Green Chemistry Metrics Applied to Benzocaine and Procaine Syntheses: Evaluation with GAPI and AGREE

Abstract

Introduction: Local anesthetics [1], including benzocaine and procaine, are essential in modern medical and dental practice, but traditional synthetic methods often rely on hazardous reagents, require high energy input, and employ solvent-intensive procedures that conflict with green chemistry principles. Recent advances have introduced quantitative assessment tools [2], such as the Green Analytical Procedure Index (GAPI) and Analytical GREEnness (AGREE), which systematically evaluate solvent use, energy consumption, and overall sustainability of chemical processes [3,4]. Objectives: This study compares literature-reported synthetic routes for benzocaine and procaine, assessing their sustainability and environmental impact with GAPI and AGREE to identify efficient and reproducible protocols suitable for small-scale academic use. Methods: A narrative literature review was conducted in May 2025 using PubMed, ScienceDirect and Google Scholar. Eligible studies described benzocaine synthesis via Fischer esterification or sustainable procaine syntheses. The selected protocols were evaluated for yield, experimental complexity, and environmental performance using AGREE and GAPI metrics according to their original guidelines, assuming a colour scale and a maximum greenness score of 1.00 for each. Results: AGREE and GAPI were applied to three protocols for each anesthetic. AGREE diagrams showed that for benzocaine, Syntheses A, B, and C achieved scores of 0.29, 0.38, and 0.49, whereas for procaine, Syntheses X, Y, and Z obtained scores of 0.24, 0.46, and 0.53, respectively. GAPI pictograms showed that benzocaine Synthesis A contained more red fields, B was dominated by yellow fields, and C displayed several green fields. For procaine, Synthesis X also showed more red fields, while Y and Z were characterized predominantly by green fields. Conclusions: These results confirm that recent protocols employing continuous‑flow, metal-free, or microwave-assisted steps thus offer greener options for the synthesis of ester-type local anesthetics. However, despite the environmental benefits, equipment costs can be a barrier to their use, especially in teaching laboratories.