Regioselective synthesis, isomerisation, oestrogenic activity, and copolymerisation of bisguaiacol F (BGF) isomers

Bisguaiacol F (BGF), a potentially safer and renewable bisphenol A (BPA) replacement made from lignin-derivable vanillyl alcohol ( p -VA), is a promising building block for future aromatic biopolymers. Unfortunately, like BPA synthesis, this electrophilic condensation reaction is also prone to regioselectivity issues, giving rise to m , p - and o , p -BGF byproducts. In this work, the hitherto unconsidered influence of m , p -BGF, viz . the main isomeric byproduct of p , p -BGF synthesis, on the physicochemical properties of poly(BGF carbonate) (BGF-PC) was systematically investigated by random copolymerisation with different fractions of pure m , p -BGF (25, 50 and 75 wt%). To do so, the elusive m , p -isomer was made in unparalleled regioselectivity (72%) by alkylation condensation of isovanillyl alcohol ( m -VA) with guaiacol. Surprisingly, no isomeric scrambling due to acid-catalysed isomerisation was encountered for pure BGF isomers, which strongly facilitates their synthesis in contrast to petrochemical bisphenol F (BPF). Furthermore, to ensure safer chemical design, an in vitro human oestrogen receptor (hER) transactivation assay was performed. Both pure m , p - and p , p -BGF displayed a significantly reduced oestrogenic potency (426457 times lower affinity than BPA) and oestrogenic efficacy (3950% of BPA's maximum induction). Interestingly, mutual comparison between p , p -BPF and p , p -BGF reveals and proves for the first time the direct link between ortho -methoxy substitution and reduced in vitro oestrogenic activity (for transactivation of hER). In contrast to o , p -BPA, viz . the main byproduct of p , p -BPA synthesis, m , p -BGF was proven suitable for utilization in thermoplastics, thereby avoiding time-consuming and labour-intensive (re)crystallizations to obtain regioisomerically pure p , p -BGF. Biobased ortho -methoxy groups ameliorate classic bisphenol chemistry in terms of synthesis, safety and processing; bisguaiacol F is used as a test case.