As the results, factors 1 to 5, and the interactions 1*2, 1*3, 1*5, 2*3, 3*4, and 4*5 showed notable effects for seven acid derivatives responses (Figure ). The coefficient plot displayed significant changes (with a confidence interval away from 0) in responses when a factor varies from low to high value. Individually, factors 1 to 5 showed positive and negative influences on the response, meaning they are not necessarily the highest values of factors that maximize reaction efficiency. There were adverse effects when increasing individual factors 1 and 3 but minor effects with factors 2 and 4 (Figure ). EDC concentration and t1 should be considered cautiously due to O-acylisourea intermediate stability and its reaction with 4-BNMA, which influences carboxylic-BNMA production (Figure ). 4-BNMA concentration and t2 have low impacts on most responses, except for the high impact of 4-BNMA concentration on benzoic-BNMA. Figure showed substantial positive effects with ACN and DCM, while MeOH and EtOH reduced the derivatization efficiency. The result indicates that the substitution with 4-BNMA (SN2) favoured aprotic solvents, which lack hydrogen bonding to nucleophiles and thus promote the reaction rate. Also, solvents with low dielectric constants (εDCM = 9.1) can eliminate the rearrangement of the O-acylisourea to the stable N-acylurea. Because of crude oil miscibility in DCM, ACN was selected for the derivatization as suitable for the LLE stage, although DCM has a more substantial impact. Additionally, positive correlations between most interaction factors and responses indicated that the consequential effects of one factor depend on the level of the other factor (Figures 4, S5, S6).