high (=90%, w/w). Previously reported yields reaching 89% as determined by high performance liquid chromatography (HPLC) peak area percentage are more akin to sample purity than reaction yield. It was hypothesized that poor dissolution and precipitation was impacting the low yields. After the reaction, the mixture hardens as it cools to room temperature which makes the material difficult to dissolve thus limiting ferulic acid in solution that can be precipitated. Initiating product workup with the addition of saturated sodium bicarbonate to the hot reaction matrix resulted in rapid dissolution of the entire material, which was immediately followed by acidification (pH=2) with hydrochloric acid. Rather than the expected quick precipitation of ferulic acid, a series of color changes from green to purple was observed over a 48hr period with limited precipitation. Components related to the apparent color were extracted from the filtrate with ethyl acetate followed by 1-butanol (concentrated in the 1-butanol fraction). Individual components of the 1-butanol extract were separated using preparative HPLC. Preliminary characterization and structure elucidation of the isolated compounds was aided by mass spectrometry, elemental analysis, and NMR.