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Selective lignin arylation for biomass fractionation and benign bisphenols


Lignocellulose is mainly composed of hydrophobic lignin and hydrophilic polysaccharide polymers, contributing to an indispensable carbon resource for green biorefineries1,2. When chemically treated, lignin is compromised owing to detrimental intra- and intermolecular crosslinking that hampers downstream process3,4. The current valorization paradigms aim to avoid the formation of new C–C bonds, referred to as condensation, by blocking or stabilizing the vulnerable moieties of lignin5,6,7. Although there have been efforts to enhance biomass utilization through the incorporation of phenolic additives8,9, exploiting lignin’s proclivity towards condensation remains unproven for valorizing both lignin and carbohydrates to high-value products. Here we leverage the proclivity by directing the C–C bond formation in a catalytic arylation pathway using lignin-derived phenols with high nucleophilicity. The selectively condensed lignin, isolated in near-quantitative yields while preserving its prominent cleavable β-ether units, can be unlocked in a tandem catalytic process involving aryl migration and transfer hydrogenation. Lignin in wood is thereby converted to benign bisphenols (34–48 wt%) that represent performance-advantaged replacements for their fossil-based counterparts. Delignified pulp from cellulose and xylose from xylan are co-produced for textile fibres and renewable chemicals. This condensation-driven strategy represents a key advancement complementary to other promising monophenol-oriented approaches targeting valuable platform chemicals and materials, thereby contributing to holistic biomass valorization.

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Fig. 1: Condensation-driven strategy for bisphenol production.
Fig. 2: Phenolic dimers from syringolated lignin model compounds.
Fig. 3: Bisphenol production from poplar.
Fig. 4: Holistic utilization of lignocellulose via the CLAF.

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Data availability

The datasets generated and analysed during the current study (besides those included in this published article and its Supplementary Information file) are available from the corresponding authors on reasonable request.


  1. Abu-Omar, M. M. et al. Guidelines for performing lignin-first biorefining. Energy Environ. Sci. 14, 262–292 (2021).

    Article  Google Scholar 

  2. Samec, J. S. Holistic approach for converting biomass to fuels. Chem 4, 1199–1200 (2018).

    Article  CAS  Google Scholar 

  3. Shuai, L. & Saha, B. Towards high-yield lignin monomer production. Green Chem. 19, 3752–3758 (2017).

    Article  CAS  Google Scholar 

  4. Rahimi, A., Ulbrich, A., Coon, J. J. & Stahl, S. S. Formic-acid-induced depolymerization of oxidized lignin to aromatics. Nature 515, 249–252 (2014).

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Renders, T., Van den Bosch, S., Koelewijn, S. F., Schutyser, W. & Sels, B. F. Lignin-first biomass fractionation: the advent of active stabilisation strategies. Energy Environ. Sci. 10, 1551–1557 (2017).

    Article  CAS  Google Scholar 

  6. Questell-Santiago, Y. M., Galkin, M. V., Barta, K. & Luterbacher, J. S. Stabilization strategies in biomass depolymerization using chemical functionalization. Nat. Rev. Chem. 4, 311–330 (2020).

    Article  CAS  PubMed  Google Scholar 

  7. Shuai, L. et al. Formaldehyde stabilization facilitates lignin monomer production during biomass depolymerization. Science 354, 329–333 (2016).

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Li, J. & Gellerstedt, G. Improved lignin properties and reactivity by modifications in the autohydrolysis process of aspen wood. Ind. Crops Prod. 27, 175–181 (2008).

    Article  CAS  Google Scholar 

  9. Ono, H.-K. & Sudo, K. in Lignin Properties and Materials Vol. 397 (eds Glasser, W. G. & Sarkanen, S.) 334–345 (ACS, 1989).

  10. Liao, Y. et al. A sustainable wood biorefinery for low–carbon footprint chemicals production. Science 367, 1385–1390 (2020).

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Cao, Z., Dierks, M., Clough, M. T., Daltro de Castro, I. B. & Rinaldi, R. A convergent approach for a deep converting lignin-first biorefinery rendering high-energy-density drop-in fuels. Joule 2, 1118–1133 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Subbotina, E. et al. Oxidative cleavage of C–C bonds in lignin. Nat. Chem. 13, 1118–1125 (2021).

    Article  CAS  PubMed  Google Scholar 

  13. Zhang, C. et al. Catalytic strategies and mechanism analysis orbiting the center of critical intermediates in lignin depolymerization. Chem. Rev. 123, 4510–4601 (2023).

    Article  CAS  PubMed  Google Scholar 

  14. Zijlstra, D. S. et al. Mild organosolv lignin extraction with alcohols: the importance of benzylic alkoxylation. ACS Sustain. Chem. Eng. 8, 5119–5131 (2020).

    Article  CAS  Google Scholar 

  15. Lan, W. & Luterbacher, J. S. A road to profitability from lignin via the production of bioactive molecules. ACS Cent. Sci. 5, 1642–1644 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Koelewijn, S. F. et al. Promising bulk production of a potentially benign bisphenol A replacement from a hardwood lignin platform. Green Chem. 20, 1050–1058 (2018).

    Article  CAS  Google Scholar 

  17. Wu, X., Galkin, M. V. & Barta, K. A well-defined diamine from lignin depolymerization mixtures for constructing bio-based polybenzoxazines. Chem Catal. 1, 1360–1362 (2021).

    Google Scholar 

  18. Zimmerman, J. B., Anastas, P. T., Erythropel, H. C. & Leitner, W. Designing for a green chemistry future. Science 367, 397–400 (2020).

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Koelewijn, S.-F. et al. Regioselective synthesis, isomerisation, in vitro oestrogenic activity, and copolymerisation of bisguaiacol F (BGF) isomers. Green Chem. 21, 6622–6633 (2019).

    Article  CAS  Google Scholar 

  20. Trullemans, L. et al. Renewable and safer bisphenol A substitutes enabled by selective zeolite alkylation. Nat. Sustain. 6, 1693–1704 (2023).

    Article  Google Scholar 

  21. Sturgeon, M. R. et al. A mechanistic investigation of acid-catalyzed cleavage of aryl-ether linkages: implications for lignin depolymerization in acidic environments. ACS Sustain. Chem. Eng. 2, 472–485 (2013).

    Article  Google Scholar 

  22. Sheng, Y. et al. Using nucleophilic naphthol derivatives to suppress biomass lignin repolymerization in fermentable sugar production. Chem. Eng. J. 420, 130258 (2021). 1-9.

    Article  CAS  Google Scholar 

  23. Funaoka, M. & Abe, I. Phenyl nucleus-exchange method for the degradation of lignin. Wood Sci. Technol. 21, 261–279 (1987).

    Article  CAS  Google Scholar 

  24. Gong, Z. et al. Phenol-assisted depolymerisation of condensed lignins to mono-/poly-phenols and bisphenols. Chem. Eng. J. 455, 140628 (2023). 1-7.

    Article  CAS  Google Scholar 

  25. Yokoyama, T. Revisiting the mechanism of β-O-4 bond cleavage during acidolysis of lignin. Part 6: a review. J. Wood Chem. Technol. 35, 27–42 (2014).

    Article  CAS  Google Scholar 

  26. Rinaldi, R. et al. Paving the way for lignin valorisation: recent advances in bioengineering, biorefining and catalysis. Angew. Chem. 55, 8164–8215 (2016).

    Article  CAS  Google Scholar 

  27. Li, Y. et al. An “ideal lignin” facilitates full biomass utilization. Sci. Adv. 4, eaau2968 (2018). 1-10.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  28. Adler, A. et al. Lignin-first biorefining of Nordic poplar to produce cellulose fibers could displace cotton production on agricultural lands. Joule 6, 1845–1858 (2022).

    Article  CAS  Google Scholar 

  29. Luterbacher, J. S., Martin Alonso, D. & Dumesic, J. A. Targeted chemical upgrading of lignocellulosic biomass to platform molecules. Green Chem. 16, 4816–4838 (2014).

    Article  CAS  Google Scholar 

  30. Meng, X. et al. Determination of hydroxyl groups in biorefinery resources via quantitative 31P NMR spectroscopy. Nat. Protoc. 14, 2627–2647 (2019).

    Article  CAS  PubMed  Google Scholar 

  31. Yan, J. et al. Selective valorization of lignin to phenol by direct transformation of Csp2–Csp3 and C–O bonds. Sci. Adv. 6, eabd1951 (2020). 1-10.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  32. Liang, J. et al. Studying paraben-induced estrogen receptor- and steroid hormone-related endocrine disruption effects via multi-level approaches. Sci. Total Environ. 869, 161793 (2023).

    Article  ADS  CAS  PubMed  Google Scholar 

  33. Sluiter, A. et al. Determination of Structural Carbohydrates and Lignin in Biomass: Laboratory Analytical Procedure (LAP) Technical Report NREL/TP-510-42618 (NREL, 2008).

  34. Yang, X. et al. Synthetic phenolic antioxidants cause perturbation in steroidogenesis in vitro and in vivo. Environ. Sci. Technol. 52, 850–858 (2018).

    Article  ADS  CAS  PubMed  Google Scholar 

  35. Koelewijn, S. F. et al. Sustainable bisphenols from renewable softwood lignin feedstock for polycarbonates and cyanate ester resins. Green Chem. 19, 2561–2570 (2017).

    Article  CAS  Google Scholar 

  36. Peng, Y., Nicastro, K. H., Epps, T. H. & Wu, C. Methoxy groups reduced the estrogenic activity of lignin-derivable replacements relative to bisphenol A and bisphenol F as studied through two in vitro assays. Food Chem. 338, 127656 (2021). 1-9.

    Article  CAS  PubMed  Google Scholar 

  37. Peng, Y., Nicastro, K. H., Epps, T. H. & Wu, C. Evaluation of estrogenic activity of novel bisphenol A alternatives, four bioinspired bisguaiacol F specimens, by in vitro assays. J. Agri. Food Chem. 66, 11775–11783 (2018).

    Article  CAS  Google Scholar 

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We thank K. Romare and J. Ståhle at SU, and X. J. Chi and X. J. Ai at DICP for assistance with NMR setting; H. J. Li, A. Bunrit and H. F. Liu at DICP for discussing strategies of lignin depolymerization; J. J. Mu at DICP for helping with energy level calculation; J. Wang, Z. Jiang and J. W. Jiang at DICP for assistance with thermoplastic synthesis and characterization; and H. Grundberg at MoRe Research for helping with Kappa number and brightness tests. N.L., K.Y., Y.L. and F.W. thank the National Key R&D Program of China (grant number 2022YFA1504904), the National Natural Science Foundation of China (grant numbers 22025206, 22008235, and 21991090), Dalian Innovation Support Plan for High Level Talents (grant number 2022RG13), China Postdoctoral Science Foundation (grant number 2020M670808), and the Liaoning Revitalization Talents Program (grant number XLYC2002012). J.R. was funded by the Swiss National Science Foundation (Sinergia, grant number CRS115_180258). T.R., S.M., G.C.-O. and J.S.M.S. thank the Swedish Energy Agency (Energimyndigheten, grant numbers 47448-1, 45903-1 and 41262-1). J.L., Q.Z. and G.J. thank the National Natural Science Foundation of China (grant number 21527901).

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Authors and Affiliations



N.L., F.W. and J.S.M.S. conceived the condensation-driven strategy. N.L. designed and participated in all the experiments. T.R., S.M., G.C.-O., K.Y. and Y.L. synthesized the lignin model compounds. K.Y. conducted experiments related to the fractionation, the catalytic depolymerization and the pulp bleaching. Z.W., H.N. and K.Y. prepared and characterized the polymer samples. J.L. performed the toxicity test. N.L., F.W., J.S.M.S. and J.R. composed the paper with input from G.Z., Q.Z., G.J. and X.P. All authors discussed the results and contributed to revising the paper.

Corresponding authors

Correspondence to Joseph S. M. Samec or Feng Wang.

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Competing interests

The inventors F.W., N.L. and K.Y. hold patent applications (CN202310931641.8 and CN202310929431.5). The other authors declare no competing interests.

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Extended data figures and tables

Extended Data Fig. 1 Identification of S-VG products.

a,b, HPLC analysis of purified S-VGs and a S-VG mixture from the α-arylation (syringolation) of VG. The purified mS-V′G and pS-V′G were obtained by flash-column separation of the S-VG mixture from the syringolation reaction. The purified mS-VG and pS-VG were obtained by deformylation of the purified mS-V′G and pS-V′G. The syringolation reaction condition: VG (0.25 mmol); syringol (0.75 mmol, 3 equiv.) in 5 mL of 88 wt% formic acid; reaction time, 1 h; reaction temperature, 80 °C. c, 1H–13C HSQC NMR spectra of VG, purified S-VG isomers, and the crude mixture of S-VGs after the syringolation reaction under the typical condition.

Extended Data Fig. 2 Proposed pathways in the tandem catalysis of arylated aryl ethers.

Exemplified by the mS-VG model, the major pathway 1 is initiated by protonation of the β-ether’s to cleave the β-aryl ether bond, resulting in a β-carbocation. The electron-rich aromatic ring (aided by the methoxy at the ortho- or para-position) then migrates to the β-carbocation in a classical anchimerically assisted (neighboring group participation) fashion to produce a spiro-phenonium intermediate. The γ-hydroxymethyl group undergoes a formaldehyde elimination reaction that cleaves the Cβ–Cγ bond, liberating formaldehyde and producing stilbene (P1). The ethylene bridge is then subject to hydrogenation, resulting in the formation of a more stable 1,2-diarylethane product (P2). The formaldehyde elimination plays a role in facilitating aryl migration but is not strictly essential, since evidence confirms a deprotonation pathway to P4. In the minor pathway 2, dearylation occurs predominantly when acid-catalyzed aryl migration is impeded. The syringyl group was protonated, resulting in rupture of Cα–Caryl bonds to release syringol. In the minor pathway 3, demethylation is initiated by the protonation of the syringyl group and is supposed to go through a water addition pathway to yield the demethylated products (P9 and its isomers). B denotes CH3C6H4SO3 or conjugate bases of other strong acids; R1 denotes H or OH.

Extended Data Fig. 3 Cellulosic pulps and hydrolysate components from the CLAF.

a,b, TCF-bleached pulp from the CLAF of pulp in 88 wt% FA at 120 °C for 30 min. a, Images of pulp isolated by the formic acid fractionation (FFP), pulp isolated by the lignin-syringolated fractionation (SFP), and bleached SFP (BSFP). b, Pulp compositions determined by the Klason method. Error bar represents s.d. based on two replicates. The bleached pulp (BSFP, 95.3% bleaching yield) reached up to 90% ISO brightness with negligible loss of cellulose chain length (DP 1065). The BSFP composition included cellulose (94.0%) and xylan (2.9%) together with only traces of Klason lignin which was confirmed by the pulp’s low Kappa number (0.6). c, Cellulase digestibility of SFPs. SFP (1 g, o.d.) was first pretreated by acidic deformylation (120 °C in 10 mL of 1 wt% sulfuric acid for 60 min) prior to cellulase-based saccharification. Enzymatic saccharification parameters: 50 °C, 10 mL of 0.05 M acetic acid/sodium acetate buffer, 20 FPU g–1substrate of Novozymes Cellic Ctec 2 loading. Yields of glucose and xylose were calculated based on the initial weight of SFP. d, Yields of xylose, furfural, and total soluble xylose (total sol. xylose), and syringol recovery in the hydrolysate from the CLAF of poplar. Note: Total sol. xylose was determined by post-hydrolysis of the fractionation hydrolysate in 4 wt% H2SO4 at 121 °C for 1 h. Increasing the fractionation temperature increased xylose yields from 8.1% (80 °C for 1 h) to 64.5% (120 °C for 0.5 h). The total sol. xylose yield increased to 90.5%, taking other forms of xylose (e.g., oligomers and xylose formylates) into account. At 120 °C, xylose yields were relatively independent of syringol addition, indicating that syringol condensation with xylose was unlikely to occur. Recovery of unreacted syringol decreased at higher temperatures, in accordance with the increased S-lignin yields, indicating that syringol was favorably coupled into the S-lignin.

Extended Data Fig. 4 Monophenols and bisphenols in the tandem catalytic depolymerization of S-lignin.

a, Yield of monomers and bisphenols referenced to the β–O–4-aryl ether content in native lignin, m/p denotes the yield of [BP2(mSG)+ BP10(mSS)] divided by the yield of [BP5(pSG)+ BP12(pSS)]. b, Mass yields of syringol, monophenols, and bisphenols based on the Klason lignin content in poplar. S-lignin was isolated by the CLAF of poplar at 120 °C for 30 min in 88% FA. The SG and SS bisphenols represent the major bisphenols (accounting for up to 70.3 wt% of the total bisphenols). c,d, A typical GC-MS spectrum and peak assignment of monophenols (c) and bisphenols (d) that were generated in the tandem catalytic depolymerization of S-lignin. Effective carbon number (ECN) of the corresponding trimethylsilyl (TMS)-derivatized compound was used to calibrate the flame ionization response for quantitative analysis by GC-FID. Empirical ECN contribution for carbon atom, oxygen atom, and TMS was +1, –1 (–0.5 for primary alcohol), and 3, respectively. The four major bisphenols (mSG, pSG, mSS, and pSS) were isolated as pure crystals and quantified using authentic purified compounds as external standards.

Extended Data Fig. 5 Identification of S-type bisphenols.

a, Quantitative calibration of bisphenol crystals by GC-FID using dodecane as the internal standard. The peak area of the silylated bisphenol was divided by the peak area of dodecane for calibration of the area ratio. b, 1H–13C HSQC NMR spectra of the four major bisphenols from S-lignin. c, Mass spectra of the four bisphenols isolated from tandem catalytic depolymerization of the syringolated lignin. The spectra were collected from GC-MS and the values were recorded from high-resolution mass spectrometry.

Extended Data Fig. 6 Synthesis of thermoplastics and thermoset epoxy resins.

a, Polyarylates were synthesized using mSG and mSS for BPA replacement. b, poly(aryletherketone) was synthesized using mSG for BPA replacement. c, Epoxy resins were synthesized using mSG and S/P-lignin oligophenols for BPA replacement. S-lignin oligophenols (SLO) were harvested from the reflux extraction of S-lignin oil (RF3), and the P-lignin oil mixture (PLOM) was collected from the tandem catalysis of P-lignin without further separation/purification. Note: The chemical structures of SLO and PLOM are used for illustration, and may not be representative of all the moieties in the mixtures.

Extended Data Fig. 7 Replacing syringol with phenol in the CLAF for bisphenol production.

a, Fractionation of native birch lignin to bisphenols by selective phenolation and subsequent tandem catalytic depolymerization. b, Comparison of aliphatic regions in HSQC spectra. Ball-milled raw birch was dispersed in DMSO-d6/pyridine-d5 (4:1). Phenolated lignin (P-lignin) and products from tandem catalytic depolymerization (P-lignin oil) were dissolved in DMSO-d6 and CDCl3, respectively. P-lignin was isolated at 100 °C for 2 h in 88 wt% FA with 80 wt% phenol loading. The tandem catalytic depolymerization of P-lignin was conducted at 200 °C for 6 h catalyzed by 2 g l–1 pTSA and Pd/C in MeOH:H2O (7:3). c, Mass yields of bisphenols and monophenols from the tandem catalytic depolymerization of P-lignin. Yields of lignin oils were calculated gravimetrically to be 70.5 wt% (0.5 h), 63.3 wt% (2 h), 68.6 wt% (6 h), 71.5 wt% (12 h), 73.7 wt% (L/S: 10), 73.4 wt% (L/S: 8), 69.6 wt% (L/S: 5), 79.8 wt% (L/S: 5a), and 76.4 wt% (L/S: 5b). The tandem catalysis at varied times was loaded with the P-lignin feedstock isolated from birch using the 1-L high-pressure reactor with an impeller. The fractionation process, involving varied liquid-to-solid (L/S) ratios, was conducted using a rotary digester, enabling high birch loading. Subsequently, the tandem catalysis was performed at 200 °C for 2 h. Note: a and b denote 60 wt% and 40 wt% phenol loadings (based on the loading weight of birch) in the CLAF.

Extended Data Fig. 8 Analyses of monophenols and P-type bisphenols.

a, A GC-MS spectrum and peak assignment of monophenols and bisphenols in the tandem catalytic depolymerization of P-lignin (pPG and pPS in the main text refer to peaks of BP26 and BP30, respectively). b, GC calibration curves of pPG and pPS, both of which were referenced by the internal standard (dodecane). c, HSQC NMR spectra of pPG and pPS in CDCl3. Note: the pPG and pPS crystals were isolated by reflux extraction followed by flash-column separation, and then purified by recrystallization from CHCl3 and heptane.

Extended Data Fig. 9 Viability of MVLN cells.

The range of bisphenol exposure concentrations in the RLA test was refined to keep a minimum of 80% cell viability as referenced to the blank. Error bar represents s.d. based on 3 replicates.

Extended Data Fig. 10 Comparison of the estrogenic activity (EA) among bisphenols.

Note: Bisphenols in Ref. A and B were synthesized by crosslinking lignin RCF monomers with a formaldehyde16,35; bisphenols in Ref. C were synthesized by a Friedel-Crafts-type alkylation between vanillyl alcohol and guaiacol19; bisphenols in Ref. D were synthesized by a Friedel-Crafts-type alkylation between isoeugenol and guaiacol20. To validate the comparison, all the EC50 and RLA data were collected in Ref. A–D based on the results from the in vitro MELN study, which are comparable to the in vitro MVLN assay in this study. Bisphenols (same with those in Ref. C) were investigated using the in vitro VM7Luc4E2 cells36,37, and the results showed similar benign properties, but were not included here in part because of the differences in the evaluation system.

Extended Data Table 1 Product distribution after CLAF and compositional analysis of isolated pulps
Extended Data Table 2 Semi-quantitative measurement of relative unit levels in native lignin, S-lignin, and P-lignin by HSQC NMR
Extended Data Table 3 Estrogenic effects of E2, BPA, BPF, pPG, pPS, mSG, mSS, pSG, and pSS using the in vitro MVLN assay

Supplementary information

Supplementary Information

This Supplementary Information file contains the following sections: Chemicals and materials; Supplementary feedstock and product characterization; Supplementary Texts 1–13; Supplementary Table 1; Supplementary Figs. 1–23; Library of compounds synthesized; and Appendixes.

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Li, N., Yan, K., Rukkijakan, T. et al. Selective lignin arylation for biomass fractionation and benign bisphenols. Nature 630, 381–386 (2024).

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