Breaking bonds and bringing disciplines together to replace one of chemistry’s most controversial molecules

Finding a replacement for the endocrine disruptor bisphenol A (BPA) was never going to be solved by synthesis alone and Helena Lundberg from KTH Royal Institute of Technology in Sweden knew that from the start. Designing a molecule is one thing; demonstrating that it is safe and performs reliably in a polymer is another.

As an organic chemist who develops synthetic transformations using electrochemistry and catalysis, Lundberg is in the business of breaking bonds. Drawing on her group’s expertise with Lewis acid catalysis, she initiated a project that ultimately identified three safe, non‑oestrogenic and sustainable alternatives to BPA that could be produced from sustainable feedstocks such as lignin‑derived phenols.

The project, which began several years ago, involved an interdisciplinary team of synthetic chemists, data scientists, toxicologists and material scientists. It started out with more than 170 potential substitutes for BPA and eventually narrowed that pool down to three candidates: bisguaiacol F (BGF) and two bissyringylmethane isomers.

‘Out of these three, we selected BGF for polymer synthesis and compared the properties of the resulting material with an analogous material prepared using BPA,’ Lundberg explains. ‘The comparison showed that our material had similar thermal properties to that of the BPA analogue but was more flexible.’ She says this could mean that BGF is better suited for applications where soft plastics are needed, such as flexible polymers in robotics or malleable materials for medical purposes, rather than rigid products like plastic bottles.

Lundberg’s group first became interested in bisphenols when one of the catalysts it worked with was found to efficiently activate benzylic alcohols and couple them with electron-rich arenes to form diarylmethanes – the core structure of bisphenols. Combined with findings by others that indicated electron-rich bisphenols display lower endocrine disruptive effects, the researchers decided to explore the matter further.

BPA has been used for decades to manufacture specific plastics and resins found in such everyday products as food containers and reusable water bottles because it provides characteristics like durability, thermal stability, transparency and corrosion-resistance. However, the chemical and its analogues have been linked to issues affecting the reproductive, metabolic and immune systems, as well as developmental problems and other health concerns.

Meanwhile, a growing body of research has raised questions about the safety of newer substitutes for BPA. Some of these replacements have turned out to be structurally similar chemicals with comparable health risks.

Her team began the BPA replacement project by outlining more than 170 hypothetical molecules, then selecting one that could be made from at least partly renewable starting materials using their catalyst system. These were then assessed using an in silico model developed by Ulf Norinder, a computational chemist at Stockholm University with decades of experience building models for predicting the properties of chemicals.

The group synthesised the most promising molecules predicted to have low oestrogenic activity and passed them to Stockholm University toxicologist Oskar Karlsson and his team for in vitro testing, which identified the three top candidates.

We could do things together that we couldn’t do alone

Finally, Lundberg’s team scaled up the synthesis of BGF. They then handed the compound to KTH polymer chemist Minna Hakkarainen, whose group incorporated it into a polymer matrix that proved to be a promising BPA replacement.

Building better chemicals from the start

Karlsson co-authored the Stockholm Declaration on Chemistry for the Future, which was unveiled in May 2025 and calls for a fundamental shift toward products that are ‘safe and sustainable by design’. ‘My interest in BPA replacements comes directly from this perspective,’ Karlsson tells Chemistry World.

‘We have repeatedly seen that replacing such chemicals without robust safety data can lead to so-called regrettable substitutions,’ Karlsson continues. ‘This project is motivated by the need to break that cycle by integrating toxicology early in the design process and identifying alternatives that are not only functional and sustainable, but also demonstrably safer.’

Karlsson is also a fellow at Sweden’s SciLifeLab, whose high-throughput in vitro testing capacity enabled efficient evaluation of many candidate bisphenols and allowed toxicological data to be integrated with computational predictions, chemistry and materials performance.

Practical uses, pending further tests

Hakkarainen expects that the BGF polymer her team engineered can be used in various applications, including as a drop-in monomer to make traditional BPA containing materials like polycarbonates and epoxy resins, or as an attractive biobased building block for new polymer structures.

But Karlsson cautions that BPA replacement candidates like BGF cannot move closer to real-world use without expanding their toxicological evaluation beyond oestrogenic effects, as well as assessing potential degradation products, life-cycle analysis and tests under industry-relevant processing conditions.

The collaboration offers a window into the realities of multidisciplinary research. ‘It was quite interesting to see how there were different timelines in the different disciplines involved,’ Lundberg states. For example, the data science and predictive models overseen by Norinder had very quick turnarounds. ‘From one day to the next, he would have massive amounts of data,’ she recalls. In contrast, the toxicological work led by Karlsson often took months to yield findings.

‘We would be waiting for a long time for those results so that we could go on and continue the research,’ Lundberg recalls. Meanwhile, results from the synthetic chemistry – both the small molecule chemistry that she led and the polymer chemistry overseen by Hakkarainen – typically took days or weeks. In any interdisciplinary collaboration, she says, understanding the differing timelines across the participating disciplines is crucial for setting realistic expectations about the study’s duration.

The impact of tiny tweaks

Another important lesson to come from the study is how tiny structural modifications can make a big difference in terms of endocrine activity. ‘The connection between a molecular structure and its activity in a biological system is very well established, but it was still very interesting to see that we could make a small change and the compound could go from essentially inactive to way more active than BPA or even oestrogen itself,’ Lundberg says. ‘You can have a hunch based on the backbone structure, but just a little alteration can make such a big difference.’

One of the most inspiring aspects of the project, Lundberg says, was how the team’s complementary expertise amplified what they could achieve. ‘We could do things together that we couldn’t do alone, and we could do it more efficiently because the findings from one part of the team informed the decision-making of other parts of the team,’ she explains.

For Lundberg, this is the real power of multidisciplinary research: it enables researchers to address bigger, more complex questions. She is adamant that many of the most pressing global issues require such collaborative approaches.

She also believes that broad perspectives help when navigating such complexity. Before becoming an organic chemist, Lundberg studied pottery and theoretical philosophy – fields that, in their own ways, shaped how she approaches research. Pottery gave her a hands-on, experimental mindset, while philosophy trained her to probe fundamental questions about the world, including what it consists of and what we can know about it.