Synthesis of polymerizable pro-drug monomers through recyclable carboxylic anhydrides
- 1Center for Biotechnology & Interdisciplinary Studies USA
- 2Materials, Science & Engineering, Rensselaer Polytechnic Institute 110 8th St. Troy NY 12180 USA
- 3Biomedical Engineering USA
Abstract
We report a greener synthetic route to polymerizable dipentenoate esters of 17β-estradiol (E2), and of boldine, which are useful precursors to poly(pro-drug) biomaterials of current interest. The existing literature on polymeric pro-drugs often relies on carbodiimide-mediated esterification, involves chlorinated solvents, toxic urea byproducts, and requires solvent-intensive chromatographic purification. We developed an efficient synthesis of the polymerizable pro-drug monomer using 4-pentenoic anhydride as an activated acylating reagent. The process mass index and solvent intensity are dramatically reduced as a result. In parallel, we also pursued an improved green synthesis of the 4-pentenoic anhydride via dehydration of 4-pentenoic acid with excess acetic anhydride, which yielded the desired product in >99% purity following fractional distillation. Recycling of unreacted anhydride and acetic acid byproduct for use in future batches introduces an element of chemical circularity. Reaction of E2 with the resulting anhydride proceeded at room temperature to afford the desired diester in 96% isolated yield. Purification is restricted to a simple aqueous workup, with no column chromatography and no need to separate out carbodiimide-derived urea impurities. Importantly, the resulting monomer was then subjected to photoinitiated thiol-ene step-growth copolymerization with 1,3-propane dithiol and it showed equivalent polymerization behavior when directly compared to the chemically identical monomer made by Steglich esterification. Under identical conditions, these two pro-E2 monomers polymerized to give practically indistinguishable molecular weight distributions and glass-transition temperatures. Substrate scope was further explored by esterification of the natural product boldine with pentenoic anhydride. This also resulted in high yield and purity by crystallization, with no chromatography needed. In contrast, the conventional DIC-mediated synthesis of boldine dipentenoate required dichloromethane and extensive silica-gel chromatography, consuming approximately 1 L of organic solvent and 125 g of spent silica gel per gram of product. These results demonstrate that carboxylic anhydrides can provide a practical alternative to carbodiimide-mediated esterification for polymerizable pro-drug synthesis while simultaneously reducing hazardous reagents, solvent use, purification burden, and solid waste.
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BibTeX
@article{leman2026synthesis,
title = {{Synthesis of polymerizable pro-drug monomers through recyclable carboxylic anhydrides}},
author = {John T. Leman and Nikita Waskiewicz and Julia M. Gregory and Edmund F. Palermo},
journal = {RSC Advances},
year = {2026},
month = nov,
doi = {10.1039/d6ra09163f},
url = {https://doi.org/10.1039/d6ra09163f},
note = {CC BY-NC 3.0},
}
RIS
TY - JOUR
TI - Synthesis of polymerizable pro-drug monomers through recyclable carboxylic anhydrides
AU - John T. Leman
AU - Nikita Waskiewicz
AU - Julia M. Gregory
AU - Edmund F. Palermo
PY - 2026
DA - 2026/11/05
JO - RSC Advances
DO - 10.1039/d6ra09163f
UR - https://doi.org/10.1039/d6ra09163f
AB - We report a greener synthetic route to polymerizable dipentenoate esters of 17β-estradiol (E2), and of boldine, which are useful precursors to poly(pro-drug) biomaterials of current interest. The existing literature on polymeric pro-drugs often relies on carbodiimide-mediated esterification, involves chlorinated solvents, toxic urea byproducts, and requires solvent-intensive chromatographic purification. We developed an efficient synthesis of the polymerizable pro-drug monomer using 4-pentenoic anhydride as an activated acylating reagent. The process mass index and solvent intensity are dramatically reduced as a result. In parallel, we also pursued an improved green synthesis of the 4-pentenoic anhydride via dehydration of 4-pentenoic acid with excess acetic anhydride, which yielded the desired product in >99% purity following fractional distillation. Recycling of unreacted anhydride and acetic acid byproduct for use in future batches introduces an element of chemical circularity. Reaction of E2 with the resulting anhydride proceeded at room temperature to afford the desired diester in 96% isolated yield. Purification is restricted to a simple aqueous workup, with no column chromatography and no need to separate out carbodiimide-derived urea impurities. Importantly, the resulting monomer was then subjected to photoinitiated thiol-ene step-growth copolymerization with 1,3-propane dithiol and it showed equivalent polymerization behavior when directly compared to the chemically identical monomer made by Steglich esterification. Under identical conditions, these two pro-E2 monomers polymerized to give practically indistinguishable molecular weight distributions and glass-transition temperatures. Substrate scope was further explored by esterification of the natural product boldine with pentenoic anhydride. This also resulted in high yield and purity by crystallization, with no chromatography needed. In contrast, the conventional DIC-mediated synthesis of boldine dipentenoate required dichloromethane and extensive silica-gel chromatography, consuming approximately 1 L of organic solvent and 125 g of spent silica gel per gram of product. These results demonstrate that carboxylic anhydrides can provide a practical alternative to carbodiimide-mediated esterification for polymerizable pro-drug synthesis while simultaneously reducing hazardous reagents, solvent use, purification burden, and solid waste.
SN - 2046-2069
ER -