Necessary reporting of reaction yield for method evaluation: Considering Knoevenagel synthesis of ferulic acid

Authors: RHEAY, HANAH - Oak Ridge Institute For Science And Education (ORISE); Compton, David; Brownstein, Korey; Skory, Christopher

Submitted to: Results in Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/8/2025
Publication Date: 5/15/2025
Citation: Rheay, H.T., Compton, D.L., Brownstein, K.J., Skory, C.D. 2025. Necessary reporting of reaction yield for method evaluation: Considering Knoevenagel synthesis of ferulic acid. Results in Chemistry. https://doi.org/10.1016/j.rechem.2025.102349.
DOI: https://doi.org/10.1016/j.rechem.2025.102349

Interpretive Summary: USDA researchers in Peoria, Illinois developed enzymatic-based technology that combines soybean oil with another natural plant component, called ferulic acid, which has desirable properties for personal care products. The resultant soy-based product is commercially sold as an antioxidant and Sun Protection Factor (SPF) boosting ingredient in the natural personal care ingredient market (US $5.3 billion in 2023 expected to grow to $7.9 billion in 2028). Manufacturing of this product is performed without the use of harsh chemicals and is confirmed to be greater than 85% naturally sourced, allowing it to carry the USDA Certified Biobased Product label. Most commercial sources of ferulic acid are imported, so there is a need to improve domestic production of this critical ingredient. It has previously been reported that vanillin, which is the main flavor component of vanilla, can be converted to ferulic acid. However, our research shows that previous reports for the conversion of vanillin to ferulic acid is not as simple or efficient as previously claimed, the actual yield and efficiency of the process is 50 to 75% lower. We further show that discrepancies in results are likely due to inconsistent calculations of ferulic acid yield and we provide a clearly defined yield determination with more useful results. The results of this research provides important information to help guide other scientists and industrial producers on potential routes for improved production of ferulic acid. Increasing the profitability of agricultural products through the development of new and improved biobased products is critical for ensuring a robust agricultural economy.

Technical Abstract: The initial goal of identifying a Knoevenagel reaction method to adapt toward continuous production of ferulic acid was hindered by the inconsistent reporting of yield metrics across relevant literature. A particular interest was taken in applying a previously described "green" Knoevenagel reaction (solvent-free, ammonium-catalyzed), however the isolated yields originally reported could not be replicated. Further, incomplete descriptions of experiment methodology compounds inconsistencies between data comparison. Reaction yield is a vital metric for evaluating the efficiency of a chemical process. A new design of experiments (DOE) was implemented targeting reaction yield of the desired product. The maximum average ferulic acid yield achieved was 48% (w/w) at 80°C and 2 h with 1.5 eq. malonic acid, 0.7 eq. NH4HCO3. Statistical analysis projects a maximum yield of 71% (w/w) at optimum conditions of 90°C, 2.4 h, 1 eq. malonic acid, and 1.2 eq. ammonium bicarbonate. Although these conditions are similar to those identified by previous work, the associated yield is notably lower. Given the highly sensitive nature of this reaction to set experiment factors and outside influences (mixing, vessel shape, etc.), it is imperative that adequate descriptions of employed experimentation and calculations be provided to allow for a meaningful evaluation of methodology and continued investigation.